JP2011515152A - Method and apparatus for irradiating a surface with continuous wave or pulsed light - Google Patents

Abstract

A method and apparatus for irradiating a surface with at least one light beam emitted from an exit surface of an optical element. The cross section of the at least one light beam is greater than about 2 cm ^{2 and} the time average irradiance at the cross section is in the range of about 10 mW / cm ² to about 10 W / cm ² . The at least one light beam has a temporal pulse width in the range between about 0.1 milliseconds and about 150 seconds and a time average irradiance in the range between about 1 mW / cm ² and about 100 W / cm ^2. A plurality of pulses may be included.

Description

This application is a continuation-in-part of US patent application Ser. No. 12 / 389,294, filed Feb. 20, 2009, which is incorporated herein by reference in its entirety. This application also claims the priority of US Provisional Application No. 61 / 037,668, filed Mar. 18, 2008, which is incorporated by reference herein in its entirety.

BACKGROUND OF THE INVENTION Field of the Invention The present invention relates generally to phototherapy, and more particularly to new devices and methods for phototherapy of brain tissue.

Description of Related Art Numerous neurology such as neurodegenerative diseases (eg Alzheimer's disease, Parkinson's disease), Huntington's disease, demyelinating disease (eg multiple sclerosis), cranial nerve palsy, traumatic brain injury, stroke, and spinal cord injury There are common illnesses, and these will probably benefit from phototherapy applications. Most of these diseases cause serious morbidity and mortality and impose a great burden on society, families and caregivers. For many neurological disorders there is no effective treatment currently applicable or applicable therapy is not sufficient to restore function, maintain quality of life, or stop disease progression.

  An example of a neurological disease that is still a major medical need that has not been met is stroke, also called cerebrovascular stroke (CVA). Stroke can be caused by a sudden disruption of blood flow to discrete areas of the brain (called ischemic stroke) caused by a thrombus remaining in an artery that supplies blood to an area of the brain, or Caused by a ruptured aneurysm or cerebral hemorrhage from a ruptured artery (called hemorrhagic stroke). In the United States, there are more than 750,000 stroke victims annually, of which approximately 85% are ischemic and 15% are hemorrhagic. A stroke results in loss of function in the affected brain region, and concomitant loss of body function in the region of the body controlled by the affected brain region. Depending on the extent and location of major damage in the brain, loss of function can vary widely from mild to severe and can be temporary or permanent. Stroke is a major cause of human suffering in developed countries, as life factors such as smoking, diet, physical activity levels, and high cholesterol increase the risk of stroke. Stroke is the third leading cause of death in most developed countries, including the United States.

  Stroke treatment is often limited to basic life support at the onset of stroke and subsequent rehabilitation. Currently, the only FDA approved treatment for ischemic stroke involves thrombolytic therapy using tissue plasminogen activator (tPA). However, tPA can only be used within 3 hours of stroke onset and there are some contraindications, so only a small percentage of stroke patients receive this drug.

  Traumatic brain injury (TBI) results in sudden physical trauma (eg, crushing or compression injury in the central nervous system, including crushing or compression injury of the brain, spinal cord, nerves, or retina), or cell death Some acute injury or seizure) occurs when the head is damaged. For example, TBI can occur when the head is subjected to a sudden and / or severe bang or when an object penetrates the skull and enters the brain tissue. The degree of brain damage can be severe, but even mild and less severe TBI is associated with neurological sequelae that can last long. Progression of neurodegenerative diseases has been associated with TBI. TBI can result in a sudden disturbance of blood flow to discrete regions of the brain. A stroke or TBI can result in loss of function in the affected brain region and concomitant loss of body function in a region of the body controlled by the affected brain region. Depending on the extent and location of major damage in the brain, loss of function can vary widely from mild to severe and can be temporary or permanent.

  There is still great interest in the discovery of new and improved therapeutic interventions for the treatment of stroke and other neurological disorders that continue to hit millions of lives each year and have few effective treatments And there is a clinical need.

SUMMARY OF THE INVENTION In one embodiment, an apparatus for irradiating a portion of a patient's scalp or skull with light is provided. The apparatus includes a light source and an output optical element in optical communication with the light source. The output optical element includes an exit surface configured to emit a pulsed light beam including a plurality of pulses having a temporary pulse width in a range between 0.1 milliseconds and 150 seconds. The cross-section of the pulsed light beam at the exit surface of the output optical element is greater than about 2 cm ² , and the time average irradiance in this cross-section is in the range of about 10 mW / cm ² to about 10 W / cm ² .

In one embodiment, a method for illuminating a surface with light is provided. The method includes irradiating the surface with at least one pulsed light beam emitted from the exit surface of the optical element. The at least one pulsed light beam includes a plurality of pulses having a temporal pulse width that ranges between about 0.1 milliseconds and about 150 seconds. The beam cross-section at the exit surface of the at least one pulsed light beam is greater than about 2 cm ² and the time average irradiance is in the range between about 1 mW / cm ² and about 100 W / cm ² .

In certain embodiments, a method of treating a patient's brain is provided. The method includes irradiating at least a portion of the brain by irradiating at least a portion of the patient's scalp or skull with at least one pulsed light beam comprising a plurality of pulses transmitted through the patient's skull. The temporal profile of the temporal profile of the at least one pulsed light beam, which is an average of 1 second in the scalp, is in the range between about 100 mW / cm ² and about 10 W / cm ² and the peak irradiance in the scalp is In a range between about 12.5 mW / cm ² and about 1000 W / cm ² .

  In one embodiment, a method for treating a patient who has experienced traumatic brain injury is provided. The method includes irradiating and stimulating a patient's brain cells by non-invasively irradiating at least a portion of the patient's scalp or skull with pulsed light that passes through the patient's skull. The temporal profile of this pulsed light includes the average irradiance per pulse, the temporal pulse width, and the pulse duty cycle. By selecting this temporal profile, the membrane potential is adjusted to improve, restore, or promote cell survival, cell function, or both of irradiated brain cells following traumatic brain injury.

  In certain embodiments, a method of treating a patient with neurodegenerative disease or depression is provided. The method includes irradiating and stimulating a patient's brain cells by non-invasively irradiating at least a portion of the patient's scalp or skull with pulsed light that passes through the patient's skull. The temporal profile of this pulsed light includes the average irradiance per pulse, the temporal pulse width, and the pulse duty cycle. By selecting this temporal profile, the membrane potential is adjusted to improve, restore, or promote cell survival, cell function, or both of the irradiated brain cells.

In one embodiment, an apparatus for irradiating a portion of a patient's scalp with light is provided. The apparatus includes a light source that includes one or more wavelengths in the range of about 630 nanometers to about 1064 nanometers. The apparatus further includes an output optical element in optical communication with the light source. The output optical element emits a light beam having a cross section at the output surface of the output optical element that is greater than about 2 cm ² and a time average irradiance in the cross section of about 10 mW / cm ² to about 10 W / cm ^2. Including the exit surface. The apparatus is further configured to be placed in thermal communication with the irradiated portion of the patient's scalp and at a rate of heat ranging from about 0.1 watts to about 5 watts from the irradiated portion of the patient's scalp. Including a thermally conductive portion configured to be removed.

In one embodiment, a method for illuminating a surface with light is provided. The method includes emitting a light beam from the exit surface of the optical element. Light beam at the exit face, and one or more wavelengths in the range of about 630 nanometers to about 1064 nanometers, and about 2 cm ² greater than cross section, about 10 mW / cm ² in the cross-section of about 10 W / cm ² With a time average irradiance in the range. The method further includes removing heat from the exit surface at a rate in the range of about 0.1 watts to about 5 watts.

  In one embodiment, an apparatus for irradiating a patient's scalp with light is provided. The apparatus includes a first portion and a second portion that is mechanically coupled to the first portion and in optical communication with the first portion. The second part is placed in thermal communication with the patient's scalp so that light from the first part propagates through the second part during operation of the device. The first portion and the second portion are configured to move relative to each other in response to the second portion being placed in thermal communication with the patient's scalp.

  In one embodiment, a method for illuminating a surface with light is provided. The method includes providing an apparatus that includes a first portion and a second portion that is mechanically coupled to the first portion and in optical communication with the first portion. The first portion and the second portion are configured to move relative to each other. The method further includes placing the second portion in thermal communication with the surface. The method further includes illuminating the surface such that light from the first portion propagates through the second portion. The method further includes moving the first portion and the second portion relative to each other in response to the second portion being disposed in thermal communication with the surface.

  In one embodiment, an apparatus for irradiating a patient's scalp with light is provided. The apparatus includes an output optical assembly that includes an exit surface, and during operation of the apparatus, light propagates through the output optical assembly along a first optical path to the exit surface. The apparatus further includes a sensor spaced from the output optical assembly. The sensor is positioned to receive radiation from the output optical assembly that passes through the output optical assembly and propagates along the second optical path, with a non-zero between the first optical path and the second optical path. Is an angle.

  In one embodiment, a method for illuminating a surface with light is provided. The method includes providing an optical element that includes a material that is substantially light transmissive and substantially thermally conductive, the optical element having a first surface and a second surface. The method further includes disposing the first surface in thermal communication with the irradiated surface. The method further includes propagating light along the first optical path through the second surface and through the first surface to the illumination surface. The method further includes detecting illumination propagating along at least a portion of the second surface along the second optical path, with a non-zero angle between the first optical path and the second optical path. is there.

  In one embodiment, a method for illuminating a surface with light is provided. The method includes providing an optical element that includes a material that is substantially light transmissive and substantially thermally conductive, the optical element having a first surface and a second surface. The method further includes disposing the first surface in thermal communication with the irradiated surface. The method further includes propagating the light along the first optical path through the second surface and through the first surface to the illumination surface. The method further includes detecting radiation propagating along the second optical path from at least a portion of the second surface, with a non-zero angle between the first optical path and the second optical path. is there.

  In one embodiment, an apparatus for irradiating a patient's scalp with light is provided. The apparatus includes a thermoelectric assembly that cools at least a first surface of the thermoelectric assembly and heats at least a second surface of the thermoelectric assembly in response to an electrical current being applied to the thermoelectric assembly. . The thermoelectric assembly is configured to be releasably mechanically coupled to the output optical assembly to thermally communicate the first surface with the output optical assembly. The thermoelectric assembly generally surrounds the first region, and during operation of the device, light that illuminates a portion of the patient's scalp propagates through the first region. The apparatus further includes a heat sink in thermal communication with the second surface of the thermoelectric assembly.

  In one embodiment, a patient wearable device is provided. The device includes a body adapted to be worn over at least a portion of the patient's scalp. The apparatus further includes a plurality of indicators corresponding to a plurality of treatment site locations on the patient's scalp, where light is applied to illuminate at least a portion of the patient's brain.

  In one embodiment, a patient wearable device is provided. The apparatus includes means for identifying a plurality of treatment site locations on the patient's scalp, where light is applied to illuminate at least a portion of the patient's brain. The apparatus further includes means for indicating to the operator the order in which treatment site positions are irradiated.

In one embodiment, a method for providing a brain phototherapy procedure is provided. The method includes identifying a plurality of treatment site locations on the patient's scalp, wherein at least one area of the treatment site locations is 1 cm ² or greater. The method further includes indicating the order of irradiation of the treatment site locations.

In certain embodiments, a method of treating a patient's brain is provided. The method includes non-invasively irradiating a first region of 1 cm ² or more of the patient's scalp with laser light for a first period. The method further includes non-invasively irradiating a second region of 1 cm ² or more of the patient's scalp with a laser beam for a second period, the first region and the second region being heavy. In addition, the first period and the second period do not overlap.

  To provide an overview of the present invention, several aspects, advantages and novel features of the present invention have been described above. However, it should be understood that not all such advantages may be obtained in accordance with a particular embodiment of the present invention. Thus, the present invention achieves one advantage or group of advantages taught herein, regardless of whether other advantages that would be taught or suggested herein are achieved. It will be implemented or executed in a way that optimizes it.

FIG. 1 schematically illustrates an example of a beam delivery device according to certain embodiments described herein. FIG. 2A schematically illustrates a cross-sectional view of an example of an output optical assembly in accordance with certain embodiments described herein. FIG. 2B schematically illustrates another example of an output optical assembly in accordance with certain embodiments described herein. FIG. 3A schematically illustrates the diffusion effect on light by the output optical assembly. FIG. 3B schematically illustrates the diffusion effect on light by the output optical assembly. FIG. 4A schematically illustrates a cross-sectional view of one of two examples of a beam delivery device according to certain embodiments described herein. FIG. 4B schematically illustrates a cross-sectional view of one of two examples of a beam delivery device according to certain embodiments described herein. FIG. 5 schematically illustrates an example of a fiber alignment mechanism in accordance with certain embodiments described herein. FIG. 6 schematically illustrates an example of a mirror corresponding to an embodiment described herein. FIG. 7 schematically illustrates an example of a first optical path of light emitted from an optical fiber in accordance with certain embodiments described herein. FIG. 8 schematically shows an example of a second optical path of radiation received by the sensor. FIG. 9A schematically illustrates an example of a thermoelectric element in accordance with certain embodiments described herein. FIG. 9B schematically illustrates two views of an example of a heat conduit according to certain embodiments described herein. FIG. 10A schematically illustrates another example of a thermoelectric element according to certain embodiments described herein. FIG. 10B schematically shows two views of another example of a heat conduit according to certain embodiments described herein. FIG. 11A schematically illustrates a cross-sectional view of an example heat sink in accordance with certain embodiments described herein. FIG. 11B schematically illustrates another example of a heat sink in accordance with certain embodiments described herein. FIG. 12A schematically illustrates one of two configuration examples of a window with a thermoelectric assembly. FIG. 12B schematically shows one of two configuration examples of a window with a thermoelectric assembly. FIG. 13A schematically illustrates an example of a support for supporting various components of a beam delivery device in a housing in accordance with certain embodiments described herein. FIG. 13B schematically illustrates another example of a support according to certain embodiments described herein. FIG. 14A schematically illustrates a cross-sectional view of an example of a support and housing configuration in accordance with certain embodiments described herein. FIG. 14B schematically illustrates another example of a support and housing configuration in accordance with certain embodiments described herein. FIG. 14C schematically illustrates another example of a support and housing configuration in accordance with certain embodiments described herein. FIG. 15A schematically illustrates one of two states of an example sensor in accordance with certain embodiments described herein. FIG. 15B schematically illustrates one of two states of an example sensor in accordance with certain embodiments described herein. FIG. 15C schematically illustrates one of two states of another example of a sensor in accordance with certain embodiments described herein. FIG. 15D schematically illustrates one of two states of another example of a sensor in accordance with certain embodiments described herein. FIG. 16A schematically illustrates one of two examples of trigger force spring and trigger force adjustment mechanism configurations in accordance with certain embodiments described herein. FIG. 16B schematically illustrates one of two examples of trigger force spring and trigger force adjustment mechanism configurations in accordance with certain embodiments described herein. FIG. 17 schematically illustrates an example of a lens assembly sensor in accordance with certain embodiments described herein. FIG. 18 is a block diagram of a control circuit including a programmable controller for controlling a light source in accordance with certain embodiments described herein. FIG. 19A is a graph showing the transmittance (arbitrary unit) of light passing through blood as a function of wavelength. FIG. 19B is a graph of light absorption by brain tissue. FIG. 19C shows the efficiency of energy delivery as a function of wavelength. FIG. 20 shows the absorption measured for 808 nanometer light passing through various rat tissues. FIG. 21A schematically illustrates an example of a pulse in accordance with certain embodiments described herein. FIG. 21B schematically illustrates an example of a pulse in accordance with certain embodiments described herein. FIG. 21C schematically illustrates an example of a pulse in accordance with certain embodiments described herein. FIG. 21D schematically illustrates an example of a pulse in accordance with certain embodiments described herein. FIG. 22A schematically illustrates an embodiment in which the device is placed in continuous thermal communication with a plurality of treatment sites corresponding to portions of the patient's scalp. FIG. 22B schematically illustrates an example where the device is placed in continuous thermal communication with a plurality of treatment sites corresponding to portions of the patient's scalp. FIG. 22C schematically illustrates an embodiment in which the device is placed in continuous thermal communication with a plurality of treatment sites corresponding to portions of the patient's scalp. FIG. 23 schematically illustrates an example of a device that can be worn by a patient for treatment of the patient's brain. FIG. 24A schematically illustrates one of the left and right sides of an example device in which an indicator corresponding to a treatment site is substantially covered with a label. FIG. 24B schematically illustrates one of the left and right sides of an example of a device in which an indicator corresponding to a treatment site is substantially covered with a label. FIG. 24C schematically shows an example of a labeling configuration as seen from above, with the apparatus of FIGS. 24A and 24B flattened. FIG. 25 is a flowchart of an example of a method for irradiating the surface with light. FIG. 26 is a flow diagram of an example of a method for irradiating a surface with light. FIG. 27 is a flowchart of an example of a method for irradiating the surface with light. FIG. 28 is a flowchart of an example of a method for irradiating the surface with light. FIG. 29 is a flow diagram of an example method for irradiating a patient's brain with at least one predetermined region of the patient's scalp exposed to laser light in a controllable manner. FIG. 30 is a flow diagram of another example of a method for treating a patient's brain. FIG. 31 is a graph of power density versus depth from the dura when the input power density is 10 mW / cm ² , as described below, the white bars correspond to the predicted power density, The black bar corresponds to the estimated minimum action PD which is 7.5 μW / cm ² . FIG. 32 shows patient composition in the NEST-1 study. FIG. 33 shows the average NIHSS over time for each treatment group in the NEST-1 study. FIG. 34 shows the mean mRS over time for each treatment group in the NEST-1 study. FIG. 35 shows patient composition in the NEST-2 study. FIG. 36 shows the distribution of mRS scores in the NEST-2 study. FIG. 37 shows the effect of TLT on the primary endpoint for a subset of the data defined by the selected baseline characteristic category in the NEST-2 study. FIG. 38 is a flow diagram of an example of a method for treating brain tissue according to an embodiment described herein. FIG. 39 is a graph of the neurological score (NSS) of mice receiving controlled / non-laser treatment (light bars) and laser irradiation (dark bars) at different time intervals after the occurrence of brain trauma. is there. FIG. 40 shows representative photomicrographs of cross sections of the brains of control non-laser treated mice and laser treated mice. FIG. 41 is a graph of lesion volume of a traumatic brain that received control (light bar) and laser treatment (dark bar) 28 days after the occurrence of head trauma. FIG. 42A shows the results of a study of stroke in a rabbit model using treatment 6 hours after embolization. FIG. 42B shows the results of a stroke study of a rabbit model with 6-hour post-embolization treatment. FIG. 42C shows the results of a stroke study in a rabbit model with 6-hour post-embolization treatment. FIG. 43A shows the results of a study of stroke in a rabbit model using 12-hour post-embolization therapy. FIG. 43B shows the results of a study of stroke in a rabbit model using 12-hour post-embolization treatment. FIG. 44 shows the effect of LLT on Aβ amyloid deposition in mice, with mean ± SEM for each group. APP transgenic animals were treated with TLT and without laser, treatment started on day 0 (age 3 months) and continued for 26 weeks (3X / week treatment). Animals were disposed and processed at 26 weeks for aminoloid accumulation. FIG. 45A shows the effect of LLT on latency to find a hidden platform (Morris water maze), with a mean ± SEM for each group. APP transgenic animals were treated with TLT and without laser, treatment started on day 0 (age 3 months) and continued until day 180 (3X / week treatment) to allow the water maze to be applied to reach the platform The time required was recorded. The animals were analyzed and processed for 180 days to determine the latency. FIG. 45B shows the effect of the LLT on the distance to find a hidden platform (Morris water maze), with a mean ± SEM for each group. APP transgenic animals were treated with TLT and without laser, treatment started on day 0 (age 3 months) and continued for 26 weeks (3X / week treatment), required for water maze to be applied to reach the platform. The distance was recorded. The animals were analyzed and processed to determine this distance. FIG. 46A shows the effect of LLT on inflammatory mediators in the brain of APP transgenic mice, with a mean ± SEM for each group. APP transgenic animals were treated with TLT and without laser, treatment started on day 0 (age 3 months) and continued for 26 weeks (3X / week treatment). Animals were disposed and processed at 26 weeks for inflammatory markers, interleukin-1 (IL-1), tumor necrosis factor-α (TNF) and transforming growth factor-β (TGF-β). . Animals were analyzed and processed and inflammatory markers were determined by immunohistochemical and image analysis. FIG. 46B shows the effect of LLT on inflammatory mediators in the brain of APP transgenic mice, with a mean ± SEM for each group. FIG. 46C shows the effect of LLT on inflammatory mediators in the brain of APP transgenic mice, with a mean ± SEM for each group. FIG. 47A shows the effect of LLT on Aβ peptide levels in the brain of APP transgenic mice, with mean ± SEM for each group. APP transgenic animals were treated with TLT and without laser, treatment started on day 0 (age 3 months) and continued for 26 weeks (3X / week treatment). The animals were sacrificed at 26 weeks and the brain was subjected to Aβ peptide analysis and compared to laserless control. Animals were analyzed and processed to determine brain Aβ peptide levels. FIG. 47B shows the effect of LLT on Aβ peptide levels in the brain of APP transgenic mice, with mean ± SEM for each group. FIG. 48A shows the effect of LLT on Aβ peptide levels in the plasma of APP transgenic mice at 13 weeks, with mean ± SEM for each group. APP transgenic animals were treated with TLT and without laser, treatment started on day 0 (age 3 months) and continued for 26 weeks (3X / week treatment), plasma was subjected to Aβ peptide analysis and compared to laserless control It was done. Blood was collected and processed from APP transgenic animals at week 13 to determine plasma Aβ peptide levels. FIG. 48A shows the effect of LLT on Aβ peptide levels in the plasma of APP transgenic mice at 26 weeks, with mean ± SEM for each group. APP transgenic animals were treated with TLT and without laser, treatment started on day 0 (age 3 months) and continued for 26 weeks (3X / week treatment), plasma was subjected to Aβ peptide analysis and compared to laserless control It was done. Blood was collected and processed from APP transgenic animals at week 26 to determine plasma Aβ peptide levels. FIG. 49A shows the effect of LLT on sAAPα levels in the brain of APP transgenic mice, with mean ± SEM for each group. APP transgenic animals were treated with TLT and without laser, treatment started on day 0 (age 3 months) and continued for 26 weeks (3X / week treatment). Animals were sacrificed at 26 weeks and brains were subjected to sAAPα protein analysis by Western blotting and compared to laserless controls. Animals were analyzed and processed to determine brain protein levels. FIG. 49B shows the effect of LLT on CTFβ levels in the brain of APP transgenic mice, with mean ± SEM for each group. APP transgenic animals were treated with TLT and without laser, treatment started on day 0 (age 3 months) and continued for 26 weeks (3X / week treatment). The animals were disposed at week 26 and the brains were subjected to CTFβ protein analysis by Western blotting and compared to laserless controls. Animals were analyzed and processed to determine brain protein levels. FIG. 50 shows the effect of LLT on CSFAβ peptide levels in APP transgenic mice, with mean ± SEM for each group. APP transgenic animals were treated with TLT and without laser, treatment started on day 0 (age 3 months) and continued for 26 weeks (3X / week treatment). The animals were disposed at 26 weeks and CSF was subjected to total Aβ peptide analysis by ELISA and compared to laserless control. Animals were analyzed and processed to determine CSFAβ peptide levels.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS Low level light therapy (“LLLT”) or phototherapy is a technique that provides light energy to a patient for therapeutic purposes at an irradiance that is lower than the irradiance used to cut, cauterize or remove biological tissue. As a result, the desired biostimulatory effect can be obtained without damaging the tissue. In non-invasive phototherapy, it is desirable to use a light source located outside the body to irradiate the internal tissue to be treated with an effective amount of light energy (eg, both incorporated herein by reference in their entirety). U.S. Pat. Nos. 6,537,304 and 6,918,922).

  Laser therapy has been shown to be effective in a variety of situations, including the treatment of lymphedema and muscle trauma and carpal tunnel syndrome. Recent research has shown that laser-generated infrared can penetrate various tissues, including the brain, and modify function. In addition, laser-generated infrared can produce effects including but not limited to angiogenesis, can modify growth factor (transforming growth factor-β) signaling pathways, and can enhance protein synthesis. Can be promoted.

  However, because the intervening tissue absorbs light energy, the intervening tissue is heated while the amount of light energy delivered to the target tissue site may be limited. In addition, since intervening tissue scatters light energy, the irradiance (or power density) or energy density delivered to the target tissue site may be limited. Attempting to avoid these effects by increasing the power and / or irradiance applied to the outer surface of the body can result in damage (eg, burning) to the intervening tissue. For example, for patients who have undergone TBI, a large amount of bleeding may occur in the skull (eg, “blood in the field”), and this blood absorbs the irradiated light. The propagation of light energy to the brain tissue under the blood-filled area may be hindered and cause an increase in temperature.

  Non-invasive phototherapy is limited by setting selected treatment parameters within certain ranges, preferably by avoiding damage to intervening tissue. A review of the existing scientific literature in this field will raise the question of whether a set of parameters that are undamaged but effective can be found for the treatment of neurological disorders. However, some embodiments provide an apparatus and method that can achieve this goal as described herein.

Such an embodiment may include the selection of the wavelength of light at which absorption by intervening tissue is below the damage level. Such an embodiment also sets the light source output to a low but effective irradiance at the target tissue site (eg, between about 100 μW / cm ² to about 10 W / cm ² ) and irradiates the head. Being treated by setting a temporal profile of light (eg, temporary pulse width, temporal pulse shape, duty cycle, pulse frequency) and setting the light energy exposure period from hundreds of microseconds to minutes Obtaining an effective energy density at the target tissue site may also be included. Other parameters can be varied in the use of phototherapy. These other parameters contribute to the light energy actually delivered to the treated tissue and can play an important role in the effectiveness of phototherapy. In certain embodiments, the portion of the brain that is irradiated can include the entire brain.

  In one embodiment, the target area of the patient's brain includes an injured area, eg, a neuron in a “risk zone”. In other embodiments, the target area includes a portion of the brain outside the risk zone. Information on biomedical mechanisms or reactions involved in phototherapy can be found in "Mechanisms of Low-Power Laser Light Action on Cellular Level" by Tiina I. Karu, SPIE Proceedings Vol. 4159 (2000), Low Power for Biological Systems Light Effect V, edited by Rachel Lubart, pages 1-17, and Michael R. Provided by Michael R. Hamblin, “Mechanisms of Low Level Light Therapy”, SPIE Proceedings Vol. 6140, 61001 (2006), each of which is herein incorporated by reference in its entirety. Incorporated by reference.

  In certain embodiments, the phototherapy devices and methods described herein are used for the treatment of physical trauma (eg, TBI or ischemic stroke) or other sources of neurodegeneration. As used herein, the term “neurodegeneration” is a process of cell destruction that occurs as a result of a primary destructive event, such as stroke or CVA, and is triggered by a cell because of the occurrence of a primary destructive event. Refers to secondary delayed and progressive destruction mechanisms. Primary destructive events include disease processes or physical damage or disorders including stroke, as well as other diseases and conditions such as multiple sclerosis, amyotrophic lateral sclerosis Dementia caused by other causes such as heat stroke, epilepsy, Alzheimer's disease, cerebral ischemia, including AIDS and focal cerebral ischemia, and also include crushing or compression damage to the brain, spinal cord, nerves or retina Includes physical trauma such as crushing or compression injury within the CNS, or acute injury or injury that causes neurodegeneration. Secondary disruption mechanisms include those that lead to the generation and release of neurotoxic molecules, including apoptosis, depletion of cellular energy due to changes in mitochondrial membrane permeability, release of excess glutamate or reuptake. Includes failure, reperfusion injury, and cytokine and inflammation activity. Both primary and secondary mechanisms contribute to the formation of “dangerous zones” for neurons, and the neurons in this zone are able to withstand at least temporary destruction events but have delayed effects Because of the risk of death.

  In certain embodiments, the devices and methods described herein are used to provide neuroprotection. As used herein, the term “neuroprotective” refers to primary destructive regardless of whether neurodegenerative loss is due to a primary destructive event or a disease mechanism associated with a secondary destructive mechanism. Refers to a therapeutic strategy for delaying or preventing the loss of otherwise irreparable neurons due to post-event neurodegeneration.

  In certain embodiments, the devices and methods described herein are used to improve neurological function, provide neurological enhancement, or restore previously lost neurological function. As used herein, the term “neurological function” includes both cognitive and motor functions. As used herein, the term “neurological improvement” includes both improvement of cognitive function and improvement of motor function. As used herein, the terms “enhanced cognitive function” and “enhanced motor function” mean to improve or enhance cognitive function and motor function, respectively.

  As used herein, the term “cognitive function” refers to cognition, including those related to knowing, thinking, learning, cognition, memory (including immediate memory, recent memory or remote memory), and judgment. And means cognitive or mental processes or functions. Signs of cognitive loss may include changes in the patient's personality, emotion, and behavior. As used herein, the term “motor function” refers to a physical function associated with muscle exercise, which is primarily conscious muscle exercise, and includes motor coordination, execution of simple and complex motor activities, and the like.

  Diseases or disorders that affect neurological function may result from long-term or sports trauma such as Alzheimer's disease, dementia, AIDS or HIV infection, Kreutzell-Jakob disease, head injury (single event trauma and multiple concussions Including other trauma), Lewy body disease, Pick disease, Parkinson's disease, Huntington's disease, drug or alcoholism, brain tumor, hydrocephalus, kidney or liver disease, stroke, depression, and cognitive impairment And other mental illnesses that cause neurodegeneration, but are not limited to these.

Beam Delivery Device Phototherapy methods for the treatment of neurological disorders described herein (eg, ischemic stroke, Alzheimer's disease, Parkinson's disease, depression or TBI) are performed using various light delivery systems. And can be explained. Such light delivery systems are described in US Pat. Nos. 6,214,035, 6,267,780, 6,273,905, each of which is incorporated herein by reference in its entirety. Shown and described in US Pat. Nos. 6,290,714 and 7,303,578, U.S. Patent Application No. 12 / 389,294, and US Patent Application Publication Nos. 2005/0108551 Al and 2007/0179571 Al. A device for low level laser therapy, such as For example, in one embodiment, the light delivery device can irradiate a portion of the patient's scalp or skull while cooling the irradiated portion of the scalp or skull. In some other embodiments, the irradiated portion of the scalp or skull is not cooled while the portion of the patient's scalp or skull is irradiated.

  These previously disclosed light delivery devices have been described primarily in the context of phototherapy treatment of stroke. However, in certain embodiments, such light delivery devices can also be used to treat phototherapy for other neurological disorders (eg, Alzheimer's disease, Parkinson's disease, depression, TBI). A patient who has undergone TBI may have an exposed portion of the skull or skull due to a wound on a portion of the patient's scalp. In certain such examples, the light delivery device can illuminate the skull or an exposed portion of the skull without light propagating through the scalp tissue. Certain embodiments described herein correspond to irradiating the brain with light applied to at least a portion of the scalp, or with light applied to at least a portion of the skull or skull without propagating through the scalp. is doing.

  FIG. 1 schematically illustrates an example of a beam delivery device 10 in accordance with certain embodiments described herein. The device 10 includes a housing 12, a flexible conduit 14 operatively coupled to the housing 12, and at least one status indicator 16. In one embodiment, the apparatus 10 includes an output optical assembly 20 that includes an exit surface 22 from which a light beam 30 is emitted. The output optical assembly 20 is configured to be releasably mechanically coupled to other components of the apparatus 10.

  In some embodiments, the housing 12 is sized to be easily held with one hand (eg, about 5.5 inches long). The housing 12 of certain embodiments further includes one or more portions 12a, 12b, which include biocompatible materials. This is because they can come into contact with the operator, the patient or both. For example, in one embodiment, one or more low durometer elastomeric materials (eg, rubber, polymer, thermoplastic) can be used. Portion 12a is configured to be grasped by a user's hand during operation of device 10. The housing 12 in one embodiment is configured to hold the exit surface 22 in place by hand and continuously move it to irradiate selected portions of the patient's skin. In certain embodiments, the housing 12 includes one or more indentations or protrusions to facilitate the user to grip the housing 12. In certain embodiments, the housing 12 is configured to be placed over a test system to measure or monitor the operating parameters of the device 10. One such example housing 12 is configured to provide alignment protrusions that engage with corresponding alignment recesses on the test system to facilitate proper alignment of the exit surface 22 with the test system. The housing 12 of one embodiment is combined into two or more parts (e.g., 60A overmolded two-piece casting) that form an outer shell in which other motion components are held. 3 piece Lustran (R) with urethane or thermoplastic elastomer overmolding. In certain embodiments, the light used by the device 10 can be damaging to the eyes when viewed by an individual. In such an embodiment, the device 10 can be configured to provide eye protection so that individuals do not see the light. For example, opaque material can be used with respect to the housing 12 and placed in place so that the light is not directly visible. In addition, an interlock may be provided to prevent the light source from operating unless the device 10 is in place, or other suitable safety measures are taken.

  In certain embodiments, the housing 12 further includes a flexible fixture 17 that generally surrounds a portion of the device 10 that is releasably provided on the output optical assembly 20. Certain embodiments of the fixture 17 provide a barrier to control, inhibit, prevent, minimize or reduce the entry of contaminants into the housing 12. As described above, since there is the fixture 17 provided with the barrier, the contaminants entering the housing 17 are less than in the case where the fixture 17 does not provide the barrier. Examples of materials for the flexible fixture 17 include, but are not limited to, rubber or other elastomers.

  In certain embodiments, conduit 14 is configured to operably couple apparatus 10 to various control, power and cooling systems provided at a distance from housing 12. In certain embodiments, the conduit 14 is configured to transmit light from the light source that is emitted from the exit surface 22 to the device 10. In some embodiments, the conduit 14 further includes one or more conductive wires (eg, one 20 conductor cable, four 6 conductor cables, a ground braid) that transmits signals to the device 10 (eg, device 10). Between the device 10 and a control system spaced from the device 10 and / or provide power from the power system to the device 10 (eg, for a thermoelectric cooler) Configured to do. In yet other embodiments, the device 10 includes a power source (eg, a battery). In certain embodiments, conduit 14 includes one or more coolant tubes (eg, 0.125 inch inner diameter) configured to allow coolant (eg, liquid or gas) to flow from the cooling system to apparatus 10. In certain embodiments, conduit 14 includes one or more connectors that are mechanically coupled to one or more corresponding connectors in housing 12. For example, the conduit 14 can include an SMA connector at one end of an optical fiber that is mechanically coupled to a corresponding SMA mount in the housing 12.

  In certain embodiments, conduit 14 includes a protective sheath around one or more fibers, wires, and tubes of conduit 14. In some embodiments, the protective sheath controls, inhibits, prevents, minimizes, or reduces light exiting the conduit 14 upon failure of at least one optical fiber. Thus, because of the sheath, less light exits the conduit 14 in the event of a fiber failure than would be without the sheath. In one embodiment, the protective sheath includes a tension relief device having a plurality of rigid segments (eg, stainless steel), each segment being generally cylindrical and having a longitudinal axis. Each segment is articulated with a neighboring segment such that the angle between the longitudinal axes of adjacent segments is limited to less than a predetermined angle. In certain embodiments, the protective sheath moves and bends the conduit 14, but advantageously the radius of curvature of the bend is used to avoid breakage of one or more fibers, wires, or tubes therein. Limit it to be large enough. In certain embodiments, the sheath includes a flexible compression spring (eg, 4 inches long) to provide bending relief and / or tension lines to ease tension.

  In one embodiment, the at least one status indicator 16 includes one, two or more light emitting diodes (LEDs) that when illuminated, visually provide information to the user regarding the status of the device 10. Including. For example, the at least one status indicator 16 may be used in one embodiment to indicate when the laser source is ready to apply laser light to a trigger engagement that has not yet occurred. In some embodiments, the LEDs may be lit to show different colors depending on whether the optical power, power or coolant flow provided to the device 10 is sufficient for the operation of the device 10. it can. In one embodiment, the at least one status indicator 16 provides information regarding whether the output optical assembly 20 is properly attached to the device 10. Other types of status indicators (e.g., flags, voice alerts) are also compatible with certain embodiments described herein.

  FIG. 2A schematically illustrates a cross-sectional view of an example output optical assembly 20 in accordance with certain embodiments described herein. FIG. 2B schematically illustrates another example 20 of an output optical assembly in accordance with certain embodiments described herein. The output optical assembly 20 includes an optical element 23 that includes an exit surface 22 and a surface 24 that faces away from the exit surface 22 as a whole. As used herein, the term “element” is used in the broadest sense and refers to, but is not limited to, one component or different part of a composite device. Output optical assembly 20 further includes a thermal conduit 25 in thermal communication with optical element 23 (eg, with a portion of surface 24). The thermal conduit 25 includes at least one surface 26 configured to be in thermal communication with at least one heat radiating surface of the device 10 (eg, a surface of a cooling mechanism). The output optical assembly 20 further includes a coupling portion 27 (eg, a spring loaded 3-pin plug device or a 4-pin plug device) configured to be releasably mounted to and removed from the housing 12. In certain embodiments, the output optical assembly 20 includes one or more springs that apply sufficient force on the at least one surface 26 toward at least one heat dissipation surface of the device 10; Ensure that the desired heat transfer occurs between the two. Various examples of output optical assembly 20 corresponding to certain embodiments described herein are described in more detail in US patent application Ser. No. 12 / 233,498, which is hereby incorporated by reference in its entirety. ing.

  In certain embodiments, the output optical assembly 20 is positioned in thermal communication with the patient's scalp or skull (eg, the optical element 23 is configured to contact the patient's scalp or skull, or , Configured to contact a thermally conductive material spaced from the patient's scalp or skull but in contact with the patient's scalp or skull). In certain embodiments where the output optical assembly 20 is cooled, the output optical assembly 20 cools at least a portion of the patient's scalp or skull (eg, the portion of the scalp or skull that is being irradiated). Thus, in some embodiments, the output optical assembly 20 is adapted to control, inhibit, prevent, minimize or reduce temperature increases in the scalp or skull caused by light. Thus, because the output optical assembly 20 cools the patient's scalp or skull portion that is being irradiated, the temperature of the patient's scalp or skull irradiated portion is such that the output optical assembly 20 cools the scalp or skull irradiated portion. Lower than if not. For example, by using the light output assembly 20 to cool the irradiated portion of the patient's scalp or skull, the temperature of the irradiated portion of the patient's scalp or skull is higher than if not irradiated, but the irradiated but cooled. It can be lower than if it was not. In one embodiment, the patient's scalp includes hair and skin covering the patient's skull. In other embodiments, at least a portion of the hair is removed prior to phototherapy treatment so that the output optical assembly 20 is in substantial contact with the scalp skin.

  The optical element 23 in one embodiment is thermally conductive and optically transmissive at wavelengths transmitted by the skin. For example, in one embodiment, the thermal conductivity of the optical element 23 is sufficient to remove heat from the irradiated portion of the patient's scalp or skull, and the optical transparency of the optical element 23 is desired in the target area of the brain. At a wavelength selected to provide an irradiance of, the desired irradiance of light is sufficient to propagate through the optical element 23 to irradiate the patient's scalp or skull. In some embodiments, the optical element 23 comprises a rigid material, while in some other embodiments, the optical element 23 is a low durometer, thermally conductive and light transmissive material (eg, a thermally conductive and light transmissive material such as water). A flexible bag or container filled with a sexual liquid. Examples of rigid materials for optical element 23 include, but are not limited to, sapphire, diamond, calcium fluoride, and zinc selenide. In one embodiment, the optical element 23 has an exit surface 22 configured to generally face the surface to be illuminated (eg, the patient's scalp or skull). In certain embodiments, the exit surface 22 is positioned to contact the illuminated surface or a substantially light transmissive and substantially thermally conductive material that contacts the illuminated surface. In one embodiment, the exit surface 22 is configured to be in thermal communication with a surface that is illuminated with light emitted from the exit surface 22. In some such embodiments, the thermal conductivity of the optical element 23 is such that the heat from the exit surface 22 flows at a sufficient rate toward the heat conduit 25 so that the skin is overheated due to irradiation. Is sufficiently high to control, suppress, prevent, minimize or reduce the skin damage or discomfort given to the patient. As described above, since the optical element 23 is thermally conductive, the damage or discomfort of the patient's skin can be reduced as compared with the case where the optical element 23 does not have sufficiently high thermal conductivity. it can. For example, the patient's skin damage or discomfort may be higher than if a portion of the patient's scalp was not irradiated, while the patient's skin damage or discomfort is caused by the optical element 23. It would be low compared to not having a sufficiently high thermal conductivity.

  In certain embodiments, optical element 23 has a thermal conductivity of at least about 10 Watts / meter-K. In certain other embodiments, the thermal conductivity of the optical element 23 is at least about 15 Watts / meter-K. Examples of materials for optical element 23 in accordance with certain embodiments described herein include sapphire with a thermal conductivity of about 23.1 Watts / meter-K, and thermal conductivity of about 895 Watts / meter-K and about Including but not limited to diamonds between 2300 Watts / meter-K.

  In one embodiment, the exit surface 22 is made to match the curvature of the scalp or skull. In one embodiment, the exit surface 22 is concave (eg, generally spherical with a radius of curvature of about 100 millimeters). By matching the curvature of the scalp or skull, the exit surface 22 advantageously controls and inhibits temperature rise in the scalp or skull than when there is a gap filled with air between the exit surface 22 and the scalp or skull. Prevent, minimize or reduce. Thus, since the exit surface 22 is matched to the curvature of the irradiated scalp or skull part of the patient, the temperature of the irradiated part of the patient's scalp or skull is such that the exit surface 22 is the same as the irradiated part of the scalp or skull It is lower than when it does not match the curvature. For example, by matching the exit surface 22 to the curvature of the irradiated portion of the patient's scalp or skull, the temperature of the irradiated portion of the patient's scalp or skull may be higher than when the patient's scalp or skull is not irradiated. It can be lower than when the patient's scalp or skull is irradiated but the exit surface 22 does not match the patient's scalp or skull part. A gap between the exit surface 22 and the scalp or skull can reduce the thermal conductivity between the exit surface 22 and the scalp or skull and increase the likelihood of heating the scalp or skull by irradiation. is there.

  In addition, a refractive index mismatch between such an air gap and the exit surface 22 and / or the scalp or skull may reflect a portion of the light propagating towards the scalp or skull from the scalp or skull. There is. In certain embodiments, the exit surface 22 is in contact with the scalp or skull to advantageously reduce substantially the air gap between the exit surface 22 and the scalp or skull in the optical path of light. In other embodiments where an intervening material (eg, a substantially light transmissive and substantially heat conductive gel) is in contact with the scalp or skull and the exit surface 22, the exit surface 22 is in contact with the intervening material. Thus, a gap between the exit surface 22 and the intervening material or a gap between the intervening material and the scalp or skull is not advantageously created. In one embodiment, the refractive index of the intervening material at the wavelength of light striking the scalp substantially matches the refractive index of the scalp (eg, about 1.3), so that the refractive index between the exit surface 22 and the scalp. It is possible to reduce the back reflection caused by the mismatch. Examples of materials corresponding to certain examples described herein include, but are not limited to, glycerol, water, and silica gel. Examples of gels with matching refractive indices are available from, but not limited to, Nye Lubricants, Inc., Fairhaven, Massachusetts.

  In certain embodiments, the exit surface 22 includes one or more optical coatings, films, layers, films, etc. adapted to reduce back reflection in the optical path of the transmitted light. By reducing back reflections, the exit surface 22 increases the amount of light transmitted to the brain, reducing the need to use higher irradiance that would otherwise cause an increase in temperature in the scalp or skull.

  In certain embodiments, the output optical assembly 20 diffuses the light before reaching the scalp or skull, and advantageously homogenizes the light beam before reaching the exit surface 22. Generally, the scalp or skull interstitial tissue is highly scatterable, which can reduce the effects of non-uniform beam intensity distribution on the irradiation of the patient's cerebral cortex. However, as a result of a non-uniform beam intensity distribution that is substantially inhomogeneous, some portions of the patient's scalp or skull that are being heated may be heated more than others (eg, the light beam "Local heating where a" hot spot "hits the patient's scalp or skull"). In certain embodiments, the output optical assembly 20 advantageously homogenizes the light beam so that the non-uniformity is less than about 3 millimeters. 3A and 3B illustrate the diffusion effect on the light by the output optical assembly 20. As shown in FIG. 3A, an example of the energy density profile of light prior to being transmitted through the output optical assembly 20 peaks at a particular emission angle. As shown in FIG. 3B, after being diffused by the output optical assembly 20, the energy density profile of the light does not have a substantial peak at a particular emission angle, but is substantially homogeneous over a range of emission angles. Distributed. By diffusing light, the output optical assembly 20 distributes light energy substantially evenly in the illuminated area, thereby causing a “hot spot” that would otherwise cause an increase in the temperature of the scalp or skull. Can be controlled, suppressed, prevented, minimized or reduced. Thus, since the output optical assembly 20 diffuses light, the temperature of the irradiated portion of the patient's scalp or skull is lower than when the output optical assembly 20 does not diffuse light. For example, by diffusing light using the output optical assembly 20, the temperature of the irradiated portion of the patient's scalp or skull may be higher than the temperature of the patient's scalp or portion of the skull when not irradiated. However, the temperature can be lower than the temperature of the patient's scalp or skull when the output optical assembly 20 is illuminated but not diffused. In addition, by diffusing the light before reaching the scalp or skull, the output optical assembly 20 can effectively increase the spot size of the light that strikes the scalp or skull, thereby favorably irradiating the scalp or skull. Reduce. This is described in US Pat. No. 7,303,578, which is incorporated herein by reference in its entirety.

  In some embodiments, the output optical assembly 20 diffuses light sufficiently so that the irradiance of light is less than the maximum acceptable level of the scalp, skull, or brain. For example, the maximum acceptable level in some embodiments is the level at which the patient feels uncomfortable or painful, and in some other embodiments, the maximum level is the level at which the patient's scalp or skull is damaged (eg, burned). In some other embodiments, the output optical assembly 20 diffuses light sufficiently so that the irradiance of the light is equal to the treatment value of the subcutaneous target tissue. Output optical assembly 20 is available from Physical Optics Corp. of Torrance, Calif., And display optics P / P of Reflexite Corp. of Avon, Connecticut. Examples of diffusers can be included, including but not limited to holographic diffusers such as NSN 1333.

  In one embodiment, the output optical assembly 20 provides a reusable interface between the device 10 and the patient's scalp or skull. In such an embodiment, the output optical assembly 20 can be cleaned or disinfected during use of the device 10, particularly during use by different patients. In other embodiments, the output optical assembly 20 provides a disposable, replaceable interface between the device 10 and the patient's scalp or skull. By using a pre-sterilized and pre-packed interchangeable interface, some embodiments can advantageously provide a disinfected interface without having to be cleaned or disinfected immediately prior to use.

  In certain embodiments, the output optical assembly 20 is adapted to apply pressure to at least the radiated portion of the scalp. For example, the output optical assembly 20 may be applied to the device 10 (eg, by manually pressing the device 10 against the patient's scalp by an operator of the device 10 or by mechanical means that generate forces such as weight, springs, tension straps, etc.). ) If there is an applied force, at least pressure can be applied to the irradiated part of the scalp. By applying sufficient pressure, the output optical assembly 20 can whiten that portion of the scalp by taking at least some amount of blood out of the optical path of light energy (general for whitening skin). For example, see AC Burton et al., “Relation Between Blood Pressure and Flow in the Human Forearm”, J. Appl. Physiology, 4th. Vol. 5, pp. 329-339 (1951), A. Matas et al., “Eliminating the Issue of Skin Color in Assessment of the Blanch Response” "Adv. In Skin & Wound Care, Volume 14 (Parts 4 and 2), 180-188 (July / August 2001), J. Niitsuma et al. Pressure ulcer form (Experimental study of decubitus ulcer formation in the rabbit ear lobe), J. Of Rehab. Res. And Dev., Vol. 40, No. 1, pp. 67-72 (January 2003)) . As blood is removed as a result of the output optical assembly 20 applying pressure to the scalp, the corresponding absorption of light energy by the blood in the scalp is reduced. As a result, the temperature rise due to blood absorbing light energy in the scalp is reduced. Furthermore, as a result, some of the light energy transmitted to the subcutaneous target tissue of the brain is increased. In one embodiment, the irradiated portion of the scalp is whitened using a pressure of at least 0.1 pounds per square inch. In some other embodiments, the irradiated portion of the scalp is whitened using a pressure of at least 1 pound per square inch. In one embodiment, the irradiated portion of the scalp is whitened using a pressure of at least 2 pounds per square inch. Other values or ranges of pressure to whiten the irradiated area of the scalp also correspond to certain embodiments described herein. The maximum pressure used to whiten the irradiated area of the scalp is limited in some embodiments by the patient's comfort level and tissue damage level.

  4A and 4B schematically illustrate cross-sectional views of two examples of a beam delivery device 10 in accordance with certain embodiments described herein. 4A and 4B, the apparatus 10 includes an output optical assembly 20 having an exit surface 22 and releasably and operatively coupled to other components of the apparatus 10. The apparatus 10 includes an optical fiber 40, a fiber alignment mechanism 50 operably coupled to the optical fiber 40, a mirror 60 in optical communication with the optical fiber 40, and a window 70 in optical communication with the mirror 60. Including. During operation of the apparatus 10, the light 30 from the optical fiber 40 propagates to the mirror 60, is reflected by the mirror 60 and propagates through the window 70. The light 30 transmitted through the window 70 propagates along the first optical path through the output optical assembly 20 and exits from the exit surface 22. In some embodiments, apparatus 10 includes additional optical elements (eg, lenses, diffusers and / or waveguides) that transmit at least a portion of the light received via optical fiber 40 to exit surface 22. In some such embodiments, additional optical elements of the apparatus 10 shape, format, or modify the light so that the light beam emitted from the exit surface 22 has the desired beam intensity profile.

  In some embodiments, the optical fiber 40 includes a stepped or graded optical fiber. In some embodiments, the optical fiber 40 is single mode, and in certain other embodiments, the optical fiber is multimode. An example optical fiber 40 corresponding to an embodiment described herein has a diameter of 1000 microns and an aperture of about 0.22.

  FIG. 5 schematically illustrates an example of a fiber alignment mechanism 50 in accordance with certain embodiments described herein. In one embodiment, the fiber alignment mechanism 50 is mechanically coupled to a portion of the optical fiber 40 and is configured to adjust the position, tilt, or both of the end of the optical fiber 40 from which light is emitted. In some embodiments, the fiber alignment mechanism 50 provides an adjustment range of at least ± 5 degrees. The fiber alignment mechanism 50 of FIG. 5 includes a connector 52 (eg, an SMA connector) mechanically coupled to the optical fiber 40, a plate 54 (eg, kinematic tilt stage) mechanically coupled to the connector 52, a plate And an adjustment screw 56 (eg, 80 turns per inch or 100 turns per inch) that is adjustably coupled to 54. By winding the adjustment screw 56, the distance between a part of the plate 54 and a corresponding part of the reference structure 58 can be adjusted. In certain embodiments, the fiber alignment mechanism 50 includes one or more locking screws configured to be clamped to secure the plate 54 relative to the reference structure 58 in a position, orientation, or both. Other configurations of the fiber alignment mechanism 50 also correspond to certain embodiments described herein.

  FIG. 6 schematically illustrates an example of a mirror 60 corresponding to an embodiment described herein. In one embodiment, the mirror 60 substantially reflects the light emitted from the optical fiber 40 and reflects this light at a non-zero angle (eg, 90 degrees). The mirror 60 of one embodiment includes a glass substrate that is coated at least on one side with a metal (eg, gold or aluminum). An example of a mirror 60 corresponding to certain embodiments described herein is a flat, generally flat glass mirror (eg, NT43 available from Edmund Optics Inc., Barrignton, NJ). -886), but is not limited thereto. The mirror 60 of some embodiments can be configured to have a certain refractive power (eg, the mirror 60 can be concave) and can be shaped, shaped or otherwise modified to produce the desired beam intensity profile. can do. In one embodiment, the perimeter of mirror 60 is adhered to support structure 62 with an adhesive (eg, OP-29 available from Dymax Corp., Torrington, Conn.).

  In one embodiment, the mirror 60 partially transmits the light emitted from the optical fiber 40. In one such embodiment, support structure 62 includes an aperture and apparatus 10 includes at least one light sensor 64 positioned to receive light transmitted through the aperture of mirror 60 and support structure 62. The at least one photosensor 64 is configured to generate a signal that provides a measure of the intensity of light reaching the mirror 60 by indicating the intensity of the received light. Examples of optical sensors 64 corresponding to certain embodiments described herein include, but are not limited to, OPT101 photodiodes available from Texas Instruments, Dallas, Texas. In one embodiment, multiple optical sensors 64 are used to provide operational redundancy to ensure that sufficient intensity of light is provided by the optical fiber 40 for operation of the device 10. In one embodiment, a diffuser 66 is arranged to diffuse the light transmitted through the mirror 60 before the light hits the light sensor 64. In one embodiment, the light sensor 64 is protected from stray light by an opaque sidewall 68 that generally surrounds the light sensor 64.

In certain embodiments, window 70 is substantially transparent to infrared. An example of a window 70 corresponding to certain embodiments described herein is a flat, generally flat CaF ₂ window (eg, a TechSpec® calcium fluoride window available from Edmund Optics, Burlington, NJ). Including, but not limited to.

  In certain embodiments, window 70 at least partially surrounds an area within device 10 that includes mirror 60. One such example window 70 substantially seals the area, preventing contaminants (eg, dust, dust) from entering the area from outside the area. For example, when the output optical assembly 20 is removed from the apparatus 10, the window 70 controls, suppresses, prevents, minimizes or reduces contaminants entering this area. Thus, since the window 70 substantially seals this area, contamination of this area is less than when the window 70 does not substantially seal this area.

  FIG. 7 schematically illustrates an example of a first optical path 32 of light 30 emitted from an optical fiber 40 in accordance with certain embodiments described herein. The light 30 that branches out of the optical fiber 40 propagates along the first optical path 32 toward the mirror 60. This light 30 is reflected by the mirror 60, propagates along the first optical path 32 through the window 70, hits or is received by the surface 24 of the optical element 23, and is directed from the exit surface 22 to the illuminating surface. Are emitted. In one embodiment, mirror 60 reflects light 30 at an angle of about 90 degrees. In one embodiment, the mirror 60 is about 2.3 inches from the face of the optical fiber 40 and the first optical path 32 has a length from the output face of the fiber to the exit face 22 of the optical element 23 of about 4. 55 inches.

  In some embodiments, the apparatus 10 further includes a sensor 80 spaced from the output optical assembly 20. FIG. 8 schematically illustrates an example of the second optical path 82 of the radiation 84 received by the sensor 80. Sensor 80 is positioned to receive radiation 84 from output optical assembly 20 that propagates through output optical assembly 20 along second optical path 82. There is a non-zero angle between the first optical path 32 and the second optical path 82. In some embodiments, the second optical path 82 is coplanar with the first optical path 32, and in certain other embodiments, the first optical path 32 and the second optical path 82 are not coplanar. . The sensor 80 in one embodiment receives radiation 84 propagating along the second optical path 82 from at least a portion of the surface 24 of the optical element 23 during operation of the device 10.

  The sensor 80 in one embodiment includes a temperature sensor (eg, a thermocouple string) configured to receive infrared radiation from a region and generate a signal indicative of the temperature of that region. Examples of temperature sensors corresponding to certain embodiments described herein include the DX-0396 thermocouple train available from Dexter Research Center, Inc. of Dexter, Michigan. It is not limited to this. In one embodiment, the field of view of sensor 80 is an area of approximately 0.26 square inches of face 24 spaced from thermal conduit 25 (eg, by a distance between 0.05 inches and 0.3 inches). including. In some other embodiments, the field of view of sensor 80 includes an area of about 0.57 square inches of surface 24.

  In some embodiments, sensor 80 generates a signal indicative of the temperature of a portion of output optical assembly 20 (eg, optical element 23) or skin in response to receiving radiation 84. In one such embodiment, device 10 further receives a signal from sensor 80 and generates a warning for a signal indicating that the temperature is above a predetermined threshold (eg, 42 degrees) temperature. A controller configured to turn off, or both, a light source of light propagating along the first optical path 32.

  In some embodiments, sensor 80 is not in thermal communication with output optical assembly 20. As shown in FIG. 8, the infrared transmissive window 70 is between the sensor 80 and the output optical assembly 20. Both the light 30 propagating along the first optical path 32 and the infrared ray 84 propagating along the second optical path 82 both propagate through the window 70. In one embodiment, sensor 80 may be wholly or at least partially within a region of housing 12 that is at least partially enclosed and substantially sealed by window 70 and contaminants from outside of this region. Do not enter this area.

  In one embodiment, the device 10 cools the irradiated portion of the scalp or skull by removing heat from the scalp or skull to control, inhibit, prevent, minimize or reduce the temperature rise in the scalp or skull. Thus, since the device 10 cools the irradiated portion of the patient's scalp or skull, the temperature of the irradiated portion of the patient's scalp or skull is lower than if the device 10 does not cool the irradiated portion of the scalp or skull. . For example, by cooling the irradiated portion of the patient's scalp or skull using the apparatus 10, the temperature of the irradiated portion of the patient's scalp or skull is more than that when the patient's scalp or part of the skull is not irradiated. May be higher, but lower than if the patient's scalp or skull was irradiated but not cooled. With reference to FIGS. 4A and 4B, in one embodiment, apparatus 10 includes a thermoelectric assembly 90 and a heat sink 100 in thermal communication with thermoelectric assembly 90. In certain embodiments, the thermoelectric assembly 90 provides a large temperature gradient in the scalp or skull that advantageously cools the patient's scalp or skull through the output optical assembly 20, which would otherwise be uncomfortable for the patient. To avoid. In certain embodiments, apparatus 10 further includes one or more temperature sensors (eg, thermocouples, thermistors) that generate an electrical signal indicative of the temperature of thermoelectric assembly 90.

  In certain embodiments, thermoelectric assembly 90 includes at least one thermoelectric element 91 and a thermal conduit 92. The at least one thermoelectric element 91 of the thermoelectric assembly 90 cools at least the first surface 93 of the thermoelectric assembly 90 in response to application of current from the thermoelectric assembly 90 and at least a second surface 94 of the thermoelectric assembly 90. Heat. The thermoelectric assembly 90 is configured to be releasably and mechanically coupled to the output optical assembly 20 such that the first surface 93 is in thermal communication with the output optical assembly 20. In one embodiment, the first surface 93 includes the surface of the thermal conduit 92 and the second surface 94 includes the surface of the thermoelectric element 91.

  In accordance with certain embodiments described herein, FIG. 9A schematically illustrates an example of a thermoelectric element 91, and FIG. 9B schematically illustrates two views of an example of a thermal conduit 92. In accordance with certain embodiments described herein, FIG. 10A schematically illustrates another example of a thermoelectric element 91, and FIG. 10B schematically illustrates two views of another example of a thermal conduit 92. The thermoelectric element 91 has a surface 95 configured to be in thermal communication with a corresponding surface 96 of the thermal conduit 92 (eg, by a thermally conductive adhesive). When a current is applied to the thermoelectric element 91, the second surface 94 is heated and the surface 95 is cooled, whereby the first surface 93 is cooled. In certain such embodiments, the first surface 93 functions as at least one heat dissipation surface of the device 10 that is configured to be in thermal communication with at least one surface 26 of the thermal conduit 25 of the output optical assembly 20. (E.g., providing a thermally conductive connection between thermoelectric assembly 26 and output optical assembly 20 by contact or engagement). Because the thermally conductive output optical assembly 20 is in thermal communication with the thermoelectric assembly 90, some embodiments advantageously provide a conduit for transferring heat away from the treatment site (eg, skin). In one embodiment, the output optical assembly 20 is pressed against the patient's skin and conducts heat away from the treatment site.

Examples of thermoelectric elements 91 corresponding to certain embodiments described herein are DT12-6 available from Marlow Industries, Dallas, Texas, Q _max = 60 W, square thermoelectric elements, and New Hampshire Including, but not limited to, a toroidal or donut-shaped thermoelectric element, Q _max = 45 W, available from Ferrotec Corp. of Bedford, Ohio. In certain embodiments, thermoelectric element 91 removes heat from output optical assembly 20 at a rate in the range of about 0.1 watts to about 5 watts or in the range of about 1 watt to about 3 watts. An example of a temperature controller for operating a thermoelectric assembly 90 in accordance with certain embodiments described herein is MPT-5000 available from Wavelength Electronics, Inc., Bozeman, Montana. Including, but not limited to. Examples of materials for the thermal conduit 92 corresponding to certain embodiments described herein include, but are not limited to, aluminum and copper. In one embodiment, thermal conduit 92 has a thermal mass in the range of about 30 grams to about 70 grams, and a thermal length between surface 93 and surface 96 in the range of about 0.5 inches to about 3.5 inches. It is in.

  In certain embodiments, the thermoelectric assembly 90 generally surrounds the first region 97, and light that illuminates a portion of the patient's skin propagates through the first region 97 during operation of the device 10. As shown in FIGS. 9B and 10B, in one embodiment, the first region 97 includes an opening through the thermal conduit 92. As shown in FIG. 10B, the first region 97 of one embodiment further includes an opening through the thermoelectric element 91. In one embodiment, thermoelectric assembly 90 includes a plurality of thermoelectric elements 91 that are spaced apart from each other and are disposed so as to generally surround first region 97. As used herein, the term “generally enclosing” is intended to be subject to the broadest reasonable interpretation and surrounds or extends around at least one edge of the region, or at least one It is arranged to surround at least one edge of the region leaving one or more gaps along the edge.

  In accordance with certain embodiments described herein, FIG. 11A schematically illustrates a cross-sectional view of an example of a heat sink 100, and FIG. 11B schematically illustrates another example of the heat sink 100. The heat sink 100 includes an inlet 101, an outlet 102, and a fluid conduit 103 in fluid communication with the inlet 101 and the outlet 102. In some embodiments, the inlet 101 and outlet 102 are tubes (eg, nylon or stainless steel hose valve locks) that provide coolant (eg, water, air, glycerol) that flows through the fluid conduit 103 and removes heat from the fluid conduit 103. A stainless steel valve (barb) configured to be connected to a clamp, or using a crimp. In certain embodiments, the coolant is provided by a cooler or other heat transfer device that cools the coolant before it is applied to the heat sink 100.

  The example of the heat sink 100 of FIG. 11A is machined from an aluminum block and a thermoelectric assembly 90 is disposed to provide thermal communication between the heat sink 100 and the second surface 94 of the thermoelectric assembly 90. The depression 104 is arranged as described above. One example of the heat sink 100 of FIG. 11B includes a first portion 105 and a second portion 106 that combine to form a coolant conduit 103. In one embodiment, a thermally conductive adhesive (eg, EP 1200 thermal adhesive available from Resinlab, LLC, Germantown, Wisconsin, bond wire using 0.005 inch stainless steel wire. The thermoelectric assembly 90 and the heat sink 100 are bonded and thermally communicated with each other.

  The output optical assembly 20 includes a thermally conductive thermal conduit 25 having at least one surface 26 configured to be in thermal communication with the first surface of the thermoelectric assembly 90. As shown in FIGS. 2A and 2B, the thermal conduit 25 generally surrounds the second region 28. During operation of the device 10, light propagates through the first region 97, the second region 28 and the optical element 23. In some embodiments, the heat sink 100 generally surrounds the third region 107 as schematically illustrated in FIG. 11B. During operation of the apparatus 10 in such an embodiment, light propagates through the third region 107, the first region 97, the second region 28, and the optical element 23.

  FIGS. 12A and 12B schematically show two examples of configurations of the window 70 along with the thermoelectric assembly 90. In one embodiment, window 70 is in thermal communication with at least a portion of thermoelectric assembly 90 (eg, using OP-29 adhesive available from Dymamax, Torrington, Conn., As shown in FIG. 12A). And bonded to the recess of the heat conduit 92). In certain embodiments, window 70 is in thermal communication with at least a portion of heat sink 100 (eg, held by an O-ring in heat sink 100), as shown in FIG. 12B. In certain embodiments, window 70 is not in thermal communication with either thermoelectric assembly 90 or heat sink 100.

  FIG. 13A schematically illustrates an example of a support 110 for supporting various components of the beam delivery device 10 within the housing 12 in accordance with certain embodiments described herein. The support 110 of FIG. 13A includes a single or integrated portion that is machined to provide various surfaces and holes that are used to mount various components of the beam delivery device 10. . FIG. 13B schematically illustrates another example of a support 110 in accordance with certain embodiments described herein. The support 110 of FIG. 13B includes multiple portions that are bolted or pinned together.

  FIG. 14A schematically illustrates a cross-sectional view of an example configuration of support 110 and housing 12 in accordance with certain embodiments described herein. In some embodiments, the support 110 is grounded, and in some other embodiments, the support 110 is isolated from ground (eg, floating). In some embodiments, the support 110 is configured to move relative to the housing 12. For example, support 110 and housing 12 are mechanically coupled by pivot 112, as schematically illustrated by FIG. 14A. The optical fiber 40, fiber adjustment device 50, mirror 60, window 70, sensor 80, and heat sink 100 are each mechanically coupled to the support 110. Output optical assembly 20 is also mechanically coupled to support 110 via thermoelectric assembly 90 and heat sink 100.

  For the configuration of FIG. 14A, the output surface 22 of the output optical assembly 20 is placed in thermal communication (eg, in contact with) the patient's scalp or skull by a user pressing the housing 12 against the scalp or skull. The pivot 112 rotates the support 110 about the pivot 112 relative to the housing 12 (eg, an angle between 1 and 2 degrees or only about 1.75 degrees) so that the exit surface 22 is toward the housing 12. Move (for example, a distance of 0.05-0.3 inches or about 0.1 inches). In one such embodiment, this movement of the support 110 and the movement of the fiber conditioner 50 and the optical fiber 40 cause a portion of the optical fiber 40 to bend (eg, near the coupling between the housing 12 and the conduit 14). ).

  This bending of the optical fiber 40 may not be desirable in certain situations. For example, it is a case where the connection with the optical fiber 40 or the fiber adjustment device 50 is fragile and is easily damaged or broken when the bending is repeated. 14B and 14C schematically illustrate another example of the configuration of the support 110 and the housing 12 in accordance with certain embodiments described herein. The support 110 includes a first support element 120 and a second support element 122 mechanically coupled to the first support element 120, and thus the first support element 120 and the second support element 120. The support element 122 is relatively movable. For example, in one embodiment, the device 10 further includes a hinge 124 (eg, a pivot or flexible portion) about which the first support element 120 and the second support element 122 are relative. Configured to deflect.

  In one embodiment, the first support element 120 is mechanically coupled to the housing 12, and the optical fiber 40, the fiber conditioner 50, the mirror 60, and the sensor 80 (each indicated by a dotted line in FIG. 14C) It is mechanically coupled to one support element 120. The second support element 122 is mechanically coupled to the window 70, the thermoelectric assembly 90, and the heat sink 100 (each indicated by a dotted line in FIG. 14C). The output optical assembly 20 is also mechanically coupled to the second support element 122 via the thermoelectric assembly 90 and the heat sink 100. Thus, in some such embodiments, the first portion of the device 10 includes the housing 12, the first support element 120, the optical fiber 40, the fiber conditioner 50, the mirror 60, and the sensor. 80, the second portion of the apparatus 10 includes a second support element 122, a window 70, a thermoelectric assembly 90, a heat sink 100, and an output optical assembly 20. The second portion is mechanically coupled to the first portion and is in optical communication with the first portion. The second portion is positioned in thermal communication with the patient's skin so that light from the first portion propagates through the second portion during operation of the device 10. The first portion and the second portion are configured to move relative to each other in response to the second portion being disposed in thermal communication with the patient's skin.

  In certain embodiments, the second portion includes the output optical assembly 20, and the first portion and the second portion are configured to relatively deflect at a non-zero angle. In some embodiments, this deflection occurs when the output optical assembly 20 applies sufficient pressure to a portion of the patient's scalp to at least partially whiten that portion of the patient's scalp. In certain embodiments, this deflection occurs when the output optical assembly 20 is placed in thermal communication with the patient's scalp or skull. In certain embodiments, device 10 further includes a spring mechanically coupled to the first portion and the second portion. The spring provides a restoring force in response to the relative movement of the first part and the second part.

  For the configurations of FIGS. 14B and 14C, the exit surface 22 of the output optical assembly 20 is in thermal communication (eg, in contact with) the patient's scalp or skull by a user pushing the housing 12 toward the scalp or skull. Be placed. The hinge 124 causes the second portion (eg, including the second support element 122) to rotate about the hinge 124 relative to the first portion (eg, including the first support element 120). This rotation is at an angle between 1 and 3 degrees (or about 2.3 degrees) to allow the exit surface 22 to move toward the housing 12 (e.g., 0.05-0.3 inches). Or only about 0.08 inch distance). In certain such embodiments where the first portion includes the optical fiber 40, the relative deflection of the first and second portions can control, inhibit, prevent, or minimize the bending or movement of the optical fiber. Or reduce (eg, control, suppress, prevent, minimize or reduce damage to the optical fiber 40). As described above, the relative movement of the first and second portions reduces the bending, movement, or damage of the optical fiber 40 as compared to the case where the first and second portions do not move relatively. .

  In certain embodiments, relative movement of the output optical assembly 20 and the mirror 60 causes the light beam 30 to be at least partially blocked or “cut off” by the thermal conduit 25 of the output optical assembly 20. For example, if the diameter of the light beam is 30 millimeters, the light beam 30 is not cut by the heat conduit 25. If the diameter of the light beam is larger, the light beam 30 is partially blocked by the heat conduit 25. If the diameter of the light beam is 31 millimeters, about 0.02% of this light beam area is blocked, and if it is 32 millimeters, about 1.56% of the light beam area is blocked and about 0.08% Less than the estimated power loss.

  In some embodiments, the apparatus 10 further detects relative movement of the first and second portions (eg, relative movement of the first support element 120 and the second support element 122). A sensor 130 configured as described above. The sensor 130 is configured to send a signal to a controller configured to receive the signal and to control the light source in response to the signal, the light source being transmitted by the device 10 that illuminates the patient's scalp or skull. Configured to generate the light used. In one embodiment, sensor 130 transmits a signal when it is detected that movement between the first portion and the second portion is greater than a predetermined threshold. In this way, the sensor 130 serves as a trigger switch used to trigger the device 10 (e.g., the first portion indicating that the device 130 is in use and the device 10 is in use). When a predetermined amount of movement between the second parts is detected, light is supplied to the device 10). The trigger switch of an embodiment is activated by pressing the output optical assembly 20 against the surface. In response to the trigger switch, the light source that supplies light to the apparatus 10 emits light only when the trigger switch is activated. Thus, in some such embodiments, in order to use the device 10, the output optical assembly 20 is pressed against the patient's skin as described above.

  FIGS. 15A and 15B schematically illustrate two states of an example sensor 130 in accordance with certain embodiments described herein. Sensor 130 includes at least one trigger flag 132 mechanically coupled to a first portion (eg, housing 12) and at least mechanically coupled to a second portion (eg, second support element 122). One optical switch 134. For example, in one embodiment, the at least one optical switch 134 is one, two or more EE-SXs available from Omron Electronics Components LLC of Schaumburg, Illinois. -Includes 1035 optical switch. In the first state, the trigger flag 132 is shifted away from the sensor light beam detected by the optical switch 134. When the output optical assembly 20 is pushed in thermal communication with the patient's scalp or skull, the optical switch 134 moves relative to the trigger flag 132 (eg, a distance of about 0.07 inches), and the trigger flag 132 is The sensor light beam is blocked so that it is not detected by the optical switch 134. In response to this second state, the sensor 130 generates a corresponding signal. In certain other embodiments, the trigger flag 132 can be arranged to block the sensor light beam in the first state and not block the sensor light beam in the second state.

  FIGS. 15C and 15D schematically illustrate two states of another example of a sensor 130 in accordance with certain embodiments described herein. Sensor 130 is mechanically coupled to a reflective element 135 mechanically coupled to a first portion (eg, first support element 120) and to a second portion (eg, second support element 122). And at least one light source / detector pair 136. For example, in one embodiment, the at least one light source / detector pair 136a, 136b is one, two, or available from Fairchild Semiconductor Corp. of San Jose, Calif. Includes more QRE1113GR reflection sensors. In the first state, the reflective surface 135 is a first distance away from the light source / detector pair 136a, 136b, so that the sensor light beam from the light source 136a is reflected by the surface 135 but is not reflected by the detector 136b. It will not be detected. When the output optical assembly 20 is pushed in thermal communication with the patient's scalp or skull, the reflective surface 135 (eg, by a distance of about 0.04 inches) causes a second distance from the light source / detector pair 136a, 136b. The sensor light beam from the light source 136a is reflected by the surface 135 and detected by the detector 136b. In response to this second state, the sensor 130 generates a corresponding signal. In certain embodiments, sensor 130 further includes a sidewall 137 configured to protect detector 136b from stray light. In some other embodiments, the reflective surface 135 can be positioned so that it reflects the sensor light beam to the detector 136b in the first state and does not reflect the sensor light beam to the detector 136b in the second state.

  In certain embodiments, apparatus 10 further includes an adjustment mechanism configured to set a predetermined threshold, change the predetermined threshold, or both. In some such embodiments, the adjustment mechanism includes a set screw that changes the relative position of the two portions of the relatively moving sensor 130. Certain embodiments further include a stop configured to limit the range of relative movement of the first portion and the second portion.

  In certain embodiments, the device 10 includes a trigger force spring 140 and a trigger force adjustment mechanism 142. FIGS. 16A and 16B schematically illustrate two examples of the configuration of the trigger force spring 140 and trigger force adjustment mechanism 142 according to an embodiment of the present invention. The trigger force spring 140 is mechanically coupled to the first part (eg, the first support element 120) and the second part (eg, the second support element 122), and the first part and the second part. Provides resilience when the parts move relatively. The trigger force adjustment mechanism 142 of FIG. 16A includes one or more shims (eg, each shim provides about 100 grams of adjustment) provided between the spring 140 and at least one of the first and second portions. ). The trigger force adjustment mechanism 142 of FIG. 16B includes one, two or more set screws. In either configuration, the trigger force adjustment mechanism 142 adjusts the amount of force that compresses the spring 140 to move the first and second portions relative to each other enough to trigger the device 10. . In one embodiment, the trigger force adjustment mechanism 142 is housing the exit surface 22 with the device 10 at least 0.1 pounds per square inch, at least 1 pound per square inch, and at least about 2 pounds per square inch. Set to be triggered by pressure applied toward 12.

  In certain embodiments, the apparatus 10 further includes a lens assembly sensor 150 configured to detect the presence of the output optical assembly 20 provided on the apparatus 10. FIG. 17 schematically illustrates an example of a lens assembly sensor 150 in accordance with certain embodiments described herein. For example, an example lens assembly sensor 150 includes at least one reflective surface 152 and at least one light source / detector pair 154a, 154b (eg, one available from Fairchild Semiconductor, Inc., San Jose, Calif.). Two or more QRE1113GR reflection sensors). The reflective surface 152 moves relative to the light source / detector pair 154a, 154b when the output optical assembly 20 is placed in thermal communication with the thermal conduit 92. For example, when the output optical assembly 20 is installed, the plug pin is pulled downward. In response to this movement, the sensor 150 generates a corresponding signal. In certain embodiments, sensor 150 further includes a sidewall 156 configured to protect detector 154b from stray light.

Control Circuit FIG. 18 is a block diagram of a control circuit 200 that includes a programmable controller 205 for controlling the light source 207 according to the embodiments described herein. The control circuit 200 applies a predetermined surface irradiance corresponding to a predetermined energy transfer profile, such as a predetermined subsurface irradiance, to the target region of the brain from the emission surface 22 with the scalp or the skull. It is configured to adjust the output of light energy generated by the light source 207 so that emitted light is generated.

  In one embodiment, programmable controller 205 includes a logic circuit 210, a clock 212 coupled to logic circuit 210, and an interface 214 coupled to logic circuit 210. The clock 212 of one embodiment provides a timing signal to the logic circuit 210 so that the logic circuit 210 can monitor and control the time interval of the applied light. Examples of timing intervals include, but are not limited to, the total treatment time, the pulse width time for the pulse of light emitted, and the time interval between the pulses of light emitted. In one embodiment, the light source 207 is selectively turned on and off to reduce the heat load on the scalp or skull and deliver selected irradiance to specific areas of the brain.

  In one embodiment, interface 214 provides a signal to logic circuit 210 that uses it to control the light emitted. Interface 214 may include a user interface or an interface to monitor at least one parameter of treatment. In some such embodiments, the programmable controller 126 is preferably responsive to signals from the sensor to adjust the treatment parameters to optimize the measured response. In this way, the programmable controller 126 provides closed loop monitoring and adjustment of various treatment parameters to optimize phototherapy. Signals provided by the user through interface 214 include patient characteristics (eg, skin type, fat percentage), selected irradiance, target time interval, and irradiance / timing profile for the emitted light. Indicates non-limiting parameters.

  In some embodiments, logic circuit 210 is coupled to light source driver 220. The light source driver 220 is coupled to a power source 230 that includes a battery in some embodiments and an alternating current source in other embodiments. The light source driver 220 is also coupled to the light source 207. The logic circuit 210 transmits a control signal to the light source driver 220 in response to a signal from the clock 212 and a user input from the user interface 214. In response to the control signal from the logic circuit 210, the light source driver 220 adjusts and controls the power applied to the light source. Control circuits other than the control circuit 200 of FIG. 18 correspond to the embodiments described in this specification.

  In one embodiment, logic circuit 110 controls the light emitted in response to signals from sensors that monitor at least one parameter of the therapy. For example, one embodiment includes a temperature sensor that is in thermal communication with the scalp or skull and provides logic circuit 210 with information regarding the temperature of the scalp or skull. In such an embodiment, logic circuit 210 responds to information from the temperature sensor and sends a control signal to light source driver 220 to adjust the parameters of the emitted light and to pre-set the temperature of the scalp or skull. Maintain below a defined level. Other examples include examples of biomedical sensors including but not limited to blood flow sensors, blood gas (eg, oxygenation) sensors, ATP production sensors, or cellular activity sensors. Such a biomedical sensor can feed back information to the logic circuit 210 in real time. In some such embodiments, the logic circuit 110 is responsive to signals from the sensor, preferably adjusting the parameters of the emitted light to optimize the measured response. In this way, logic circuit 110 provides a closed loop monitor and adjustment of various parameters of the emitted light to optimize phototherapy.

Light Parameters Various parameters of the light beam emitted from the exit surface 22 are conveniently selected to provide treatment while controlling the damage or discomfort caused to the patient by heating the scalp or skull with light, Suppress, prevent, minimize or reduce. Although described separately, these various parameters below can be combined with each other within the range of values disclosed in accordance with the examples described herein.

Wavelength In one embodiment, light in the visible to near infrared wavelength range is used to irradiate the patient's scalp or skull. In some embodiments, the light is substantially monochromatic (ie, light having a single wavelength or light having a narrow wavelength range). For this reason, the amount of light transmitted to the brain is maximized and the wavelength of light is selected in some embodiments to be at or near the transmission peak (or at or near the absorption minimum) for the intervening tissue. The In one such example, the wavelength corresponds to a peak in the tissue's transmission spectrum of about 820 nanometers. In certain other examples, the light is between about 630 nanometers and about 1064 nanometers, between about 600 nanometers and about 980 nanometers, between about 780 nanometers and about 840 nanometers, about Includes one or more wavelengths between 805 nanometers and about 820 nanometers, or includes wavelengths of about 785, 790, 795, 800, 805, 810, 815, 820, 825, or 830 nanometers . An intermediate wavelength in the range of between about 730 and about 750 nanometers (eg, about 739 nanometers) appears to be suitable for penetrating the skull, but other wavelengths are also suitable and used. To get. In other embodiments, multiple wavelengths are used (eg, irradiation simultaneously or sequentially). In one embodiment, the peak of the wavelength distribution of light is at the peak wavelength, and the line width is less than ± 10 nanometers from the peak wavelength. In one such embodiment, the line width of the light is less than 4 nanometers and 90% of the total energy. In one embodiment, the center wavelength is (808 ± 10) nanometers, the spectral linewidth is less than 4 nanometers, and the full width of 90% of the energy.

In certain embodiments, the light is generated by a light source that includes one or more laser diodes that each provide coherent light. In embodiments where the light from the light source is coherent, the emitted light can cause “speckle” due to coherent interference of the light. This speckle includes intensity spikes that can occur near the target tissue being born and treated by wavefront interference effects. For example, the average irradiance or power density can be about 10 mW / cm ² and the power density of such intensity spikes near the brain tissue to be treated can be about 300 mW / cm ² . In some embodiments, this increased power density due to speckle improves the effectiveness of treatment using coherent light compared to treatment using incoherent light for deeper tissue illumination. In addition, speckle can increase power density without overheating the tissue being irradiated. Light in a speckle field or isolated region that contains these intensity spikes is polarized, and in one embodiment, this polarized light exceeds unpolarized light of the same intensity or irradiance Bring improved efficiency.

  In one embodiment, the light source includes at least one continuous-emitting GaAlAs laser diode having a wavelength of about 830 nanometers. In another example, the light source includes a laser light source having a wavelength of about 808 nanometers. In yet another embodiment, the light source includes at least one vertical cavity surface emitting laser (VCSEL) diode. Other light sources in accordance with the embodiments described herein include, but are not limited to, light emitting diodes (LEDs) and filtered lamps.

  In certain embodiments, the one or more wavelengths are selected to work with one or more chromophores in the target tissue. Unless limited by theory or by specific mechanisms, chromophore irradiation increases ATP generation in target tissues and / or controls, inhibits, prevents, minimizes or reduces apoptosis in damaged tissues This is believed to produce an effective effect that will be further explained below.

  Some chromophores such as water or hemoglobin are ubiquitous and absorb light to such an extent that little or no light energy is propagated into the tissue. For example, water absorbs light above about 1300 nanometers. Thus, this range of energy is almost impossible to penetrate tissue due to moisture content. However, water is transmissive or nearly transmissive at wavelengths between 300 and 1300 nanometers. Another example is hemoglobin, which is highly absorbent in the region between 300 and 670 nanometers but is reasonably permeable above 670 nanometers.

  Based on these broad assumptions, an “IR window” can be defined in the body. Within this window, there are several wavelengths that are rather easy to penetrate. This consideration does not include the wavelength dependent scattering effect of the intervening tissue.

  The usefulness of various wavelengths has been sought by directly measuring the absorption / transmittance of various tissues. FIG. 19A is a graph showing the light transmittance (arbitrary unit) for blood as a function of wavelength. Blood has low absorption in the region above 700 nanometers, but is particularly transmissive at wavelengths above 780 nanometers. It appears that absorption at wavelengths below 700 nanometers is large and therefore not effective for treatment (except for local indications).

  FIG. 19B is a graph of light absorption by brain tissue. Absorption in the brain is large for wavelengths between 682 and 980 nanometers. This range is also the copper center in mitochondrial absorption. Since the brain is a metabolically very active tissue (the brain represents about 20% of blood flow and oxygen consumption), it is particularly rich in mitochondria. Therefore, if a light stimulation effect occurs, absorption in the range of 620 to 980 nanometers is expected.

  19A and 19B can be combined to calculate the efficiency of energy delivery as a function of wavelength, as shown in FIG. 19C. When targeting the brain, wavelengths between 780 and 880 nanometers are preferred (efficiency above 0.6). The peak efficiency is about 800 to 830 nanometers (efficiency is 1.0 or more). These wavelengths are not absorbed by water or hemoglobin and are likely to penetrate the brain. When these wavelengths reach the brain, they are absorbed and converted into useful energy by the brain.

  These effects can be shown directly in rat tissue. Absorption of light at 808 nanometers was measured through various rat tissues, as shown in FIG. Soft tissues such as skin and fat absorb little light. Muscles rich in mitochondria absorb more light. Even bone is quite permeable. However, as noted above, brain tissue and spinal cord tissue fully absorb 808 nanometers of light.

Irradiance or Power Density In certain embodiments, the time average irradiance or power density of the light beam at the exit surface 22 of the output optical assembly 20 is about 10 mW / cm ² to about 10 W / cm ^{2 in} the cross section of the light beam. between, between about 100 mW / cm ² to about 1000 mW / cm ^2, is between between about 500 mW / cm ² to about 1W / cm ^2, or about 650 mW / cm ^2, of about 750 mW / cm ^2. For a pulsed light beam, the time average irradiance is averaged over a long period of time compared to the temporary pulse width of the pulse (eg, average for a few hours, one second, or several seconds longer than the temporary pulse width). For a continuous wave (CW) light beam whose irradiance varies with time, the time average irradiance can be the average of the instantaneous irradiance averaged over a longer period than the characteristic period of light beam variation. In some embodiments, a duty cycle of between 1% and 80%, between 10% and 30%, or about 20% is about 12.5 mW / cm ² to about 1000 W in the cross section of the light beam. / Cm ² , between about 50 mW / cm ² and about 50 W / cm ² , between about 500 mW / cm ² and about 5000 mW / cm ² , between about 2500 mW / cm ² and about 5 W / cm ² , or about It can be used with peak irradiance at the exit surface 22 of the output optical assembly 20 between 3.25 W / cm ² and about 3.75 W / cm ² . In one embodiment, the energy or fluence (eg, peak irradiance multiplied by the temporal pulse width) of the pulsed light beam at the exit surface 22 of the output optical assembly 20 is about 12.5 μJ / cm ² to about 1 J / cm ² . during, between about 50μJ / cm ² to about 50 mJ / cm ^2, between about 500μJ / cm ² to about 5 mJ / cm ^2, between about 2.5 mJ / cm ² to about 5 mJ / cm ² or about 3,. is between 25 mJ / cm ² to about 3.75mJ / cm ^2.

The cross-sectional area of the light beam of an embodiment (eg, multimode beam) can be approximated using an approximation of the beam intensity distribution. For example, as described in more detail below, the measurement of the beam intensity distribution can be approximated by a Gaussian (1 / e ² measurement) or by a “top hat” distribution, and a selected perimeter of the beam intensity distribution Can be used to demarcate the region of the light beam. In one embodiment, the irradiance at the exit surface 22 is selected to provide the desired irradiance at the subcutaneous target tissue. The irradiance of the light beam is preferably controllably variable, and the luminescence energy can be adjusted to provide a selected irradiance in the subcutaneous tissue being treated. In one embodiment, the light beam emitted from the exit surface 22 is continuous and the total radiated power is in the range of about 4 watts to about 6 watts. In one embodiment, the radiated power of the light beam is 5 watts ± 20% (CW). In some embodiments, the peak power of the pulsed light is in the range of about 10 watts to about 30 watts (eg, 20 watts). In one embodiment, the peak power of the pulsed light multiplied by the duty cycle of the pulsed light produces an average radiated power in the range of about 4 watts to about 6 watts (eg, 5 watts).

In certain embodiments, the time average irradiance in a subcutaneous target tissue (eg, approximately 2 centimeters deep below the dura mater) is at least about 0.01 mW / cm ² and about 1 W / cm ² at the tissue level. It is. In various examples, the time average subcutaneous irradiance in the target tissue is at least about 0.01, 0.05, 0.1, 0.5, 1, 5, 10, 15, depending on the desired clinical outcome. 20, 30, 40, 50, 60, 70, 80, or 90 mW / cm ² . In some embodiments, the time-averaged subcutaneous irradiance at the target tissue is about 0.01 mW / cm ² to about 100 mW / cm ^2, about 0.01 mW / cm ² to about 50 mW / cm ^2, from about 2 mW / cm ² to about 20 mW / cm ² , or about 5 mW / cm ² to about 25 mW / cm ² . In some embodiments, a range of between 1% and 80%, 10% and ranges between 30% or about 20% duty cycle, 0.05 mW / cm ² to about 500 mW / cm ^2,, about 0. It can be used with a peak irradiance at the target tissue of 05 mW / cm ² to about 250 mW / cm ² , about 10 mW / cm ² to about 100 mW / cm ² , or about 25 mW / cm ² to about 125 mW / cm ² .

  In one embodiment, the irradiance of the light beam is selected to provide a predetermined irradiance in the subcutaneous target tissue (eg, approximately 2 centimeters deep from the dura mater). Selection of the appropriate irradiance of the light beam emitted from the exit surface used to obtain the desired subcutaneous irradiance preferably includes consideration of scattering by intervening tissue. Additional information regarding the scattering of light by tissue can be found in US Pat. No. 7,303,578, which is hereby incorporated by reference in its entirety, and V. V. Tuchin, “Tissue Optics: Light Scattering Methods and Instruments for Medical Diagnosis”, SPIE Press (2000), Bellingham, Washington, 3 On page -11.

  Phototherapy for the treatment of neurological disorders (eg ischemic stroke, Alzheimer's disease, Parkinson's disease, depression or TBI) is the irradiance or power density (ie power per unit area or per unit time) given to the tissue. The number of photons per unit area) and energy density (ie energy per unit area or number of photons per unit area) are important factors in determining the relative effectiveness of low-level phototherapy. Based in part on the discovery that it seems. This finding is particularly applicable with respect to treatment and rescue survival, but it compromises the risk zone neurons around the primary injury. Some examples described herein are considered to be important factors in determining the relative effectiveness of phototherapy, given a selected wavelength of light energy: Based at least in part on the finding that it is the irradiance and / or energy density of the light delivered to the tissue (as opposed to the total power or energy delivered to the tissue).

  Without being bound by theory or specific mechanisms, the delivery of light energy of a certain range of irradiance and energy density has the desired biostimulatory effect on the intracellular environment and has previously been found in endangered neurons. It is thought that proper function is returned to mitochondria that were not functioning or malfunctioning. Biostimulatory effects can include interaction with chromophores in the target tissue, thereby facilitating the generation of ATP and / or damage with reduced blood flow (eg, due to stroke or TBI) Control, suppress, prevent, minimize or reduce apoptosis of the affected cells. Because stroke and TBI correspond to blockage of blood flow in parts of the brain, the effect of increasing blood flow with phototherapy may not be so important for the effectiveness of phototherapy for stroke or TBI patients. Additional information regarding the role of irradiance and exposure time can be found in Hans H. H. et al., Incorporated herein by reference in its entirety. F. Hans H.F.I.van Breugel and P.I. R. PR Dop Bar, “Power Density and Exposure Time of He-Ne, the power density and exposure time of He-Ne laser irradiation are more important than total energy in photobioregulation of human fibroblasts in vitro. Laser Irradiation Are More Important Than Total Energy Dose in Photo-Biomodulation of Human Fibroblasts In Vitro), Lasers in Surgery and Medicine, Vol. 12, pp. 528-537 (1992). In addition, the importance of irradiance used in phototherapy with respect to devices and methods used in brain tissue phototherapy is discussed in US Pat. No. 7,303, each of which is hereby incorporated by reference in its entirety. 578, US Patent Application Publication Nos. 2005/0170851 A1, 2007/0179570 A1, and 2007/0179571 A1. These previous discussions on irradiance were primarily related to stroke phototherapy, but also apply to TBI phototherapy. For example, in one embodiment, a greater total power in the scalp or skull can be used in conjunction with a larger spot size in the scalp or skull to obtain the desired average power density of the brain to treat TBI. . Thus, by increasing the spot size on the scalp or skull, the desired average power density in the brain can be obtained, and because the power density on the scalp or skull is lower, the scalp, skull or brain is overheated. Reduce the possibility of

  In some embodiments, delivering a neuroprotective amount of light includes selecting a surface irradiance of light energy at the scalp or skull that corresponds to a predetermined irradiance at a target region of the brain. . As described above, light propagating through the tissue is scattered and absorbed by the tissue. The calculation of the irradiance applied to the scalp or skull to deliver a predetermined irradiance to a selected target area of the brain is preferably as the light propagates through the skin and other tissues such as bone and brain tissue Consider the attenuation of light energy. Factors known to affect the attenuation of light propagating from the scalp or skull to the brain are skin pigmentation, the presence of hair in the area to be treated, type and color, the amount of fatty tissue, the presence of damaged tissue, the thickness of the skull Including, but not limited to, the patient's age and sex, and the location of the target area of the brain, particularly the depth of the area with respect to the surface of the scalp or skull. (For a general discussion of light absorption by melanin in the body, for example, “Optical Absorption Spectra of Melanins-a Comparison of Theoretical and Experimental Results” "See accelrys.com/references/case- studies / melanins_partll.pdf.) The higher the skin pigmentation level, the higher the irradiance is given to the scalp and the predetermined irradiance of light energy is the subcutaneous part of the brain Is transmitted to. The target area of the patient's brain can be identified in advance, such as by using standard medical imaging techniques.

  The irradiance chosen to be delivered to the target area of the patient's brain depends on a number of factors, including the wavelength of light radiated, the type of CVA (ischemic or hemorrhagic), and the effects. Includes, but is not limited to, the clinical status of the patient, including the extent of the brain area received. The irradiance or power density of the light energy delivered to the target area of the patient's brain is also adjusted to be combined with one or more other therapeutic agents, particularly neuroprotective agents, to achieve the desired biological effect. You may get In such examples, the selected irradiance may also depend on the selected therapeutic agent or agents that are added.

Temporal Pulse Width, Temporary Pulse Shape, Duty Cycle, Repeat Rate and Irradiance Per Pulse FIG. 21A schematically illustrates a generalized temporal profile of a pulsed light beam according to certain embodiments described herein. This temporary profile includes a plurality of pulses (P ₁ , P ₂ ,..., P _i ), each pulse having a temporary pulse width during which the instantaneous intensity or irradiance I ( t) is substantially non-zero. For example, for the pulsed light beam of FIG. 21A, pulse P ₁ has a temporary pulse width from time t = 0 to time t = T ₁ , and pulse P ₂ has time t = T ₂ to time t = T _3. a temporary pulse width to the pulse P _i has a temporary pulse width from the time t = T _i to time t = T i _{+ 1.} The temporary pulse width can also be referred to as “pulse on time”. There is a period of time between pulses, during which the beam intensity or irradiance is substantially zero. For example, the pulse P ₁ is temporally separated from the pulse P ₂ by t = T ₂ −T ₁ . The time between pulses can also be called “pulse off time”. In some embodiments, the pulse-on times of the pulses are substantially equal, and in some other embodiments, the pulse-on times are different from each other. In some embodiments, the pulse-off times between pulses are substantially equal, and in some other embodiments, the pulse-off times between pulses are different from each other. As used herein, the term “duty cycle” has the broadest reasonable interpretation and includes, but is not limited to, pulse on time divided by the sum of pulse on time and pulse off time. For some pulsed light beams, the duty cycle is less than one. The duty cycle and temporal pulse width values sufficiently define the repetition rate of the pulsed light beam.

  Each pulse may have a transient pulse shape that describes the instantaneous intensity or irradiance I (t) of the pulse as a function of time. For example, as shown in FIG. 21A, the temporal pulse shape of the pulsed light beam is irregular and not the same between the various pulses. In certain embodiments, the temporal pulse shape of the pulsed light beam is substantially the same between the various pulses. For example, as schematically shown in FIG. 21B, the pulses can have a square temporary pulse shape, with each pulse having a substantially constant instantaneous irradiance over the pulse on time. In some embodiments, the peak irradiance of the pulses are different from each other (see, eg, FIGS. 21A and 21B), and in some other embodiments, the peak irradiances of the pulses are substantially equal to each other (see, eg, FIGS. 21C and 21D). . Various other temporal pulse shapes (eg, triangles, trapezoids) also correspond to certain embodiments described herein. FIG. 21C schematically shows a plurality of trapezoidal pulses, each pulse having a rise time (eg, corresponding to the time between zero instantaneous irradiance and the peak irradiance of the pulse) and a fall time (eg, of the pulse). Corresponding to the time between the peak irradiance and zero instantaneous irradiance). In some embodiments, rise and fall times can be expressed relative to a certain percentage of the peak irradiance of the pulse (eg, rise / fall time to 50% of the peak irradiance of the pulse).

As used herein, the term “peak irradiance” of pulse P _i is the broadest reasonable interpretation and includes the maximum value of instantaneous irradiance I (t) during the temporary pulse width of the pulse. However, it is not limited to this. In some embodiments, the instantaneous irradiance varies during the temporal pulse width of the pulse (see FIGS. 21A and 21C), and in certain other embodiments, the instantaneous irradiance is substantially equal during the temporal pulse width of the pulse. (See FIGS. 21B and 21D).

As used herein, the term “pulse irradiance” I _{Pi of} the pulse P _i is interpreted in the widest reasonable sense, and the instantaneous irradiance I of the pulse P _i at the temporal pulse width of the pulse shown by the following equation: Including, but not limited to, the integration of (t).

As used herein, “total irradiance” I _TOTAL has the broadest reasonable interpretation and includes, but is not limited to, the sum of the pulse irradiances of the pulses shown in the following equation.

As used herein, the term “time average irradiance” I _AVE is interpreted in the widest reasonable _sense and is the instantaneous irradiance I in the period T compared to the temporal pulse width of the pulse, as shown in the following equation: Including, but not limited to, the integration of (t).

For example, for a plurality of rectangular pulses with different pulse irradiance I _Pi and different temporary pulse widths ΔT _i , the time average irradiance in period T is equal to that shown in the following equation:

As another example, for multiple rectangular pulses with equal pulse irradiance I _p , equal transient pulse width, and equal pulse off time (duty cycle is D), the time average irradiance is I _AVE = I _P · D equal. For example, as shown in FIG. 21D, the time average irradiance (indicated by the dotted line) is less than the pulse irradiance of the pulse.

The pulse irradiance and duty cycle can be selected to provide a predetermined time average irradiance. In one embodiment, the time average irradiance is equal to the irradiance of a continuous wave (CW) light beam, the pulsed light beam and the CW light beam have the same number of photons or luminous flux. For example, a pulsed light beam with a pulse irradiance of 5 mW / cm ² and a duty cycle of 20% gives the same number of photons as a CW light beam with an irradiance of 1 mW / cm ² . However, unlike CW light beams, pulsed light beam parameters can be selected to deliver photons in such a way as to obtain results that are not obtainable with CW light beams.

  For example, selective photothermal decomposition has previously been performed using a pulsed light beam for hair removal, tattoo removal or kinking, in which case by exposing selected portions of the skin to a sufficiently high temperature. Respectively, damage the hair follicles (eg, temperatures higher than 60 degrees Celsius), remove tattoo ink (temperatures much higher than 60 degrees Celsius), or cause collagen molecules to contract (eg, 60 degrees Celsius to 70 degrees Celsius). While avoiding unwanted damage or discomfort by keeping the rest of the skin at a sufficiently low temperature. The parameters of these pulsed light beams are selected to bring the selected part of the skin to the desired high temperature by absorption of light by the selected chromophore while dissipating heat during the pulse-off time (thermal relaxation) Keep other areas of the skin (characterized as time) at a lower temperature. J. et al. J. Lepselter et al., “Biological and clinical aspects in laser hair removal”, J. Dermatological Treatment, Vol. 15, pp. 72-83 (2004). As noted, the pulse-on time for hair removal is between the thermal relaxation time for the epidermis (about 3-10 milliseconds) and the thermal relaxation time for the hair follicle (about 40-100 milliseconds). Is selected. In this way, the hair follicle can be heated to a sufficiently high temperature to damage the hair follicle without undue damage to the surrounding skin.

  Unlike such treatments based on thermal damage to at least a portion of the skin, certain embodiments described herein utilize pulse parameters that do not cause thermal damage to at least a portion of the skin. . In one embodiment, one or more of the pulsed light beam's temporal pulse width, temporal pulse shape, duty cycle, repetition rate, and pulse irradiance is selected, and any part of the skin has a temperature above 60 degrees Celsius. Do not heat to temperatures above 55 degrees Celsius, temperatures above 50 degrees Celsius, or temperatures above 45 degrees Celsius. In one embodiment, any portion of the skin can be selected in degrees Celsius above the baseline temperature by selecting one or more of the temporal pulse width, temporal pulse shape, duty cycle, repetition rate, and pulse irradiance of the pulsed light beam. Avoid heating to temperatures above 30 degrees, temperatures above 20 degrees Celsius above baseline, or temperatures above baseline 10 degrees Celsius. In one embodiment, any part of the brain can be selected in degrees Celsius above the baseline temperature by selecting one or more of the temporal pulse width, temporal pulse shape, duty cycle, repetition rate, and pulse irradiance of the pulsed light beam. Avoid heating to temperatures above 5 degrees, temperatures above 3 degrees Celsius above baseline temperature, or temperatures above 1 degree Celsius above baseline temperature. As used herein, the term “baseline temperature” is interpreted in the broadest reasonable sense, including but not limited to the temperature that a tissue would have if the tissue was not irradiated with light. Unlike previous low light level therapies, the pulsed light beam has an average radiated power in the range of about 1 watt to about 6 watts or in the range of about 4 watts to about 6 watts.

  In some embodiments, the pulse parameters are selected to obtain other effects beyond those that can be obtained when using a CW light beam. For example, CW irradiation of brain cells in vivo results in effective stroke treatment, but it is more difficult to use CW irradiation for the treatment of TBI, and as part of that reason, the irradiated scalp, skull, or skull There may be excess blood in the area (eg, intracranial hemorrhage). This excess blood may be between the light source and the target brain tissue to be irradiated, so that the light applied to the scalp or skull is absorbed in large quantities before it can propagate to the target tissue. This absorption can reduce the amount of light reaching the target tissue and can overheat the intervening tissue to undesirable levels.

  In certain embodiments described herein, pulsed irradiation may provide a more effective treatment. Pulsed irradiation can give higher peak irradiance in a shorter time, thereby allowing more power to propagate to the target tissue while thermally relaxing intervening tissue and blood between pulses Thereby avoiding excessive heating of the intervening tissue. This thermal relaxation time scale is typically in the range of a few milliseconds. For example, the thermal relaxation time constant of human skin (eg, the time it takes for tissue to cool from an elevated temperature to one-half of that temperature) is about 3-10 milliseconds, and human hair follicles The thermal relaxation time constant of is about 40-100 milliseconds. Thus, the previous irradiation of the pulsed light on the body for hair removal has an optimized temporary pulse width greater than 40 milliseconds, where the time between pulses is several hundreds Milliseconds.

  However, this time-scale pulsed light advantageously reduces intervening tissue and blood heating, but does not provide an optimal amount of effectiveness compared to other time scales. In certain embodiments described herein, not optimized to reduce thermal effects, but instead between one or more cells involved in the survival, regeneration or recovery of brain cell capacity or viability Alternatively, the patient's scalp or skull is irradiated with pulsed light having parameters optimized to stimulate, excite, induce or support intracellular biological processes. Thus, in some of these embodiments, the selected temporary profile may result in a temperature of the irradiated tissue that is higher than the temperature obtained as a result of the other temporary profile. It is more effective than the temporary profile. In one embodiment, pulse parameters are selected to take advantage of biological process dynamics rather than optimizing tissue thermal relaxation. In one embodiment, a transient profile (eg, one pulse) selected to adjust membrane potential to improve, restore or promote cell survival, cell function or both of irradiated brain cells following traumatic brain injury. Per peak irradiance, temporal pulse width, and pulse duty cycle). For example, in one embodiment, the pulsed light has a temporary profile that assists in one or more of the intercellular or intracellular biological processes involved in the survival or regeneration of brain cells, which is the heat of the irradiated tissue. Do not optimize static relaxation. In some embodiments, the brain cells survive longer after irradiation compared to the survival of brain cells without irradiation. For example, light in certain embodiments may have a protective effect on brain cells or cause a regeneration process within the brain cells.

In one embodiment, a temporal profile (eg, peak irradiance, temporal pulse width, and duty cycle) is selected to take advantage of biological process dynamics while pre-determining the irradiated portion of the scalp or skull at a predetermined temperature. Keep below. This pre-determined temperature is an optimum that can be achieved for other temporal profiles (eg peak irradiance, temporal pulse width and other values of duty cycle) optimized to minimize the temperature rise of surrounding tissue due to irradiation. Higher than the conversion temperature. For example, a temporary profile with a peak irradiance of 10 W / cm ² and a duty cycle of 20% has a time average irradiance of 2 W / cm ² . Such a pulsed light beam gives the irradiated surface the same number of photons as a continuous wave (CW) light beam with an irradiance of 2 W / cm ² . However, because of the “dark time” between pulses, the pulsed light beam can result in a smaller temperature rise compared to the CW light beam. In order to minimize the temperature rise of the irradiated part of the scalp or skull, the temporary pulse width and duty cycle are selected so that most of the heat generated per pulse is transferred before the next pulse reaches the irradiated part. Can be dissipated. In some embodiments described herein, rather than optimizing the temporal parameters of the beam to minimize temperature rise, the temporal parameters are selected to effectively timing the biomolecular processes involved in photon absorption. Increase effectiveness by being close to or close enough. Rather than having a temporary pulse width on the order of hundreds of microseconds, certain embodiments described herein utilize a temporary pulse width that does not optimize thermal relaxation of the irradiated tissue (eg, milliseconds, tens of microseconds). Milliseconds, hundreds of milliseconds). Since these pulse widths are much longer than the thermal relaxation time scale, the resulting temperature rise is greater than that of the smaller pulse widths, but is still greater than for CW light beams due to the heat dissipation of the time between pulses. Is also small.

Numerous studies have investigated the effects of in vitro irradiation of cells with pulsed light on various aspects of the cells. Incoherent pulse radiation at a wavelength of 820 nanometers for in vitro cell adhesion (pulse repetition frequency 10 Hz, Halus width 20 milliseconds, dark period between pulses 80 milliseconds, and duty factor (ratio of pulse duration to pulse period) 20 %) Mechanism of action found that 820 nanometer pulsed infrared increases cell-matrix adhesion. (TI Karu et al., Incorporated herein by reference in its entirety, "Cell adhesion to the extracellular matrix is due to 820 nm pulsed radiation and chemicals that modify the activity of the enzyme in the cell membrane." (Cell Attachment to Extracellular Matrices is Modulated by Pulsed Radiation at 820 nm and Chemicals that Modify the Activity of Enzymes in the Plasma Membrane), Lasers in Surgery and Medicine, Vol. 29, pages 274-281 (2001)). This study hypothesizes that modulation of monovalent ion flux in the cell membrane, rather than arachidonic acid release, is involved in the cell signaling pathway activated by irradiation at 820 nanometers.Membrane conductance of ventral photoreceptor cells The study of the light-induced changes in the light-absorbing phase has been found to be dependent on the pulse parameters and exhibit two light-induced processes (all of which are described herein). , JE Lisman et al., “Two Light-Induced Processes in the Photoreceptor Cells of Limulus Ventral Eye”. "J. Gen. Physiology, 58, 544-561 (1971).) The study of laser-activated electron injection into oxidized cytochrome c oxidase has shown the kinetics of establishing the reaction sequence of the proton pump mechanism. Observed. Also, some of its thermodynamic properties have a time constant of approximately a few milliseconds. (I. Belevich et al., “Exploring the proton pump mechanism of cytochrome c oxidase in real time,” incorporated herein by reference in its entirety. real time) ", Proc. Nat'l Acad. Sci., 104, 2685-2690 (2007) and I. Bervich et al.," Proton-coupled electron transfer drives the proton pump of cytochrome c oxidase (Proton- (Nature, 440, 829-832 (2006).) In vivo studies of nerve activation based on pulsed infrared light cause action potential propagation. A photothermal effect was proposed from the transient tissue temperature changes that caused the activation of direct or indirect transmembrane ion channels. (J. Wells et al., “Biophysical mechanisms responsible for pulsed low-level laser, incorporated herein by reference in its entirety,” excitation of neural tissue) ", Proc. SPIE, Vol. 6084, p. 60840X (2006).)
In some embodiments, the temporal profile of the pulsed light beam includes peak irradiance, temporal pulse width, temporal pulse shape, duty cycle, and pulse repetition rate or frequency. In embodiments where the pulsed light beam is transmitted through an area of the scalp or skull that contains excessive amounts of bleeding due to at least one physical trauma (eg, due to intracranial bleeding), peak irradiance, temporal pulse width, one o'clock pulse shape, and select at least one of duty cycle, and pulse repetition rate or frequency, in the light beam cross-section, between about 10 mW / cm ² to about 10 W / cm ^2, from about 100 mW / cm ² to about during the 1000 mW / cm ^2, between between about 500 mW / cm ² to about 1W / cm ^2, or about 650 mW / cm ^2, of about 750 mW / cm ^2, in the exit surface 22 of the output optical assembly 20, the time-averaged radiation Provides illuminance (averaged over a period that includes multiple pulses). In one such example, the time average irradiance (eg, about 2 centimeters deep below the dura mater) in the brain cells being treated is greater than 0.01 mW / cm ² .

In one embodiment, the peak irradiance per pulse of the cross section of the light beam at the exit surface 22 of the output optical assembly 20 is between about 10 mW / cm ² and about 10 W / cm ² , between about 100 mW / cm ² and about 1000 mW. between / cm ^2, between about 500 mW / cm ² to about 1W / cm ^2, between about 650 mW / cm ² to about 750 mW / cm ^2, between about 20 mW / cm ² to about 20W / cm ^2, about 200mW / Cm ² to about 2000 mW / cm ² , about 1 W / cm ² to about 2 W / cm ² , about 1300 mW / cm ² to about 1500 mW / cm ² , about 1 W / cm ² to about 1000 W / cm 2 there between ^2, between about 10 W / cm ² to about 100W / cm ^2, the range between between about 50 W / cm ² to about 100W / cm ^2, or about 65W / cm ^2, from about 75W / cm ² . In some embodiments, the temporary pulse shape is generally rectangular, generally triangular, or other shapes. In some embodiments, the pulse has a rise time (eg, 10% of peak irradiance to 90% of peak irradiance) less than 1% of pulse on time, or a fall time (eg, peak from 90% of peak irradiance). (Up to 10% of irradiance) is less than 1% of the pulse-on time.

  In some embodiments, the temporal pulse width (eg, pulse on time) of the pulse is between about 0.001 milliseconds and about 150 seconds, between about 0.01 milliseconds and about 10 seconds, and about 0.1 milliseconds. For a range of about 1 second, between about 0.5 and about 100 milliseconds, between about 2 and about 20 milliseconds, or between about 1 and about 10 milliseconds. In one embodiment, the pulse width is about 0.5, 1, 2, 4, 6, 8, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280 or 300 milliseconds. In one embodiment, the temporal pulse width is in the range between about 0.1 milliseconds and 150 seconds.

  In certain embodiments, the time between pulses (eg, pulse off time) is between about 0.01 milliseconds and about 150 seconds, between about 0.1 milliseconds and about 100 milliseconds, and about 4 milliseconds. And about 1 second, between about 8 and about 500 milliseconds, between about 8 and about 80 milliseconds, or between about 10 and about 200 milliseconds. In some embodiments, the time between pulses is about 4, 8, 10, 20, 50, 100, 200, 500, 700, or 1000 milliseconds.

  In some embodiments, the pulse duty cycle is in the range between about 1% and about 80% or in the range between about 10% and about 30%. In some embodiments, the pulse duty cycle is about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90%.

Beam Size and Beam Profile In some embodiments, the nominal diameter of the light beam emitted from the output optical assembly 20 is in the range of about 10 millimeters to about 40 millimeters, in the range of about 20 millimeters to about 35 millimeters, or Equal to about 30 millimeters. In certain embodiments, the cross-sectional area is generally circular and the radius is in the range of about 1 centimeter to about 2 centimeters. In some embodiments, the cross-sectional area of the light beam emitted from the emission surface 22, at the exit plane 22 of the optical element 23 is in the range of about 2 cm ² or greater than or about 2 cm ² to about 20 cm ^2. In one embodiment, the diameter of the aperture of the output optical element 23 is less than 33 millimeters.

As used herein, beam diameter is defined as the largest chord around the region of the scalp or skull that is irradiated by the light beam at an intensity of at least 1 / e ² of the maximum intensity of the light beam. The circumference of the light beam used to determine the diameter of the beam is defined in one embodiment as the point where the intensity of the light beam is 1 / e ² of the maximum intensity of the light beam. The maximum useful diameter of certain embodiments is limited by the size of the patient's head and by heating by irradiation of the patient's head. The minimum useful diameter of certain embodiments is limited by heating and the total number of treatment sites actually possible. For example, covering a patient's skull with a beam having a small beam diameter correspondingly uses multiple treatment sites. In one embodiment, the irradiation time per treatment site can be adjusted to provide a desired irradiation dose accordingly.

  Specifying the total luminous flux in the circular aperture with a specific radius centered at the exit hole (“enclosed energy”) identifies the power (irradiance) distribution in the light beam emitted from the exit surface 22 It is a method to do. “Enclosed energy” can be used to ensure that the light beam is not too focused, not too large, or too small. In one embodiment, the light beam emitted from the exit surface has a total radiated power, and the light beam is less than 75% of the total radiated power and is 20 millimeters in diameter centered on the light beam at the exit surface 22. It has the total luminous flux inside the circle of the cross section. One such embodiment has a total luminous flux inside a 26 millimeter diameter cross-sectional circle centered on the light beam at the exit surface 22 that is greater than 50% of the total radiated power.

  In some embodiments, the beam intensity profile has a semi-Gaussian profile, and in some other embodiments, the beam intensity profile has a “top hat” profile. In one embodiment, the light beam is substantially free of high flux regions or “hot spots” in the beam intensity profile where the local flux averaged over a 3 millimeter by 3 millimeter area is 10% greater than the mean flux. Certain embodiments of the device 10 advantageously avoid a large temperature gradient in the patient's skin that would otherwise cause discomfort to the patient by generating a light beam that is substantially free of hot spots.

Spread In some embodiments, the spread of the beam exiting the exit surface 22 is significantly less than the scattering angle of the light inside the irradiated body tissue, which is typically a few degrees. In some embodiments, the angle of spread of the light beam is greater than zero and less than 35 degrees.

  The greater the distance between the light source and the observer, the smaller the relationship between the light source diameter and beam spread considerations. For example, the diameter of the end of the optical fiber 40 that provides light is about 1 millimeter. At closer distances, when viewed from a particular location, light rays from the edge of the optical fiber can reach the observation point at very different angles. However, as the observation point moves away from the light source, the angle difference becomes smaller and the light source looks more like a point light source.

  In one embodiment, with the output optical assembly 20 mounted on the apparatus 10, the optical distance between the exit surface 22 and the end of the optical fiber 40 is about 82.7 millimeters. The spread of the beam defined by the numerical aperture of the optical fiber 40 and the exit hole of the optical element 23 is about 23 degrees. In one embodiment, the optical distance between the window 70 and the end of the optical fiber is about 57.5 millimeters without the output optical assembly 20 resting on the device 10, and the optical fiber 40 The beam spread defined by the numerical aperture and the exit aperture of the window 70 is about 16 degrees. When the diameter of the light source is about 1 millimeter, the angular ambiguity of the beam divergence is about ± 0.35 degrees. In this way, the angular ambiguity is much smaller than the beam divergence angle, regardless of whether the output optical assembly 20 is mounted on the device 10, so that the optical fiber 40 is a point. It can be treated as a light source. In some such embodiments, the beam spread or radiant intensity (eg, measured in watts / steradian) can be calculated directly from the beam profile or from the irradiance.

Treatment Time In certain embodiments, treatment per treatment site is performed continuously for a period of about 10 seconds to about 2 hours, a period of about 1 to about 10 minutes, or a period of about 1 to 5 minutes. For example, the treatment time per treatment site in one embodiment is about 2 minutes. In other examples, light energy is delivered for at least one treatment period that is about 5 minutes, or for at least one treatment period that is at least 10 minutes. In some embodiments, the shortest treatment time is limited by the biological reaction time (approximately in microseconds). In some embodiments, the maximum treatment time is limited by heating and the actual treatment time (eg, treatment ends within about 24 hours from the onset of stroke). Light energy can be pulsed during the treatment period, or light energy can be provided continuously during the treatment period. If the light is pulsed, the pulses can be 2 milliseconds long and have a frequency of 100 Hz, although longer pulse lengths and lower frequencies can be used, or at least about 10 nanoseconds long The frequency can be up to about 100 kHz.

  In some embodiments, treatment may be terminated after one treatment period, and in other embodiments, treatment may be repeated for at least two treatment periods. The time between successive treatment periods can be at least 2, at least about 1 to 2 days, or at least 1 week for a period of about 5 minutes, 24 hours. The length of treatment time and frequency of treatment period depend on several factors, including the results of image analysis of the patient's functional recovery and injury (eg, infarct). In certain embodiments, one or more treatment parameters can be adjusted in response to a feedback signal from a device that monitors the patient (eg, magnetic resonance imaging).

Cooling Parameters In one embodiment, the apparatus 10 includes an output optical element 23 that is in optical communication with a light source. The output optical element 23 includes an exit surface 22 configured to emit a light beam according to the previously disclosed optical parameters. In some embodiments, the apparatus 10 is further configured to be in thermal communication with the irradiated portion of the patient's scalp or skull and configured to remove heat from the irradiated portion of the patient's scalp or skull. Including parts. In some embodiments, the thermally conductive portion includes an output optical element 23. In one embodiment, the thermally conductive portion is releasably coupled to the output optical element 23.

In certain embodiments, the thermally conductive portion removes heat from the irradiated portion of the patient's scalp or skull. This cooling of the scalp or skull can improve patient comfort by controlling, suppressing, preventing, minimizing or reducing the temperature rise of the scalp or skull due to irradiation. Thus, by cooling the patient's scalp or skull portion being irradiated, the temperature of the patient's scalp or skull irradiated portion is lower than if the scalp or skull irradiated portion is not cooled. For example, by cooling the irradiated portion of the patient's scalp or skull, the temperature of the irradiated portion of the patient's scalp or skull is higher than the temperature of the patient's scalp or portion of the skull when not irradiated, but cooled. If not, lower than the temperature of the patient's scalp or skull part. In addition, this scalp or skull cooling can be a double-blind study of the effectiveness of phototherapy treatment by masking the heating of the scalp or skull due to irradiation. (For example, B. Catanzaro et al., “Managing Tissue Heating in Laser Therapy to Enable Double-Blind Clinical Study”, (See Mechanisms for Low-Light Therapy, Proc. Of the SPIE, Vol. 6140, pages 199-208 (2006).)
In certain embodiments, heat is removed from the irradiated portion of the patient's scalp or skull by a thermally conductive portion at a rate in the range of about 0.1 watts to about 5 watts or in the range of about 1 watt to 3 watts. . In one embodiment, the thermally conductive portion is configured to keep the irradiated portion of the patient's scalp or skull below 42 degrees Celsius. The thermally conductive portion of an embodiment is configured to be in thermal communication with the exit surface 22 and to maintain the exit surface temperature in the range of 18 degrees Celsius to 25 degrees Celsius under a 2 Watt thermal load. . For a general description of scalp cooling, see, eg, F.S. E. M.M. See FEM Janssen et al., “Modeling of Temperature and perfusion during scalp cooling”, Phys. Med. Biol., 50: 4065-4073 (2005). . In some embodiments where pulsed light is used, the heat removal rate may be lower, or cooling may not be performed for a range of pulse dosimetry and timing.

Pressure Parameter In one embodiment, the device 10 is configured such that a pressure that exceeds a predetermined threshold pressure in a direction in which the thermally conductive portion moves relative to the second portion of the device 10 Configured to move the thermally conductive portion relative to the second portion of the device 10 when applied to the active portion. The predetermined threshold pressure is sufficient to cause the thermally conductive portion to be in thermal communication with a portion of the patient's scalp or skull. In certain such embodiments, device 10 is configured to generate a signal (eg, binary, analog or digital) when the thermally conductive portion moves relative to the second portion.

  In one such embodiment, sensor 130, together with trigger force spring 140 and trigger force adjustment mechanism 142, is device 10 being applied to the patient's scalp or skull at a pressure above a predetermined threshold pressure. Provides a mechanism for detecting whether or not. In certain such embodiments, the sensor 130 may be configured when the emitting surface 22 is placed in thermal communication with the patient's scalp or skull with sufficient pressure to exceed the restoring force of the trigger force spring 140. A movement between the first part of 10 and the second part of the device 10 is detected. When a threshold pressure is applied to the emission surface 22 to move the first and second portions relatively, the sensor 130 detects this movement and generates a corresponding signal. In certain embodiments, apparatus 10 further includes a controller operably coupled to light source 2 and sensor 130. The controller is configured to receive a signal from the sensor 130 and to turn on the light source when the signal indicates a pressure above a predetermined threshold pressure.

  In one embodiment, the threshold pressure is set to a pressure that whitens the portion of the patient's scalp that is irradiated. In one embodiment, the threshold pressure is 0.1 pounds per square inch, and in some other embodiments, the threshold pressure is 1 pound per square inch or about 2 pounds per square inch. is there.

  In some embodiments where pulsed light is used, the amount of whitening may be less, or whitening may not be utilized for a range of pulse dosimetry and timing. For example, in certain embodiments, a patient may be more sensitive to pressure applied to the scalp or skull (eg, a TBI patient). Thus, in some embodiments, device 10 does not apply sufficient pressure to the patient's scalp (eg, does not apply pressure to the patient's scalp) to whiten the irradiated portion of the scalp during irradiation. In certain other embodiments where it is desirable to whiten the irradiated area of the scalp, the maximum pressure used to whiten the irradiated area of the scalp is limited by the patient's comfort level and tissue damage level. For example, when pressure is applied to the scalp, the brain or skull of a TBI patient can crack or tear, which can adversely affect the brain. If pressure is applied, the amount is at least partially determined by the amount of pressure that the patient can withstand to the extent that no further damage is caused by the application of pressure.

Irradiation of multiple portions of the scalp or skull FIGS. 22A-22C schematically illustrate an embodiment in which the device 10 is arranged in continuous thermal communication with multiple treatment sites corresponding to portions of a patient's scalp. Shown in In one such embodiment, as shown in FIG. 22A, light emitted from the exit surface 22 propagates through the scalp to the brain and is dispersed in a direction generally parallel to the scalp. In certain embodiments where the patient is undergoing TBI, at one or more of the treatment sites, a portion of the skull is exposed and at least a portion of the light is not transmitted through the scalp tissue, but is exposed to the exposed portion of the skull. In some embodiments, the treatment sites on the patient's scalp do not overlap. There is preferably a sufficient spacing between the treatment sites (eg, 20 treatment sites), and the light emitted from the exit surface 22 to illuminate the treatment site on the patient's scalp propagates through the intervening tissue to the patient. A region of the brain of the patient, wherein the region is one or more regions of the target tissue of the patient's brain that are illuminated by the light emitted from the exit surface 22 when a nearby treatment site of the patient's scalp is illuminated And overlap. FIG. 22B schematically illustrates this overlap as an overlap of circular spots 160 at the target tissue at a reference depth at or below the surface of the brain. FIG. 22C schematically illustrates this overlap as a graph of irradiance at the reference depth of the brain along line L-LL in FIGS. 22A and 22B. The sum of the irradiance from neighboring treatment sites (indicated by the dotted line in FIG. 22C) gives a more uniform distribution of light in the target tissue to be treated. In such an embodiment, the total irradiance is preferably below the brain damage threshold and above the effective threshold. In some embodiments, portions of the brain irradiated by irradiating the treatment area of the scalp do not overlap. In one such embodiment, the treatment area on the scalp is positioned to irradiate as much cortex as possible.

Example of Wearable Device FIG. 23 schematically illustrates an example of a device 500 that can be worn by a patient for treatment of the patient's brain. Device 500 includes a body 510 and a plurality of indicators 520. The body 510 is adapted to be worn over at least a portion of the patient's scalp when the device 500 is worn by the patient. The plurality of indicators 520 correspond to the locations of multiple treatment sites on the patient's scalp, where light is irradiated to illuminate at least a portion of the patient's brain. The at least one indicator 520 is substantially transmissive (eg, substantially transparent or substantially translucent) of the light emitted from the exit surface 22 to illuminate at least a portion of the patient's brain. Includes some.

  In certain embodiments, at least one of the indicators 520 indicates a position within the region of the patient's scalp that corresponds to the location of the treatment site. In some such embodiments, this location is the center of that region of the patient's scalp. In certain embodiments, adjacent treatment sites have non-overlapping areas or have spaced perimeters. In some such embodiments, the perimeters are spaced at least 10 millimeters or at least 25 millimeters apart.

  In one embodiment, each indicator 520 includes a hole or opening through body 510 where beam delivery device 10 can be placed to irradiate the portion of the patient's scalp exposed by the hole or opening. In some embodiments, the aperture has a substantially circular perimeter and the diameter is in the range between 20 and 50 millimeters or in the range between 25 and 35 millimeters. In one embodiment, the aperture has a substantially elliptical perimeter and the minor axis is greater than 20 millimeters and the major axis is less than 50 millimeters. Other shapes for the apertures also correspond to certain embodiments described herein.

In some examples, the plurality of indicators 520 includes at least ten indicators 520 that span the patient's scalp, and in some other examples, the plurality of indicators 520 includes twenty indicators 520. In some other embodiments, the plurality of indicators 520 includes between 15 and 25 indicators 520. In some embodiments, the area of the light transmissive portion of each indicator 520 is at least 1 cm ² , in the range between 1 cm ² and 20 cm ² , or in the range between 5 cm ² and 10 cm ² .

  In some embodiments, the body 510 includes a hood, and in other embodiments, the body 510 includes a cap or can be worn on the patient's head and assists in directing the indicator 520 on the patient's head. It has another composition which fulfills. In some embodiments, the body 510 includes a stretchable or flexible material generally along the patient's scalp. In one embodiment, the body 510 comprises nylon-backed polychloroprene or Tyvek®. In some embodiments, different sized (eg, small, medium, large) bodies 510 may be utilized to accommodate different sized heads. In certain embodiments, the body 510 is disposable for a single use, advantageously preventing subsequent infection or spread of disease between patients.

  In one embodiment, the indicator 520 is configured to guide the operator to irradiate the patient's scalp, one at a time, in a predetermined sequence, continuously at the location of the corresponding treatment site. In certain embodiments, wearable device 500 further includes a plurality of labels 522, each label being near a corresponding indicator. Label 522 conveniently provides each indicator 520 with one or more numbers, letters, or symbols (eg, a barcode) to distinguish the various indicators 520 from each other. In some such embodiments, label 522 is mechanically coupled to a corresponding indicator so that it is visible to the user of beam delivery device 10.

  24A and 24B schematically illustrate the left and right sides of an example of the device 500, respectively, and the label 522 substantially covers the indicator 520 corresponding to the treatment site. In certain embodiments, label 522 is advantageously used to track which treatment sites have already been irradiated and which treatment sites have not yet been irradiated. In certain such embodiments, at least a portion of each label 522 is a portion of the body configured to be removed from the device 500 when the treatment site corresponding to the indicator 520 is treated (eg, a pull-off tab or flap). including. In certain embodiments, label 522 includes a removable portion of body 510 that covers a corresponding indicator 520. In some such embodiments, prior to irradiating the treatment site location corresponding to indicator 520, the corresponding label 522 may be removed to allow access to the portion under the patient's scalp.

  In one embodiment, label 522 has a continuous code that the operator enters into the controller prior to irradiation, informing the controller of the next treatment site to be irradiated. In certain other embodiments, each label 522 includes a bar code or radio frequency identification device (RFID) readable by a sensor electrically coupled to the controller. The controller in such an embodiment tracks which treatment site has already been irradiated, and in one such embodiment, the controller can cause the beam delivery device 10 to optically and properly detect the appropriate treatment site on the patient's scalp. It only activates the light source when it is in thermal communication.

  FIG. 24C schematically illustrates an example of a labeling configuration as viewed from above with the flattened view of the apparatus 500 of FIGS. 24A and 24B. The labeling rules of FIG. 24C correspond to irradiation of both one-half of the patient's brain, or hemisphere. Other labeling rules also correspond to the embodiments described herein.

  In one embodiment, the label 522 is advantageously used to optically and thermally couple the beam delivery device 10 to a continuous treatment site corresponding to the indicator 520 to treat the patient's brain at various treatment sites. The operator is guided to irradiate each site sequentially through the indicator 520, one at a time in a predetermined order. For example, in the labeling configuration of FIG. 24C, the operator first irradiates treatment site “1”, then irradiates treatment sites “2”, “3”, “4”, etc., one 20 treatment sites at a time. Irradiation can be performed sequentially. In some such embodiments, a predetermined order of treatment sites is selected to advantageously reduce the temperature rise that may result from continuous irradiation of treatment sites adjacent to each other.

  In some embodiments, the predetermined order irradiates a first treatment site location on a first side of the patient's scalp (eg, site “2” in FIG. 24C), and then a second of the patient's scalp. Irradiate a second treatment site location on the side (eg, site “3” in FIG. 24C), and then apply a third treatment site location on the first side of the patient's scalp (eg, site “4” in FIG. 24C). Including irradiation. In some such embodiments, the predetermined sequence further includes irradiating the fourth treatment site location on the second side of the patient's scalp after irradiating the third treatment site location. In one embodiment, two consecutively irradiated treatment site locations are separated by at least 25 millimeters.

  For example, in certain embodiments, the predetermined order includes at least a portion of the following order of treatment sites.

1. 1. Right frontal head 2. Left frontal head Right front lower parietal part 4. 4. Left rear central parietal region Upper right parietal region 6. 6. Frontal right side Left frontal head 8. Left upper upper parietal region 9. Left rear lower parietal region 10. 10. Right rear lower parietal region Right upper upper parietal region 12. Right front center parietal region 13. Left front lower parietal region 14. Left front upper frontal head 15. Upper left occipital region 16. Front left central parietal region 17. Right posterior central parietal region 18. Front right upper front 19. Upper right occipital region 20. For example, the predetermined order of an embodiment includes 2, 3, 4, or more of these treatment sites in the relative order. The order of treatment sites in certain embodiments includes 2, 3, 4 or more of these treatment sites in a relative order opposite to the above order. Some embodiments utilize at least a portion of the relative order described above without irradiation of additional treatment sites between two treatment sites shown in succession, and some other embodiments may use the relative order described above. At least a portion of this sequence is utilized with one or more additional treatment sites between two treatment sites shown in succession. In some embodiments, the exact anatomical location of each treatment site may be adjusted from the above to accommodate variations in the size of the patient's head (eg, very large or very small). Good. Thus, in some embodiments, there is some variation in the location of the treatment site for any given individual.

  In one embodiment, the device 500 serves as a template for marking the patient's scalp to indicate the location of the treatment site. The opening of the device 500 can be used to guide the user to place the mark on the patient's scalp, which then applies the beam delivery device 10 to the scalp to irradiate the patient's brain. Before it can be removed from the patient's scalp. The mark guides the operator while remaining on the patient's scalp and irradiating the patient's brain.

Direction of Light Delivery FIGS. 25-28 are flow diagrams of example directions for illuminating a surface with light. As will be described in more detail below, the method will be described with reference to the beam delivery device 10 and its components described herein. Other configurations of the beam delivery device also correspond to methods according to the examples described herein.

  The method 610 of FIG. 25 includes preparing the beam delivery device 10 at an operation block 612. The beam delivery device 10 includes a first portion and a second portion mechanically coupled to the first portion and in optical communication with the first portion. The first portion and the second portion are configured to move relatively as detailed above. The method 610 further includes placing the second portion in thermal communication with the surface at operation block 614 (eg, coupling the second portion to the surface in a releasable and operable state). The method 610 further includes illuminating the surface at operation block 616 such that light from the first portion propagates through the second portion. The method 610 further includes moving the first portion and the second portion relative to each other in response to the second portion being placed in thermal communication with the surface at operation block 618.

  The method 620 of FIG. 26 includes providing the optical element 23 at the operation block 622. The optical element 23 comprises a substantially optically transmissive and substantially thermally conductive material, and the optical element 23 comprises a first surface 22 and a second surface as detailed above. 24. The method 620 further includes disposing the first surface 22 in thermal communication with the irradiated surface at operation block 624 (eg, releasably and operatively coupled to the irradiated surface. To do). The method 620 further includes, at operation block 626, propagating light along the first optical path 32 through the second surface 24 and the first surface 22 to the illumination surface. The method 620 further includes detecting radiation propagating along the second optical path 82 from at least a portion of the second surface 24 at operation block 628, the first optical path 32 and the second optical path. There is a non-zero angle between the paths 82. In some embodiments, the first surface 22 and the second surface 24 are opposed in generally opposing directions, and the second surface 22 is not along the second optical path 82.

  The method 630 of FIG. 27 includes providing the thermoelectric assembly 90 at the operation block 632. The thermoelectric assembly 90 includes a first surface 93 and a second surface 94 as detailed above, and the thermoelectric assembly 90 generally surrounds the first region 97. The method 630 further includes providing the light output assembly 20 at the operation block 633. The method 630 further mechanically couples the first surface 93 of the thermoelectric assembly 90 releasably to the output optical assembly 20 at operation block 634 such that the first surface 93 is thermally coupled to the output optical assembly 20. To communicate with. Method 630 further includes cooling first surface 93 and heating second surface 94 at operational block 636. The method 630 further includes propagating light through the first region 97 and hitting the illuminated surface at operation block 638. In certain embodiments, the first surface 22 and the second surface 24 are generally opposed in opposite directions, and the first surface 22 is not along the second optical path 82.

  In certain embodiments, the output optical assembly 20 includes an optical element 23 and a thermally conductive portion 25 that generally surrounds the second region 28. The thermally conductive portion 25 is in thermal communication with the optical element 23. In certain such embodiments, releasably and mechanically coupling first surface 93 to output optical assembly 20 releasably and mechanically couples first surface 93 to thermally conductive portion 25. Including that. In certain such embodiments, the method 630 further includes placing the optical element 23 in thermal communication with the illumination surface, and propagating the light includes transmitting the light to the first region 97, the second. The region 28 and the optical element 23 to be applied to the irradiation surface. In certain embodiments, the method 630 further includes providing the heat sink 100 in thermal communication with the second surface 94 of the thermoelectric assembly 90. The heat sink 100 generally surrounds the third region 107 and propagating light means that light is transmitted through the third region 107, the first region 97, the second region 28, and the optical element 23. Including.

The method 640 of FIG. 28 includes emitting a light beam from the exit surface 22 of the optical element 23 at operation block 642. The light beam at the exit surface 22 has one or more wavelengths in the range of about 630 nanometers to about 1064 nanometers, has a cross section greater than about 2 cm ² , as detailed above, It has a time average irradiance in the range of about 10 mW / cm ² to about 10 W / cm ² in cross section. The method 640 further includes removing heat from the exit surface 22 at a rate in the range of about 0.1 watts to about 5 watts at operation block 644. The method 640 further includes directing a light beam onto the illuminated surface at operation block 646.

  The method 640 of an embodiment further includes positioning the exit surface 22 in thermal communication with the illumination surface (eg, using the exit surface 22 with respect to the exit surface 22 in a direction generally toward the illumination surface. Pressure is applied to the irradiated surface by applying force, which is greater than about 0.1 pounds per square inch or equal to about 2 pounds per square inch).

  In some embodiments, applying the light beam to the illuminated surface is performed for a period of 10 seconds to 2 hours, a period of 60 seconds to 600 seconds, or a period of about 120 seconds. In one embodiment, the steps of operation blocks 642, 644, and 646 are performed simultaneously. The method 640 of an embodiment further moves the exit surface 22 from a first position where the light beam is directed to the first portion of the illuminated surface to a second position, and an operation block 642. , 644, and 646 are repeated to apply the light emitted from the exit surface 22 to the second portion of the irradiated surface. The first part and the second part do not overlap in some embodiments. By repeating this method, the light emitted from the emission surface 22 can be applied to the 20 portion of the irradiation surface. In some such embodiments, the 20 portions of the illuminated surface do not overlap. However, in certain embodiments, the portions of the patient's brain that are irradiated by illuminating these 20 portions of the patient's scalp do not overlap.

  The illuminated surface of one embodiment of the method described above with reference to FIGS. 25-28 includes a portion of the patient's scalp or skull. In certain other embodiments, the surface illuminated by the light measures one or more parameters (eg, irradiance, total power, beam size, beam profile, beam uniformity) of the light that illuminates the surface. Includes a portion of the configured light detection system. In certain such embodiments, the method further includes measuring one or more parameters of light from device 10 that strikes the surface. For example, the light detection system can include a portion of the apparatus 10 configured to test a light beam emitted from the exit surface 22 immediately prior to patient treatment. In this way, the light detection system can be used to ensure that the light beam applied to the patient's scalp or skull has the desired therapeutic parameters.

  In one embodiment, treatment of a patient is performed by identifying multiple (eg, about 10) treatment sites on the patient's scalp or skull, directing a light beam to each treatment site, and irradiating each treatment site with a light beam. Done. As described in more detail below, in one embodiment, a treatment site is identified using a device that includes a plurality of indicators each corresponding to the location of the treatment site. In one such embodiment, the treatment site is continuously irradiated with a light beam from the exit surface. In certain other embodiments, the treatment site is identified with another mark instead. For example, each treatment site can be identified by a marking made on the scalp, or can be identified by a structure placed near the scalp or skull. Each treatment site can then be irradiated. In some embodiments, each treatment site is illuminated with light from the exit surface, while the exit surface is in contact with the scalp or skull or in contact with an intervening light transmissive element that contacts the scalp or skull. is doing. In certain other embodiments, the scalp or skull does not contact the exit surface or intervening elements. In one embodiment, each treatment site is irradiated using one beam delivery device that moves continuously from one treatment site to another. In certain other embodiments, multiple treatment sites are simultaneously irradiated using multiple beam delivery devices. In some such embodiments, the number of beam delivery devices is less than the number of treatment sites, and multiple beam delivery devices move continuously to irradiate the treatment sites.

  FIG. 29 is a flow diagram of an example method 700 for irradiating a patient's brain with controllably exposed laser light to at least one predetermined region of the patient's scalp or skull. As described in more detail below, the method 700 is described with reference to the wearable device 500 and the beam delivery device 10 described herein. Other configurations of wearable device 500 and beam delivery device 10 also correspond to method 700 in accordance with the embodiments described herein.

  The method 700 includes providing the beam delivery device 10 at an operation block 710. In one embodiment, the beam delivery device 10 includes an exit surface 22 configured to emit a light beam. Other configurations of the beam delivery device 10 other than those described above also correspond to certain embodiments described herein.

  The method 700 further includes placing the wearable device 500 on the patient's scalp at operation block 720. Device 500 includes a body 510 and a plurality of indicators 520. In one embodiment, each indicator 520 substantially transmits the light beam emitted from the exit surface 22. Other configurations of the wearable device 500 other than those described above also correspond to certain embodiments described herein.

  The method 700 further includes, at operation block 730, positioning the exit surface 22 in thermal communication with the irradiated patient's scalp or skull treatment site. The method 700 further includes illuminating the treatment site with light emitted from the exit surface 22 at operation block 740. In some embodiments, the light beam is transmitted through indicator 520.

  In some embodiments, providing the light emitting device 600 at the operation block 710 includes preparing the beam delivery device 10 for use in treating a patient. In some embodiments, preparing the beam delivery device 10 includes cleaning a portion of the beam delivery device 10 from which laser light is output. In some embodiments, preparing the beam delivery device 10 includes verifying power calibration of the laser light output from the beam delivery device 10. Such verification includes measuring the intensity of light output from the beam delivery device 10 and comparing the measured intensity to an expected intensity level.

  In certain embodiments, placing the wearable device 500 on the patient's scalp at the action block 720 includes preparing the patient's scalp for treatment. For example, in one embodiment, preparing a patient's scalp for treatment includes removing hair from a predetermined area of the patient's scalp to be irradiated. Removal of the hair (eg, by shaving) advantageously reduces heating of the patient's scalp by the hair that absorbs the laser light from the beam delivery device 10. In certain embodiments, placing the wearable device 500 on the patient's scalp in action block 720 may cause the wearable device 500 to be placed on the scalp or skull that is illuminated by the patient with each indicator 520 in place. Positioning to indicate a corresponding portion of.

  In some embodiments, placing the exit surface 22 in thermal communication with the treatment site at operation block 730 includes pressing the exit surface 22 against the treatment site. In one embodiment, by pressing the exit surface 22 against the treatment site in this manner, pressure is applied to the portion of the patient's scalp at the treatment site to whiten the portion of the patient's scalp that is conveniently irradiated.

  In some embodiments, irradiating the treatment area of the patient's scalp or skull in motion block 740 may be performed by applying light from the emission surface 22 by pressing the emission surface 22 against the treatment site with a predetermined level of pressure. Including causing emission. In some embodiments, the emission of light from the exit surface 22 is continued only if a predetermined level of pressure is maintained by pressing the exit surface 22 against the treatment site. In one embodiment, light is emitted from the exit surface 22 to the treatment site for a predetermined period.

  In certain embodiments, the method further includes irradiating additional treatment sites on the patient's scalp or skull during the treatment process. For example, after irradiating the first treatment site corresponding to the first indicator as described above, the emission surface 22 is disposed so as to contact the second indicator corresponding to the second treatment site, and the emission surface The second treatment site can be irradiated with the light emitted from 22. Various treatment sites on the patient's scalp or skull can be irradiated one after another in a predetermined order. In such an embodiment, the predetermined order is represented by an indicator on wearable device 500. In some such embodiments, the beam delivery device 10 interfaces with an indicator of the wearable device 500 to prevent various treatment sites from being irradiated out of a predetermined order. Includes system.

  FIG. 30 is a flow diagram of another example of a method 800 for treating a patient's brain. This method 800 is described below with reference to the wearable device 500 and the beam delivery device 10 described herein. Other configurations of wearable device 500 and beam delivery device 10 also correspond to method 700 according to the embodiments described herein.

The method 800 includes, at operation block 810, non-invasively irradiating a first region of at least 1 cm ² of the patient's scalp or skull with laser light for a first time period. The method 800 further includes non-invasively irradiating at least a 1 cm ² second region of the patient's scalp or skull with the laser light for a second period of time at operation block 820. The first region and the second region do not overlap, and the first period and the second period do not overlap. In certain embodiments, there is at least a 10 millimeter gap between the first region and the second region. In one embodiment, the first region is above the first hemisphere of the brain and the second region is above the second hemisphere of the brain.

  In certain embodiments, the method 800 further includes identifying the first region and the second region by placing a template on the patient's scalp. The template includes a first indicator in a first region and a second indicator in a second region. For example, the first indicator can include a first opening in the template and the second indicator can include a second opening in the template. In certain embodiments, the method 800 further places the laser light source in a first position to irradiate the first region non-invasively and moves the laser light source to the second position to non-invasively the second region. Irradiation.

  In some embodiments, the method 800 further includes increasing the transmittance of the first region for laser light and increasing the transmittance of the second region for laser light. Increasing the transmittance of the first region may include applying pressure to the first region to at least partially whiten the first region, first irradiating the first region non-invasively. Removing the hair from the region, providing a refractive index matching material to the first region, or combining two or more of these strategies. Increasing the transmittance of the second region includes applying pressure to the second region to at least partially whiten the second region, second before irradiating the second region non-invasively. Removing the hair from the region of the substrate, providing a refractive index matching material to the second region, or combining two or more of these strategies.

  FIG. 38 is a flow diagram of an example method 900 for treating a patient's brain according to certain embodiments described herein. The method 900 results in operation block 910 with a patient having at least one neurological disorder (eg, Alzheimer's disease, Parkinson's disease, depression) or physical trauma (eg, ischemic stroke or traumatic brain injury) in the brain. Including providing a patient with reduced blood flow of at least some brain cells of the patient. The method 900 further includes, at operation block 920, irradiating at least a portion of the patient's scalp or skull with a pulsed light beam that includes a plurality of pulses that pass through the patient's skull. The pulsed light beam has a temporal profile that supports one or more intercellular or intracellular biological processes involved in brain cell survival or regeneration. For example, the pulsed light beam of one embodiment improves cell survival (eg, increases neuronal survival), cell function of irradiated brain cells by adjusting membrane potential through the skull, Or an average irradiance per pulse, sufficient to do both, and a temporary profile including the temporary pulse width and duty cycle.

  In certain embodiments, providing a patient includes identifying a patient having at least one neurological disorder or physical trauma in the brain. In certain such embodiments, identifying the patient may be communicating with the patient, or communicating with another person with knowledge of the patient's health or experience, and neurology to the patient's brain. Including determining whether there is a physical disability or physical trauma. In certain other embodiments, identifying the patient includes examining the patient's body (eg, head or skull) for evidence of physical trauma to the patient's brain. This examination in certain embodiments includes the use of invasive or non-invasive medical devices, techniques or probes (eg, magnetic resonance imaging devices). In certain other embodiments, identifying the patient includes testing the patient's mental ability for evidence that the patient's brain has a neurological disorder or trauma (eg, neurological). Judge patient ability based on functional criteria). One of ordinary skill in the art can identify a patient according to various embodiments described herein. In some embodiments, providing the patient receives information regarding the results of the patient's past identification (eg, communication, examination, or test performance) as a patient with at least one neurological disorder or physical trauma. including.

  In some embodiments, irradiating at least a portion of the patient's scalp or skull with a pulsed light beam generates a pulsed light beam and directs the pulsed beam to irradiate at least a portion of the patient's scalp or skull. including. An example pulsed light beam has a wavelength, time average irradiance, beam size, beam profile, spread, temporal pulse width, duty cycle, repetition rate, and peak irradiance per pulse as described herein. Have. Various light delivery devices can be used to generate a pulsed light beam and direct the pulsed light beam to the patient's scalp or skull, which is hereby incorporated by reference in its entirety. , 303,578, 6,214,035, 6,267,780, 6,273,905, and 6,290,714, and US Patent Application Publication No. 2007/0179570 A1, 2007/0179571. Including, but not limited to, the apparatus disclosed in No. A1 and 2005/0108951 A1.

  In certain embodiments, irradiating at least a portion of the patient's scalp or skull identifies one or more treatment sites (eg, at least 10, between 2 and 100, or between 15 and 25) and treatment sites Continuous irradiation with a pulsed light beam. In certain embodiments, the one or more treatment sites are as described herein (eg, by a device worn by the patient and including one or more openings, by markings made on the scalp, or by scalp Or by a structure placed near the skull). In some embodiments, as described herein, each treatment site is irradiated by a device that contacts or does not contact the scalp or skull. In certain such embodiments, the irradiated portion of the scalp is whitened during irradiation, not whitened during irradiation, cooled during irradiation, or not cooled during irradiation.

  In one embodiment, the patient's scalp is prepared for treatment prior to irradiation. For example, in some embodiments, preparing a patient's scalp for treatment includes removing at least a portion of the hair or almost all of the hair from a predetermined area of the patient's scalp to be irradiated. By removing the hair (eg, by shaving the hair substantially away from the irradiated portion of the scalp), heating of the patient's scalp by the hair that advantageously absorbs light from the light emitting device is reduced. In other such embodiments, the hair is not shaved or removed prior to irradiation. For example, irradiation of the patient's scalp can be performed with pulsed light having a wavelength, temporary pulse width and duty cycle that avoids harmful heating of the patient's scalp due to light absorption by the hair.

In some embodiments, the parameters of the pulsed light beam used to irradiate the patient's scalp or skull are selected to do one or more of the following. (I) Increase neuronal survival of brain cells after at least one physical trauma. (Ii) support one or more intercellular or intracellular biological processes involved in the survival or regeneration of brain cells. Or (iii) adjusting the membrane potential to improve, recover or promote cell survival, cell function or both of irradiated brain cells after traumatic brain injury. In one example of such an embodiment, the beam diameter of the pulsed light beam at the exit face of the device is in the range between 10 and 40 millimeters, and the average irradiance per pulse is 10 mW / cm ² and 10 W / cm. ^The one or more wavelengths are in the range between 780 nanometers and 840 nanometers, and the temporal pulse width is between 0.1 and 150 milliseconds or 0.1 milliseconds. It is in the range between 300 milliseconds. In some embodiments, the duty cycle can range between 10% and 30%. Other ranges for these parameters of the pulsed light beam can be selected in accordance with various other embodiments described herein.

Neurological Function Scale The neurological function scale can be used to characterize or otherwise characterize the effectiveness of the various examples described herein. The neurological function scale typically uses multiple levels or points, each point corresponding to one aspect of the patient's condition. The number of points for a patient can be used to quantify the patient's condition, and an improvement in the patient's condition can be represented by a change in the number of points. An example of a neurological function scale is the National Institutes of Health Stroke Scale (NIHSS) that can be used for short-term measurements of efficacy (eg, 24 hours). The NIHSS is a comprehensive and objective scale that utilizes a 7 minute physical examination, a 13 item scale, and 42 points. 0 points correspond to normal examinations, 42 points (maximum) basically correspond to coma, and above 15-20 points indicate that the effects of stroke are particularly severe. NIHSS has previously been used for tPA testing in the treatment of ischemic stroke, with a change of 4 points at 24 hours and a total score of 0 or 1 at 3 months indicating favorable results. Other neurological functional scales are the modified Rankin Scale (mRS), Barthel Index (BI), Glasgow Outcome, Glasgow Coma Scale, Canadian Neurology Including, but not limited to, a genetic scale and a stroke impact scale such as SIS-3 or SIS-16. On some scales, an improvement in the patient's condition is indicated by a decrease in the number of points. For example, mRS is a total of 6 points, 0 corresponds to normal function and 6 corresponds to death. On other scales, improvement in patient status is indicated by an increase in the number of points. For example, the Glasgow outcome has 5 points, 0 corresponds to death and 5 corresponds to full recovery. In certain examples, two or more of the neurological function scales can be used in combination and can provide a long-term measure of efficacy (eg, 3 months).

  For stroke, the US Food and Drug Administration (FDA) and neurological organizations have shown interest in clinical patient results 90 days after stroke, the most common and accepted method for measuring efficacy is NIHSS and mRS. The FDA is flexible as to how the neurological function scale can be used. For example, mRS is permitted to be used in a dichotomy with (i) a score 0-1 successful, or (ii) a scale shift indicating patient improvement along a 5 point scale. You can see and analyze.

  In certain embodiments described herein, a patient who exhibits signs of ischemic stroke is treated by irradiating multiple treatment sites on the patient's scalp. This irradiation is performed using irradiation parameters (e.g., wavelength, irradiance, irradiation duration, etc.) that, when applied to members of the patient's treatment group, are based on at least one neurological functional scale. This produces an average difference of at least 2% between the group and the placebo group, and this at least one neurological function scale is analyzed in a dichotomous or other way, NIHSS, mRS, BI, Glasgow Outcome, Glasgow Coma Scale, Selected from the group consisting of the Canadian Neurological Scale, SIS-3, and SIS-16. Some other examples produce an average difference of at least 4%, an average difference of at least 6%, or an average difference of at least 10% between the treatment group and the placebo group based on at least one neurological function scale; The at least one neurological functional scale is analyzed in a dichotomous or other manner and comprises the group consisting of NIHSS, mRS, BI, Glasgow Outcome, Glasgow Coma Scale, Canadian Neurological Scale, SIS-3, SIS-16 More selected. In one embodiment, irradiation of the patient's scalp causes a change in the patient's condition. In some such embodiments, the change in patient condition corresponds to a change in the number of points indicative of the patient condition. In certain such embodiments, irradiation results in a 1 point change, 2 point change, 3 point change, or more than 3 point change of the neurological function scale.

Transmission power density (PD) measurement in the human brain The transmission of laser light having a wavelength of about 808 nanometers has been sought through successive layers of human brain tissue. Laser light with a wavelength (808 ± 5) nanometers and a maximum output of about 35 watts was applied to the surface of the cortex using a beam delivery device that approximated the beam profile after the laser light passed through the human skull. Through a portion of human brain tissue, peak power density measurements are made using an Ocean Optics spectrophotometer model USB2000, serial number G1965, and the scattered beam diameter is measured by Sony model DCR- Approximation was made using IP220 and serial number 132289.

  New human brain and spinal cord specimens (acquired within 6 hours after death) were collected and placed in physiological Dakins solution. The buffy coat layer, the arachnoid layer, and the vasculature were intact. The brain is divided into a sagittal shape at the center, and the divided portion is put in a container. ) And 1.5 centimeters (± 0.2 centimeters). PD measurements are shown in Table 1.

FIG. 31 is a graph of the depth from the dura and the PD when the input PD is 10 mW / cm ² , as described below, the white bar corresponds to the predicted value of the PD, and the black bar is the estimated minimum It corresponds to a practical PD of 7.5 μW / cm ² .

Based on previous animal experiments, a conservative estimate of the smallest known PD in brain tissue that can show efficacy in stroke animal models is 7.5 μW / cm ² . This estimated minimum practical PD was derived from an experiment that applied 10 mW to the rat brain surface, and 7.5 μW / cm ² PD was measured directly at 1.8 centimeters from the surface. This stroke model consistently provides significant effectiveness and includes 1.8 centimeters from the laser probe for stroke. Note that this 7.5 μW / cm ² is a conservative estimate, and the same irradiance or power density at the brain surface consistently provides significant efficacy in the 3 centimeter rabbit clot shower model. . It should also be noted that power density measurements in human brain experiments do not take into account the effects from CNS filled grooves where laser energy should be easily transmitted. However, even if we conservatively estimate 7.5 μW / cm ² as the minimum power density disturbance and neglect the expected transmission benefit from the groove, the above experiment shows that about 10-15 W transmitted over the cortex Confirm that / cm ² (according to the male dosimetry example) is effective at least 3.0 centimeters from the surface of the brain.

In Vivo Thermal Measurement In vivo thermal measurement was performed to determine the heating effect of laser light with a wavelength of approximately 808 nanometers in living tissue. A 808 nanometer GaAlAs laser source was placed in direct contact with the skin of the heads of living rabbits and rats. The laser source had an approximately Gaussian beam profile with a beam diameter of 2.5-4.0 millimeters (1 / e ² ). A thermocouple probe (Model Bat-12 from Physitemp Instruments Inc., Clifton, NJ) was placed under the dura mater in the subcutaneous tissue and measurements were taken on various Recorded by irradiance or power density. The results of these measurements are shown in Table 2.

  Minimal heating (eg, less than 0.5 ° C.) occurs in the subdural region at 4 times the treatment energy density. The “heat sink” effect of living tissue that minimizes the heating that can occur in the cortex is much greater in humans than in rats or rabbits. This is because the heat sink and blood flow volume are much larger, which further limits the undesirable effects of heating in the stroke area. Thus, in certain embodiments described herein, a therapeutic dose of energy is delivered to the stroke area without causing unwanted heating of the dura mater.

Phototherapy example 1
An example of phototherapy (Lampl Y, Zivin JA, Fisher M, Lew R. Welin L, Dahlof B, Borenstein P, Andersson B, Perez l, Caparo C, Ilic S, which is hereby incorporated by reference in its entirety. Oron U., “Infrared laser therapy for ischemic stroke: Results of the NeuroThera Effectiveness: NeuroThera Effectiveness and Safety Trial-1 (NEST-1) and Stroke. 2007; 38: 1843-1849) are 40 to 85 years of ischemic stroke within 24 hours of stroke onset in a small randomized controlled trial. It shows the safety and efficacy of transcranial phototherapy (TLT) for human treatment. NeuroThera Laser System treatment strategies have included the use of infrared laser technology and have shown significant and sustained beneficial effects in animal models of ischemic stroke.

  The NeuroThera laser system (NTS) used in this NEST-1 study utilized infrared laser technology including photobiological stimulation. There are many documents that document the photobiological stimulation effects of infrared laser therapy both in vitro and in vivo. The biological effect of infrared laser therapy is limited to the wavelength and not due to thermal effects. The energy in this region of the electromagnetic spectrum is non-ionizing and therefore there is no hazard associated with UV light. It has been demonstrated that irradiation with specific infrared wavelengths can penetrate deep into the brain. This form of therapy is distinct from photodynamic therapy, which involves the use of light energy to penetrate the body and activate photosensitive drugs.

Photobiological stimulation involves increased adenosine triphosphate (ATP) formation after energy absorption within mitochondria. Compounds that absorb energy in the spectral region of interest are known as chromophores. There is evidence to show that the major mitochondrial chromophore for photobiological stimulation is cytochrome c oxidase. This enzyme complex contains two copper centers, Cu _A and Cu _B. This major chromophore for the NTS wavelength is in the Cu _A center with a broad absorption peak at about 830 nm in oxidized form. NTS delivers 808 nm energy, which is within the absorption peak and can penetrate non-invasively into the brain. Cytochrome c oxidase is a terminal enzyme in the cellular respiratory chain, located in the inner mitochondrial membrane. This plays a central role in eukaryotic bioenergetics by delivering protons at the inner membrane and thereby driving the formation of ATP by oxidative phosphorylation. In addition to obtaining increased ATP formation, photobiological stimulation can initiate secondary cellular signaling pathways. The overall result is improved energy metabolism, increased cell viability, and may also include prevention of apoptosis in the periphery of ischemia and improved nerve recovery mechanisms.

  In vivo studies have shown that infrared laser therapy can be beneficial in the treatment of acute myocardial infarction, acute ischemic stroke, peripheral nerve injury and spinal cord injury. Previous studies have shown that infrared therapy for experimental ischemic stroke treatment results in New Zealand rabbits (rabbit small clot embolization stroke model [RSCEM]) and Sprague-Dawley rats (permanent middle aortic occlusion) in two different animal models. Shows the positive impact of. Lapchak shows that RSCEM laser treatment 6 hours after stroke onset improves behavioral performance and produces a permanent effect measured 21 days after embolization. De Taboada and Oron also show that laser treatment up to 24 hours after stroke onset in permanent middle cerebral artery occlusion is evident at 14, 21 and 28 days after stroke compared to the sham control group Show, showing a significant improvement in neurological deficits. Currently, the assumed mechanism of infrared laser therapy for stroke involves mitochondrial stimulation, which leads to subsequent preservation of tissue around the ischemia and improved nerve recovery. The exact mechanistic pathway has not yet been elucidated.

Study Design NEST-1 is a future, multifaceted, international, double-blind, randomized, simulated (placebo) conducted in six medical centers in three countries, Israel, Peru and Sweden. It was a controlled trial. This study examined the initial safety and efficacy of infrared wavelength laser therapy for the treatment of patients within 24 hours after the onset of ischemic stroke.

  This study was conducted in accordance with FDA / ICH Good Clinical Practice guidelines and applicable local regulatory requirements. Investigators have found that this study is in line with the 1983 revision of the Declaration of Helsinki, or the laws and current rules in biomedical research involving human patients in countries where research has been conducted that gives patients more protection To guarantee that it was done in full compliance. Protocols and information about patients and healthcare providers were approved by each center's ethics committee or institutional ethics committee. An independent data monitoring committee specific to the country reviewed safety throughout the study.

  Eligible patients must be between 40 and 85 years of age and clinically diagnosed with ischemic stroke (within 24 hours of stroke onset) resulting in significant neurological deficits (total NIHSS score is medical) NTS treatment was started at the time of hospital admission from 7 to 22) and within 24 hours from the onset of stroke. The patient or probable legal representative wrote the informed consent in writing before enrolling in the study.

Exclusion criteria Patients were excluded if the following were true: If there is evidence of intracranial, subdural, or subarachnoid hemorrhage on the CT scan, or clinical findings suggesting subarachnoid hemorrhage even though the initial CT scan was normal; The patient is subject to intravenous or intraarterial administration of tissue plasminogen activator or other thrombolytic therapy for the treatment of acute ischemic stroke and administration of tissue plasminogen activator or other thrombolytic therapy If applied; if the patient had a stroke at the onset of stroke; if serum glucose was> 400 mg / dL (22 mmol / L) or <40 mg / dL (2.2 mmol / L); If the patient had persistent hypertension when necessitating treatment or active treatment (systolic blood pressure> 18 at two 30 minute intervals during the baseline period) if defined as mmHg or diastolic blood pressure> 110 mmHg); if sustained hypotension (defined as systolic blood pressure <80 mmHg or diastolic blood pressure <50 mmHg); if estimated septic embolism; Or, if known to have an acquired hemorrhagic predisposition (eg, oral anticoagulant therapy with longer active partial thromboplastin time or prothrombin time than usual, unsupported clotting factor deficiency or prothrombin time longer than usual) ); If the patient has skin symptoms (ie hemangiomas, scleroderma, psoriasis, rash or open wound) at the site selected for infrared energy irradiation; the patient has had another trial in the past 4 weeks in the past If enrolled or participated in a drug or device study; 14 days prior to screening visit New medications are initiated; severe intellectual deficits, severe neurological deficits or disorders (dementia, multiple infarcted dementia, progressive multiple sclerosis) that may interfere with the patient's assessment of independent function Symptom) in the patient; there was evidence of a non-stroke disorder that was considered severe or life-threatening in the investigator's view, such as active severe infection, pneumonia, pulmonary embolism, or gastrointestinal bleeding If the patient is likely to become pregnant; if the patient is comatose or conscious at a level of dying; or investigator indicates that the patient is medically ineligible to participate in the study Is determined.

Study Group, Evaluation Criteria, and Baseline Elements All patients received standard medical management therapy for acute ischemic stroke. In addition, they all received the same NTS treatment. A pre-programmed randomized code in the NeuroThera laser system determined whether the treatment was an active treatment or a pseudo (placebo) treatment. The treatment tool was made invisible to patients and clinicians. The National Institutes of Health Stroke Scale (NIHSS) was evaluated at screening to enroll in the study and again, just prior to randomization to the treatment group. Outcome indicators (NIHSS, modified Rankine scale [mRS], Barcel index, and Glasgow outcome scale) were determined at 30, 60, and 90 days. Neurological scores and clinical data were collected with a standard case report at each visit of a trained investigator.

  Baseline elements were collected including patient statistics, time to treat, medical history, vital signs, and predetermined laboratory values. Factors included age, sex, time from stroke onset to hospital, time from stroke onset to treatment, and overall medical history.

  After completion of NTS treatment, the patient entered the study follow-up phase until one of the following occurred: That is, if the patient decides to cease study participation, the sponsor or ethics committee / applicable regulatory body terminates the study, the investigator decides to cease study participation in the patient or site, or the patient This is the case where you have participated in the study for 90 ± 10 days.

NTS Therapy Device The NTS used in the NEST-1 study was an investigational device intended to provide non-invasive transcranial laser therapy for patients diagnosed with acute ischemic stroke. The laser wavelength of 808 nm is the near infrared part of the electromagnetic spectrum and is not visible to the naked eye. The energy in this near-infrared spectrum is non-ionizing and has nothing to do with the danger of ionizing radiation. The NTS device used in NEST-1 includes a class IV laser system that transfers energy to a hand-held probe placed over the shaved head of the patient by a trained operator via a fiber optic cable. Deliver. This device is portable and is similar in size to portable ultrasound equipment.

NTS is manufactured by PhotoThera, Inc. The complete treatment plan established for the NEST-1 study removes hair from the patient's scalp and then applies NTS for 2 minutes at each of the 20 predetermined locations on the scalp (actively Treatment or sham / control treatment). This predetermined site is identified by a cap placed on the patient's head. This system is designed to deliver about 1 Joule / cm ² of energy over the entire surface of the cortex, regardless of the location of the stroke. The sham procedure is identical to the active procedure except that no laser energy is delivered from the device to the patient.

  Based on current knowledge of technology and risk assessment analysis, the most important known danger in NTS treatment is the possibility of retinal damage when the beam enters the eye lens and reaches the retina. Another possible danger is that the skin is burned and the scalp is scratched by shaving the head. The skin can burn if the device is not used as intended (eg, repeated treatments at the same location).

Statistical Methods Effectiveness results are reported based on a global analysis and include all 120 patients randomized on both sides. The safety results were based on the same 120 patients, including all patients who were also treated.

  Patients were evaluated at baseline, 30, 60, and 90 days after baseline. The analysis mainly focuses on 90-day evaluation. NIHSS was the primary outcome that was proactively identified and the mRS, Glasgow Outcome Scale and Barcel Index score were secondary outcomes.

  The baseline value category of NIHSS score and the time from stroke onset to treatment were included in the analysis as a hierarchy or covariate. The three NIHSS hierarchies were 7-10, 11-15, and 16-22. Categories for time from stroke onset to treatment were “less than 12 hours” and “12-24 hours”, the NIHSS scale is not an interval scale. Therefore, NIHSS score categories were used to remove potential inhomogeneities.

  The NIHSS result was broken down into a binary result, bNIH, and “success” could occur in either of the following two ways: 90 days NIHSS score 0-1 or 90 days from baseline It is a score decrease (change) of 9 or more points.

  There are two forms of 90-day results for mRS. The 7-category ordered variable form is analyzed throughout the distribution of scores based on the 0-6 mRS scale (total mRS), and the binary mRS has a score of 0-2 plus (success) and a score of 3-6 minus ( Failure).

  Total mRS (“shift in Rankin”), binary mRS and bNIH results were tested using the classified Cochran-Mantel-Haentsel (CMH) test or g van Elteren test It was done. This test uses a modified ridit score and is therefore a direct extension of the two-sample Wilcoxon test. For bNIH and binary mRS results, use logistic regression analysis to investigate the effects of covariates and site random effects, especially evaluating how adding these factors changed the estimation of treatment effect did.

  The analysis was performed in SAS version 9 using PROC FREQ to obtain results for the Van Erteren CMH test, and was performed using PROC GENMOD and PROC LOGISIC to obtain the results of logistic regression analysis. At this time, there was a medical center as a random effect. Patient number odds ratios were obtained from PROC GENMOD.

  This study includes guidance on the overall consideration of the FDA / ICH E8 clinical trial (FDA / ICH E8 Guidance on General Considerations for Clinical Trials) and on the statistical principles of the FDA / ICH E9 clinical trial (FDA / ICH E9 Guidance on Statistical Principles for Clinical Trials), it was an exploratory study rather than a confirmatory study. Primary safety and efficacy outcome measures and their analysis were proactively identified. Multiple secondary and exploratory survey analyzes were defined in the protocol or designed and performed in an open-label after the end of the study. No corrections were made for multiple comparisons.

  This study involved 122 eligible adults who were diagnosed with acute ischemic stroke between 40 and 85 years of age within 24 hours of onset and provided written informed consent with any racial background Of patients were enrolled. 2 patients are not included in any analysis for declined prior to randomization, leaving the remaining 120 patients the efficacy analysis. Of the 120 patients, 79 were randomized to the active treatment group and 41 were randomized to the sham control group. FIG. 32 shows the patient composition in this study. There was only one patient without follow-up (0.8%). There were no significant differences in baseline characteristics (see Table 3, baseline patient statistics and other baseline characteristics). Research data were reviewed by independent data monitoring committees in each country and no serious adverse effects on the device were reported.

Efficacy analysis The proportion of patients who received positive treatment and obtained positive bNIH results was 70%, which was higher than the proportion of patients who received sham-controlled treatment and obtained positive bNHH results (51%; CMH Test, P = 0.035, classified by severity and time from stroke onset to treatment; P = 0.048, classified by severity only). The therapeutic effect was also important for other options in the hierarchy for CMS analysis. Logistic regression analysis confirmed that the results controlled for both fixed covariates (eg, age, gender, time to treatment, baseline severity, past stroke) and random effects at the medical site. Controlling only for baseline severity, logistic regression gave a number-of-patient odds ratio in favor of 1.40 treatment (95% CI, 1.01-1.93). Of the 79 patients treated, 38% achieved both a final NIHSS score of 0-1 and an improvement of ≧ 9 points, 20% had only an improvement of ≧ 9 points, and 11% had a final score 0-1 but no improvement of ≧ 9, 30% did not give any results. Among the 41 control group patients, the corresponding ratios were 29%, 7%, 15% and 49%.

  Differences in mean NIHSS scores between treatment groups appeared immediately after treatment and were evident throughout the 90 day study period. FIG. 33 shows the time course and average NIHSS for each treatment group. Patients in the active treatment group showed a significant improvement in NIHSS score change from baseline to 90 days compared to the sham control group (P = 0.021, CMH test categorized by time to treatment) ).

The same significant pattern was seen also about the binary mRS result (0-2 vs. 3-6). The percentage of patients who received positive treatment and received positive binary mRS results was 60%, which is higher than those who received sham controlled treatment and received positive binary mRS results (44%; CMH test) , P = 0.034, classified by severity and time to treatment; P = 0.043, classified only by severity). Only the CMH test without hierarchy was not significant (P <0.11λ ² test). The percentage of positive outcomes varies greatly in the baseline severity hierarchy. Controlling only for baseline severity, logistic regression gave a number of patient odds ratio favoring treatment of 1.38 for binary mRS results (95% CI, 1.03-1.83).

  The effect of NTS on the total mRS score at 90 days or on the final assessment analyzed for the total distribution of scores on the 0-6 mRS scale when compared to sham treatment was significant. Cochrane Mantel Henzernon parametric classified in the categories of (1) Baseline NIHSS score and time to treatment (P = 0.020) and (2) Baseline NIHSS score only (P = 0.026, see Table 4) A rank test was used.

  FIG. 34 shows the time course and average nRS for each treatment group. When classified by baseline severity, similar results were seen for the three outcomes (bNIH, binary mRS, and total mRS). All three results had significance levels <0.05 (see Table 5, two-sided significance levels for the Van Erteren CMH test). When the time to treatment was also controlled (0-12 hours vs. 12-24 hours), there was little significance. However, in larger sample size trials, time to treatment would be expected to have a greater connection to results.

  The results of analysis using the Glasgow Outcome Scale and Barcel Index are similar to those for NIHSS and mRS. Patients who received active treatment were categorized by baseline NIHSS score and time to treatment than those who received sham controlled treatment, Glasgow Outcome Scale (CMH Test P = 0.056) and Barcel Index Scale ( Good results were obtained when measured with CMH test P = 0.035).

  Logistic regression analysis showed a negligible effect of covariate adjustment on the logistic regression coefficient for treatment. The results in Table 6 show that the effect of treatment is stable for two binary results and three different nested covariate sets. In fact, the therapeutic effect tends to increase as covariates are added. In addition, the treatment logistic regression coefficients did not change when hospital sites were treated as repeated measures. It is shown that 95% CI is not centered around the consistency of the regression coefficients. In all models except one, the probability value for treatment is <5%. In the bNIH outcome model, the covariate “severity” is not significant and the time to treatment is significant only once for P = 0.0496. However, for binary mRS results, the covariate “severity” is significant with P <0.001 in all three models. This indicates that a 9 point decrease in NIHSS score captures variability in treatment effects in the baseline severity category. We have investigated a large number of additional covariates, including the gender, age and past stroke covariates, then all other covariates have negligible predicted values. I found out. Gender was significant in the binary mRS model with P <0.01. Otherwise, these factors were not statistically significant. Referring to Table 6, the results for two sets of nested multivariate models are shown. One set of models is for outcome bNIH and one set of models is for outcome binary mRS (time to treatment indicates time from onset to treatment). The first P value relates to simple logistic regression and the second P value relates to logistic regression for the element “site” included as a repeated measures effect.

Safety analysis Table 7 (mortality and SAE) shows mortality and SAE by treatment group and total. There is no significant difference in mortality between the active treatment group and the sham control group. Table 7 shows the number of patients by treatment group by total number for significant adverse events, underlying disease deterioration, cardiovascular SAE, infection, or central nervous system SAE. These data indicate that there are no significant differences between treatment groups for these criteria. For those who tend to differ between treatment groups, such as infection rates or central nervous system SAE rates, patients who received active treatment may have obtained better results than patients who received sham controlled treatment.

Discussion The NEST-1 trial provides the first evidence regarding the safety and efficacy of infrared laser therapy within 24 hours after stroke onset for the treatment of human ischemic stroke. The outcome variable scale used in the NEST-1 study had an excellent correlation R = 0.79-0.92. The correlation coefficient of the NEST-1 test is essentially the same as reported in the literature by Lyden and his colleagues who examined tissue plasminogen activator data. That is, the result variables have a correlation coefficient of about 0.8 (absolute value) or more. Consistency with this past study proves that the results were properly and consistently evaluated.

  This result indicates that infrared laser therapy may be beneficial for patients with a wide range of strokes without increasing the rate of adverse events. Furthermore, this relatively large effect suggests that the Phase III trial should not require a significant number of subjects.

  Patients who received aggressive treatment had a higher rate of positive NIHSS results than those who received sham-controlled treatment. The results were similar to those using other neurological outcome scales. There was no significant difference between treatment groups for mortality or SAE, but sample size (n = 120) was insufficient to find small differences. When there was a trend of differences between treatment groups, patients who received active treatment appeared to have less SAE than patients who received sham-controlled treatment. The safety profile of NTS treatment shown in this study was clear. There were no adverse consequences that could be attributed to the laser therapy treatment.

  BNIH results with a 9-point change include baseline severity variability (NIHSS score 7-22), indicating overall potential benefit. In contrast, binary nRS results do not account for changes from baseline. Thus, when the analysis controls for baseline severity, results based on binary results are highly consistent. Controlling for baseline severity, analysis by the CMH test and analysis by logistic regression gave a patient odds ratio that favored treatment above 1.40 for bNIH results and above 1.38 for binary mRS results .

  This overall potential benefit is also shown through the total mRS analyzed through the entire distribution of Rankine scores from 0 to 6. mRS is a simple and reliable outcome measure when implemented consistently by trained clinicians. The total mRS analysis considers the entire range of patient results. As a result, total mRS is increasingly viewed as a primary outcome measure for ischemic stroke trials, including neuroprotective techniques.

  This preliminary study had a pre-specified analysis plan, with the primary results of bNIH, the NIHSS binary format that considered a final score 0-1 or 9 point reduction as a success. However, our announcement of several analytical techniques focuses on type 1 errors. We have described several approaches to the same assumptions. The assumption is that in order to confirm non-parametric results, some have mRS results, some have NIHSS results, and some use logistic regression. These results showed substantial agreement between these results and methods. They also showed that after controlling for NIHSS baseline severity, other factors had little or no effect on the magnitude of the therapeutic effect. Therefore, multiple comparative corrections such as Bonferroni correction were not shown. This is because, in particular, Bonferroni correction assumes that the assumptions are independent of each other. Another reason for the various analyzes is to correlate the magnitude of the effect with the results of the primary analysis by a nonparametric CMH test. A simple estimate of the magnitude of the effect was obtained from both other tests and a simple percentage of success of the binary results and reported the odds ratio of the number of patients obtained from logistic regression.

  Much can be inferred from the treatment window extending to 24 hours after the onset of stroke. The proven treatment window for thrombolytics is 3 hours. However, the effectiveness of this form of therapy will already expand. The first neuroprotective study to show efficacy was the NXY-059 study. Although this study had a 6-hour treatment window, most patients were treated within 4 hours. A reasonable argument is that all previous neuroprotective therapies were unsuccessful, but the reason for the success of the NXY-059 study was that the average time to treatment was kept very low. The treatment window for NEST-1 is 24 hours, and the time to treatment is much longer for the treatment of acute ischemic stroke than for almost all other clinical trials (median 18 hours). The main problem with stroke treatment was that many patients appear after 6 hours. Thus, an extended treatment window of 24 hours will allow treatment of more ischemic stroke patients.

  Although the mechanism of action of infrared laser therapy for stroke is not fully understood, the numerous effects of this type of irradiation are documented. Infrared laser therapy is a physical process that can cause biochemical changes at the tissue level. The putative mechanism of NTS treatment includes stimulation of ATP formation by mitochondria and may also include prevention of apoptosis in the periphery of ischemia and improvement of nerve recovery mechanisms. Another example of a physical process of neurological damage is hypothermia. Animal model studies have shown few, if any, therapies that have consistently reduced stroke-related disorders such as hypothermia. It is clear that infrared irradiation probably has its effect independent of blood flow recovery, and this mechanism is probably associated with improved energy metabolism and improved cell survival.

  Another advantage of this form of therapy is that treatment can be started quickly without prior clinical testing, non-invasive procedures or extended training of clinicians performing the therapy. Furthermore, there is no need to know the location of vascular occlusion for NTS treatment. Thus, this form of therapy tends to require much less infrastructure for acute stroke therapy or thrombus removal compared to almost all other types of devices and medical methods available to date.

  Although the results of the NEST-1 study are promising and will show that infrared laser therapy may be a treatment for human ischemic stroke when initiated within 24 hours of stroke onset Larger confirmatory studies have been accepted to demonstrate safety and efficacy.

Phototherapy example 2
Another example of phototherapy (NeuroThera Effectiveness and Safety Trial-2 (NEST-2)) is almost identical to the above study, but is larger and 40 Includes patients aged 90 to 90 years. NEST-2 was a double-blind, placebo (pseudo) controlled trial with 660 patients enrolled at 57 centers in 4 countries. Patients must be 40 to 90 years of age, have a baseline NIHSS score of 7 to 22, have a clinical diagnosis of ischemic stroke, no evidence of hemorrhagic infarction by CT scan or MRI, and have not received tPA Qualified for inclusion. The start of treatment had to be within 24 hours after the onset of stroke. The inclusion and exclusion criteria are summarized in Table 8.

Randomization and Treatment Patients were randomly assigned to TLT or sham treatment at a 1: 1 ratio. All patients received the same TLT procedure, including removal of the patient's scalp hair followed by application of a laser probe to the patient's head. The total treatment time was approximately 2 hours. After consent, an interactive speech randomization system was used, with dynamic randomization at the center to ensure that treatment assignments were distributed on average. All patients received standard therapeutic medical management throughout the trial.

Study Management This study was conducted in accordance with FDA / ICH Good Clinical Practice (GCP) guidelines and applicable local regulatory requirements. The trial was also conducted in full compliance with the 1983 revision of the Declaration of Helsinki, where patients received greater protection, or the laws and current regulations in biomedical research involving human patients in the country where the study was conducted . This study was designed and supervised by the steering committee. Each center's ethics committee or in-house ethics committee and an independent data monitoring committee (DMC) performed safety tests. DMC regularly reviewed data on serious adverse events between groups. The patient or legal representative provided written informed consent prior to enrollment in the study. Data management and statistical analysis were performed by an independent contract research organization (Parexel, Waltham, Mass) and a research sponsor (Photocera, Carlsbad, Calif.). After database lock and independent review by the DMC, the steering committee had full access to the test data and was responsible for analysis and interpretation of the results.

Treatment
The NeuroThera Laser System (NTS) includes a device with a hand-held housing that irradiates selected portions of the patient's scalp. NTS uses energy at a wavelength of 808 nm that is near infrared, non-ionized and invisible to the naked eye. Experiments with cadaver showed that the optimum amount of laser energy could penetrate to a depth of approximately 2 cm in the brain. Wavelength and irradiance level dosimetry was based on transmission experiments with new, unfixed human corpses. Results of Monte Carlo simulations, in vitro experiments, review of literature using infrared therapy for other signs, and preclinical studies in valid stroke animal models. The overall treatment plan established for NEST-2 involved applying a handheld probe to 20 predetermined locations on the shaved scalp for 2 minutes at each location. This predetermined site is identified by a cap placed on the patient's head, regardless of the location of the stroke. The sham procedure is the same as the TLT procedure except that no laser energy is delivered to the patient from the device.

  Based on current knowledge of technology and risk assessment analysis, the most important known danger in TLT is that the retina can be damaged if the beam enters the eye and is focused on the retina This, as a result, causes permanent damage. Because of this potential eye hazard, the procedure must be performed in a laser safe environment by a trained user.

Clinical evaluation Patients were evaluated by inspectors who did not know the treatment group. All inspectors were trained by NIHSS and were certified for mRS. NIHSS is a neurological function scale ranging from 0 to 42, and a score between 7 and 22 is considered a moderate to severe neurological disorder. mRS is a disability index ranging from 0 (no signs) to 6 (death). Outcome measures (mRS and NIHSS) were assessed and assessed at 5, 30, 60 and 90 days in addition to baseline. Baseline data was collected, including age, gender, patient statistics, time from stroke onset to hospital arrival, time to treatment, pre-stroke mRS, vital signs, and complete medical history.

Safety assessment Vital signs, neurological scores, concomitant medications, adverse events, and serious adverse events were recorded from study participation until day 90. Unresolved serious adverse events were followed for another 30 days.

  The Data Monitor Committee examined mortality, adverse events, and serious adverse events, as well as the expected and unexpected device effects during the study. After evaluating safety data for the first 100 to 400 patients, we did not stop recruiting for further studies. Due to early registration, there was no interim analysis of efficacy. Neuroimaging evaluation was completed at baseline and 5 days plus 2 days of follow-up.

Statistical analysis All analyzes are comprehensive. Results were obtained from two 90 day scores, mRS and NIHSS score. Patients who did not visit on the 90th had their last observation postponed. The mRS results are as follows. (1) The overall order scale was 0 to 6, and (2) as a result of the bisection method, a favorable result (success) was set to 0 to 2 scores, and an unfavorable result (failure) was set to 3 to 6 scores. The NIHSS results are as follows. (1) Change in score from baseline to 90 days using an overall order scale of 0 to 42 (death is score 42), and (2) As a result of dichotomy, success was achieved in two ways, 90 days Score 0-1 or 9 or more points as a 90-day beneficial change from baseline.

  The temporary efficacy outcome measure was dichotomous with mRS 90 day endpoints as success (mRS 0-2) and failure (mRS 3-6). The null hypothesis that the rate of success does not differ between treatments was tested using multiple logistic regression, and the two pre-specified covariates were: (1) the severity of the stroke at baseline, and (2) the stroke Time from onset to randomization (TFSO). There are three levels of baseline stroke severity: NIHSS scores 7 to 10 (moderate), 11 to 15 (somewhat severe), and 16 to 22 (severe). There are two levels of TFSO: 0 to 12 hours and 12 to 24 hours. The randomization procedure was balanced (but not classified) for these factors.

  Secondary analysis determined the sensitivity of the results to covariate selection, test procedure selection, and analysis result selection. The logistic model was performed on primary outcome measures using additional covariates of age, gender, CAD history, diabetes history, and stroke history. In order to change the test procedure for logistic regression of the bisection results, the same non-parametric “shift” test of the bisection results was used. Obviously, this shift test is the Cochrane Mantel Haenzel (CNH) test and ranks the results using rigid scores (the van Elteren test, Stokes ME, Davis CS, Koch GC, Categorical Data Analysis Using the SAS System II Cary, NC: SAS Institute, Inc .; 2000). In the literature on stroke, the shift test is often applied only to the full range of the mRS scale, but we applied it to all dichotomy and order results. Logistic regression was performed using only bisection results. All tests were adjusted for baseline severity and TFSO. The odds ratio was calculated only for the test of the bisection result.

  Safety endpoints included mortality and all adverse events including treatment and device related adverse events. Safety endpoints were summarized using descriptive statistics and tables. This analysis was performed in SAS version 9.1.

Results Baseline characteristics Patients were enrolled between January 2007 and April 2008. A total of 660 patients were randomized as shown in FIG. 35 (331 TLT and 327 pseudo). There were 7 patients (1.1%) who were not followed up. Groups were balanced for baseline characteristics (see Table 9). The mean time from stroke onset is 14.6 ± 5.9 hours (range 2.7 to 23.9) for the TLT group and 14.7 ± 6.1 hours (2.5 to 23 hours) for the pseudo group. The median time was 15 and 16 hours for the TLT group and the pseudo group, respectively. Baseline NIHSS mean score was 13.1 (range 7 to 22) for TLT and 13.2 (range 7 to 23) for pseudo group. The median NIHSS score was 12 for TLT and 13 for the pseudo group.

Clinical Results Of the 660 patients, 331 received TLT, 327 received sham treatment, and 120 (36.3%) of TLT groups obtained successful results, while in the sham group OR1.38 (95% CI, 0.95 to 2), as shown in FIG. 36 showing the distribution of mRS scores, where it was 101 (30.9%) (P = 0.094) .00). The mRS score is as follows. 0 is no symptom, 1 is symptomatic but no serious disability, 2 is minor, 3 is moderate, 4 is rather severe, 5 is severe disability, and 6 is death.

  The results of the secondary analysis for the previously identified results were consistent with the results of the primary analysis. Logistic regression analysis of primary outcome measures with the addition of covariates yielded treatment OR-1.34 (95% CI, 0.94 to 2.03). All covariates except gender and stroke history were significant. A shift test classified as success with mRS score 0-2 and categorized for baseline severity and TFSO shows an insignificant trend for better results, with a TLT probability value of 0.091 and OR1.38 ( 95% CI, 0.95 to 2.01). For ordered mRS with a score of 0-6, the shift test trend supported TLT with a probability value of 0.113. The odds ratio of all subsets for the primary outcome measures showed an insignificant trend, which supported TLT treatment except for patients with severe stroke at baseline. FIG. 37 shows the effect of TLT on the subset of data defined by the primary endpoint, the category of selected baseline characteristics. A simple unadjusted odds ratio for TLT compared to sham treatment for a 90-day result of success, defined as mRS score 0-2. The horizontal axis represents 95% CI. Probability values for testing the interaction between the primary endpoint and the categories within each subgroup are also shown. CAD indicates coronary artery disease and TFSO indicates the time from stroke onset to randomization.

  For NIHSS score results by dichotomy with two factors in success, the shift test trend favors TLT, OR is 1.23 (95% CI, 0.88 to 1.73) and probability value is 0 .23. Logistic regression analysis results for NIHSS results by dichotomy were very similar. An extension of the logistic regression analysis separated the two success factors, 90 day NIHSS score 0-1 and change from baseline ≧ 9 points, treating these as related results, OR 1.30 (95% CI, 0.96 to 1.75), supporting TLT, with a probability value of 0.086. With respect to the order results of changes in NIHSS scores from baseline to 90 days, when tested for baseline severity and TSFO, the shift test showed a TLT group with a probability value of 0.65. In patients with deep infarction, there was no difference in response between the active and sham groups.

Safety analysis Mortality, serious adverse event (SAE) rates, and adverse event (AE) rates were substantially the same. TLT group and sham group were 58 (17.5%) and 57 (17.4%) deaths, 125 (37.8%) and 137 (41.8%) SAE, and 92.7% and 93.6% of subjects had at least one adverse event. There were no SAEs directly related to TLT. The proportion of patients with hemorrhagic changes at 5 days in the TLT group was 49 (14.8%) and 56 (17.1%) in the sham group. There were no differences in safety results between the two groups.

Discussion The NEST-2 test results presented here provide evidence of TLT safety. The effective size of the TLT for the treatment of ischemic stroke in humans within 24 hours of stroke onset is statistically significant for effectiveness, even if the baseline severity imbalance of stroke and time to treatment is corrected Although it was insufficient to meet the conventional level of sex, it has consistently shown better results with respect to TLT.

  Baseline severity is pre-specified in three categories: NIHSS = 7-10, 11-15, and 16-22. Patients with baseline NIHSS 16-22 had a combined bisection mRS success rate of 8% (n = 224, TLT 7.0%, sham 9.1%). When limited to 434 patients with moderate and rather severe stroke (baseline NIHSS score 7-15), post hoc analysis found significant and beneficial effects (P = 0.044). For these 434 patients, the success rate of mRS by TLT dichotomy showed an absolute improvement of 9.7% (TLT 51.6%, sham 41.9%). Similar beneficial effects were also found in the NEST-1 test for bisection mRS.

  The failure to initially find the optimal treatment population recalls the tPA development program. When tPA therapy was performed between 0 and 6 hours, the group treated for all measurements improved compared to the placebo group, but the final results did not yield statistical significance. Again, there were strong signs of efficacy, which were only seen after several trials were completed and appropriate subjects and exclusion criteria were established, clearly establishing the clinical benefits of tPA. It was done. The TLT can discover treatment groups that are necessarily helped by treatment by conducting further tests. However, compared to tPA, TLT has no deleterious side effects, so the therapeutic obstacle should be even lower.

  There are potential weaknesses in notable research. Previous human experience with TLT was insufficient to allow this study to proceed correctly. The study should have been able to exclude patients with mRS ≧ 2 before severe stroke and pre-stroke at baseline. It is also possible that TLT has no effect on stroke recovery. However, trends in substantial preclinical studies, NEST-1 studies, and current trials refute this undesirable interpretation.

  New features of this form of therapy are about the destructive effects of past electromagnetic energy, burning out solid tumor parts with a gamma knife, various types of radiation therapy, and both skin damage removal and various ophthalmic applications. Has been used almost exclusively. Preclinical studies have shown that infrared energy produces potential effective effects by changing biochemical pathways, and these changes are not due to thermal effects. Based on preclinical studies, it is believed that when TLT is applied, the brain temperature rises slightly and energy produces an effective effect by altering several biochemical reactions. It has been found that infrared energy can stimulate mitochondria, increase ATP formation, reduce apoptosis, and possibly enhance nerve recovery mechanisms. The exact nature and balance of these responses in the human ischemic brain is not well understood, and therefore the exact mechanism of action of TLT is not yet known. Nevertheless, this represents an entire new range of potential photobiochemical therapies for various diseases. Cerebral trauma and hemorrhagic stroke are obvious areas of extension, and TLT may be useful for a range of neurodegenerative diseases that may involve mitochondrial dysfunction.

CONCLUSION NEST-2 included a very wide range of stroke patients with respect to baseline severity, pre-stroke disorders, and time to treatment. In this entire population, TLT was safe but did not significantly improve patient outcomes measured by both mRS and NIHSS. However, all of the outcome indicators showed a positive trend in this direction. Post-mortem analysis has shown meaningful and beneficial effects in patients with moderate to rather severe ischemic stroke within 24 hours of onset. Further clinical studies in this redefined population should be considered.

Phototherapy example 3
Another example uses the closed head trauma (CHI) model of mice to study neurobehavioral and histological results of trauma-treated mice, thereby reducing TBI low-level laser therapy (LLLT). Efficacy was examined (A. Oron et al., “Low level laser therapy applied transcranially after traumatic brain injury in mice is a long-term neurology, incorporated herein by reference in its entirety. "Low-Level Laser Therapy Applied Transcranially to Mice following Traumatic Brain Injury Significantly Reduces Long-Term Neurological Deficits"", Journal of Neurotrauma, Vol. 24, No. 4, 2007).

  A total of 24 male Sabra mice (type Hebrew University) weighing 25-35 g were studied. The mice were housed in groups of 6 per cage and reversed for 12 hours / 12 hours light / dark light recycling. Food and water were provided by constant feeding. This study was conducted according to the guidelines of the Animal Protection Committee at the Hebrew University of Jerusalem, Israel. CHI trauma was induced in the mouse head using an anesthetized ether and a weight drop apparatus. After a sagittal incision in the scalp, the mouse was fixed by hand and a truncated Teflon cone was placed 3 mm lateral to the midline and 1 mm behind the left coronary suture. Following this, a metal rod (94 g) was dropped freely onto the cone from a pre-calibrated height.

  Motor function and reflex of traumad mice were evaluated at different time intervals after CHI using a neurological severity score (NSS) modified to emphasize motor function. This neurological test was based on the ability of mice to perform 10 different tasks (shown in Table 10) to assess the motor ability, balance, and agility of the mice. A score of 0 for a normal undamaged mouse is given because 1 point was given for the inability to perform each task. The severity of the injury is determined by the initial NSS and is assessed 1 hour after CHI, referred to as NSS1, and is a reliable predictor of later outcome. Thus, fatal or near-fatal damage is defined as NSS19-10 for mice, severe damage is NSS1 7-8 in mice, moderate damage is NSS1 5-6, Minor injury to mice has an NSS1 of less than 4.

CHI was applied to all mice and mice were assigned to control groups or laser treatment groups as described below. Neurological score (NSS) assessment was performed 1 hour after injury. The range of NSS scores for mice is from 4 to 6, indicating mild to moderate trauma. The mice were then divided into 3 groups of 8 animals per group to ensure that the average NSS for each group was similar and to ensure that the average severity of injury in all groups was similar. Two groups of mice received two different doses (10 and 20 mW / cm ² ) of low level phototherapy, and the third group corresponded to sham therapy control and received the same treatment as the laser therapy group, No actual laser irradiation was received.

Laser treatment was performed 4 hours after CHI using a laboratory laser with a wavelength of 808 nm and a maximum output of 200 mW equipped with a metal-lined glass optical fiber (3 mm diameter). The fiber optic so that it makes complete contact (sagittal incision) with a point at the midline of the skull 4 mm behind the coronal suture of the skull after the skin has been removed from the area by a small longitudinal incision. A laser beam was irradiated by placing the distal end of the lens. In preliminary experiments, the entire cortical portion of the new skull was removed from mice 4 hours after TBI. The distal end of the laser optical fiber was placed at the same skull location as above. The power density of the laser after passing through the skull was measured by placing the laser power meter probe under the dura mater (Ophir Inc., Jerusalem, Israel). Based on previous measurements, this location was chosen to be sufficient to illuminate the entire brain due to the scattering of the laser beam by the skull (1.2 cm beam diameter measured with an infrared viewer). The laser irradiation power density at the tip of the optical fiber was set to deliver power densities of 10 and 20 mW / cm ^{2 to} the brain. The laser irradiation duration was 2 minutes (energy density 1.2-2.4 J / cm ² ). The laser power and energy density were selected based on preliminary experiments with various laser parameters applied in the CHI mouse model. Similar laser parameters were used in previous rat and rabbit stroke models where beneficial effects were evident.

  Cortical tissue defects were evaluated in sections that had undergone brain trauma. At the end of the 4 week follow-up period, the mice were anesthetized and the brains of the mice were perfused with 4% paraformaldehyde solution and fixed in the same formaldehyde solution for 3 days. A 2 mm thick sample was removed from the traumatic area of the brain. The location of this area was found to be at the top of the brain by a small clot that served as a sufficient marker of the spot where the skull was hit during trauma. A portion of the brain cut at 2 mm thickness was processed with an automated tissue processor and embedded in paraffin. An 8 micron thick coronal sample was prepared from each cut out portion of the 2 mm thick brain. Three sections randomly taken from each brain cut were stained with hematoxylin and eosin and processed for quantitative measurement of the damaged area of each sample. This brain area was calculated separately in each hemisphere [ipsilateral (traumatic part) and contralateral] in each tissue section. The brain hemisphere volume was then calculated by multiplying the average area of the three samples by the cutout thickness of 2 mm. Lesion volume (percentage) was expressed as the volume of the contralateral hemisphere subtracted from the volume of the contralateral hemisphere minus the volume of the contralateral hemisphere.

  Data were analyzed using a one-way analysis of variance (ANOVA) followed by a Student Neuman Keuls test (using Sigma Stat software from Sigma, St. Louis, MO). Data from this study described below are presented as mean ± standard deviation. A value of p less than 0.05 was considered statistically significant.

The severity of injury reflected by NSS at 1 hour is similar in both groups of mice, 4.8 ± 0.7 and 4.8 ± 0.7 in control mice (n = 8) and laser treated mice (n = 16), respectively. It was 4.8 ± 0.8. There was no statistical difference between mice that received 10 and 20 mW / cm ² during the entire follow-up period, and the results were collectively stored as one laser-treated mouse group.

  FIG. 39 is a graph of neurological score (NSS) for control / non-laser treated (light bar) and laser irradiated (black bar) mice at different time intervals after causing brain trauma. At 24 hours after CHI, there was no significant difference among sham laser mice, control mice, and trauma mice, and mice that received active laser treatment 4 hours after trauma were observed. However, after 48 hours, laser treated mice showed a significant improvement in NSS compared to control untreated mice (p = 0.05 at 48 hours and then p <0.05). The large difference between laser treated and control mice persisted until day 28 after TBI, with laser treated mice having a 26-27% lower neurobehavioral score compared to control mice.

  FIG. 40 shows representative photomicrographs of cross-sections of brains of controlled non-laser treated and laser treated mice. Note the damage (L) in the control micrograph compared to the minimal damage (arrow) in the laser treated brain. FIG. 41 is a graph of lesion volume (scale bar = 5 mm; ** p <28) of the control traumatic brain (light bar) and laser-treated traumatic brain (black bar) 28 days after head injury. 0.01). At 28 days after TBI, sham-controlled mice (12.1 ± 1.3%) have significantly more cortical tissue at the damaged site compared to laser treated mice (1.4 ± 0.1%). A high defect was indicated (p <0.001).

  The results of this study show for the first time that low-level laser therapy applied 4 hours after TBI improves short- and long-term (28 days) neurobehavioral function and reduces brain tissue defects. This result confirms previous findings in rat and rabbit models that low-level phototherapy applied transcranial improves functional outcome after stroke. This result is consistent with the assumption that the abnormal physiology and the secondary mechanisms of cerebral ischemia and head injury are very similar, and includes both harmful and protective mechanisms in common. However, recent studies on the effects of low-level phototherapy on stroke rats have shown that beneficial effects on neurological function are evident only a few weeks after laser irradiation, In the described study, a marked improvement in the overall neurological function of laser-treated mice compared to sham-controlled mice was already important at 5 days after trauma. This phenomenon can be explained in part based on the rapid increase in ATP content after laser irradiation in the ischemic heart. Furthermore, increases in total antioxidants, angiogenesis, heat shock protein content, and anti-apoptotic activity after low-level laser therapy have been previously discovered in ischemic heart and skeletal muscle, and in ischemic / traumatic brains It can be shown as a process that can also be weakened by low-level laser therapy. Modifying the above process with low-level laser therapy is consistent with better neurological results and a significant reduction in the magnitude of injury in laser-treated mice compared to the controls found in this study. Can contribute. Another mechanism that may contribute to long-term neurological function improvement in post-TBI laser-irradiated mice involves neuronal development brought about by low-level laser therapy recently discovered in laser-treated stroke rats. Neuronal development may also explain, in part, a significant reduction in the magnitude of damage in laser treated mice compared to control mice, as shown in this study.

  The results of this study are also clinically relevant. Laser treatment is applied 4 hours after trauma, which is a reasonable time for the patient to arrive at the emergency room in the hospital. Previous safety studies in rats showed changes in functional neurological outcomes or brain histopathology in those treated with low-level laser therapy at different intensities or frequencies for both short- and long-term intervals. There wasn't.

Phototherapy example 4
The photobiostimulatory effects of near infrared phototherapy (NILT) have been documented for both in vitro and in vivo models (see, eg, L. Detaboada et al., “Transcranial application of low-energy laser irradiation improves neurological deficits in rats following acute stroke ", Lasers Surg. Med. 38: 70-73 (2006)). The energy in the infrared region of the electromagnetic spectrum is non-ionizing and does not exhibit any of the hazards associated with ultraviolet light. By irradiating brain tissue at a specific infrared wavelength (eg, 808-810 nanometers), the irradiation can penetrate the brain (see, eg, S. Ilic et al., “Effects of power pulses, continuous and pulse frequencies , and number of sessions of low-level laser therapy on intact rat brain ”, Photomed. Laser Surg. 24: 458-466 (2006)), can stimulate the formation of adenosine triphosphate (ATP) by mitochondria ( For example, see AP Sommer et al., “Stressed cells survive better with light”, J. Proteome. Res. 1: 475 (2002)). The main mitochondrial chromophore involved in photobiological stimulation is the enzyme cytochrome c oxidase, a terminal enzyme in the cellular respiratory chain within the inner mitochondrial membrane. Cytochrome c oxidase (COX) plays a central role in the bioenergy of cells by sending protons to the inner membrane, thereby facilitating the formation of ATP by oxidative phosphorylation. The overall result of NILT is improved energy metabolism and potentially improved cell viability (both neurons and non-neurons).

Photon energy delivered using NILT or gallium arsenide diode near-infrared lasers may be useful in treating behavioral functional deficits associated with embolic stroke (eg, PA Lapchak et al., “Transcranial infrared laser therapy improves clinical rating scores after embolic strokes in rabbits ”, Stroke 35: 1985-1988 (2004)). These rabbit small thromboembolic stroke models (RSCEM) studies have been conducted from an embolic stroke using a continuous wave of light (CW) with high power density (25 mW / cm ² ) and a long treatment time (10 minutes). NILT within 6 hours has been shown to significantly improve behavioral function. Lower energy and shorter treatment time improved behavior when prescribed early after embolization. However, undesirable side effects associated with using high power density, such as an increase in both skin and brain temperature directly under the laser probe, are also documented. Study by Michael Chopp and colleagues (for example, A. Oron et al., “Low-level laser therapy applied transcranially to rats after induction of stroke significantly reduces long-term neurological deficits”, Stroke 37: 2620-2624 (2006 )) Uses a rat intermediate artery occlusion (MCAO) model and shows that laser therapy can significantly improve behavioral deficits using a rodent stroke model. Unlike the RSCEM study described above, where laser light therapy is neuroprotective when performed within 6 hours after embolization in the MCAO model, laser treatment was effective only when performed 24 hours after stroke onset, but 4 It was not effective in time. Laser phototherapy in the MCAO model also reduced neurological deficits and there was no corresponding reduction in stroke lesion volume. Since there were no obvious statistically significant differences between the infarct areas of ischemic stroke control rats and laser-irradiated rats, the authors improved the function of noninvasive laser phototherapy interventions by inducing neuronal development It was assumed that it could be. This was demonstrated using doublecortin immunocytochemistry, migratory and bromodeoxyuridine markers, and proliferating cell markers. Nevertheless, in both models, laser beam therapy with CW energy delivery resulted in behavioral improvements.

CW NILT delivery and pulse wave (PW) frequency settings were examined to determine the most effective treatment plan using RSCEM born by injecting blood clots into the cerebral vasculature. As a result of RSCEM, which is a model of multiple infarct ischemia, behavioral defects caused by ischemia that can be quantitatively measured by the clinical rating scale by the bisection method were observed. The use of a clinical rating scale in rabbits (behavioral endpoint) is comparable to the use of the National Institutes of Health Stroke Scale (NIHSS) in stroke patients and is the primary behavior of all clinical trials for new treatments of acute ischemic stroke Is an endpoint. For the studies described below, three different treatment plans are used: 1) CW power density of 7.5 mW / cm ² , 2) Pulse model 1 (P1) with a frequency of 300 kHz pulse of 1 kHz, or 3) 100 Hz This is a pulse model 2 (P2) using a frequency of 2 ms pulses. Lower power density settings and pulse mode frequencies have been shown to be safer irradiation methods because they cause little heating or no tissue damage.

Experimental Procedures Surgery The Veterans Bureau approved the surgery and therapeutic procedures used in this study. The surgery was performed in a sterile controlled environment with room temperature of 22.8-23.2 ° C. Using RSCEM, a male New Zealand white rabbit weighing 2.2-2.55 kg is anesthetized with halothane / O ₂ and a catheter is inserted into the common carotid artery (CCA) through which microclots are formed. Injected. Temporarily, one CCA branch was exposed and the external carotid artery was joined just distal to the branch. The catheter was inserted into the CCA and secured with a string. The incision was closed around the catheter to allow access to the distal end outside the animal's neck. The catheter line was then filled with heparinized saline and capped with an infusion cap. Rabbits were allowed to recover from anesthesia until they fully awakened and behaved normally. When the rabbit recovered from anesthesia, it was self-retaining and had normal core body temperature (for example, PA Lapchak et al., “Neuroprotective effects of the spin trap agent disodium-[(tert-butylimino) m ethyl] benzene-1, 3-disulfonate N-oxide (generic NXY-059) in a rabbit small clot embolic stroke model: combination studies with the thrombolytic tissue plasminogen activator ”, Stroke 33: 1411-1415 (2002)).

Rabbit embolic stroke For RSCEM, blood was collected from one or more donor rabbits and allowed to condense at 37 ° C. for 3 hours. The large clot was then suspended in phosphate buffered saline containing 0.1% bovine serum albumin and the polytron-generated fragment was sequentially passed through a metal screen and a nylon filter. The resulting small clot suspension was labeled “Cobalt-containing NEN-Trac microspheres” so that the amount of clot that remained in the post-embolization brain could be calculated. For embolization, the rabbits were placed in a Plexiglas restraint, the catheter infusion cap was removed, and heparinized saline was removed from the carotid catheter system. The clot particle suspension was then quickly injected into the brain through the catheter, which was then flushed with sterile saline. The rabbit was fully awake during the embolization procedure and was self-holding (ie, no artificial respiration or other external support was required). By using an awakened unanesthetized rabbit, the effect of embolization on clot injection and subsequent behavior can be quickly observed.

Clinical evaluation score behavior and quantum dose-response analysis Using clinical evaluation score and quantum analysis is an advanced method for determining how a large stroke “patient” population, in this case rabbits, will respond to treatment And is a suitable primary endpoint to be used when treatments are being developed to support clinical trials. In order to evaluate the quantitative relationship between the amount of clot and behavioral defects, a logistic sigmoidal quantum analysis curve was fitted to this amount. A wide range of clot volumes was used to create behaviorally normal or abnormal animals. In the absence of neuroprotective treatment, a small number of microclots do not cause large apparent neurological defects. However, when a large number of micro blood clots are injected, they always cause brain damage and can lead to death. Abnormal rabbits with brain damage include those with one or more of the following signs: ataxia, tilt, rotation, coma, eye movements, balance dysfunction, limb / face dysfunction And in some cases includes paraplegia. With a simple bisection evaluation system, there are reproducible complex results and low intra-rater variation (<5%), and each animal is behaviorally normal or abnormal by an inexperienced observer. It was evaluated. Using quantum analysis, behavioral changes were detected following pharmacological intervention. With this simple evaluation system, complex results for groups of animals are highly reproducible. A separate curve was generated for each treatment state and a statistically significant increase in the value or amount of microclots that produced a neurological deficit in 50% of the animal group compared to the control group was a behavioral improvement Indicates.

Power and statistical analysis The power analysis of the quantum quantity-response curve is α =. 05 and β =. Assuming 90, a coefficient of variation of 15% and a means difference of 20%, 14 animal sample sizes were shown to be required for each group. However, past experience has required about 20 animals per group, which is difficult to prepare or because of early loss due to post-ischemic death, but well before treatment Applicable. Behavioral data were expressed as P ₅₀ (mean ± SEM) in mg clots for the number of rabbits in each group (n). P ₅₀ values were analyzed using the t test, which included Bonferroni correction as appropriate. In the study, the entire sham treatment control group was treated in parallel with the treatment group, and all groups were evaluated using the same behavioral analysis scale described above to remove experimental or investigator bias. The NILT treatment group was compared with the direct control group. For all animals in this study, the pink skin was exposed by shaving the hair on the scalp over the skulls of all rabbits used in this study prior to carotid catheter placement. All shaved rabbits were randomly assigned to treatment groups prior to embolization, and randomization was hidden until all postmortem analysis was completed.

Near-infrared light therapy Rabbits were placed in Plexiglas restraints for the duration of treatment. The probe was placed in direct contact with the skin because the hair on the head area was shaved before placing the laser probe on the skin side by side. An Acculaser low energy laser with a fiber optic cable and a laser probe measuring 2 centimeters in diameter (OZ Optics Ltd., Berkeley, CA) was used (wavelength 808 ± 5 nanometers). Device design studies have allowed these specifications to allow light to penetrate to a depth of approximately 2.5-3 centimeters in the rabbit skull and brain, placed on the surface of the skin behind the midline bregma. Shows that the light beam covers most of the brain. Using the above specifications, the average energy delivered to the brain was 0.9-1.2 Joules. Table 11 shows details on the three different treatment plans used in this study: 1) CW, 2) P1 using a frequency of 300 kHz pulse of 1 kHz, and 3) P2 using a frequency of 2 ms pulse of 100 Hz. is there.

Results Transcranial NILT improves clinical assessment score: 6-hour treatment In this study, 48 hours was used as a time to measure behavioral endpoints in determining the relative effectiveness of different treatment regimens. In the previous 2004 Lapchak study cited above, the behavioral improvement that appeared after 48 hours was measurable by 21 days after treatment. In this study, a power density setting of 7.5 mW / cm ² and a treatment period of 2 minutes were used. Three different modes, CW, P1 and P2, were used to define an effective plan for NILT. The main difference between these three modes is the brain illumination duty cycle and total time.

Figures 42A-42C show the results of a study using a 6 hour post-embolization treatment. The black circles represent the control group primitive data and the triangles represent the laser treatment group primitive data. A normal animal for a particular clot weight is represented by a symbol shown at 0 on the y-axis, and an abnormal animal for a particular clot weight is represented by a symbol shown at 100 on the y-axis. NILT initiated at 6 hours post-embolization using all three treatment regimes resulted in improved behavioral function compared to the cumulative control group when behavior was measured at 24 hours post-treatment. As shown in FIG. 42A, NILT given as CW increases the P ₅₀ value to 2.06 ± 0.59 mg (n = 29, P = 0.099), which is 1.01 ± 0. It was not statistically different from the P ₅₀ value of the control group, which was 25 mg (n = 31). However, when NILT was given as PW using P1 or P2 mode, behavioral function increased significantly, which was reflected by the group's significantly increased P ₅₀ value. P ₅₀ values are 1.89 ± 0.29 mg (n = 25, P = 0.0248) and 1.92 ± 0.15 mg (n = 25, P = 0.0248) for the P1 and P2 groups, respectively, as shown in FIGS. 42B and 42C. n = 33, P = 0.024).

Effect of transcranial NILT on behavioral function when started 12 hours after embolization In a previous 2004 lap chuck study cited above, laser therapy was reported to be ineffective when applied to rabbits 24 hours after stroke. Yes. Thus, it is important to determine whether the NILT treatment window can be extended beyond 6 hours using the CW or P1 plan. For this series of experiments, the cumulative control group described above was used and this group had a P ₅₀ value of 1.01 ± 0.25 mg (n = 31). This cumulative control group was used because it was previously documented that the baseline P ₅₀ value of the embolized rabbit was fairly constant over time and by experiment. is there. The use of cumulative control groups in this study can reduce the use of large numbers of rabbits.

Figures 43A and 43B show the results of a study using 12 hours post-embolization treatment. The black circles represent the control group primitive data and the triangles represent the laser treatment group primitive data. A normal animal for a particular clot weight is represented by the symbol shown at 0 on the y-axis, and an abnormal animal for a particular clot weight is represented by the symbol shown at 100 on the y-axis. NILT initiated at 12 hours post-embolization using any of the treatment plans did not show significant behavioral improvement compared to the cumulative control group when behavior was measured at 24 hours post-treatment . As shown in FIG. 43A, NILT given as CW increased the P ₅₀ value to 2.89 ± 1.76 mg (n = 29, P = 0.279). In addition, as shown in FIG. 43B, when NILT was given using P1 as PW, the P ₅₀ value was 2.40 ± 0.99 mg (n = 24, P = 0.134). Thus, it had increased average P ₅₀ value, intrinsic diversity in the reaction of the treatment groups NILT the treatment is prevented from showing a statistically significant difference. Neither the CW plan nor the P1 plan was effective in significantly increasing the P ₅₀ value, so the effect of NILT using the P2 plan at 52 hours of embolization was not investigated.

Discussion The main objective of this study was to directly assess the effects of CW and PW transcranial NILT on clinical assessment scores after multiple small clot embolization strokes in rabbits. To achieve this goal, RSCEM was used. This is a preclinical animal model useful for developing new stroke therapies that can be applied immediately in the clinic. In this model, the major cause of stroke or ischemic injury is related to giving blood clots that remain in the blood vessels of the cerebrum, which means that many strokes in humans involved in cerebral blood flow disturbances and clinical disorders Is the same cause. In addition, RSCEM is a model of multiple infarct ischemia that uses the scale of clinical evaluation as the primary endpoint based on the motor function elements of NIHSS for human stroke.

In this study using RSCEM, transcranial NILT performed on embolized rabbits improved behavioral assessment scores, especially for motor function, 6 hours after embolic stroke. There are three important aspects to this discovery. First, the low power density (7.5 mW / cm ² ) of estimated brain penetration 2.5 / 3 cm used in this study was effective in improving clinical assessment scores (eg motor function). Second, application of near-infrared light for 2 minutes promoted functional recovery when NILT was applied transcranially to embolized rabbits. Third, this study was designed to determine whether CW therapy had different effects compared to pulse therapy. Interestingly, CW therapy increased the _P50 value of the group, but the resulting increase was not statistically significant compared to control. However, both pulse treatment methods significantly increased P ₅₀ values compared to control.

Previous 2004 Rapchuk studies have tested high power density (25 mW / cm ² ) laser therapy using a 10 minute CW method and show that laser therapy improves behavioral function after embolic stroke in rabbits. It was done. Studies here show that a power density of 7.5 mW / cm ² and a treatment time of 2 minutes can produce an effective effect in a treatment of 6 hours after prolonged embolization. However, in this study, there was no “statistically” significant behavioral improvement as a result of CW therapy. However, pulse therapy resulted in a statistically significant increase in behavior with either the P1 or P2 regime. These results for low power density NILT can be compared to those previously reported using a rodent stroke model with some significant differences compared to this study. When a permanent cerebral ischemia is induced using a rodent filament model, the rat MCAO study cited above is effective against early laser treatment (ie, 4 hours after filament placement). Could not show. However, this study found that laser treatment was effective when applied 24 hours after stroke, and that beneficial effects were observable up to 21 days after stroke. The duration of the laser treatment effect is comparable to that previously published. However, even though previous 2004 Rapchuk studies have shown that NILT reduces behavioral deficits due to stroke in rabbits when applied 6 hours after stroke, this does not allow NILT to occur 12 hours after stroke. There was no “statistically” significant behavioral improvement when started.

There appears to be an important difference between the published results of the rodent filament permanent occlusion model cited above and the rabbit embolic stroke model 2004 lap chuck study described above. This difference may simply be related to the causes of stroke in the two models. Place a plastic filament in the rodent middle cerebral artery and keep it at 1-2% halothane, 70% N ₂ O and 30% O ₂ , blood glucose, pH, pO ₂ and pCO ₂ and rectum Monitoring temperature (all levels not shown in published literature) will represent an extreme artificial model of stroke. The rabbit embolic stroke model described here used a rabbit 3 hours after placement of the carotid catheter so that the rabbit was self-holding and unanesthetized when embolization occurred. In addition, new clots prepared from donor rabbits were used for embolization on the day blood was collected and allowed to clot without additives. Thus, during the embolization procedure, the rabbit was awake and behaved normally. Because of the differences between the two models, the difference in NILT effect is not as surprising. The different findings obtained as a result of using two different ischemic stroke animal models will reveal somewhat the mechanism of action of NILT in the ischemic brain. In rat model studies, laser therapy can cause neuronal development in the brain, mainly when applied 24 hours after ischemia, and the markers associated with neuronal development in the brain. It was proposed that there was a coincidence increase. Furthermore, the physiological effects of laser therapy are not observed immediately, but require a delay of 2 to 4 weeks after treatment. The authors have shown that laser therapy induces the formation of new neurons and neuronal support cells in the brain, and that new neuronal pathways are required to improve behavior after laser therapy. Unfortunately, this idea does not support the method of hematoxylin and eosin (H & E) staining of lesion volumes in laser-treated and controlled ischemic brains. Because there is no statistically significant difference in lesion volume between the two groups, suggesting little or no neuron formation in the brain.

  Unlike the delayed effect of laser therapy in the rat model, in the rabbit model, NILT is effective when applied 5 minutes to 6 hours after embolization, and the behavioral effect of NILT is measured within 24-48 hours of embolism Is possible. The results described herein indicate that NILT induces a rapid response element (RRE) in the post-embolization brain that results in improved behavior, which is independent of neuronal development or long-term remodeling. This is an effect that seems to be present. Furthermore, in stroke patients enrolled in the NeuroThera Effectiveness and Safety Trial (NEST-1), a significant decrease in NIHSS score is evident by 5 days after laser treatment, which is continuous up to 90 days after treatment. Improved (Y. Lampl et al., “Infrared laser therapy for ischemic stroke: a new treatment strategy: results of the NeuroThera Effectiveness and Safety Trial-1 (NEST-I)”, Stroke 38 (6): 1843-1849 (2007 )reference). This finding is consistent with the results of a rabbit embolic stroke model study, indicating that laser therapy facilitates rapid recovery of function after ischemic stroke.

  In summary, the results of experimental stroke studies suggest that NILT would be useful in patients if applied between 6 and 24 hours of stroke. Based on correlated preclinical and clinical acute ischemic stroke studies, the 6-hour treatment window observed in RSCEM will be comparable to approximately 18 hours in stroke patients. The reason is as follows. In RCSEM, tPA effectively improves behavior when given 1-1.5 hours after embolization, and in patients, the treatment window for tPA is approximately 3-6 hours after the onset of stroke. Thus, there appears to be a 2- to 3-fold difference between the times observed for the effectiveness of tPA in the rabbit model compared to the patient. According to this hypothesis, in RSCEM, NILT is effective up to 6 hours after stroke, and as predicted by this model, the previously cited NEST-1 clinical trial shows that patients are treated within 24 hours after stroke. If laser therapy was found to improve clinical evaluation score. Thus, due to the time differences mentioned above, NILT would be useful for patients if they visited the hospital within 24 hours of a stroke.

The above NEST-1 study shows that when laser therapy is initiated 2-24 hours after stroke, transcranial laser therapy may be a useful approach to treat motor dysfunction caused by ischemic stroke I suggest that. The first test of the NEST-1 study used the CW mode, with a power density of 10 mW / cm ² and 20 minutes of irradiation at each of the 20 predetermined scalp locations for 2 minutes. Preliminary results of the NEST-1 trial of 120 acute ischemic stroke patients (bias design 1: 2) with treatment times between 2 and 24 hours (median time 18 hours) are more in the laser treatment group Of patients showed good results from baseline to 90 days as measured by mean change in NIHSS and mRS scores compared to control group (P = 0.035, severity and Classification by time to treatment, P = 0.048, classification by severity only). The positive results documented for NILT in animal models of stroke are the NEST-II study funded by the manufacturer of a transcranial laser device called Photocera, ie cross-spective, comprehensive analysis, multilateral, international, And prompted the start of a double-blind study.

  NILT effectively improves behavioral deficits when applied to rabbit brains using PW light energy. Although the data support the use of NILT therapy in a clinical setting, the different results obtained with CW and PW therapy show that using NILT PW mode improves overall motor function and health status for patients Indicates that it will be most effective.

Phototherapy example 5
Another example of a study conducted in a contract with Neurological Testing Service, Inc. (Charleston, SC) included infrared transcranial laser therapy (TLT), Alzheimer's disease ( AD) was tested for efficacy in an amyloid precursor peptide (APP) transgenic mouse model. Laser beam therapy was performed at various doses 3 times a week for 26 weeks, starting at 3 months of age. The results were compared with no laser (control group). Animals were examined for amyloid burden, inflammatory markers, brain Aβ levels, plasma Aβ levels, CSFAβ levels, sAPP levels, and NS behavioral changes. The number of Aβ plaques was significantly reduced in the brain when laser therapy was performed in a dose-dependent manner. Application of laser therapy showed a dose-dependent decrease in amyloid burden. All the therapies were effective in reducing amyloid deposition. All laser treatments reduced the effect on behavior as seen in advanced amyloid deposition. Overall, laser therapy was effective in limiting the extent of Aβ amyloid in the brain and in reversing the effects of Aβ peptide deposition and behavioral defects in mice. In addition, laser therapy was able to reduce the expression of inflammatory markers in APP transgenic mice. Aβ peptide levels varied significantly in the brain of APP transgenic mice and there were no noticeable differences in plasma Aβ peptide levels. Studies show an increase in sAPPβ and a decrease in sAPPβ levels, consistent with inhibition of β-secretase activity. These studies suggest that laser beam therapy is a strong candidate for the treatment of AD.

The following abbreviations used herein have the following definitions:
Abbreviations: Definitions Aβ: Abeta APP: Amyloid precursor protein Aβ peptide: Abeta peptide AD: Alzheimer's disease 4G8: Abeta peptide antibody PTI: Photocera NTS: Neurological Testing Service BACE: Beta secretase IL-1: Inter Leukin-1
TNF-α: tumor necrosis factor-α
TGF-β: transforming growth factor-β
Aβ including senile plaques is one of the neuropathological features of Alzheimer's disease (AD), and great efforts have been made to understand the relationship of Aβ and Aβ including Aβ to AD. Most of this work has focused on factors that affect Aβ biosynthesis and its deposition. Aβ peptide is mainly two peptides of either 40 or 42 amino acids that are generated via internal proteolysis of its precursor, which is amyloid precursor protein (APP). In addition to senile plaques including Aβ, various neurocytoskeletal changes are a major feature of AD neuropathology. These include neurofibrillary tangles, phospho-tau, including those present in free dystrophic neurites and neuritic senile plaques, and synaptic loss. It is still debated whether these abnormal features are the result or cause of neuronal loss. Regardless of the exact mechanism, this neuronal and synaptic deficiency leads to cognitive decline. Autosomal dominant AD that begins early is directly associated with mutations in one of several genes: APP, presenilin 1 (PS1) or presenilin 2 (PS2). Of note, in addition to several risk factor genes, the APOE4 allele alters the risk of later-onset AD, and mutations or polymorphisms in several other genes have similar AD. Clearly it can lead to a phenotype.

  Aβ peptides are obtained from APP that are cleaved by the sequential action of β and γ secretases. β-site APP cleaving enzyme (BACE) is one of the membrane-bound aspartyl proteases that results in the cleavage of APP outside the membrane releasing a soluble APP-β (sAPPβ) fragment. In addition, the gamma secretase enzyme (PS-1 and PS-2 complex) cleaves the transmembrane region to release the Aβ peptide and carboxyl terminus. The α-secretase enzyme is the main APP activity that cleaves in the middle of the Aβ peptide and prevents the generation of Aβ peptide. The altered function of these enzymes can lead to increased production of Aβ peptides that can contribute to the cause of AD. Numerous studies have shown that mutations in the APP gene or presenilin result in increased β-secretase cleavage and increased production of both Aβ1-40 and Aβ1-42. In addition, removal of cholesterol using cholesterol-lowering drugs resulted in a decrease in Aβ peptide synthesis and sAPP-β. Thus, understanding the mechanisms associated with changes in Aβ processing and the role of β-secretase in the process will assist in the design of selective inhibitors of β-secretase and ultimately the design of treatment for AD.

Methods and Materials An amyloid precursor protein (APP) transgenic model of mouse Aβ peptide amyloidosis was used. APP transgenic mice received no laser or laser therapy as outlined below, starting at 3 months of age and performed for less than 3X / week for 26 weeks. At the end of the experiment, the animals were subjected to behavioral analysis, disposed of, and the brain was divided in half and prepared as follows. One half of the brain is examined for Aβ plaque burden in the brain (ie, the number of plaques) and examined for inflammatory markers, and the second half of the brain is for brain Aβ peptide and sAPP levels. Homogenized. The animals were treated daily at 1 pm, tested on days 176-179 for range of motion, and a final examination was performed at week 26 (4 hours after treatment). Animals were disposed of immediately after training and plasma, CSF and brain were collected for analysis.

  A baseline for amyloid deposition was determined using the control APP group (the treatment was simulated with no laser, no laser energy). This group was started with 3 month old mice and the study continued for 26 weeks, reaching 9 months of age. In addition, at the end of the study, the animals underwent behavioral (Morris water maze) analysis. NTS was not obscured by study parameters. The laser was prepared by PTI and shipped to NTS. Animals were examined for behavioral studies, amyloid burden, Aβ peptide analysis, inflammatory markers, sAPP levels, brain and plasma for Aβ analysis. All studies were completed by each group of animals and all protocols were performed after 26 weeks. The endpoints are as follows:

Brain amyloid load (left hemisphere).
Inflammatory markers in the brain (IL-1, TNF-alpha, TGF-β).

Aβ 1-40, 1-42 in the brain (1/2 from animals / plasma from all animals).
Plasma Aβ levels (13 and 26 weeks: 4 hours after administration).

  SAPPα and β levels from the brain. Brain collection for brain / plasma / CSFAβ peptide levels (26 weeks only).

Total anatomical examination.
Behavioral analysis-MWM was performed during the last week of treatment and animals were disposed after the last application. Testing includes tracking swimming distance and platform arrival time.

  Male APP transgenic mice (NTS) weighing approximately 35-40 grams were each allowed free access to food and water before and during the experiment. The animals received laser therapy. The laser was prepared by PTI and shipped to NTS. The APP mice (male) used in this experiment were human APP genes (Swedish and London mutants) in mouse eggs under the control of growth factor B (PDGF-B) chain gene promoter obtained from platelets. Was designed by microinjecting. Mice were generated on a C57BL / 6 background and grown by MTI. Animals were housed in the 12:12 light: dark cycle at the Medical University of South Carolina Animal Facility. The animals were housed in standard non-sterile rodent microisolator cages with a filter cage top and 4 animals in one cage. The animals were fed ad libitum and kept in sibling mating. Transgenic animals were identified by PCR analysis. Mice were generated from this configuration, resulting in amyloid deposits beginning at age 4 months. The animals were 3 months old and maintained for 26 weeks and were disposed of for amyloid quantification.

  For histological examination, the animals were anesthetized and anesthesia was performed by intraperitoneal injection of bentobarbital sodium (50 mg / kg). The animals were perfused with 4 ° C. phosphate buffered saline (PBS) and then with 4% paraformaldehyde. The brain was removed and placed in 4% paraformaldehyde overnight. The brain was treated with paraffin and implanted. Ten consecutive 30 μm thick samples were obtained from the brain. Tissue samples were deparaffinized, washed with Tris buffered saline (TBS) pH 7.4 and blocked in the appropriate serum (mouse). These samples were blocked overnight at 4 ° C. and then applied to the primary antibody at 4 ° C. overnight to detect amyloid deposits in the brains of transgenic animals (Aβ peptide antibody, 4G8, Signet). These samples were washed in TBS, secondary antibody (Vector Laboratories) was added and incubated for 1 hour at room temperature. After washing, these samples were incubated according to the instructions of the Vector ABC Elite Kit (Vector Laboratories) and colored with diaminobenzoic acid (DAB). The reaction was stopped in water and the cover was removed after xylene treatment. The amyloid area of each sample is determined by a computer-aided image analysis system, which is derived from a power Macintosh computer with a Quick Capture frame capture device, a Hitachi CCD camera mounted on an Olympus microscope, and a camera stand. Become. NIH image analysis software, v. 1.55 was used. Images were captured and the total area of amyloid was determined for 10 samples. A single operator who was not informed of the treatment status performed all measurements. The amyloid volumes of these samples were summed and divided by the total number of samples to calculate the amyloid volume per animal.

For quantitative analysis, the levels of human Aβ _1-40 and Aβ _1-42 in the brain of APP transgenic mice were measured using enzyme immunoassay (ELISA) (IBL, 1-40 is 27718, 1 -42 is 27711). Aβ _1-40 and Aβ _1-42 were extracted from mouse brain as follows.

1. Weigh half of frozen brain.
2. Prepare a tissue homogenization buffer by adding a 1: 1000 dilution of protease inhibitor cocktail (PIC, Sigma) just before use (THB—see formula below).

  3. Homogenized brain hemisphere in 1 mL THB + PIC for each 100 mg of tissue (eg, 220 mg brain hemisphere was homogenized using 2.2 ml buffer).

  4). Homogenized brain (using polytron) and samples were aliquoted and frozen in liquid nitrogen.

Tissue homogenization buffer (THB)
(250 mM sucrose, 20 mM Tris base, 1 mM EDTA, 1 mM EGTA)
5 mL: 1 M Tris base (pH 7.4)
21.4 g: Sucrose 0.5 mL: 0.5 M EDTA
1.0 mL: 0.25 ECTA
Add ddH ₂ 0 to 250 mL.

It was sterilized and treated aseptically.
Stored at 4 ° C.

The ELISA assay was performed as described by the manufacturer (IBL).
1) Wells for reagent blanks were sought. Each 100 μL of “4, EIA buffer” was placed in a well.

  2) The well, test sample, and dilution criteria for the test sample blank were determined. Next, 100 μL of each test sample blank, test sample and reference dilution were placed in the appropriate wells.

  3) The pre-coated plate was incubated overnight at 4 ° C. after being covered with a lid.

  4) Each well of the pre-coated plate was washed extensively with wash buffer using wash bolts (3 times). Each well was then filled with wash buffer and the pre-coated plate was placed for 15-30 seconds. The wash buffer was completely removed by striking from a pre-coated plate. This procedure was performed 8 times or more. The remaining liquid was then completely removed from all wells by hitting a pre-coated plate onto a paper towel.

  5) 100 μL of labeled antibody solution was pipetted into test sample wells, diluted standards and test sample blanks.

  6) The pre-coated plate was incubated for 1 hour at 4 ° C. after being covered with the lid of the plate.

7) The pre-coated plate was washed (4) 9 times in the same manner as above.
8) The required amount of “6, chromogen” was pipetted into a disposable test tube. Next, 100 μL was pipetted from the test tube into the well.

  9) The pre-coated plate was incubated for 30 minutes at room temperature in the dark.

  10) 100 μL of “7, stop solution” was pipetted into the well. This liquid was mixed by striking the side of the precoated plate.

  11) A plate reader was run and measurements were performed at 450 nm. The measurement must be performed within 30 minutes after the addition of “7, stop solution”.

For quantitative analysis of Aβ peptide levels in plasma and CSF, enzyme immunoassay (
ELISA) was used to measure the levels of human Aβ _1-40 and Aβ _1-42 in plasma and CSF of APP transgenic mice (IBL, 1-40 for 27718, _1-42 for 27711). Aβ _1-40 and Aβ _1-42 ELISAs were performed as described above. Blood was collected by saphenous vein collection or cardiac puncture (terminal bleeding) in lithium: heparin, and plasma was prepared by centrifugation. CSF was collected and analyzed.

  For sAPP assay in half of the brain, in Western blot analysis, extract containing 20-50 μg of total protein was mixed with Tris / glycerin reduction buffer, denaturing loading buffer, loaded and loaded with 8% Electrophoresis on a Tris / glycerin gel (Invitrogen). The gel was transferred to a nitrocellulose membrane, incubated with a primary antibody followed by a secondary antibody conjugated with horseradish peroxidase and processed for visualization by highly chemiluminescent ECL Plus®. The 6E10 single coulomb antibody Ab (Signet, Dedham, Mass.) Recognizes the first 17 amino acids of the Aβ peptide. 6E10Ab is used in Western blots to detect soluble APPα. SAPPβ was detected by Western blot using rabbit 869 antibody. The secondary antibody was conjugated with horseradish peroxidase and was obtained from Jackson ImmunoResearch (West Grove, PA).

  For immunohistochemical analysis for cytokine assessment in one half of the brain, tissue samples were deparaffinized and washed in Tris buffered saline (TBS) at pH 7.4 and appropriate serum (goat). ) Blocked. Samples were blocked overnight at 4 ° C. and then the primary antibody was applied overnight at 4 ° C. Samples were washed in TBS, secondary antibody was added and incubated for 1 hour at room temperature. Samples were incubated after washing as directed by the Vector ABC Elite Kit and stained with diaminobenzoic acid (DAB). The reaction was stopped in water and the cover was removed after xylene treatment.

  Behavioral analysis was performed using the Morris water maze test. All mice were tested once in the Morris water maze at the end of the experiment. Mice were trained in a 1.2 m open field water maze. The pool was filled with water to a depth of 30 cm and kept at 25 ° C. An evacuation platform (10 cm square) was placed 1 cm below the surface of the water. The platform was removed from the pool during the test. A cue test was performed in a pool surrounded by white curtains to hide extra maze cues. All animals received non-spatial pre-training (NSP) for 3 consecutive days. These tests are to prepare the animals for the final behavioral test to seek memory preservation to find the platform. These trials were not recorded (for training purposes only). For training and learning studies, the curtain was removed for further maze clues (which identified animals with swimming impairments). On day 1, the mouse is placed on the hidden platform for 20 seconds (Study 1) and for Test 2-3 the animal is placed at a distance of 10 cm from the platform where the clue is shown or from the hidden platform (Study 4). By the way, it was released into the water. In this way, the mouse was allowed to swim to the platform. On the second day of the trial, the hidden platform was randomly moved between the center of the pool or the center of each quadrant. The animals were released into the pool, randomly turned to the wall and given 60 seconds to reach the platform (3 trials). In the third test, the animals were tested three times, twice using a hidden platform and once using a cueed platform. Two days after NSP, the animals underwent a final behavioral test (Morris water maze test). During these three trials (three per animal), the platform was centered on one quadrant of the pool and the released animals were randomly facing the wall. The animals were allowed to find the platform or swim for 60 seconds (latency, time taken to find the platform). All animals were tested within 4-6 hours of dosing and were randomly selected for testing by an operator who did not know the test group. The animals were tested on days 176-179 for non-spatial pre-training and a final test was performed on day 180.

  Results are expressed as mean ± standard error (SEM). The significance of differences in amyloid and behavioral studies was analyzed using t-tests. Comparisons were made between the 9 month old APP control group (baseline group—starting at 3 months of age) and 9 month old treated mice. The following difference of 0.05 was considered important. The percent change in amyloid and behavior was determined by calculating the sum of the data for each group and dividing by the comparison (ie treatment / 9 months control =% change). Animals that developed severe complications after laser irradiation were excluded from the study.

  Animals (100 mice) received laser irradiation without laser or started at 3 months of age and continued at 3X / week for 2 minutes and 6 months. The animals were male and were randomly assigned to different treatment groups as shown in Tables 12 and 13.

(1) Total number of animals = 100.
(2) These values are based on tissue permeation and scatter measurements performed on mice in previous TLT studies (ischemic stroke and TBI) to measure scalp / skull permeation and scatter in two APP mice. Based on updates. The measured data was used to calculate the radiant power in the skin—Table 13, which is necessary to deliver the indicated irradiance to the animal's dura mater.

(3) These are calculated values, indicating the average irradiance of the continuous TLT and the peak irradiance of the pulse TLT. Irradiance at skin = radiant power / beam area = radiant power / (π * (0.1 cm) ² ) = radiant power / 0.0314 cm ² .

Results The laser was given to NTS as a powder. Amyloid burden was determined in animals treated with laser therapy and animals that were not laser treated. Table 14 and FIG. 44 show the results. The laser-free group showed amyloid burden up to 2%, which is the standard amyloid level in this particular model up to 9 months of age (previous study). Laser therapy showed a dose-dependent decrease in amyloid burden when compared to the vehicle group. For all doses except CW, the amount of amyloid is actually lower than the 9-month control group, indicating that laser therapy can not only stop amyloid deposition but also cause a reversal of amyloid levels. This indicates that laser therapy can reduce amyloid in these mice. None of the studies resulted in death. The animals were examined for gross abnormalities after disposal. No overall pathological features were detected in these animals.

  Behavioral effects (behavior and distance) of treatment with laser therapy were determined in APP transgenic mice at the end of the experiment. Mice were given a Morris water maze task and latency and distance were determined. Table 15 and FIG. 45A show the results. Control without laser shows a latency of 48.58 seconds, which is standard in this particular model up to 9 months of age (previous study). All animals treated with laser showed significant differences in latency compared to the control group. This indicates that laser treatment was able to reduce the latency of these mice.

  Table 16 and FIG. 45B show the comparison results of the movement distance in the water maze. Media control shows a distance of 75.53 inches, which is standard in this particular model up to age 9 months (previous study). All animals showed significant differences in distance compared to the control group. This indicates that laser therapy was able to reduce the behavioral effects in these mice.

  The effect of laser therapy was determined on the expression of inflammatory markers (IFM) in the brain of APP transgenic mice (FIGS. 46A-46C and Table 17). Table 17 and FIGS. 46A-46C show the results for animals that ended 26 weeks after the start of treatment. Control without laser showed a specific coloration of inflammatory markers (IL-1, TNF and TGF-β) as shown in Table 17, which is standard in this particular model up to age 9 months. Yes (previous study). All doses of laser therapy showed significant differences from control animals. This indicates that laser therapy was able to reduce IFM in these mice.

  The effect of laser therapy was determined for changes in Aβ peptide in the brain of APP transgenic mice (FIGS. 47A and 47B and Tables 18 and 19). Measurement of Aβ1-40 and Aβ1-42 peptides (can extract guanidine) in the brain showed an increase in APP transgenic mice aged 3 to 9 months. Table 18 and FIG. 47A show the results for animals that ended 26 weeks after the start of treatment. Control shows the level of Aβ1-40 in the brain as shown in Table 18, which is standard in this particular model up to age 9 months (previous study). All doses of laser therapy showed a decrease in Aβ1-40 compared to control, which was significant. This indicates that laser therapy was able to reduce Aβ1-40 in these mice.

  Table 19 and FIG. 47B show the results for animals that terminated at 26 weeks after the start of treatment for Aβ1-42 peptide levels. Control shows the level of Aβ1-42 in the brain as shown in Table 19, which is standard in this particular model up to age 9 months (previous study). All doses of laser therapy showed a significant decrease in Aβ1-42 when compared to control. This indicates that laser therapy was able to reduce Aβ1-42 peptide levels in these mice.

  The effect of laser therapy was determined for changes in Aβ peptide levels in the plasma of APP transgenic mice (FIGS. 48A and 48B and Tables 20 and 21). Measurements of total Aβ peptide in plasma were performed at weeks 13 and 26 in 3 to 9 months treated APP transgenic mice. As can be seen from Tables 20 and 21 and FIGS. 48A and 48B, total plasma Aβ peptide levels were similar for all groups for the 90 day period. As research progressed and animals were treated with laser therapy, there was a significant change in the apparent plasma total Aβ peptide profile. This indicates that laser therapy was able to reduce plasma Aβ peptide levels and also changed brain Aβ peptide levels.

  The effect of treatment with TTP-5854 laser therapy on sAPPα and CTFβ levels in the brain was determined for APP transgenic mice at the end of the experiment. Brain tissue was subjected to extraction and Western blot analysis for sAPPα and CTFβ levels after treatment. Tables 22 and 23 show the results for animals that ended 26 weeks after the start of treatment. Control shows a given level of sAPPα and CTFβ in the brain, which is standard in this particular model up to 9 months of age (previous study). Laser therapy showed significant differences in both sAPPα and CTFβ levels when compared to control. For sAPPα, all doses of laser therapy showed significant differences from control (Table 22 and FIG. 49A). Also for CTFβ, all doses of laser therapy showed significant differences from control (Table 23 and FIG. 49B). This indicates that laser therapy allowed an increase in sAPPα and a decrease in CTFβ in these mice, suggesting a shift from β- to α-secretase activity.

  Treatment with laser therapy for CSFAβ peptide levels was sought in APP transgenic mice at the end of the experiment (Figure 50 and Table 24). Mice received an ELISA for Aβ peptide levels. This is because a small amount of CSF was obtained. Table 24 shows the results for animals that ended 26 weeks after the start of treatment. Control shows the Aβ peptide levels shown in Table 24, which is standard in this particular model up to 9 months of age (previous study). CW and Pulse I showed no significant difference in CSF when compared to control. However, pulse II and pulse III laser therapy showed significant differences from control (Table 24 and FIG. 50). This indicates that laser therapy was able to reduce Aβ peptide levels in the brain in these mice at a specific dose.

  Statistical analysis was performed on the samples as described by GraphPad Prism (version 4.00). Changes in different parameters up to the 0.05 level were significant. This is due not only to the number of animals in each group, but also to the number of samples taken for each measurement from each animal (20). Therefore, the number is reliable. These numbers are within the range of acceptable results.

  The animals were examined for gross abnormalities after disposal. No global pathological features were detected in most of the animals except group E (pulse III). The animals showed some lesions in the brain after treatment. Several weeks later lesions began to appear on the animal's skin. These were switched to 1 minute treatment, ice, and 1 minute treatment with no further damage.

Discussion Transgenic mice expressing a mutant form of the human APP gene began to deposit amyloid fibrils by 6 months of age. This process is associated with Aβ peptides with increased deposition in the brain. Recent studies show that applying laser light therapy can serve to protect against various neuronal damage. In this study, LLT was tested in an APP model to determine efficacy against amyloid burden, inflammatory markers, brain Aβ levels, plasma and CSFAβ levels, and behavioral changes. Application of LLT in a dose-dependent manner significantly reduced the number of Aβ plaques in the brain. The application of LLT shows a variable effect, with the greatest effect being reduced amyloid deposition with increasing dose.

  NTS was not obscured by the studies outlined by PTI. Overall, laser beam therapy was effective in limiting the extent of Aβ amyloid in the brain and in altering the amount of Aβ peptide deposition and behavioral defects in mice.

  The description and illustrations presented herein are intended to acquaint others skilled in the art with the invention, its principles, and practical applications. A person skilled in the art can adapt and apply the present invention in its most suitable form to the requirements of a particular application. Accordingly, the specific embodiments of the invention described are not intended to be exhaustive or limiting of the invention.

Claims (170)

A device for irradiating a portion of a patient's scalp or skull with light,
A light source;
An output optical element in optical communication with the light source, wherein the output optical element emits a pulsed light beam including a plurality of pulses having a temporary pulse width in a range between 0.1 milliseconds and 150 seconds. The cross section of the pulsed light beam is larger than about 2 cm ² at the output surface of the output optical element, and the time average irradiance of the pulsed light beam is about 10 mW / cm ^{2 in the} cross section. From about 10 W / cm ² .   2. The pulsed light beam stimulates, activates, induces or supports one or more intercellular or intracellular biological processes involved in brain cell survival, regeneration, restoration of work or viability. The device described in 1.   The pulsed light beam has a duty cycle, and the temporal pulse width and the duty cycle determine cell survival, cell function or both of the brain cells irradiated by the pulsed light beam passing through the skull and adjusting the membrane potential. The apparatus of claim 1, wherein the apparatus is sufficient to improve. The beam diameter of the pulsed light beam at the exit surface is in the range between 10 millimeters and 40 millimeters, and the average irradiance per pulse is in the range between 10 mW / cm ² and 10 W / cm ² ; The apparatus of claim 1, wherein the one or more wavelengths are in the range between 600 nanometers and 980 nanometers, and the duty cycle is in the range between 10% and 30%. A method of irradiating the surface with light,
Illuminating the surface with at least one pulsed light beam emitted from an exit surface of the optical element, wherein the at least one pulsed light beam has a temporary pulse width between about 0.1 milliseconds and about 150 seconds. A plurality of pulses in the range, the beam cross section of the at least one pulsed light beam at the exit surface is greater than about 2 cm ² , and the time average irradiance is between about 1 mW / cm ² and about 100 W / cm ² . In range. The method of claim 5, wherein a beam cross section at the exit surface is in a range between about 1 cm ² and about 20 cm ² . 6. The method of claim 5, wherein the average irradiance per pulse at the exit surface is in the range between about 10 mW / cm < ² > and about 10 W / cm < ² >. 6. The method of claim 5, wherein the average irradiance per pulse at the exit surface is in the range between about 100 mW / cm < ² > and about 1 W / cm < ² >.   6. The method of claim 5, wherein the temporal pulse width is in a range between about 0.1 milliseconds and about 100 milliseconds.   The method of claim 5, wherein the at least one pulsed light beam has one or more wavelengths, the one or more wavelengths ranging between about 600 nanometers and about 980 nanometers.   6. The method of claim 5, wherein the duty cycle of the at least one pulsed light beam is in the range between about 1% and about 80%.   6. The method of claim 5, wherein a beam divergence angle at the exit surface of the at least one pulsed light beam is greater than zero and less than 35 degrees.   The irradiated surface includes at least a portion of a scalp or skull of a patient having at least one physical trauma in the brain, and at least a portion of the at least one pulsed light beam is transmitted through the skull and of the patient's brain. The method according to claim 5, wherein at least a part is irradiated.   The method of claim 13, wherein the irradiated surface includes an irradiated portion of the scalp, and the irradiated portion of the scalp is not whitened while the portion of the scalp is irradiated.   14. The method of claim 13, wherein the irradiated surface includes an irradiated portion of the scalp, and the irradiated portion of the scalp is whitened while the scalp portion is being irradiated.   14. The method of claim 13, wherein the irradiated surface is cooled during irradiation of the irradiated surface.   The method of claim 13, wherein the irradiated surface is not cooled during irradiation of the irradiated surface.   The irradiated surface includes an irradiated portion of the scalp, and the method further includes removing at least a portion of the hair from the irradiated portion of the scalp prior to irradiation of the irradiated portion of the scalp. 14. The method of claim 13, comprising:   14. The method of claim 13, wherein irradiating the surface comprises sequentially irradiating a plurality of treatment sites on the scalp with a pulsed light beam.   20. The method of claim 19, wherein the plurality of treatment sites includes at least 10 treatment sites.   The method of claim 19, wherein the plurality of treatment sites includes between 15 and 25 treatment sites. 14. The method of claim 13, wherein an average irradiance at the scalp or skull is selected to provide an average irradiance greater than 0.01 mW / cm < ² > at a depth of about 2 centimeters below the dura mater.   14. The method of claim 13, wherein light is transmitted through an area of the patient's skull that contains excessive amounts of bleeding due to the at least one physical trauma.   6. The method of claim 5, wherein the illuminated surface comprises a portion of a light detection system configured to measure one or more parameters of the pulsed light beam.   25. The method of claim 24, further comprising measuring one or more parameters of a pulsed light beam impinging on the illuminated surface. A method of treating a patient's brain, the method comprising:
Irradiating at least a portion of the brain by irradiating at least a portion of the brain by irradiating at least a portion of the patient's scalp or skull with at least one pulsed light beam comprising a plurality of pulses that pass through the skull of the patient The beam has a temporary profile, said temporal profile ranging between about 100 mW / cm ² and about 10 W / cm ² , the time average irradiance of the scalp averaged over 1 second, and about 12.5 mW A method comprising peak irradiance at the scalp in a range between / cm ² and about 1000 W / cm ² .   27. The method of claim 26, wherein the temporary profile does not optimize thermal relaxation of irradiated tissue. 27. The at least one pulsed light beam according to claim 26, wherein the beam cross-section at the scalp is greater than about 2 cm < ² > and one or more wavelengths range between about 780 nanometers and about 840 nanometers. Method.   27. The temporary profile further includes a temporary pulse width in a range between about 0.1 milliseconds and about 300 milliseconds, and a duty cycle in a range between about 10% and about 30%. The method described in 1.   27. The method of claim 26, wherein irradiating at least a portion of the scalp or skull comprises sequentially irradiating a plurality of treatment sites with a plurality of pulsed light beams.   27. The method of claim 26, wherein irradiation of at least a portion of the scalp or skull is performed for a period of 60 seconds to 600 seconds.   A method of treating a patient suffering from traumatic brain injury comprising: non-invasively irradiating at least a portion of the patient's scalp or skull with pulsed light penetrating the patient's skull; Irradiating and stimulating brain cells, wherein the pulsed light has a temporary profile including an average irradiance per pulse, a temporary pulse width, and a pulse duty cycle, and the temporary profile is selected to select the trauma A method of adjusting membrane potential to improve, restore or promote cell survival, cell function or both of irradiated brain cells after traumatic brain injury. 33. The method of claim 32, wherein the average irradiance per pulse is in a range between about 10 mW / cm < ² > and about 10 W / cm < ² >. The method of claim 32, wherein the pulsed light comprises a light beam having a beam cross-sectional area in a range between ² cm ² and 20 cm ² .   35. The method of claim 32, wherein the temporal pulse width is in a range between about 0.1 milliseconds and about 300 milliseconds.   35. The method of claim 32, wherein the pulse duty cycle is in a range between about 10% and about 30%.   A method of treating a patient with neurodegenerative disease or depression, wherein the method irradiates at least a portion of the patient's scalp or skull with pulsed light that passes through the patient's skull to irradiate the patient's brain cells. The pulsed light has a temporary profile comprising an average irradiance per pulse, a temporary pulse width, and a pulse duty cycle, wherein the temporary profile is a cell survival of irradiated brain cells, A method selected to modulate membrane potential to improve, restore or promote cell function or both.   38. The method of claim 37, wherein the neurodegenerative disease comprises Alzheimer's disease or Parkinson's disease. An apparatus for irradiating a part of a patient's scalp with light, the apparatus comprising:
A light source comprising one or more wavelengths in the range of about 630 nanometers to about 1064 nanometers;
An output optical element in optical communication with the light source, the output optical element including an exit surface, wherein the exit surface has a cross section at the exit surface of the output optical element greater than about 2 cm ² and the cross section Is configured to emit a light beam having a time average irradiance in the range of about 10 mW / cm ² to about 10 W / cm ² ,
Heat is placed in thermal communication with the irradiated portion of the patient's scalp and at a rate in the range of about 0.1 watts to about 5 watts from the irradiated portion of the patient's scalp. The apparatus further comprising a thermally conductive portion configured to be removed. 40. The apparatus of claim 39, wherein the cross section ranges from about 2 cm < ² > to about 20 cm < ² >.   40. The apparatus of claim 39, wherein the cross section is generally circular and the radius is in the range of about 1 centimeter to about 2 centimeters. 40. The apparatus of claim 39, wherein the time average irradiance is in the range of about 500 mW / cm < ² > to about 1 W / cm < ² >.   40. The apparatus of claim 39, wherein the light has one or more wavelengths in the range of about 805 nanometers to about 820 nanometers.   44. The apparatus of claim 43, wherein the light has a wavelength distribution with a peak at a peak wavelength and a line width less than ± 10 nanometers from the peak wavelength.   44. The apparatus of claim 43, wherein the line width of the light is less than 4 nanometers and the total width is 90% of energy.   40. The apparatus of claim 39, wherein the light beam is continuous.   47. The apparatus of claim 46, wherein the total radiant power of the light beam emitted from the exit surface is in the range of about 4 watts to about 6 watts.   48. The apparatus of claim 47, wherein the light beam has a total luminous flux inside a 20 millimeter diameter cross-sectional circle centered on the light beam at the exit surface that is no more than 75% of the total radiation power.   49. The apparatus of claim 48, wherein the light beam has a total luminous flux inside a 26 millimeter diameter cross-section circle centered on the light beam at the exit surface that is 50% or more of the total radiant power.   40. The apparatus of claim 39, wherein the light beam is pulsed.   40. The apparatus of claim 39, wherein the thermally conductive portion includes an optical output element.   52. The apparatus of claim 51, wherein the thermally conductive portion is releasably coupled to the optical output element.   40. The apparatus of claim 39, wherein the rate is in the range of about 1 watt to about 3 watts.   40. The apparatus of claim 39, wherein the thermally conductive portion is configured to keep the temperature of the irradiated portion of the patient's scalp below 42 degrees Celsius.   40. The thermally conductive portion is in thermal communication with an exit surface and is configured to maintain the exit surface temperature in the range of 18 degrees Celsius to 25 degrees Celsius under a 2 Watt thermal load. Equipment.   40. The apparatus of claim 39, wherein the divergence angle of the light beam is greater than zero and less than 35 degrees.   57. The apparatus of claim 56, wherein the light beam has a divergence angle of about 16 degrees.   57. The apparatus of claim 56, wherein the light beam has a divergence angle of about 28 degrees.   The device is configured such that the thermally conductive portion moves relative to a second portion of the device, the movement of the thermally conductive portion relative to the second portion being a predetermined threshold. 40. The device of claim 39, wherein a pressure above a pressure is generated when applied to the thermally conductive portion in a direction that the thermally conductive portion moves relative to a second portion of the device.   And further comprising a sensor configured to generate a signal indicative of the movement in response to movement of the thermally conductive portion relative to the second portion of the device, wherein the predetermined threshold pressure is 60. The device of claim 59, wherein the device is large enough to thermally communicate a thermally conductive portion with a portion of the patient's scalp.   61. The controller of claim 60 further comprising a controller operably coupled to the light source and the sensor, the controller configured to receive the signal and turn on the light source in response to the signal. apparatus.   61. The apparatus of claim 60, wherein the threshold pressure is 0.1 pounds per square inch.   61. The apparatus of claim 60, wherein the threshold pressure is about 2 pounds per square inch.   40. The apparatus of claim 39, wherein the output optical element has an aperture that is less than 33 millimeters in diameter.   40. The apparatus of claim 39, wherein the exit surface is concave.   66. The apparatus of claim 65, wherein the exit surface is generally spherical and has a radius of curvature of about 100 millimeters. A method of irradiating a surface with light, the method comprising:
(A) emitting a light beam from an exit surface of the optical element, wherein the light beam at the exit surface has one or more wavelengths in the range of about 630 nanometers to about 1064 nanometers, and about 2 cm ² And a time average irradiance in the range of about 10 mW / cm ² to about 10 m / cm ^{2 in} the cross section,
(B) removing heat from the exit surface at a rate in the range of about 0.1 watts to about 5 watts;
(C) applying a light beam to the irradiated surface.   The illuminated surface includes a portion of a light detection system configured to measure one or more parameters of the light beam, and the method further includes one or more parameters of the light beam impinging on the illuminated surface. 68. The method of claim 67, comprising measuring.   68. The method of claim 67, wherein the irradiated surface comprises a portion of a patient's scalp.   70. The method of claim 69, further comprising positioning the exit surface in thermal communication with the illuminated surface.   71. The method of claim 70, further comprising the step of applying pressure to the irradiated surface, wherein the pressure is greater than 0.1 pounds per square inch.   72. The method of claim 71, wherein the step of applying pressure to the irradiated surface comprises applying a force to the exit surface in a direction generally toward the irradiated surface.   72. The method of claim 71, wherein the pressure is about 2 pounds per square inch.   70. The method of claim 69, wherein the step of applying a light beam to the illuminated surface is performed for a period of 10 seconds to 2 hours.   70. The method of claim 69, wherein the step of applying a light beam to the illuminated surface is performed for a period of 60 to 600 seconds.   70. The method of claim 69, wherein the step of applying a light beam to the illuminated surface is performed for a period of about 120 seconds.   70. The method of claim 69, wherein (a), (b), and (c) are performed simultaneously. (D) moving the exit surface from a first position where a light beam is applied to a first portion of the illuminated surface to a second position;
70. The method of claim 69, further comprising: (e) repeating (a)-(c) to irradiate light emitted from the exit surface to a second portion of the illuminated surface.   79. The method of claim 78, wherein the first portion of the irradiated surface and the second portion of the irradiated surface do not overlap each other.   79. The method of claim 78, further comprising: (a)-(e) repeating the step of applying light emitted from the exit surface to 20 portions of the illuminated surface.   81. The method of claim 80, wherein the 20 portions of the exiting surface do not overlap each other. An apparatus for irradiating a patient's scalp with light, the apparatus comprising:
A first part;
A second portion mechanically coupled to the first portion and in optical communication with the first portion, wherein the second portion is configured to allow light from the first portion to operate the device. Being disposed in thermal communication with the patient's scalp so as to pass through the second part, wherein the first part and the second part are configured such that the second part is in contact with the patient's scalp. An apparatus configured to move relatively in response to being placed in thermal communication.   The apparatus of claim 82, wherein the second portion includes an output optical assembly.   The first portion and the second portion when the output optical assembly applies sufficient pressure against the portion of the patient's scalp to at least partially whiten the portion of the patient's scalp; 83. The apparatus of claim 82, configured to deflect with respect to each other at a non-zero angle.   The first portion and the second portion are configured to relatively deflect at a non-zero angle when an output optical assembly is positioned to be in thermal communication with the patient's scalp. 82. Apparatus according to 82.   The first portion includes an optical fiber, and the relative deflection of the first portion and the second portion controls, inhibits, prevents, minimizes, or reduces bending or movement of the optical fiber; The apparatus of claim 85.   The first portion includes a first support element, the second portion includes a second support element, and the apparatus further includes a relative relationship between the first support element and the second support element. 83. The apparatus of claim 82, comprising a hinge that is the center of deflection.   90. The apparatus of claim 87, wherein the hinge includes a pivot axis.   90. The apparatus of claim 87, wherein the hinge includes a flexible portion.   The apparatus further includes a spring mechanically coupled to the first portion and the second portion, wherein the spring is responsive to relative movement of the first portion and the second portion. 83. The device of claim 82, providing a restoring force.   The apparatus of claim 82, further comprising a sensor configured to detect relative movement of the first portion and the second portion.   The sensor is configured to transmit a signal to a controller, the controller is configured to receive the signal and control a light source in response to the signal, the light source configured to cause the device to scan a patient's scalp. 92. The apparatus of claim 91, configured to generate light used for irradiating.   94. The apparatus of claim 92, wherein the sensor sends the signal to the controller when detecting that movement between the first portion and the second portion is greater than a predetermined threshold. .   94. The apparatus of claim 93, further comprising an adjustment mechanism configured to set the predetermined threshold, change the predetermined threshold, or both. .   The apparatus of claim 82, further comprising a stop configured to limit a range of relative movement of the first portion and the second portion. A method of irradiating a surface with light, the method comprising:
Providing a device, the device comprising:
A first part;
A second portion mechanically coupled to the first portion and in optical communication with the first portion, wherein the first portion and the second portion are configured to move relative to each other. And
Placing the second portion in thermal communication with the surface;
Illuminating the surface such that light from the first portion is transmitted through the second portion;
Moving the first portion and the second portion relative to each other in response to the second portion being disposed in thermal communication with the surface.   The surface includes a portion of a light detection system configured to measure one or more parameters of light illuminating the surface, and the method further includes one or more of the light from the device impinging on the surface 99. The method of claim 96, comprising measuring the parameters of:   97. Arranging the second portion in thermal communication with the surface comprises releasably and operatively coupling the second portion to the surface. Method.   99. The method of claim 96, wherein the surface comprises a portion of a patient's scalp. An apparatus for irradiating a patient's scalp with light, the apparatus comprising:
An output optical assembly including an exit surface, and during operation of the device, light propagates through the output optical assembly along a first optical path to the exit surface;
The sensor further includes a sensor spaced from the output optical assembly, the sensor positioned to receive radiation from the output optical assembly that propagates through the output optical assembly along a second optical path. The angle between the first optical path and the second optical path is a non-zero angle.   The output optical assembly includes a first optical element that includes a rigid, substantially light transmissive, and substantially heat conductive material, the first optical element having a first surface and a second surface. And wherein the first surface is configured to be disposed in thermal communication with the portion of the patient's scalp during operation of the device, and the second portion is configured to operate during the operation of the device. Configured to receive light propagating along one optical path, wherein the sensor is from at least a portion of the second surface of the first optical element to the second optical path during operation of the apparatus. 101. The apparatus of claim 100, configured to receive radiation propagating along.   102. The apparatus of claim 101, wherein the first optical element comprises sapphire.   102. The apparatus of claim 101, wherein the first optical element comprises diamond, calcium fluoride, or zinc selenide.   101. The apparatus of claim 100, wherein the sensor generates a signal indicative of a temperature of the scalp or a portion of the output optical assembly in response to received light.   Propagating along the first optical path to receive a signal from the sensor and to generate a warning in response to the signal indicating that the temperature is above a predetermined threshold 105. The apparatus of claim 104, further comprising a controller configured to turn off the light source or both.   The apparatus of claim 100, wherein the sensor comprises a thermocouple string.   107. The apparatus of claim 106, wherein the sensor is not in thermal communication with the output optical assembly.   And further comprising a second optical element comprising an infrared transmissive material, wherein the radiation propagates along the first optical path and the light including the infrared and propagating along the second optical path during operation of the apparatus. 101. The apparatus of claim 100, wherein both infrared rays propagate through the second optical element.   109. The apparatus of claim 108, wherein the infrared transmissive material comprises calcium fluoride.   The second optical element at least partially surrounds a region in the device, the region being a region that is substantially sealed so that contaminants do not enter the region from outside the region. Item 108. The apparatus according to Item 108.   111. The apparatus of claim 110, wherein the sensor is at least partially within the region.   The output optical assembly is releasably coupled to a portion of the device, and the second optical element is configured to remove contaminants that enter the region while the output optical assembly is removed from the portion of the device. 111. The apparatus of claim 110, wherein the apparatus is controlled, suppressed, prevented, minimized or reduced. A method for irradiating a surface with light, the method comprising:
Providing an optical element comprising a substantially light transmissive and substantially thermally conductive material, the optical element having a first surface and a second surface;
Placing the first surface in thermal communication with the irradiated surface;
Propagating light along the first optical path through the second surface and through the first surface to the illuminated surface;
Detecting radiation propagating along a second optical path from at least a portion of the second surface, the angle between the first optical path and the second optical path being a non-zero angle Is that way.   114. The method of claim 113, wherein the first surface and the second surface are generally opposed in opposite directions, and the first surface is not along the second optical path.   Arranging the first surface in thermal communication with the irradiated surface includes releasably and operatively coupling the first surface to the irradiated surface. 120. The method according to item 113.   114. The method of claim 113, wherein the irradiated surface comprises a portion of a patient's scalp. An apparatus for irradiating a patient's scalp with light, the apparatus comprising:
A thermoelectric assembly, wherein the thermoelectric assembly is responsive to a current applied to the thermoelectric assembly to cool at least a first surface of the thermoelectric assembly and to heat at least a second surface of the thermoelectric assembly. The thermoelectric assembly is releasably mechanically coupled to an output optical assembly and configured to thermally communicate the first surface with the output optical assembly, the thermoelectric assembly being in a first region. And during operation of the device, light that illuminates a portion of the patient's scalp propagates through the first region;
The apparatus further includes a heat sink in thermal communication with the second surface of the thermoelectric assembly. The output optical assembly comprises:
A thermally conductive portion configured to be in thermal communication with a first surface of the thermoelectric assembly, the thermally conductive portion generally surrounding a second region;
An optical element comprising a rigid, substantially light transmissive and substantially thermally conductive material, said optical element being in thermal communication with said thermally conductive portion and during operation of said device 117. The device of claim 117, wherein the device is arranged to be in thermal communication with a portion of the scalp of the device, wherein light during operation of the device propagates through the first region, the second region, and the optical element. The device described.   119. The heat sink generally surrounds a third region, and light propagates through the third region, the first region, the second region, and the optical element during operation of the device. The device described in 1.   118. The apparatus of claim 117, wherein the thermoelectric assembly includes a plurality of thermoelectric elements.   118. The apparatus of claim 117, wherein the heat sink includes a fluid tube, the fluid tube configured to allow a coolant to flow through the fluid tube and remove heat from the fluid tube.   122. The apparatus of claim 121, wherein the coolant comprises water.   118. The apparatus of claim 117, wherein the term optical element comprises sapphire.   118. The apparatus of claim 117, wherein the optical element comprises diamond, calcium fluoride, or zinc selenide. A method of irradiating a surface with light, the method comprising:
Providing a thermoelectric assembly including a first surface and a second surface, the thermoelectric assembly generally surrounding the first region, the method further comprising:
Preparing an output optical assembly;
Mechanically coupling the first surface of the thermoelectric assembly to the output optical assembly in a releasable manner so that the first surface is in thermal communication with the output optical assembly;
Cooling the first surface and heating the second surface;
Propagating light through the first region to impinge on the illuminated surface. The output optical assembly includes an optical element and a thermally conductive portion that generally surrounds a second region, wherein the thermally conductive portion is in thermal communication with the optical element and defines the first surface. Releasably mechanically coupling to the output optical element includes releasably mechanically coupling the first surface to the thermally conductive portion, the method further comprising:
Placing the optical element in thermal communication with the illuminated surface;
Propagating light, and propagating the light comprises propagating the light through the first region, the second region, and the optical element to strike the irradiated surface. 126. The method of claim 125.   Providing a heat sink in thermal communication with a second surface of the thermoelectric assembly, wherein the heat sink generally surrounds a third region and propagating the light comprises: 127. The method of claim 126, comprising transmitting through three regions, the first region, the second region, and the optical element.   126. The method of claim 125, wherein the irradiated surface comprises a portion of a patient's scalp. A device wearable by a patient, the device comprising:
A body adapted to be worn over at least a portion of the patient's scalp;
A plurality of indicators corresponding to a plurality of treatment site locations on the patient's scalp, where the light is irradiated to illuminate at least a portion of the patient's brain. At least one of said indicator area of at least 1 cm ^2, including a light transmissive portion of the body, according to claim 129. Area of the light-transmitting portion is in the range between 1 cm ² and 20 cm ^2, apparatus according to claim 130. Area of the light-transmitting portion is in the range between 5 cm ² and 10 cm ^2, apparatus according to claim 130.   131. The apparatus of claim 130, wherein the light transmissive portion includes an opening through the body.   143. The device of claim 133, wherein the opening has a substantially circular perimeter and a diameter in the range between 20 and 50 millimeters.   143. The device of claim 133, wherein the opening has a substantially circular perimeter and a diameter in the range between 25 and 35 millimeters.   143. The device of claim 133, wherein the opening has a substantially elliptical perimeter, and the minor axis of the ellipse is greater than 20 millimeters and the major axis is less than 50 millimeters.   129. The apparatus of claim 129, wherein at least one of the treatment site locations includes a region of a patient's scalp and at least one of the indicators indicates a position within the at least one region of the treatment site location. .   138. The apparatus according to claim 137, wherein the location is in the center of the region.   131. The apparatus of claim 129, wherein adjacent treatment site locations of the plurality of treatment site locations have areas that do not overlap each other.   131. The apparatus of claim 129, wherein adjacent treatment site locations of the plurality of treatment site locations have perimeters spaced apart.   141. The apparatus of claim 140, wherein the spacing between the perimeters is at least 25 millimeters.   129. The apparatus of claim 129, wherein the body comprises Tyvek®.   The plurality of indicators are configured to guide an operator to irradiate the patient's scalp sequentially, in a predetermined order, one at a time at corresponding treatment site locations. 129. The apparatus according to item 129.   145. The apparatus of claim 143, wherein at least one of the indicators includes a portion configured to be removed from the apparatus to indicate that a corresponding treatment site location has already been illuminated.   145. The apparatus of claim 143, wherein the predetermined order is configured to reduce a temperature rise in the patient's scalp that can result from continuous irradiation of treatment site locations in close proximity to each other.   The predetermined sequence includes irradiation of a first treatment site location on a first side of the patient's scalp, irradiation of a second treatment site location on the second side of the next patient's scalp; 145. The apparatus of claim 143, comprising irradiation of a third treatment site location on the first side of the next patient's scalp.   147. The predetermined sequence of claim 146, further comprising irradiation of a fourth treatment site location on the second side of the patient's scalp after irradiation of the third treatment site location. apparatus.   144. The apparatus of claim 143, wherein the spacing between two consecutively irradiated treatment site locations of the plurality of treatment site locations is at least 25 millimeters. A device wearable by a patient, the device comprising:
Means for identifying a plurality of treatment site locations on the patient's scalp, where light is applied to illuminate at least a portion of the patient's brain;
Means for indicating a sequential sequence for irradiating the treatment site location to an operator.   149. The apparatus of claim 149, wherein the means for identifying includes a body adapted to be worn by the patient on the patient's scalp while at least a portion of the patient's brain is illuminated.   156. The apparatus of claim 150, wherein the means for indicating includes a plurality of openings through the body, each opening indicating a corresponding treatment site location.   149. The apparatus of claim 149, wherein the means for identifying comprises a template configured to be placed on the patient's scalp.   The means for indicating includes a plurality of holes through the template and a plurality of marks on the patient's scalp, the template prior to being irradiated of at least a portion of the patient's brain. 153. The apparatus of claim 152, wherein the apparatus is adapted to be removed from a scalp and the plurality of marks remain on the patient's scalp while at least a portion of the patient's brain is irradiated. A method for demonstrating a brain phototherapy procedure, the method comprising:
Identifying a plurality of treatment site locations on the patient's scalp, wherein at least one area of the treatment site locations is at least 1 cm ² ;
Showing the sequential order of irradiation of the treatment site locations.   155. The method of claim 154, wherein the spacing between two of the treatment site locations shown to be continuously irradiated is at least 10 millimeters.   157. The method of claim 154, wherein two of the treatment site locations shown to be continuously irradiated are located on different hemispheres of the patient's brain.   The step of identifying the plurality of treatment site locations includes positioning a body over a patient's scalp, the body including a plurality of light transmissive portions corresponding to the plurality of treatment site locations. 154. The method according to 154.   158. The method of claim 157, wherein at least one of the light transmissive portions includes an opening through the body.   The step of indicating the sequential order includes marking a portion of the patient's scalp within the area of the opening to create a mark that remains on the patient's scalp when the body is removed from the patient's scalp. 159. The method of claim 158.   158. The method of claim 157, wherein the body further includes a plurality of indicators corresponding to the plurality of light transmissive portions, the plurality of indicators indicating the sequential order. A method of treating a patient's brain, the method comprising:
Non-invasively irradiating a first region of at least 1 cm ² of the patient's scalp with laser light for a first period of time;
Non-invasively irradiating at least 1 cm ² of a second region of the patient's brain with a laser beam for a second period of time, wherein the first region and the second region do not overlap, And the second period does not overlap.   Further comprising identifying the first region and the second region by placing a template on a patient's scalp, wherein the template includes a first indicator of the first region and a second region of the second region. 164. The method of claim 161, comprising a second indicator.   163. The method of claim 162, wherein the first indicator includes a first opening in the template and the second indicator includes a second opening in the template.   Disposing a laser light source at a first position to irradiate the first region non-invasively, moving the laser light source to a second position to irradiate the second region non-invasively; 164. The method of claim 161, further comprising:   164. The method of claim 161, further comprising increasing the transparency of the first region to laser light and increasing the transparency of the second region to laser light.   166. The method of claim 165, wherein increasing the permeability of the first region comprises applying pressure to the first region to at least partially whiten the first region.   166. The method of claim 165, wherein increasing the permeability of the first region comprises removing hair from the first region prior to non-invasively irradiating the first region.   166. The method of claim 165, wherein increasing the transparency of the first region comprises providing an index matching material to the first region.   166. The method of claim 161, wherein the first region and the second region are at least 10 millimeters apart.   166. The method of claim 161, wherein the first region is over a first hemisphere of the brain and the second region is over a second hemisphere of the brain.