WO2022226606A1 - Implantable semi-invasive eti-nd device to elicit repetitive waves of spreading depression - Google Patents

Abstract

This invention relates to a brain implantable ETI neurodepressor (ND) device (ETI-ND) that silences abnormal electrical activity related to drug-resistant seizures, and thereby prevents brain damage and sudden unexpected death in epilepsy. The ND mechanism, mediated by slow waves of cortical Spreading Depression (SD), self-propagates in the brain. The ETI-ND device is a 3-in-1 antiseizure system, composed of electrocorticography (EEG) electrode arrays, intracranial pressure (ICP) and thermal sensors (iTemp) (504,503,502). The device can be placed epidural or subdural. Flexible EEG electrode-arrays enable high-sensitive measures of EEG waves while ICP and iTemp measures contribute to more targeted & individualized seizure care. Repetitive waves of SD are triggered by ETI-ND-mediated chemical, physical, thermal or electrical stimuli applied to the brain. iTemperature and ICP measures help the CPU, embedded in the hardware device, manage EEG signals and elicit personalized SD-mediated antiseizure responses. The ETI-ND system can monitor EEG activity, responding in a real-time on a 24-7 basis.

Description

IMPLANTABLE SEMI-INVASIVE ETI-ND DEVICE TO ELICIT REPETITIVE WAVES

OF SPREADING DEPRESSION

FIELD OF THE INVENTION [0001] The inventions disclosed herein involve devices implanted at the top or under the exposed dura mater 408, after extensive craniotomy procedures, to detect and stop electrographic seizures and treat epilepsy. Specifically, the system triggers waves of Leao Spreading Depression (SD) 301, leading to a silencing of abnormal electrical brain activity. The phenomenon of excitability inhibition propagates as a wave in the gray matter by means of contiguity, regardless of functional divisions or arterial territories. ICP and iTemperature measures (multimodal detection) contribute to develop a personalized treatment of epileptic patients and to prevent onset of electroencephalographic (EEG) abnormal discharges. The electrode-to-tissue interface neurodepressor (ETI-ND) device invention is tailor made for drug-resistant seizures (“personalized medicine”) in epileptic patients facing a year-long wait to repair extensive cranial defects (FIG. 1). BACKGROUND OF THE INVENTION

[0002] The skull 401 is hard and inflexible, while the brain is soft with the consistency of gelatin. The brain is encased by three meningeal layers of protective covering inside the skull. The outermost layer, the dura mater 408, contributes to compartmentalization of the brain and maintenance of intracranial pressure (ICP).

[0003] Studies have suggested that the dura mater 408, directly underneath the skull 401 , exerts its influence on cranial sutures by transmitting biomechanical tensional forces via fibrous tracts. Cerebrospinal fluid (CSF) 405 fills the ventricles 406 of the brain and the space between the pia mater and the arachnoid, innermost layers. The primary function of the meninges and of the cerebrospinal fluid is to protect the nervous system (CNS). [0004] The dura mater 408 is partitioned into several septa, which support the brain. The outer portion of the dura over the brain serves as a covering, or periosteum, of the inner surfaces of the skull bones. The strong dural layer has been described by B. McLean ‘as the box (dura mater) within a box (the skull 401). [0005] Studies indicate that changes of the container of the brain affect pressure-volume relationships. Cerebral volume consists of 3 components: cerebral tissue 402,403, blood, and CSF 405. Monroe and Kellie theorized that for ICP to remain normal, the components must compensate for increased volume or ICP will increase. Once neurons become injured, however, the brain’s ability to compensate is finite, decompensation can occur rapidly, and damage to the vulnerable adjacent tissues (termed ‘secondary injury’) will ensue, frequently leading to seizures.

[0006] The pressure in the cranial vault is normally <20 mm Hg (Lassen, 1959). The clinical implication of the change in volume of the component is an increase in ICP, leading to a decrease in cerebral blood perfusion and/or to herniation of the brain.

[0007] The brain cannot shrink, and compensation is possible only through a reduction in the amount of fluid present in the ventricles 406 or of blood in the vessels or by a neurosurgical procedure termed ‘decompressive craniectomy’ (DCT), a procedure performed to reduce ICP. Cranioplasty (cranial repair) 101, 102 should be performed as soon as the brain is lax to mitigate many of the late complications (FIG. 1) (Rozental’s group) - DOI: 10.21203/rs.3.pex-1384/v1 .

[0008] ICP monitoring is key in neurocritical care, including TBI, hemorrhage, stroke, and intracranial hypertension. Information which can be derived from ICP and its waveforms includes cerebral perfusion pressure, regulation of cerebral blood flow and volume (FIG. 2). These parameters support customized medicine and critical prognosis (Czosnyka and Pickard, 2004).

[0009] The configuration of the ICP pulse wave, generated by arterial pulse, represent a sum of three major components: #1 ) the P1 wave, also known as the percussion wave, correlates with the arterial pulse transmitted through the choroid plexus into the CSF 405, and via a column of fluid into the EVD transducer; #2) the P2 wave, also known as the tidal wave, represents cerebral compliance, it can be thought of as a "reflection" of the arterial pulse wave bouncing off the springy brain parenchyma; and, #3) the P3 wave, also known as the dicrotic wave, correlates with the closure of the aortic valve, which makes the trough prior to P3 the equivalent of the dicrotic notch (FIG. 2A,B,C, FIG. 6B,C). All these waves are rarely >4mmHg in amplitude, or 10-30% of the mean ICP. [0010] The brain thickness, using MRI assays, as the distance between the ventricular system and the cortical surface varies between 3.45cm and 4.58cm (Duffner et al. , 2003). Average measures of distance between the scalp and the surface of the cortex is 1 .45 ± 0.25cm (Lu et al., 2019).

[0011] Increased invasiveness put the electrodes in closer proximity to neurons, which allows for improved stimulation and signal detection. As such, invasive EEG using a grid of epidural or subdural electrodes 408, or electrocorticography (ECoG), has clear advantages over traditional scalp EEG (FIG. 4) including an increased signal-to-noise ratio, superior spatial resolution, and greater spectral frequency. [0012] Epilepsy, a broad term used for a brain disorder that causes seizures, affect a great number of children and adults, races and ethnic groups worldwide (Patel and Moshe, Epilepsia Open, 2020). It is the 4th most common neurological disease and it can substantially impair quality of life, such as loss of consciousness, altered motricity, sensory disturbances or perturbation of the autonomic nervous system - that regulates bodily functions, such as cardiovascular and respiratory systems. The result is a multitude of pathways for seizure spread to impact autonomic and respiratory brainstem regions, through the NTS nucleus of the tractus solitarius (parasympathetic outflow) and the RVLM rostral ventrolateral medulla (sympathetic outflow), involved in “Sudden Unexpected Death in Epilepsy” (SUDEP).

[0013] According to the WHO (06/2019), around 50 million people worldwide have epilepsy, making it one of the most common neurological diseases globally. Of note, «80% of people with epilepsy live in low- and middle-income countries. The risk of premature death with epilepsy is up to >3 times higher than for general population. [0014] About ¾ of people with epilepsy living in low-income (LI economies) countries do not get the treatment they need. Unfortunately, not all patients can afford the costs of cranial open vault repair to relieve psychological and hemodynamics drawbacks and to increase both mental and social performances.

[0015] Epilepsy is a debilitating toll and a clinical conundrum, especially because 30% with the condition are not controlled by existing pharmacological treatments;

[0016] Neuronal synchrony activity can be brought about by several mechanisms, including enhancement of excitatory synaptic transmission, abnormal excitatory connections, decreased activity of inhibitory synaptic transmission, increased synchrony of inhibitory neuronal networks. Chemical synapses are undoubtedly necessary in the generation of most, if not all, types of seizures.

[0017] Reduction in life expectancy can be up to 2 years for people with a diagnosis of idiopathic/cryptogenic epilepsy, and the reduction can be up to 10 years in people with symptomatic epilepsy.

[0018] Seizures are classified into two major groups: i) Generalized seizures, affecting both sides of the brain (absence seizures and tonic-clonic seizures [‘grand mal seizures’]); and, ii) Focal seizures, located in just one area of the brain (also called ‘partial seizures’). [0019] Epileptic patients who continue to have abnormal discharges are at greater risk of a number of complications, ranging from brain injuries to SUDEP, one of the most common cause of death from seizures (F. Lado and S.L. Moshe, Epilepsia, 2009). Key features of epileptic seizures are increase in brain temperature (iTemperature) preceded by an increase in cortical blood flow, edema, increase in ICP in association with changes in heart rate and arterial pressure, and increase in GJ-coupling among neural cells. Detection of early events can reduce epilepsy risks.

[0020] Brain temperature, as an independent therapeutic target variable, has received increasingly intense clinical attention. While hyperthermia worsens outcome after brain injury (Dietrich et al. , 1996), brain hypothermia represents the most potent neuroprotectant approach in a number of common neurological diseases, including TBI, stroke and epilepsy. Seizure-susceptibility is attenuated by hypothermia therapy (Atkins CM et al., Eur. J. Neurosci. 2010) and prognosis and a number of studies, including ours (Fig. 2D), suggest that =39°C is a critical intracerebral temperature threshold worsening outcome of neurological diseases.

[0021] CSF 405 temperature, measured directly in the frontal horn of the lateral ventricle 406 («5 cm below the brain surface), is on average 0.3-0.9°C above body temperature (Hirashima et al., 1998; Rossi et al., 2001). Reports on human brain temperatures confirmed a thermal gradient from the hotter core to the cooler periphery (Whitby, 1971 ; Mellergard and Nordstrom, 1990; Hirashima et al., 1998).

[0022] Hypoxic-ischemic encephalopathy (HIE), is the brain injury caused by O2 deprivation, also known as perinatal asphyxia. The newborn's body can compensate for brief periods of depleted O2, but if the asphyxia lasts, brain tissue is compromised - “Gap junctions: Impact of seizures following perinatal HI insults on the extent of delayed neurotoxicity”, Epilepsy Foundation (US), Special Grants Program (2002) to Moshe S and Rozental, R.; Blockade of GJs in vivo provides neuroprotection following perinatal global ischemia. Stroke 36(10), 2005 (Rozental’s group).

[0023] Gap junctions (GJs), specializations of cell surfaces, mediate electrical synchrony and metabolic cooperation between apposed cells by providing conduits for the exchange of ions and small molecules (<1.5 kDa) by diffusion directly from one cell to another. These macrochannels appear as a plaque-like contact among cells, widespread in both the immature and adult brain - work by our group: “Molecular physiology of gap junction channels formed by connexin43”. In Ion Channels to Cell-Cell Conversations (R. Torre and J.C. Saez, eds.) Plenum Press, 1997; “Cell-cell communication via gap junctions”. In Fundamental Neuroscience (Zigmond, Bloom, Landis, Roberts and Squire, Eds.), Academic Press, 1999; “Gap junctions in the nervous system”. Brain Res. Reviews 32(1 ), 2000; “Dispelling myths about Cxs, pannexins and P2X7 in HI CNS” 2017.

[0024] GJs are built up by docking of two hemi-channels, each hemi-channel is composed of six protein subunits, called connexins (Cxs) (DeRobertis and DeRobertis, 1980). At least 20 Cx subtypes have been identified and at least 9 are expressed in the brain (Cx26, Cx30, Cx32, Cx33, Cx36, Cx37, Cx40, Cx43, Cx45 and Cx47). For most of them, orthologs in the human genome have been found - follows studies by our group: “Temporal expression of neuronal connexins during hippocampal ontogeny”. Brain Res. Reviews 32(1 ), 2000; “Nervous system diseases involving gap junctions”. Brain Res. Reviews, 2000.

[0025] Two Cxs are likely to be the major players in neurons and astrocytes: Cx36 is the specific Cx subtype expressed in CNS neurons (Rozental et al. , 2000), while Cx43 accounts for approximately 95% of all functional GJs expressed in cortical astrocytes - studies by our group: “Cell to cell signaling: An overview emphasizing gap junctions”. Cellular and Molecular Neuroscience (Ed: J. Byrne & J. Roberts), 2003; “Functional Properties of Channels Formed by the Neuronal GJ Protein Connexin36”. J. Neuroscience 19 (22): 1999.

[0026] Cx36 expression in the CNS appears to be restricted to neurons. Studies by our group: ‘Simple strategy for screening connexin-identity using RT-PCR assays’. Braz. J. Med. Biol. Res 32 (8): 1999; ‘Nervous system diseases involving GJs’. Brain Res. Reviews 32(1 ), 2000. ‘Gap junction-mediated bidirectional signaling between human fetal hippocampal neurons and astrocytes’. Dev. Neurosci. 23, 2001.

[0027] Cx43 expression has been established in astrocytes and a variety of studies support a role for interastrocytic GJs in cell death (Lin et al., 1998; Rami et al., 2001 ). Numerous roles have been postulated for GJ in the brain, including propagation of waves of spreading depression (SD) 301 and seizures. Intercellular communication mediated by GJs mediates direct exchange of ions and signaling molecules between cells thereby synchronizing electrical activity between neurons and metabolic activity within astrocytes, neurons and from one cell type to another. - studies by our group: Gap junctions: The “kiss of death” and the “kiss of life”. Brain Res. Reviews 32(1 ), 2000; “How to Close a Gap Junction Channel: Efficacies and Potencies of Uncoupling Agents”. Methods Mol. Biol. 154, 2001 ; “Reentrant Spiral Waves of Spreading Depression”, PNAS, 2012; “functional gap junctions are formed between rodent microglia and neurons”. J Neurosci Res. 82(3), 2005; “Molecular physiology of gap junction channels formed by connexin43”. In Ion Channels to Cell-Cell Conversations (R. Torre and J.C. Saez, eds.) Plenum Press, 1997; Alterations in metabolism and gap junction expression may determine the role of astrocytes as "good Samaritans" or executioners. Glia 50(4), 2005.

[0028] A HI penumbra is characterized by the potential for functional recovery, without damage, provided that local blood flow can be reestablished - as described in a number of studies, including ours - “Prevention of cerebral vasospasm by local delivery of cromakalim in subarachnoid hemorrhage”. J Neurosurq. 110(5), 2009; “Blockade of GJs in vivo provides neuroprotection following perinatal global ischemia”. Stroke 36(10), 2005; “Reentrant Spiral Waves of Spreading Depression” PNAS 109(7): 2585-2589, 2012 (FIG. 3 A)

[0029] During the ischemic subacute phase, GJ-mediated intercellular coupling increases within the penumbra, and between cells within the penumbra and adjacent healthy cells, to support exchange of vital metabolites through intercellular communication, and multiple electrical and biological signals are triggered by periinfarct tissue, triggering physiological waves of SD 301, which, in turn, antagonize electrographic seizures in areas adjacent to the penumbra.

[0030] A typical epilepsy patient experiences tonic-clonic motor seizures, which are EEG defined as ‘periods of abnormal brain electrical activity’. Such periods shall be referred to herein as ‘ictal’. Thus, on one hand, ictal period refers to states such as a seizure. On the other hand, interictal refers to the period between seizures.

[0031] The development of multi-electrode arrays for use in humans has provided new levels of temporal and spatial resolution for recording seizures. There is a sharp delineation between areas showing intense hypersynchronous firing and adjacent territories where there is only low-level, unstructured firing.

[0032] Investigations in TBI and hypoxic brain injury suggest that several drugs and assays may target SD waves 301. Manipulations in the occurrence and nature of SD waves can alter the threshold for seizure activity, and perhaps minimize immediate and long-term sequelae associated with epilepsy (Kramer et al. , 2017). Of note, the time period of electrical cortical silence (« 5 min) induced by a single wave of Spreading Depression lasts > 4x longer than ‘bursts’ of generalized seizures activity (Aiba et al., J Neurophysiol 107: 1032-1041 , 2012) (FIG. 3B) - most electrographic seizures last from 30 sec to two min.

[0033] SD 301 is a slow diffusion-mediated self-sustained wave of generalized depolarization of gray matter that does not respect synaptic connectivity and severely disrupts neuronal function. SD results in a temporary collapse of transmembrane ionic gradients and membrane potential and is characterized by a negative field potential IQ- 20 mV in amplitude and 1-2 min in duration, propagating at a velocity of a few millimeters/min. The advancing wave front is accompanied by a K⁺ efflux into the interstitial space, followed by a long lasting electrical silence, (FIG. 3A) - PNAS 109(7), 2012 (Rozental’s group). [0034] Studies showed that intercellular coupling through GJs is required for SD 301 propagation. Of interest, we described that single SD waves were self-sustained for 20 min up to at least 2 h (4-36 cycles), and that the impact of SD waves may be understood on the basis of the minutes-long depolarization associated with the collapse of ionic gradients across excitable membranes and changes in the extracellular: intracellular ratio of water volume. Further, Na⁺ channel activation in not essential for SD propagation (in contrast to action potentials). In addition, we reported that small increases in extracellular K⁺ — altered from 4 to 6 to 8 mM (as happens during seizures) — is sufficient to increase the “excitability” of the nervous tissue to SD waves, with respect to shortening of the refractory period to these slow waves. Thus, SD waves may be elicited repetitively in a time frame in which the nervous tissue is still refractory to action potentials generation and propagation (absolute refractory period) - PNAS 109(7):2585-2589, 2012 (Rozental’s group).

[0035] Since its original extensive description by Leao (Leao A.A.P., 1944), thousands of publications have characterized the phenomenon (SD). In human or in animal models, in vitro or in in vivo, SD can be elicited by a wide variety of stimuli. These include mechanical stimulation, tetanic or direct current (DC) stimulati, KCI, hypo/hyper-osmotic medium (e.g., a droplet of H2O [50 pL]), mechanical (e.g., vibration, balloon-stretching), photonics (e.g., pulse lasers) and thermal-based (cold or heat) catheter microtubing, metabolic inhibitors, ouabain, glutamate receptor agonists (e.g. glutamate release from astrocytes activating dendritic processes), and endothelin. Of these, stimulation with KCI has been the most widely used, and most models of SD include elevations in [K⁺]₀ (extracellular K⁺) as a critical event in the initiation of SD (Martins Ferreira, Nedergaard and Nicholson, 2000). [0036] The seminal work of SD (Leao A.A.P., 1944 - J Neurophysiol 7: 359-390, 1944) unveiled that cortical stimulation was followed by a flattening of the spontaneous ECoG waves traced by the Grass oscillograph. The ECoG activity in the electrodes nearest to the stimulated area was silenced first, and then the extinction spread in orderly sequence from one electrode pair to the next, eventually covering almost all the cortex. Recovery of the ECoG waves occurred in the same sequence as their previous depression. Accordingly, Aiba et al. (J Neurophysiol 107: 1032-1041, 2012) showed that the time period of electrical cortical silence (« 5 min) induced by a single wave of SD lasts > 4x longer than ‘bursts’ of generalized seizures activity 301 (FIG. 3B). It is worth noting that most seizures last from 30 sec to two min. While the concept of Leao cortical SD- mediated blockade of EEG discharges is not new, it has not yet been optimized for a device-system to abolish seizures.

[0037] Intracranial monitoring of waves of SDs 301 can be performed with platinum electrodes in unfiltered DC-coupled recordings (Hartings JA et al., 2017 - “Direct current ECoG for clinical neuromonitoring of spreading depolarizations”, J. Cereb Blood Flow Metab 2017, Vol. 37(5) 1857-1870). The SDs are characterized by negative DC shifts throughout recordings.

[0038] EEG waveforms may be characterized based on their location, amplitude, frequency, morphology, continuity (rhythmic, intermittent or continuous), synchrony, symmetry, and reactivity. However, the most frequently used method to classify EEG waveforms is by the frequency, so that EEG waves are named based on their frequency range: delta (0.5 to 4Hz); theta (4 to 7Hz); alpha (8 to 12Hz); sigma (12 to 16Hz) and beta (13 to 30Hz). In addition, there are other waveforms such as infra slow oscillations (ISO) (< 0.5Hz) and high-frequency oscillations (HFOs) (> 30Hz).

[0039] BCI are systems that allow communication, through wired or wireless networks, between the brain and a variety of machines. The BCI system works in three main steps: collecting brain signals, interpreting them and outputting commands to a connected machine according to the signal received.

[0040] BCI is separated in three categories depending on the method used to collect brain signals: i) non-invasive; ii) semi-invasive; and, iii) invasive. Accordingly, the EEG signal is taken by placing electrodes on the scalp, so on the most external part ( non- invasive) , the ECoG signal can be taken from electrodes placed in the dura 408 or in the arachnoid ( semi-invasive ) or the intraparenchymal signal is taken directly implanting electrodes in the cortex ( invasive ) (FIG. 2, FIG. 4, FIG. 7).

[0041] EEG provides the recording of electrical activity of the brain from the surface of the scalp. It takes thousands of snapshots of electrical activity across different sensors in a single sec. The spatial resolution of EEG is determined by the number of electrodes used. Typically at least 32 electrodes are used, up to 256. In general, spatial resolution for EEG is low (e.g., compared to ECoG and fMRI) because the signal needs to travel through different layers up to the skull 401.

[0042] ECoG uses electrodes placed on the exposed surface of the brain to measure electrical activity from the cerebral cortex. The electrodes may be placed on top of the dura mater (epidural) or under the dura mater (subdural) 408.

(FIG. 4). The strip or grid electrodes covers a large area of the cortex (from 4 to 256 electrodes). The positive characteristics of ECoG are: i) high spatial resolution and signal fidelity; ii) resistance to noise; iii) lower clinical risk and robustness over long recording period; and, iv) higher amplitude.

[0043] Deep brain stimulation (DBS) is a neuromodulation procedure designed to help in the management of refractory seizures. DBS involves implanting electrodes into specific areas of the brain, and then stimulating these areas with small regular electrical pulses modulated by electrical stimulation devices (ESDs). In this context, only a few developers, including NeuroPace, claim to perform and detect seizures prior to their onset. However, NeuroPace efficacy is limited to 67% during the first year of the therapeutic procedure. The estimated cost of the system is about $37,000 ($35,000-$40,000), out of reach to a large fraction of individuals.

[0044] Implantable devices have been developed aiming to provide both detection/prediction of ictal activity and electrostimulation for attenuating or stopping an epileptic seizure, like NeuroPace (US Pat. No. 6,810.285). The EEG recording electrodes at a depth of up to about 1 to 2 cm into the brain lobes - at most 1/3 to 1/4 of the average distance between the scalp and the ventricle 406, are connected to the implant device implanted on the outer surface of the cranium - used for the detection of ictal activity as well as the delivery of DC electrostimulation.

[0045] Examples mentioned so far, and particularly those utilizing batteries, have constant voltage sources. Once the current is established, it is thus also a constant. Direct current (DC) is the flow of electric charge in only one direction. It is the steady state of a constant-voltage circuit. Most well-known applications, however, use a time-varying voltage source. Alternating current (AC) is the flow of electric charge that periodically reverses direction. If the source varies periodically, particularly sinusoidally, the circuit is known as an alternating current circuit.

[0046] Fluctuating DC does not exist, but, at the instant of connection of a DC voltage to a load, a transient current flow through the conductors (wires, PCB traces, etc.) charging up their capacitances. This transient current is AC, and is actually a propagating EM wave that generates fluctuating EM fields (magnetic and electric) as it travels along. Afterwards, the current is DC and there is no more propagating EM wave. The EM fields are static instead of fluctuating. AC current travels at the speed of light in the medium, which is about 300,000 kilometers/sec for a bare wire in air, and about 210,000.000 km/s for a wire with a thick layer of PVC insulation. Continuous DC currents, on the other hand, are associated with a continuous flow of electrons from the negative to the positive terminal - travelling at a velocity of about 4 kilometers (about 3 miles)/hr. [0047] The literature shows that both DC and AC stimulation support effective neurostimulation outcomes (e.g., Fusca, Ruhnau, Demarchi, Weisz, & Neuling, 2015). However, because of unique aspects of AC stimulation properties, it may command the wider range of clinical applications going forward (Antal & Paulus 2013; Herrmann et al., 2013).

[0048] DC is commonly found in many extra-low voltage applications and some low- voltage applications, especially where these are powered by batteries or solar power systems (since both can produce only DC). Most electronic circuits require a DC power supply. The DC current, unlike AC, does not change the magnitude and polarity with time. It is characterized by a constant magnitude and direction and as the direction and magnitude not changes so the frequency of the current is zero. In contrast, the AC current displays Time Period and Frequency.

[0049] DC stimulation tends to modulate neuronal activity in a polarity-dependent way, either increasing local neural excitation (anodal stimulation) or decreasing it (cathodal stimulation), depending on which of two electrodes is placed over a target area. That is, DC stimulation mainly affects the firing rate of neurons in the target area. Stimulation may be continuous or intermittent (pulsed). EEG findings support the notion that DC stimulation’s site-specific effects also can provoke sustained and widespread changes in other parts of the brain via the brain’s multicircuit networks (Zaghi et al., 2009; Tanaka & Watanabe 2009; Jaberzadeh & Zoghi, 2013).

[0050] tDCS is applied to modulate excitability of dysfunctional neurons. Accordingly, weak electrical pulses (in the range of 0.1 - 2 mA [0.002 amps), applied through electrodes placed on top of the scalp, with conduction to the scalp facilitated by conductive gels, modulate the static DC fields altering the firing rates of neurons. Clinically, tDCS has shown to improve cognitive functions (such as memory, attention, or language processing) as well as motor functions (such as strength or dexterity) in patients with neurological conditions (Boggio et al., 2006; Reis et al., 2009; Orban de Xivry et al., 2011 ; BOtefisch et al., 2004; Fregni et al. , 2005; de Vries et al., 2010; Galea and Celnik, 2009). Frequently used parameters include an electrode size of 25-35 cm², a current of 1-2 mA for up to 20-40 min, for 1 up to 20 sessions; shown to be safe and effective (Brunoni et al., 2012).

[0051] Another way of modulating an electric field is by stimulating the neural tissue through an electrode-to-tissue interface (ETI). Accordingly, implantable and partially implantable devices/systems are available, such as a "System for Treatment of Neurological Disorders' (US Pat. No. 6,016,449). The system is reported to be configured so that, when the neurostimulator detects EEG activity believed to be associated with a seizure or to be a precursor of a seizure in the ECoGs, it will deliver electrical stimulation to targeted areas of the brain with the goal of eliminating seizure activity and/or reducing the severity of the seizures.

[0052] The magnitude of this capacitive current is key to safety of neurostimulation, and has been characterized for some materials from which electrodes are commonly fabricated. Platinum, for example, yields a theoretical charge storage capacity of 200 pC/cm² (micro coulombs) and a practical charge storage capacity of 50 pC/cm². Oxide materials such as iridium oxide may reversibly store more than 1000 pC/cm². These charge densities are more than sufficient for a pulsatile or a high frequency stimulation in most cases. By comparison, a typical DBS of 3 mA for a 90 pS pulse width on a 5.7 mm² electrode passes 5 pC/cm². On the other hand, low frequency, non-pulsatile electrical stimulation is constrained in most cases by these limits. For instance, a 1 Hz sinusoid delivered at 1 mA peak-to-peak on a 5.7 mm electrode passes 2800 pC/cm² per phase. [0053] The sources for electrical stimulation presented above can be grouped into different categories: (1 ) pulsatile or AC stimulation; (2) DC stimulation; and (3) non- pulsatile and near-DC stimulation. Non-pulsatile or near-DC stimulation and DC stimulation are expected to be less effective than to pulsatile or to AC stimulations when applied through an implanted ETI because of charge densities and the inability to maintain charge balancing during delivery (Merril et al. (2005).

[0054] Quality and sensitivity of subdural and epidural EEG signals simultaneously recorded are comparable and superior to that of scalp recordings, because of the nature of the transfer function across the skull 401 (John et al., Nature, 2018).

[0055] The cranium attenuates signals in a non-linear, frequency dependent fashion suggesting a capacitive, filtering effect at very high frequencies (100 Hz-10 MHz) (Faes et al., 1999). Pfurtscheller and Cooper in 1975 showed frequency-dependent attenuation up to 70 Hz (Duun-Henriksen et al. , 2013; Pfurtscheller et al., 1975).

[0056] The quality of recordings from endovascular or epidural arrays are comparable to recordings from subdural arrays, with reduction in electrode size resulting in enhanced spatial resolution across all arrays (John et al., 2018, Nature). However, while the long term use of endovascular arrays raises concern of platelets thrombus formation, the EEG findings obtained with both epidural and subdural arrays provide support for high quality and high sensitivity intracranial recordings.

[0057] Therapeutic hypothermia (TH) has shown benefits in various clinical settings, including post-cardiac arrest and neonatal HIE, and has been found to control ICP in patients with TBI and stroke. Experimentally, TH has been shown to have anticonvulsant and neuroprotective effects after a variety of conditions, including SE - US Pat. No. 9,770,360 B2 - granted to Rozental R, 2017 for a “Therapeutic Brain Cooling System and Spinal Cord Cooling System”.

[0058] Autogenous bone grafts remain the gold standard for cranial reconstruction. While several problems remain that limit the wide utilization of such option, customized PMMA implants, titanium mesh, porcelain implants and high-performance thermoplastics, such as LCP, PPS or PEEK (Polyetheretherketone), among others which are available - ‘A Comprehensive 3D-Molded Bone Flap Protocol for Patient-Specific Cranioplasty’ Prot Exchange (2021) (Rozental’s group);

[0059] Treating AED-resistant epileptic patients, who underwent decompressive craniectomy, remains a clinical conundrum. But, placing the system on top of the dura following DCT has advantages, among them: 1 ) lack of bone tissue (scattering effect of bone) improves long-term recordings of EEG (seizures, waves of SD) 301 and ICP (P1 , P2and P3 waves) measures; 2) acquisition of ICP measures and real time wireless transmission of high resolution EEG signal through the patients skin (the only tissue above the device); 3) battery replacement.

[0060] The choice of electrode strips versus grids is based on the location and degree of coverage desired of suspected epileptogenic regions (FIG. 7). Subdural electrodes are usually manufactured from soft, flexible, thin transparent Silastic sheets that have small metal contacts and wires embedded within them. Both stainless steel and platinum contacts are available. Commercial providers offer an array of choices in varying dimensions. A common configuration spaces the 5 mm electrode centers 1 cm apart. Various sizes of grids are available, such as 4 ^c 5 cm and 6 x 8 and 8 ^c 8 cm. Both strips and grids have electrode leads.

[0061] Ventriculoperitoneal shunt catheters (VPS) are placed inside one of the brain’s ventricles 406 to divert fluid away from the brain and restore normal flow and absorption of CSF 405. The procedure, proved to be safe, has good clinical and hemodynamic results. Thus, a single VPS catheter (intracranial lengths 4-9cm, 1.5 mm ID, 3.0 mm OD) 407 can be employed for as long as clinically indicated.

[0062] A variety of pressure sensors are currently available, including MXenes, a kind of two-dimensional unit that displays an ‘accordian-like shape’. MXenes have emerged as a unique class of layered-structured material with key features, as good conductivity (comparable to metals), enhanced ionic conductivity, hydrophilic property (derived from their hydroxyl or oxygen-terminated surfaces), and mechanical flexibility (Xin M et al., Front Chem 21 April 2020). Their unique accordion-like appearance, attractive electronic, optical, and magnetic properties, including energy storage (Lukatskaya et al., 2013; Ghidiu et al., 2014; Anasori et al., 2017), electromagnetic shielding (Shahzad et al., 2016), and sensing (Chen et al., 2015) confers a unique level of specificity to be used intracranium.

BRIEF SUMMARY OF THE INVENTION

PREAMBLE - Nearly 1/3 of patients with epilepsy continue to have seizures despite advancements in bioengineering and medicine. Of note, epileptic patients, with uncontrolled seizures, in resource-deficient countries face wait times of years - or stand in line over their lifetime - for relief of ‘sinking skin flap syndrome’. Some of the difficulties in managing treatment-refractory epilepsy, in the absence of cranial repair, can be ameliorated by the ability to detect and abolish clinical seizures. Such systems would also be able to prevent SUDEP, accidents and limit injury.

[0063] ETI-ND: The ETI-ND device is a light-weight “3-in-1 sensor system” (EEG/ iTemperature/ICP), an important seizure monitoring tripod, combined with 1 effector electrode system to trigger SD waves 301, is mechanically flexible and stretchable to meet patient needs (FIGS. 5-6). The ETI-ND device is composed of 4 different modal units: i) EEG sensors (grids/flexible strip electrodes; ii) thermal sensor (n=1-10); iii) ICP (accordion-like shape or single-layer pressure) (n=1-10); and SD electrodes (n=1-10). The different modal units contained within a single physical enclosure, namely the ‘housing’ (FIGS. 5-6), may comprise a plurality of spatially separate units each performing a subset of capabilities mentioned above. Of note, the combined multiple functions (EEG, thermal and pressure sensors and SD electrodes) and capabilities of the subsystems described above may be performed by electronic hardware, computer software (or firmware), or a combination thereof.

[0064] It includes a remote terminal that wireless collects information from the device’s ‘central processing unit’ (CPU) 507 and transfers it to a patient data management system, where neurologists may evaluate seizure activity and provide a tailored feedback through the ‘’Communication System” (FIG. 6A), updating the CPU 507 by fine-tuning the seizure ‘Detection Subsystem” (FIGS. 5-6).

[0065] As a result, an active feedback loop triggers waves of SD more efficiently, capable of leading to a silencing of brain excitability. These early detection systems are able to effectively abort seizures, tailoring antiseizure treatment.

[0066] Therapeutic strategy (more accurate detection): increases in ICP and iTemperature are closely associated with partial and generalized seizures. Thus, changes in ICP can be a useful surrogate marker of seizures on the intensive care unit in association with changes in heart rate and arterial pressure (Yang et al. Epilepsy Res., 2002). On a parallel track, focal seizures produce an increase in local cerebral metabolism and blood flow, leading to changes in brain temperature within a few sec of seizure onset. (FIG. 2, FIG.6A,B,C; FIG. 7).

[0067] An ETI device, 3-in-1 sensor system, capable of monitoring ICP and iTemperature measures (FIG. 6): an implantable device according to the invention is tailored made for detecting and abolishing epileptic, high frequency EEG discharges, and EEG seizures in real-time on a 24-7 basis.

[0068] The ETI device system includes a low-power CPU, as well as customized electronic circuit modules in a detection subsystem (FIG. 6A). As described herein, the detection subsystem, which in the context of the present application is a form of detection of abnormal EEG discharge patterns, ictal and electrographic seizures, and monitor SD slow waves, triggered by the ETI system to abolish the abnormal electrical activity. [0069] An ETI system for detecting and abolishing seizures of a living being semi-invasive (epidural or subdural) 404, wherein the system comprises: EEG sensors for detecting brain fast and slow electrical activity, ‘accordian-like pressure sensors’ (e.g., multi-layer sensors or single layer pressure sensors), and a set of thermosensors; an analyzer that receives the intracerebral blood arterial pressure information and derives at least one parameter that correlates with ICP (e.g., a time delay between systolic maximum and the dicrotic notch) to provide ICP data from the blood pressure information; and an output device (e.g., a monitor, cell phone) for displaying the ICP and iTemperature data.

[0070] An aspect of one of the embodiments disclosed herein includes the realization that maximizing treatment outcomes can be achieved by providing epileptic patient with an implantable ETI system that is configured to trigger and to detect neurodepressive waves of SD 301 , followed by an electrical silence (i.e., refractory period), during which ictal discharge can not propagate (FIG. 3B).

[0071] In another embodiment, a set (n=1-10) of compact size thermal sensors, although wired to the epidural/subdural “housing” (EEG/ICP), are placed on another domain (intraparenchymal) 407 to allows for rigorous iTemperature monitoring. On such example provided below, 5 thermal sensors are placed along an intraparenchymal conduit extending downwardly from the ‘housing’ (level of the ETI-ND system implantation - level 0) to the vicinity of the cerebrospinal fluid (CSF) 405, 407 (ventricles 406) (FIG. 4, FIG. 8). Sensors are therefore positioned at 1 cm, 2 cm, 3 cm, 4 cm (to assess parenchymal temperatures), wherein the 5^th sensor directly senses the temperature of the CSF 405 (i.e. , temperature of the liquor) ( baseline temperature), providing a signal representative of the thermal gradient from the hotter core to the cooler periphery to the temperature device circuitry by way of the conduit 604 (FIG. 8).

[0072] In some embodiments, the ETI-ND system can be implanted within the bone defect 408, placed either over the exposed dura mater, or subdural, facing the brain parenchyma. As such, an existing large-sized cranial defect, arising from many etiologies, can easily accommodate the ETI-ND.

[0073] In the event of cranial defect reconstruction (cranioplasty), the implantable ETI- ND system can be repositioned and fixed on the inner face of the cranial prostheses (periosteum/pericranium placement). The attachment of the ETI-ND system to the prostheses is independent of the physical and mechanical properties of material used for its construction (e.g., PMMA bone-like cement, titanium mesh, PEEK polymer, ceramics). BRIEF DESCRIPTION OF THE FIGURES

[0074] FIG. 1 illustrates cranial reconstruction on patients who could not afford medical support. (A) Cranial defect printout 101. (B) customized PMMA prosthesis 102; (C) assembled models to test precision prior to fixation 102. (D) Postoperative CT. Notice the coaptation of the prosthesis to the bone defect. (E) view of the cranial defect after craniectomy. (F) 30 days postoperative follow-up patient J.S.S. shows a great cranial symmetry. Bone defect features: surface area (cm²): 148.70; prosthetic volume (cm³): 53.30. DOI: 10.21203/rs.3.pex-1384/v1 (Rozental’s group, 2021 ).

[0075] FIG. 2 illustrates ICP and brain temperature monitoring in TBI patients (A) A mechanical NI-sensor & transducer set 201 consists of a support bar for detection of local bone tissue or prosthesis deformations adapted with strain sensors. The equipment filters, amplifies, and digitalizes the signal from the pressure sensor (Sensor PICNI2000), and sends the data to a computer. Detection of these deformations, modeled by finite elements calculations, reveals: i) the Percussion P1 wave (cerebral arterial pulsation); while, ii) the tidal P2 wave (brain ‘compliance’). Bone defect features: surface area (cm²): 145.50; prosthetic volume (cm³): 51.17. (B) Abnormal noncompliant ICP waveform before cranioplasty (sensor positioned adjacent to the bone defect). Under abnormal conditions (e.g., decompressive craniectomy), brain compliance starts decreasing resulting in reversal of P1 :P2 ratio (i.e., P2>P1 ) which is a sensitive predictor of poor brain compliance. (C) Immediately after cranioplasty, a ‘normal-like’ ICP waveform is reestablished - DOI: 10.21203/rs.3.pex-1384/v1 (Rozental’s group, 2021 ); (D) Post craniotomy undergoing brain microdialysis and iTemperature monitoring (Upper left panel). Simultaneous recordings of central and peripheral changes in AP (Upper right panel). (Bottom panel) Brain iTemperature monitoring over 72 hrs. Methods: ICP, cerebral perfusion pressure, cerebrovascular pressure reactivity index and microdialysis markers during 72 hrs (sampling rate/hr) (CMA Microdialysis AB; LICOX probe, perfusion flow rate of 0.3 ml/min, dialysis probe length 10-mm).

[0076] FIG. 3 is interplay between slow waves (SD) 301 and fast waves (seizure discharge). The negative direct current shift (<0.05 Hz) 301 is an important identifier of cortical depolarization, followed by a long-lasting period of electrical silence (‘refractory period) of the nervous system. (A) the hallmark of SD 301 is a DC shift in the milli-Hertz range (<0.05 Hz) that reflects the mass breakdown of electrochemical membrane gradients and reaches up to 20mV in amplitude. The depolarization block of synaptic activity, along with subsequent factors, further cause suppression of cortical activity, known as SD, in the functional range of 0.5-70 Hz. (B) stimulation of waves of SD resulting in prompt depression of brain excitability. Representative responses showing SD recording (top) and electrocorticographic (ECoG; middle) and relative ECoG (bottom) power following a single SD wave 301 generated by electrical stimulation. SD was recorded as large, long-lasting negative DC potential shift coupled with transient suppression of ECoG activity (Aiba et al. , J Neurophysiol 107: 1032-1041 , 2012). Of note, the time period of electrical cortical silence (« 5 min) induced by a single wave of SD lasts > 4x longer than ‘bursts’ of generalized seizures activity (last from 30 sec to two min). [0077] FIG. 4 illustrates the fitting positions (non-invasive, semi-invasive and invasive monitoring) to place electrodes, sensors and ETI devices relative to cortical neuroanatomy: skull 401, grey matter 402, white matter 403; ETI-ND ‘housing’ 404. [0078] FIG. 5 is a schematic illustration of the ETI-ND device system. The hardware 505, 506 can be viewed in two layers. (Superior layer) 505: (1 ) electrode interface. (2) detection subsystem; (3) SD interface; (4) stimulation subsystem; (5) CPU/microcontroller; (6) memory subsystem; (7) communication system; ( ) energy 508. (Inferior layer) 506: electrodes to trigger SD waves 501, Thermal sensors 502, Pressure sensor 503 and EEG sensors 504. The ETI-ND system is mechanically flexible and stretchable to meet patient needs.

[0079] FIG. 6 (A) is a block diagram illustrating the main functional subsystems of the ETI-ND implantable system according to the invention, as shown in FIG. 5; (B) is a schematic illustration of an extensive cranial defect (14 cm larger diameter), after a DCT procedure (lateral view), showing the placement of an implantable ETI-ND device system (shown in A) according to an embodiment. The diagram depicts the electronic components (sensors and electrodes) within the lower layer 506 (i.e. , the case and the components of the hardware within the upper layer 505 of the system, as shown in FIG. 5, were removed for clarity) placed on top of the dura. (C) The outermost small rectangle (left hand side) delineates the area containing stimulation electrodes to trigger SDs 501; the small gray rectangle (adjacent to the large circle) delineates the area containing thermal sensors 502; thermal recordings illustrated underneath; the large black circle (middle) delineates the area containing the pressure receptor(s) 503 - above recordings of normal ICP waves (P1 , P2, P3); the larger rectangle area delimits the area containing AC-EEG sensors 504 (epilepsy and electrographic discharges monitoring); EEG tracing samples (right hand side); scale: vertical bar: 1 mV; horizontal bar: 1 sec) and DC-EEG sensors (SD monitoring - negative shifts recordings [bottom recordings, in black]; scale: vertical bar 10 mV);

[0080] FIG. 7 illustrates EEG video-monitoring in the management of patients with refractory epilepsy. (A) Schematic display of EEG electrode positions anterofrontal (AF), frontal (F), frontocentral (FC), central (C), centroparietal (CP), parietal (P), parietooccipital (PO), and temporal (T); (B) Optimal EEG window size for neural seizure detection; (C) Recording of a typical seizure event (duration 1 min).

[0081] FIG. 8 illustrates optional intraparenchymal catheters 407 that can be attached to the ETI-ND device. Two models, wherein having the distal tip (5^th sensor) into the ventricle 406, were conceived: (i) model #1 - senses the temperature of the CSF 405,601 ( baseline temperature ); and, (ii) model #2 - senses ICP 602. In both catheter options 604, iTemperature sensors 603 are positioned at 1 cm, 2 cm, 3 cm, 4 cm 604 along the parenchyma. These thermal sensors (l^st-4^th unit 603) provide a signal representative of the gradient from the hotter core to the cooler periphery.

DETAILED DESCRIPTION OF THE INVENTION (PREFERRED EMBODIMENT)

[0082] Mechanistically: interplay between cortical SD and seizures 301. Membrane excitability is a general term used to encompass the processes of activation of ion channels and energy-dependent pumps critical for the generation of an action potential, underlying seizures and epilepsy, and that subsequently restore the local environment such that neurons can generate and maintain impulse conduction. In the absence of SD waves, the functional recovery of a neuron, after an activation process terminates, takes up to 100 msec (Baker et al. , 1987). In terms of underlying physiological processes, the refractory period results from inactivation of transient Na⁺ channels (Hodgkin and Huxley, 1952). As such, the refractory period may be prolonged in neurons by waves of SD, due to maintained neuronal depolarization and slowing Na⁺ channel kinetics of reactivation. Of note, a single episode of a triggered SD wave 301 can induce a prolonged period of electrical cortical silence (> 5 min) (‘refractory period’). Thus, sequential application of brief stimuli to trigger SD waves (e.g., one pulse at each 2-4 min), prolong the refractory period to ongoing seizures, improving seizure control in AED-resistant epilepsy.

[0083] There are a few devices available that can detect repeated shaking movements during a seizure. These may work with tonic-clonic seizures or focal motor seizures with enough movements to trigger the device. Seizures without big movements (such as absence seizures and many types of focal or partial seizures), are not detected by these devices. Therefore, a more effective seizure alert is required to notify caregivers and prevent life threating conditions, such as SUDEP.

The disclosure will be further described with reference to the accompanying drawings, by way of example and without intending to be limiting.

[0084] An implantable device according to the invention for detecting and abolishing epileptic seizures (ictal high frequency and interictal EEG oscillations) in real-time on a 24-7 basis while monitoring EEG 504, iTemperature 502, and ICP 503 measures. The ETI-ND device includes a low-power CPU, as well as customized electronic circuit modules in a detection subsystem (hardware - upper layer) 505 (FIGS. 4-5A). As described herein, the detection subsystem, which in the context of the present application is a form of detection of EEG electrographic discharge patterns and/or slow waves, among them waves of SD. Generally, as described herein, an event (such as an epileptic seizure or electrographic pattern) may be detected, not statistical or stochastic in nature, as indicative of the event and promptly elicit an SD wave 501 (interplay sensor interface/detection subsystem/SD interface/stimulation of SD electrode to elicit a SD wave 301,505, 506 (FIG. 5B,C).

[0085] The invention, and particularly the EEG detection subsystem thereof, is specifically adapted to perform much of the signal processing and prompt analysis requisite for accurate and effective event detection and perform a positive feedback loop to trigger waves of SD 301. The CPU (507) remains in a resting ‘sleep’ state characterized by relative inactivity and is periodically awakened by interrupts from the detection subsystem to perform tasks related to ICP wave and iTemperature measures, or to detect triggered SD waves, enabled by a different module (DC) of the same device system. [0086] Delineations between ictal and postictal may not be obvious, thus, an update of personalized criteria and adjustment of threshold for seizure detection in a particular patient is required. The ETI-ND’s EEG circuitry is sensitive to subtle changes in ICP and iTemperature measures of individual epileptic patients, improving the criteria of detection/validation window of threshold to trigger SD waves 301. Three patterns of responses/processes are considered (FIG. 6A): i) ‘SHORTEST LOOPING PATH’ - the electrode interface/detection subsystem/stimulation subsystem/SD interface/elicited SDs - this allows for faster actions to occur by promptly activating the SD interface (e.g., during monitoring of an EEG event that is associated with ictal activity, showing fast spike-and- wave, polyspike-and-wave and slow wake superimposed with fast activity patterns); ii) ‘FULL SELF-LOOP’ - electrode interface/detection subsystem/CPU/Memory subsystem/CPU/stimulation subsystem/SD interface/elicited SDs - offers a more sophisticated/personalized approach to the variety of hemodynamic data (EEG, ICP and iTemperature); and, iii) ‘LONGEST LOOPING PATH’ - ETI-ND/communication system/PC/cloud network.

[0087] Accordingly, in one embodiment of the invention, a system according to the invention includes a CPU 507, a detection subsystem located therein that includes a waveform analyzer. Identification of consistent distinguishing features between preictal and interictal epochs (cycles within a given dataset) in the EEG is an essential step towards performing seizure validation and eliciting ND responses (i.e. , SDs) 301 to counteract abnormal electrical activity. The ETI-ND system separates preictal and interictal states based on the analysis of the high frequency activity and amplitude (i.e., temporal summation of the synchronous activity) of EEG waves, quantifying the similarities between their underlying states and a reference state. A discriminant analysis is then used in the features space to classify epochs. Performance is assessed based on sensitivity and false positive rates and validation is performed. The waveform analyzer includes waveform feature analysis capabilities (such as wave characteristics) as well as window-based analysis capabilities (such as line length and area under the curve), and both aspects are combined to provide enhanced electrographic event detection. A CPU (FIG. 5, FIG. 6A) is used to consolidate the results from multiple EEG sensors and coordinate responsive action when necessary. In another embodiment of the invention, pressure and thermal sensors (mesh networked monitoring platform, grid electrodes or flexible strip electrodes - to conform to the dural surface) may give an accurate measurement of intracranial ICP and iTemperature and therefore help tailor threshold for EEG seizure detection and thereby effectively elicit personalized SD responses and prevent “kindle”.

[0088] The ETI-ND system also includes a remote monitor that wirelessly collects information from the device and transfers it to a patient data management system, where physicians may view and follow-up seizure activity, reprogram the internal memory of the device (learning procedure) and adjust therapy progress, enabling neurologists to personalize and optimize therapy over time (personalized treatment) (LONGEST LOOP PATH) (FIG. 6A).

[0089] European guidelines have stated that MRI at 1.5 T can be performed safely following the manufacturer instructions in patients with MRI-system (class lla); [0090] The ETI-ND system can be powered 508 by either a small battery unit, inductive coupling, or by body heat (Fujitsu Laboratories Ltd).

[0091] Optional invasive catheters (6-10 cm long parenchymal probe) 407, 604 (FIG. 8): iTemperature 601,603 or iTemperature & ICP sensors 602,603. The sensor can be attached to a probe-like extension that can extend from the vicinity of the ETI-ND (subdural or epidural), through the dura, and down to the level of the CSF 405 («5 cm). The probe can include a pressure sensor (model 2) 602 or a thermal sensor (model 1) 601 attached thereto and positioned to communicate directly with the CSF 405 (FIG. 4). The subdural sensor of the invention can thus directly sense the pressure or the temperature of the CSF. Accordingly, the additional subdural thermal sensors can provide a direct reading of the thermal gradient across the brain parenchyma (FIG. 4). A ‘housing’ 404, can contain the other elements of the ICP monitoring system, such as the battery and the electronics (FIG. 6A), and any other required components (FIG. 5). The ETI-ND system can also be placed on the inner face of the prosthesis (FIG. 1, FIG. 4), during cranial repair 101, 102, facilitating implanting an intraparenchymal (FIG. 4) monitoring system 407 under adverse seizure conditions.

Claims

1. An implantable semi-invasive flexible ETI-ND device, placed subdural or epidural, for detecting cortical EEG seizures, comprised of:

• EEG sensors (504), iThermal sensors (brain temperature) (502) and ICP sensors

(503);

• An implantable ‘housing’ (404), containing the hardware (505,506);

• A CPU (505), embedded in the hardware device, placed within the ‘housing’, composed of structured hardware- and software-based architecture to analyze and generate three response speeds and level of complexities: i) ‘SHORTEST LOOPING PATH’ - the electrode interface/detection subsystem/stimulation subsystem/SD interface/elicited SDs; ii) ‘FULL SELF-LOOP’ - electrode interface/detection subsystem/CPU/Memory subsystem/CPU/stimulation subsystem/SD interface/elicited SDs; and, iii) ‘LONGEST LOOPING PATH’ - ETI-ND/communication system/PC/cloud network/mobile; and, an output device for displaying ICP data.

2. An implantable semi-invasive flexible ETI-ND device, according to claim 1, wherein the CPU (507) is powered (508) by a small battery unit, using inductive charging or body heat.

3. An implantable semi-invasive flexible ETI-ND device, according to claim 1, wherein the ‘analyzer’ is comprised of:

• time analyses, frequency analyses and wavelet domain analyses (507);

• analog to digital conversion, digital filtering, pressure pulse, iTemperature and EEG detection, pulse averaging and parameter extraction;

• the ‘analyzer’ evaluates a plurality of time derivatives of the EEG (504), iTemperature (502) and blood pressure (503) wave forms;

• an SD interface (501 ) to induce neurodepressive waves of spreading depression (301 ).

4. An implantable semi-invasive flexible ETI-ND device, according to claims 1 and 3, wherein the EEG sensor (504) is comprised of a DC or AC current sensor.

5. An implantable semi-invasive flexible ETI-ND device, according to claims 1, 3 and 4, wherein said pressure sensor (503) is comprised of an ‘accordian-like’ shape sensor or single layer pressure sensors, wherein detecting a feature is comprised of a time delay between systolic maximum and the dicrotic notch.

6. An implantable semi-invasive flexible ETI-ND device, according to claims 1, 3, 4 and

5, wherein the thermal sensor (502) is comprised of chip glass thermistors or NTC thermistors, thermopile, thermocouple, or thermal sensors of other kinds, including but not limited to MEMS technology (micro-electro-mechanical systems sensors).

7. An implantable semi-invasive flexible ETI-ND device, according to claim 6, wherein the thermal sensors (601, 603) are placed invasively intraparenchymal along a catheter 6F conduit (407,604), or other catheter sizes, extending downwardly from the ‘housing’ level {level 0) to the vicinity of the cerebrospinal fluid (CSF) (405, 407) (ventricles (406)); wherein sensors are positioned at 1 cm, 2 cm, 3 cm & 4 cm to assess parenchymal temperatures (603); wherein the 5^th sensor directly measures the temperature of the CSF (405, 601), providing a baseline temperature ; this is a key component of the thermal gradient from the hotter core to the cooler cortical periphery by way of the conduit connected (604) to the ‘housing’ circuitry.

8. An implantable semi-invasive flexible ETI-ND device, according to claims 1, 6 and 7, wherein the 5^th sensor (ICP) (602) of the conduit (604) is positioned into the ventricle (406) and directly measures the ICP data of the CSF (405) - dual mode catheter ICP and thermal sensors (1^st, 2^nd, 3^rd and 4^th sensors) (602,603).

9. An implantable semi-invasive flexible ETI-ND device, according to claim 1 , placed on top of the dura or subdural, wherein the CPU has been programmed to automatically elicit repetitive waves of SD (301) at 2-5 min interval by the topical delivery of brief pulses of 1- 100 pL hipo- or hypertonic-solutions; by mechanical stimuli such as vibration, balloon stretching; photonics such as pulse lasers; thermal-based cold or heat catheter microtubing or by applying topical ND pulses to the brain; all of these modalities are controlled by EEG, iTemperature and ICP feedback.

10. An implantable semi-invasive flexible ETI-ND device, according to claim 1, wherein the ‘housing’ can be attached to a variety of customized prostheses as PMMA implants (102), titanium mesh, porcelain implants and high-performance thermoplastics, such as LCP, PPS or PEEK, among others, which are manufactured to promote cranial repair (101, 102) of epileptic patients.

11. An implantable semi-invasive flexible ETI-ND device, according to claim 1, wherein brain temperature (iTemperature) (502) and ICP (503) measures, provided by sensors surrounding the ETI- ND system (505,506), help the CPU (507), embedded in the hardware, automatically adjust threshold for EEG seizure detection and thereby effectively elicit SD (301) responses in a real-time on a 24-7 basis.