Carlo Miniussi

Recent developments in neuroscience have emphasised the importance of integrated distributed networks of brain areas for successful cognitive functioning. Our current understanding is that the brain has a modular organisation in which segregated networks supporting specialised processing are linked through a few long-range connections, ensuring processing integration. Although such architecture is structurally stable, it appears to be flexible in its functioning, enabling long-range connections to regulate the information flow and facilitate communication among the relevant modules, depending on the contingent cognitive demands. Here we show how insights brought by the coregistration of transcranial magnetic stimulation and electroencephalography (TMS–EEG) integrate and support recent models of functional brain architecture. Moreover, we will highlight the types of data that can be obtained through TMS–EEG, such as the timing of signal propagation, the excitatory/inhibitory nature of connections and causality. Last, we will discuss recent emerging applications of TMS–EEG in the study of brain disorders.

h i g h l i g h t s tES is a painless and safe technique. tDCS induced sensations are modulated by electrode size and intensity. Sham stimulation might not be an effective blinding method with anodal tDCS. a b s t r a c t Objective: The goals of this work are to report data regarding a large number of stimulation sessions and to use model analyses to explain the similarities or differences in the sensations induced by different parameters of tES application. Methods: We analysed sensation data relative to 693 different tES sessions. In particular, we studied the effects on sensations induced by different types of current, categories of polarity and frequency, different timing, levels of current density and intensity, different electrode sizes and different electrode locations (areas). Results: The application of random or fixed alternating current stimulation (i.e., tRNS and tACS) over the scalp induced less sensation compared with transcranial direct current stimulation (tDCS), regardless of the application parameters. Moreover, anodal tDCS induced more annoyance in comparison to other tES. Additionally, larger electrodes induced stronger sensations compared with smaller electrodes, and higher intensities were more strongly perceived. Timing of stimulation, montage and current density did not influence sensations perception. The analyses demonstrated that the induced sensations could be clustered on the basis of the type of somatosensory system activated. Finally and most important no adverse events were reported. Conclusion: Induced sensations are modulated by electrode size and intensity and mainly pertain to the cutaneous receptor activity of the somatosensory system. Moreover, the procedure currently used to perform placebo stimulation may not be totally effective when compared with anodal tDCS. Significance: The reported observations enrich the literature regarding the safety aspects of tES, confirming that it is a painless and safe technique.

The benefits that physical exercise confers on cardiovascular health are well known, whereas the notion that physical exercise can also improve cognitive performance has only recently begun to be explored and has thus far yielded only controversial results. In the present study, we used a sample of young male subjects to test the effects that a single bout of aerobic exercise has on learning. Two tasks were run: the first was an orientation discrimination task involving the primary visual cortex, and the second was a simple thumb abduction motor task that relies on the primary motor cortex. Forty-four and forty volunteers participated in the first and second experiments, respectively. We found that a single bout of aerobic exercise can significantly facilitate learning mechanisms within visual and motor domains and that these positive effects can persist for at least 30 minutes following exercise. This finding suggests that physical activity, at least of moderate intensity, might promote brain plasticity. By combining physical activity–induced plasticity with specific cognitive training–induced plasticity, we favour a gradual up-regulation of a functional network due to a steady increase in synaptic strength, promoting associative Hebbian-like plasticity. How often have we heard, " Mens sana in corpore sano " , i.e., " a sound mind in a sound body " , which suggests that only a healthy body can sustain a healthy mind. Nevertheless, although this adage has been widely used for some time, its foundational notions must still be substantiated. While the benefits that physical activity confers on car-diovascular health are well known, the idea that exercise can also increase brain " performance " has only recently begun to be investigated by neuroscientists. Thus, whether and how physical exercise makes us cognitively more resourceful has been only partially explored. Several recent studies have shown that regular aerobic physical exercise might improve cognitive functions by helping functional recovery after brain injury and by preventing cognitive decline in normal ageing (for a review see 1). Moreover, many observational studies have noted good cognitive performance in subjects who report practicing regularly physical activity 2,3. Consistent with these observations, there are also structural imaging studies confirming an association between physical activity and increased grey matter volume in subjects that exercise regularly in comparison with sedentary people 4–6. Nevertheless, some of these studies have been criticized because of the presence of other direct causal links between physical activity and cognitive performance; for instance, high cognitive abilities are more likely to be associated with higher educational levels, which are, in turn, often associated with a more health-conscious life style. To overcome these problems, other studies have concentrated on the benefits of the acute effects of physical activity on cognitive processing, irrespective of the previous fitness of tested subjects. These studies compared the subjects' cognitive performance immediately before and after a single bout of aerobic exercise (for a review see 7), and some found an improvement in attention, visuospatial functions, memory, language and executive functions e.g. 2,8–11. However, many studies have reported no significant improvement in cognitive performance after physical activity, as shown in a recent review of more than 30 studies 12. Evidence from animal studies suggest that neurotrophic factors (i.e., brain-derived neurotrophic factor-BDNF) might play a key role in such effects 13,14 , and this evidence has also been confirmed in research on humans 15–17. These studies have shown a relevant and constant increase of BDNF concentration up to 60 minutes following aerobic exercise. Specific work on BDNF has shown that this factor plays a pivotal role in the induction of activity-dependent neuroplasticity 18. Thus, it can be inferred that the advantage of physical exercise may involve directly affecting synaptic plasticity by favouring the strengthening of network structures, supporting neurogenesis and favouring

Evidence suggests that Alzheimer's disease (AD) is part of a continuum, characterized by long preclinical phases before the onset of clinical symptoms. In several cases, this continuum starts with a syndrome, defined as mild cognitive impairment (MCI), in which daily activities are preserved despite the presence of cognitive decline. The possibility of having a reliable and sensitive neurophysiological marker that can be used for early detection of AD is extremely valuable because of the incidence of this type of dementia. In this study, we aimed to investigate the reliability of auditory mismatch negativity (aMMN) as a marker of cognitive decline from normal ageing progressing from MCI to AD. We compared aMMN elicited in the frontal and temporal locations by duration deviant sounds in short (400 ms) and long (4000 ms) inter-trial intervals (ITI) in three groups. We found that at a short ITI, MCI showed only the temporal component of aMMN and AD the frontal component compared to healthy elderly who presented both. At a longer ITI, aMMN was elicited only in normal ageing subjects at the temporal locations. Our study provides empirical evidence for the possibility to adopt aMMN as an index for assessing cognitive decline in pathological ageing. Auditory mismatch negativity (aMMN) is an event-related potential (ERP) component occurring approximately 100–200 ms after a detectable change (deviant stimulus) in a repetitive and predictive sequence of sounds (standard stimuli) 1. aMMN appears maximal at the central-frontal electrodes with an inversion of polarity at the mas-toids, which is consistent with neural generators located in the temporo-frontal network 2,3. aMMN recorded from temporal electrodes is associated with the encoding of the physical features of the stimuli and the maintenance of the sensory memory trace; while aMMN recorded from frontal electrodes has been linked to involuntary capture of attention triggered by the occurrence of the deviant tone 4–7. The aMMN elicitation arises from an automatic comparison between the deviant sensory input and the sensory-memory trace representing the preceding stimuli 8. MMN is also considered an index of the efficiency of the auditory system to extract regularities in a sequence of sounds and to detect abnormalities based on predictions, according to the predictive coding theoretical framework 9. aMMN is commonly used in clinical settings for indexing (i) auditory discrimination accuracy, (ii) sen-sory–memory duration 5 , and (iii) general cognitive decline 10. Recording aMMN at different inter-stimulus intervals (ISI) (typically, short ISI are less than 500 ms, whereas long ISI are more than 2 sec) is an experimental modulation used to investigate the accuracy of sensory memory encoding (short ISI) and the integrity of maintenance of sensory information (long ISI). By gradually extending ISI, the aMMN eventually vanishes, which enables one to assess sensory-memory duration. It has been found that in healthy participants, acoustic memory decays after a few seconds because aMMN is no longer elicited if the ISI is longer than 10 seconds 11,12. Because aMMN is elicited in the absence of direct control of voluntary attention, it is considered an automatic orienting towards salient events, and for this reason, it is particularly useful for the investigation of clinical populations in which prolonged sustained attention tasks are difficult to perform. Interestingly, Näätänen and colleagues have recently proposed MMN as an index of the cognitive decline occurring in a large number of