Level Of Cortical Excitability Research Articles

Stroke Recovery-Related Changes in Cortical Reactivity Based on Modulation of Intracortical Inhibition.

Cortical excitation/inhibition dynamics have been suggested as a key mechanism occurring after stroke. Their supportive or maladaptive role in the course of recovery is still not completely understood. Here, we used transcranial magnetic stimulation (TMS)-electroencephalography coupling to study cortical reactivity and intracortical GABAergic inhibition, as well as their relationship to residual motor function and recovery longitudinally in patients with stroke. Electroencephalography responses evoked by TMS applied to the ipsilesional motor cortex were acquired in patients with stroke with upper limb motor deficit in the acute (1 week), early (3 weeks), and late subacute (3 months) stages. Readouts of cortical reactivity, intracortical inhibition, and complexity of the evoked dynamics were drawn from TMS-evoked potentials induced by single-pulse and paired-pulse TMS (short-interval intracortical inhibition). Residual motor function was quantified through a detailed motor evaluation. From 76 patients enrolled, 66 were included (68.2±13.2 years old, 18 females), with a Fugl-Meyer score of the upper extremity of 46.8±19. The comparison with TMS-evoked potentials of healthy older revealed that most affected patients exhibited larger and simpler brain reactivity patterns (Pcluster<0.05). Bayesian ANCOVA statistical evidence for a link between abnormally high motor cortical excitability and impairment level. A decrease in excitability in the following months was significantly correlated with better motor recovery in the whole cohort and the subgroup of recovering patients. Investigation of the intracortical GABAergic inhibitory system revealed the presence of beneficial disinhibition in the acute stage, followed by a normalization of inhibitory activity. This was supported by significant correlations between motor scores and the contrast of local mean field power and readouts of signal dynamics. The present results revealed an abnormal motor cortical reactivity in patients with stroke, which was driven by perturbations and longitudinal changes within the intracortical inhibition system. They support the view that disinhibition in the ipsilesional motor cortex during the first-week poststroke is beneficial and promotes neuronal plasticity and recovery.

TrkB receptor-dependent PV neurons regulate visual orientation discrimination in mice

The neurotrophin-tyrosine receptor kinase B (TrkB) signaling pathway plays an important role in regulating the balance of excitation and inhibition in the primary visual cortex (V1). Previous studies have revealed its mechanism of regulating the level of cortical excitability by increasing the efficiency of excitatory transmission, but it has not been elucidated how TrkB receptors regulate the balance of excitation and inhibition through the inhibitory system, which in turn affects visual cortex function. Therefore, the objective of this study was to investigate how the TrkB signaling pathway specifically regulates the most important inhibitory neuron-PV neurons affects the visual cortex function of mice. The expression of TrkB receptor on PV neurons in the V1 region was specifically reduced by the virus, the functional changes of inhibitory and excitatory neurons in the primary visual cortex were recorded by multi-channel electrophysiological in vivo. The orientation discrimination ability of mice was tested by behavioral experiments, and altered orientation discrimination ability of mice was tested by behavioral experiments. The results showed that reduced expression of TrkB receptors on PV inhibitory neurons in primary visual cortex significantly increased the response intensity of excitatory neurons, reduced the orientation discrimination ability of inhibitory and excitatory neurons, and increased the signal-to-noise ratio, but the orientation discrimination ability at the individual level in mice showed a decrease. These results suggest that the TrkB signaling pathway does not modulate the function of PV neurons solely by increasing excitatory transmission targeting PV neurons, and its effect on neuronal signal-to-noise ratio is not due to enhancement of the inhibitory system.

TMS-evoked responses are driven by recurrent large-scale network dynamics.

A compelling way to disentangle the complexity of the brain is to measure the effects of spatially and temporally synchronized systematic perturbations. In humans, this can be non-invasively achieved by combining transcranial magnetic stimulation (TMS) and electroencephalography (EEG). Spatiotemporally complex and long-lasting TMS-EEG evoked potential (TEP) waveforms are believed to result from recurrent, re-entrant activity that propagates broadly across multiple cortical and subcortical regions, dispersing from and later re-converging on, the primary stimulation site. However, if we loosely understand the TEP of a TMS-stimulated region as the impulse response function of a noisy underdamped harmonic oscillator, then multiple later activity components (waveform peaks) should be expected even for an isolated network node in the complete absence of recurrent inputs. Thus emerges a critically important question for basic and clinical research on human brain dynamics: what parts of the TEP are due to purely local dynamics, what parts are due to reverberant, re-entrant network activity, and how can we distinguish between the two? To disentangle this, we used source-localized TMS-EEG analyses and whole-brain connectome-based computational modelling. Results indicated that recurrent network feedback begins to drive TEP responses from 100 ms post-stimulation, with earlier TEP components being attributable to local reverberatory activity within the stimulated region. Subject-specific estimation of neurophysiological parameters additionally indicated an important role for inhibitory GABAergic neural populations in scaling cortical excitability levels, as reflected in TEP waveform characteristics. The novel discoveries and new software technologies introduced here should be of broad utility in basic and clinical neuroscience research.

Simultaneous transcranial electrical and magnetic stimulation boost gamma oscillations in the dorsolateral prefrontal cortex

Neural oscillations in the gamma frequency band have been identified as a fundament for synaptic plasticity dynamics and their alterations are central in various psychiatric and neurological conditions. Transcranial magnetic stimulation (TMS) and alternating electrical stimulation (tACS) may have a strong therapeutic potential by promoting gamma oscillations expression and plasticity. Here we applied intermittent theta-burst stimulation (iTBS), an established TMS protocol known to induce LTP-like cortical plasticity, simultaneously with transcranial alternating current stimulation (tACS) at either theta (θtACS) or gamma (γtACS) frequency on the dorsolateral prefrontal cortex (DLPFC). We used TMS in combination with electroencephalography (EEG) to evaluate changes in cortical activity on both left/right DLPFC and over the vertex. We found that simultaneous iTBS with γtACS but not with θtACS resulted in an enhancement of spectral gamma power, a trend in shift of individual peak frequency towards faster oscillations and an increase of local connectivity in the gamma band. Furthermore, the response to the neuromodulatory protocol, in terms of gamma oscillations and connectivity, were directly correlated with the initial level of cortical excitability. These results were specific to the DLPFC and confined locally to the site of stimulation, not being detectable in the contralateral DLPFC. We argue that the results described here could promote a new and effective method able to induce long-lasting changes in brain plasticity useful to be clinically applied to several psychiatric and neurological conditions.

TMS for the characterization of different types of dementia disorders: A systematic review and meta‐analysis

AbstractBackgroundAt early stages, dementia disorders share similar clinical symptoms. For an appropriate classification, more practical and non‐invasive diagnostic methods are needed. Transcranial magnetic stimulation (TMS) assess non‐invasively the imbalance of cortical excitability and related neurotransmitters levels in the brain(1‐3). Characterizing the spectrum of dementia with TMS could enable a more accurate diagnosis and optimize interventions at earlier stages.MethodWe conducted a systematic review following PRISMA guidelines. Our search strategy included terms related to dementia of different etiologies and TMS. It was conducted in 4 databases (MEDLINE, EMBASE, Ovid and Scopus) from origin to April 2021. Two authors screened the studies in a 2‐stepwise approach. Original studies comparing dementia disorders using TMS were included. Risk of bias was assessed using QUADAS. Meta‐analyses comparing diverse TMS parameters between AD to FTD, DLB and VAD as well as FTD to DLB were made.ResultOur search yielded 2702 results, with 227 articles reviewed in full text. Finally, 14 articles were included in the review(4,5,14–17,6–13) and 11 in the meta‐analysis(4–14). A total of 983 patients were analyzed: Alzheimer disease (AD) 50.25%, frontotemporal dementia (FTD) 28.89%, dementia with Lewy bodies (DLB) 10.57%, vascular dementia (VaD) 5.59% and other dementias 4.7%. In the comparison between AD to FTD, the mean difference of resting motor threshold (RMT) short‐latency afferent inhibition (SAI), short‐acting cortical inhibition (SICI), intracortical facilitation (ICF) and central motor conduction time (CMCT) were statistically significant (Fig 1‐2). No significant difference when comparing the AD group to DLB nor VaD. Finally, RMT and SAI were the only parameters that differed between patients diagnosed with FTD and DLB (Fig 3). The main concerns of risk of bias were the retrospective study design and differences in diagnosis method and TMS protocols.ConclusionThe meta‐analysis of observational studies showed that TMS measurements as biomarkers seem to be useful for differentiating FTD from AD and DLB in patients with mild‐stage dementia. Accurate classification may allow more appropriate interventions and slow disease progression. However, study design and protocols may limit our results. Hence, more homogenous, and prospective studies with bigger sample size are needed.

Distinct patterns of activity in individual cortical neurons and local networks in primary somatosensory cortex of mice evoked by square-wave mechanical limb stimulation.

Artificial forms of mechanical limb stimulation are used within multiple fields of study to determine the level of cortical excitability and to map the trajectory of neuronal recovery from cortical damage or disease. Square-wave mechanical or electrical stimuli are often used in these studies, but a characterization of sensory-evoked response properties to square-waves with distinct fundamental frequencies but overlapping harmonics has not been performed. To distinguish between somatic stimuli, the primary somatosensory cortex must be able to represent distinct stimuli with unique patterns of activity, even if they have overlapping features. Thus, mechanical square-wave stimulation was used in conjunction with regional and cellular imaging to examine regional and cellular response properties evoked by different frequencies of stimulation. Flavoprotein autofluorescence imaging was used to map the somatosensory cortex of anaesthetized C57BL/6 mice, and in vivo two-photon Ca2+ imaging was used to define patterns of neuronal activation during mechanical square-wave stimulation of the contralateral forelimb or hindlimb at various frequencies (3, 10, 100, 200, and 300 Hz). The data revealed that neurons within the limb associated somatosensory cortex responding to various frequencies of square-wave stimuli exhibit stimulus-specific patterns of activity. Subsets of neurons were found to have sensory-evoked activity that is either primarily responsive to single stimulus frequencies or broadly responsive to multiple frequencies of limb stimulation. High frequency stimuli were shown to elicit more population activity, with a greater percentage of the population responding and greater percentage of cells with high amplitude responses. Stimulus-evoked cell-cell correlations within these neuronal networks varied as a function of frequency of stimulation, such that each stimulus elicited a distinct pattern that was more consistent across multiple trials of the same stimulus compared to trials at different frequencies of stimulation. The variation in cortical response to different square-wave stimuli can thus be represented by the population pattern of supra-threshold Ca2+ transients, the magnitude and temporal properties of the evoked activity, and the structure of the stimulus-evoked correlation between neurons.

No Effect of Transcranial Direct Current Stimulation over Left Dorsolateral Prefrontal Cortex on Temporal Attention.

Selection mechanisms that dynamically gate only relevant perceptual information for further processing and sustained representation in working memory are critical for goal-directed behavior. We examined whether this gating process can be modulated by transcranial direct current stimulation (tDCS) over left dorsolateral prefrontal cortex (lDLPFC)-a region known to play a key role in working memory and conscious access. Specifically, we examined the effects of tDCS on the magnitude of the "attentional blink" (AB), a deficit in identifying the second of two targets presented in rapid succession. Thirty-four participants performed an AB task before (baseline), during and after 20 min of 1-mA anodal and cathodal tDCS in two separate sessions. On the basis of previous reports linking individual differences in AB magnitude to individual differences in DLPFC activity and on the basis of suggestions that effects of tDCS depend on baseline brain activity levels, we hypothesized that anodal tDCS over lDLPFC would modulate the magnitude of the AB as a function of individual baseline AB magnitude. Behavioral results did not provide support for this hypothesis. At the group level, we also did not observe any significant effects of tDCS, and a Bayesian analysis revealed strong evidence that tDCS to lDLPFC did not affect AB performance. Together, these findings do not support the idea that there is an optimal level of prefrontal cortical excitability for cognitive function. More generally, they add to a growing body of work that challenges the idea that the effects of tDCS can be predicted from baseline levels of behavior.

Low-frequency electrical stimulation reduces cortical excitability in the human brain

Effective seizure control remains challenging for about 30% of epilepsy patients who are resistant to present-day pharmacotherapy. Novel approaches that not only reduce the severity and frequency of seizures, but also have limited side effects are therefore desirable. Accordingly, various neuromodulation approaches such as cortical electrical stimulation have been implemented to reduce seizure burden; however, the underlying mechanisms are not completely understood. Given that the initiation and spread of epileptic seizures critically depend on cortical excitability, understanding the neuromodulatory effects of cortical electrical stimulation on cortical excitability levels is paramount. Based on observations that synchronization in the electrocorticogram closely tracks brain excitability level, the effects of low-frequency (1 Hz) intracranial brain stimulation on the levels of cortical phase synchronization before, during, and after 1 Hz electrical stimulation were assessed in twelve patients. Analysis of phase synchronization levels across three broad frequency bands (1–45 Hz, 55–95 Hz, and 105–195 Hz) revealed that in patients with stimulation sites in the neocortex, phase synchronization levels were significantly reduced within the 55–95 Hz and 105–195 Hz bands during post-stimulation intervals compared to baseline; this effect persisted for at least 30 min post-stimulation. Similar effects were observed when phase synchronization levels were examined in the classic frequency bands, whereby a significant reduction was found during the post-stimulation intervals in the alpha, beta, and gamma bands. The anatomical extent of these effects was then assessed. Analysis of the results from six patients with intracranial electrodes in both hemispheres indicated that reductions in phase synchronization in the 1–45 Hz and 55–95 Hz frequency ranges were more prominent in the stimulated hemisphere. Overall, these findings demonstrate that low-frequency electrical stimulation reduces phase synchronization and hence cortical excitability in the human brain. Low-frequency stimulation of the epileptic focus may therefore contribute to the prevention of impending epileptic seizures.

TMS‐measures of cortical excitability are abnormal in amyloid‐positive MCI, relate to amyloid burden, and predict faster cognitive decline

AbstractBackgroundAlzheimer’s disease (AD) is associated with increased cortical excitability, including a risk of seizures and epileptiform discharges. Transcranial magnetic stimulation (TMS) can be used to index cortical excitability non‐invasively, and previous studies have revealed increased TMS excitability measures in AD. However, it is not yet known if TMS shows increased cortical excitability in amyloid‐β positive mild cognitive impairment (Aβ+ MCI), how TMS excitability relates to other AD biomarkers, or the extent to which cortical excitability may predict disease progression.MethodTMS was applied to left motor cortex in 18 participants with Aβ+ MCI (aged 70±8.9, 9 females). Resting motor threshold (RMT) was measured as the minimum TMS intensity required to elicit a motor evoked potential on 5/10 trials. The primary analyses tested if RMT differed between Aβ+ MCI participants and a cohort of 36 older healthy controls (OHC; aged 63±9.7, 17 females). Separate linear models in Aβ+ MCI tested the relationship of RMT with hippocampal volume, Aβ burden on [18F]Florbetapir PET, and the Clinical Dementia Rating – Sum of Boxes (CDR‐SB). CDR‐SB was reassessed after 1‐2 years follow‐up, and a CDR‐SB Change Score was calculated to measure cognitive decline. The relationship with RMT and CDR‐SB Change Score was tested using a simple linear regression.ResultThe primary linear model controlling for age, gender, and scalp‐to‐cortex distance (SCD) showed a between‐group difference in RMT (B=3.62, p=0.023, Figure 1), with Aβ+ MCI showing lower RMT reflecting higher levels of cortical excitability. The covariate of SCD (B=1.92, p&lt;0.001) was also significant. Secondary models with the same covariates showed that lower RMT was related to greater Aβ burden (B=‐0.43, p=0.016), but not hippocampal volume or CDR‐SB. In the subgroup of 10 Aβ+ MCI participants with longitudinal follow‐up, lower RMT predicted of worsening cognition on CDR‐SB Change Score (R=0.74, p=0.015, Figure 2).ConclusionIncreased cortical excitability is found in Aβ+ MCI, is related to amyloid burden, and appears to predict greater longitudinal cognitive decline. TMS measures of cortical excitability may be useful as measures of target engagement for future therapies aimed at delaying disease progression in the early symptomatic stages of AD.

Effect of Ezogabine on Cortical and Spinal Motor Neuron Excitability in Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of the motor nervous system. Clinical studies have demonstrated cortical and spinal motor neuron hyperexcitability using transcranial magnetic stimulation and threshold tracking nerve conduction studies, respectively, although metrics of excitability have not been used as pharmacodynamic biomarkers in multi-site clinical trials.To ascertain whether ezogabine decreases cortical and spinal motor neuron excitability in ALS.This double-blind, placebo-controlled phase 2 randomized clinical trial sought consent from eligible participants from November 3, 2015, to November 9, 2017, and was conducted at 12 US sites within the Northeast ALS Consortium. Participants were randomized in equal numbers to a higher or lower dose of ezogabine or to an identical matched placebo, and they completed in-person visits at screening, baseline, week 6, and week 8 for clinical assessment and neurophysiological measurements.Participants were randomized to receive 600 mg/d or 900 mg/d of ezogabine or a matched placebo for 10 weeks.The primary outcome was change in short-interval intracortical inhibition (SICI; SICI-1 was used in analysis to reflect stronger inhibition from an increase in amplitude) from pretreatment mean at screening and baseline to the full-dose treatment mean at weeks 6 and 8. The secondary outcomes included levels of cortical motor neuron excitability (including resting motor threshold) measured by transcranial magnetic stimulation and spinal motor neuron excitability (including strength-duration time constant) measured by threshold tracking nerve conduction studies.A total of 65 participants were randomized to placebo (23), 600 mg/d of ezogabine (23), and 900 mg/d of ezogabine (19 participants); 45 were men (69.2%) and the mean (SD) age was 58.3 (8.8) years. The SICI-1 increased by 53% (mean ratio, 1.53; 95% CI, 1.12-2.09; P = .009) in the 900-mg/d ezogabine group vs placebo group. The SICI-1 did not change in the 600-mg/d ezogabine group vs placebo group (mean ratio, 1.15; 95% CI, 0.87-1.52; P = .31). The resting motor threshold increased in the 600-mg/d ezogabine group vs placebo group (mean ratio, 4.61; 95% CI, 0.21-9.01; P = .04) but not in the 900-mg/d ezogabine group vs placebo group (mean ratio, 1.95; 95% CI, -2.64 to 6.54; P = .40). Ezogabine caused a dose-dependent decrease in excitability by several other metrics, including strength-duration time constant in the 900-mg/d ezogabine group vs placebo group (mean ratio, 0.73; 95% CI, 0.60 to 0.87; P < .001).Ezogabine decreased cortical and spinal motor neuron excitability in participants with ALS, suggesting that such neurophysiological metrics may be used as pharmacodynamic biomarkers in multisite clinical trials.ClinicalTrials.gov Identifier: NCT02450552.

TDCS Facilitation of Picture Naming: Item-Specific, Task General, or Neither?

The aim of the present study was to clarify the conditions under which anodal tDCS applied to left hemisphere language sites may facilitate picture naming latencies in healthy young adults. We built upon previous studies by directly testing for item-specific and generalized effects of tDCS through manipulation of item-familiarization and through testing for both online and offline effects of stimulation, in the same paradigm. In addition, we tested for the robustness of these effects by comparing two left hemisphere sites critical for lexical retrieval. Twenty-eight healthy young adults completed two testing sessions receiving either anodal (1.5 mA, 20 min) or sham stimulation (1.5 mA, 30 s) in each session. Half of the participants received tDCS over the left inferior frontal region and the other half over the left posterior superior temporal region. All participants were asked to a name a set of pictures and their response latencies were compared at three time points (before, during, and after the end of stimulation). The stimulus set was constructed so that some items were presented at all time points, some before and after stimulation, and some during stimulation only. A parsimonious linear mixed effects model (LMM) revealed robust repetition priming effects as latencies were reliably faster for previously named items in all conditions. However, active tDCS did not produce any additional facilitation in relation to sham, and even led to slower performance in the IFG group when the stimulated items differed from those tested at baseline and post-test. Our findings add to the present debate about the efficacy of single-session tDCS for modulation of lexical retrieval in healthy young adults. We conclude that future research should take a more systematic, step-wise approach to the application of tDCS to the study of language and that more sensitive experimental paradigms, which include a training element, are more adapted to the study of cognitive processes in populations with optimal levels of cortical excitability.

No Evidence That Baseline Prefrontal Cortical Excitability (3T-MRS) Predicts the Effects of Prefrontal tDCS on WM Performance.

Transcranial direct current stimulation (tDCS) over the left dorsolateral prefrontal cortex (lDLPFC) is a promising tool to enhance working memory (WM) in clinical as well as healthy populations. Yet, tDCS does not affect everyone similarly: whereas tDCS improves WM in most individuals, some individuals do not, or actually show detriments in WM performance after stimulation. One hypothesis that has been put forward to account for individual differences in tDCS response is that baseline cortical excitability levels in the stimulated cortex may determine the strength and the direction of the effects of tDCS. Specifically, by locally affecting neuronal excitability, tDCS may interact with baseline cortical excitability levels, thereby pushing or pulling individuals toward or away from an optimal level of cortical functioning. In the current study, we put this hypothesis to the test with regard to prefrontal cortex stimulation and WM. In 20 healthy male participants, using magnetic resonance spectroscopy (MRS) at 3T, we measured concentrations of Glutamate and GABA in the lDLPFC and calculated individual Glutamate/GABA ratios as a measure for cortical excitability. Subsequently, in two stimulation sessions, we once applied anodal and once cathodal tDCS over the lDLPFC (20 min, 1 mA). Stimulation was always applied in the second block of three blocks of a WM updating task. Surprisingly, at the group-level, we found no effects of anodal or cathodal stimulation on WM performance. Yet, in line with previous studies, large individual variability was observed in the strength and direction of tDCS effects; whereas about half of the participants improved, the other half showed lower accuracy after stimulation. This was true for both anodal and cathodal tDCS. Nevertheless, contrary to our expectations, individual baseline prefrontal cortical excitability did not predict these individual differences in the effect of anodal or cathodal stimulation on WM accuracy. Future studies with larger sample sizes, which use higher magnetic field strengths (e.g., 7T) to measure cortical excitability and/or apply individualized stimulation protocols, are necessary to shed more light on the influence of baseline cortical excitability on effects of anodal and cathodal tDCS over lDLPFC on WM performance.

Cortical excitability variability: Insights into biological and behavioral characteristics of healthy individuals

Motor threshold (MT) measured by transcranial magnetic stimulation (TMS) has diagnostic utility in central nervous system disorders. Its diagnostic sensitivity may be enhanced by identification of non-pathological factors which may influence this measure. The aim of this study was to provide a description of MT variability across physiological and non-pathological behaviour characteristics in a large cohort, including hemispheric asymmetries. In a cross-sectional study, age, handedness, physical activity level, body mass index, gender/menstrual cycle phase, glycemic index and degree of stress were collected from 115 healthy participants. The resting MT of the first dorsal interosseous muscle to TMS was recorded in both hemispheres and served as an indicator of the cortical excitability level. Repeated measures ANOVAs revealed higher MT values in the non-dominant hemisphere, elderly people, stressed individuals and women with amenorrhea. Other biological and behavioral individual characteristics did not influence cortical excitability. Although the degree of interhemispheric difference varied (range: 0.2 to 4.3), depending on biological and behavioral characteristics, this variation was not significant (0.1 ≤ p ≤ 0.8). In conclusion, MT varied considerably between subjects. The difference between the hemisphere excitability that was less influenced by external factors, may be an alternative method of TMS measure to identify pathological changes of cortical excitability.

Impaired Visual Habituation in Idiopathic Generalized Epilepsy with Photosensitivity Patients.

In this study, our goal was to analyze further the cortical excitability levels in idiopathic generalized epilepsy (IGE) patients with and without photosensitivity. Forty-two patients (16 men and 26 women; mean age 30±8 years; range: 18-43 years) with IGE and thirty healthy age-matched control subjects (15 men and 15 women; mean age 35±3 years; range: 20-45 years) were enrolled for the investigation. We investigated the following two groups: 18 subjects with IGE with photosensitivity (IGE+PS), and 24 patients with IGE without photosensitivity (IGE-PS). Pattern reversal and potential inter-peak amplitudes, N75-P100 and P100-N145, as well as the corresponding latencies (N75, P100, and N145) for one hundred responses were measured 6 times. A linear regression slope was used for N75-P100 and P100-N145. Statistical analysis showed difference between groups where the IGE+PS had reduced N75-P100 compared to IGE-PS and controls. In IGE+PS group, the amplitude of N75-P100 was drastically reduced receiving antiepileptic therapy compared to those not receiving any anti-epileptic treatment (p=0.035). These results show that the IGE+PS group has a different photoparoxysmal response phenotype driven by an unknown and distinct molecular mechanism. Pre-activation cortical excitability may be increased in IGE+PS patients compared to the IGE-PS or in healthy group. PR-VEP habituation may project the pathophysiological mechanisms underlying photosensitivity and it may be potential biomarker in patients with IGE+PS.

P 161 Coupling of brain arousal and autonomic regulation in the transition from wakefulness to sleep onset during an auditory oddball task in the resting state

Background Simultaneous downregulation of the autonomic and central nervous system activity enables the gradual physiological state change from wakefulness to sleep onset. Dysregulation of central or autonomic arousal has been found in neurological ( Silvani et al., 2016 ) and psychiatric disorders ( Hegerl and Hensch, 2014 , Hegerl et al., 2012 , Schulz et al., 2016 , Schwabedal et al., 2016 ), often associated with dysregulated sleep-wake patterns. Aim We investigated the hypothesis that brain-autonomic co-regulation affects the attentive process in the transition from wakefulness to sleep onset. We propose that the degree to which autonomic and brain dynamics are correlated predicts the level of cortical excitability or inhibition and sleep onset behavior in this transition. To test our hypothesis, we explored electroencephalogram (EEG), electrocardiogram (ECG) and skin conductance data recorded during a 2-h resting state oddball experiment. Methods 39 healthy study participants underwent a 2-h resting EEG with eyes closed including ECG-derived heart rate (HR) and measurement of skin conductance level (SCL). The Vigilance Algorithm Leipzig (VIGALL 2.1) was used to assess brain arousal regulation based on automatic EEG-vigilance stage classification of 1-s EEG segments. These vigilance stages (=vigilance; V) were scored and cross-correlated with HR and SCL over a range of ±100 s, and a mean period of vigilance fluctuations was estimated from the frequency of maxima after low-pass filtering. Mean amplitudes of event-related potentials N100 and P200 to standard and deviant stimuli at Cz were calculated as indices of cortical excitability (N100) and cortical inhibition (P200) ( Cortoos et al., 2014 ). Results In all subjects, higher max cross-correlation coefficients (V-HR mean: r = 0.362, range: −0.069 to 0.762; SD = 0.192; V-SCL mean: r = 0.277, range: −0.299 to 0.629; SD = 0.211) were associated with longer mean periods of cortico-autonomic signals (V-HR: r = 0.462, p = .003; V-SCL: r = 0.516, p = .001). The cross-correlation of V with either HR and SCL partitioned the subjects into two groups (group no lag: n0 = 20, τ = 0; group lag: n1 = 19, τ (range) = −98 to −87) dependent on the time lag of maximal correlation. Subjects in n0, who fell asleep more often (indexed by the frequency of falling asleep: t37 = 2.49, p = .018) during the 2-h EEG compared to subjects in n1, had higher max cross-correlation coefficients (V-HR: t37 = 4.24, p = 1.43E−4; V-SCL: t37 = 5.02, p = 1.35E−5) and displayed an increased standard (t30.235 = 3.19, p = .003) and deviant P200 amplitude (t37 = 3.63, p = .001) compared to subjects in n1. No significant group differences were found for N100 amplitudes and KSS score either before or after the recording. Conclusion Healthy individuals with no time lag between cortical and autonomic signals showed a stronger brain-autonomic coupling and increased P200 amplitudes (indicating a higher level of cortical inhibition) compared to individuals with a temporal misalignment. This may explain differences in sleep-onset behavior between groups. Present results indicate possible diagnostic value in the assessment of brain-autonomic regulation, for example in disorders with sleep-related symptoms such as insomnia, dementia or depression.

Automatized set-up procedure for transcranial magnetic stimulation protocols

Transcranial Magnetic Stimulation (TMS) established itself as a powerful technique for probing and treating the human brain. Major technological evolutions, such as neuronavigation and robotized systems, have continuously increased the spatial reliability and reproducibility of TMS, by minimizing the influence of human and experimental factors. However, there is still a lack of efficient set-up procedure, which prevents the automation of TMS protocols. For example, the set-up procedure for defining the stimulation intensity specific to each subject is classically done manually by experienced practitioners, by assessing the motor cortical excitability level over the motor hotspot (HS) of a targeted muscle. This is time-consuming and introduces experimental variability. Therefore, we developed a probabilistic Bayesian model (AutoHS) that automatically identifies the HS position. Using virtual and real experiments, we compared the efficacy of the manual and automated procedures. AutoHS appeared to be more reproducible, faster, and at least as reliable as classical manual procedures. By combining AutoHS with robotized TMS and automated motor threshold estimation methods, our approach constitutes the first fully automated set-up procedure for TMS protocols. The use of this procedure decreases inter-experimenter variability while facilitating the handling of TMS protocols used for research and clinical routine.

Modulating transcallosal and intra-hemispheric brain connectivity with tDCS: Implications for interventions in Aphasia.

Transcranial direct current stimulation (tDCS) can enhance or diminish cortical excitability levels depending on the polarity of the stimulation. One application of non-invasive brain-stimulation has been to modulate a possible inter-hemispheric disinhibition after a stroke. This disinhibition model has been developed mainly for the upper extremity motor system, but it is not known whether the language/speech-motor system shows a similar inter-hemispheric interaction. We aimed to examine physiological evidence of inter- and intra-hemispheric connectivity changes induced by tDCS of the right inferior frontal gyrus (IFG) using arterial-spin labeling (ASL) MRI. Using an MR-compatible DC-Stimulator, we applied anodal stimulation to the right IFG region of nine healthy adults while undergoing non-invasive cerebral blood flow imaging with arterial-spin labeling (ASL) before, during, and after the stimulation. All ASL images were then normalized and timecourses were extracted in regions of interest (ROIs), which were the left and right IFG regions, and the right supramarginal gyrus (SMG) in the inferior parietal lobule. Two additional ROIs (the right occipital lobe and the left fronto-orbital region) were taken as control regions. Using regional correlation coefficients as a surrogate marker of connectivity, we could show that inter-hemispheric connectivity (right IFG with left IFG) decreased significantly (p < 0.05; r-scores from 0.67 to 0.53) between baseline and post-stimulation, while the intra-hemispheric connectivity (right IFG with right SMG) increased significantly (p < 0.05;r-scores from 0.74 to 0.81). A 2 × 2 ANOVA found a significant main effect of HEMISPHERE (F(8) = 6.83, p < 0.01) and a significant HEMISPHERE-by-TIME interaction (F(8) = 4.24, p < 0.05) in connectivity changes. The correlation scores did not change significantly in the control region pairs (right IFG with right occipital and right IFG with left fronto-orbital) over time. Using an MR-compatible DC stimulator we showed that ASL-MRI can detect tDCS-induced modulation of brain connectivity within and between hemispheres. These findings might affect trial designs focusing on modulating the non-dominant hemisphere to enhance language/speech-motor functions.

The Tactile Window to Consciousness is Characterized by Frequency-Specific Integration and Segregation of the Primary Somatosensory Cortex.

We recently proposed that besides levels of local cortical excitability, also distinct pre-stimulus network states (windows to consciousness) determine whether a near-threshold stimulus will be consciously perceived. In the present magnetoencephalography study, we scrutinised these pre-stimulus network states with a focus on the primary somatosensory cortex. For this purpose participants performed a simple near-threshold tactile detection task. Confirming previous studies, we found reduced alpha and beta power in the somatosensory region contralateral to stimulation prior to correct stimulus detection as compared to undetected stimuli, and stronger event-related responses following successful stimulus detection. As expected, using graph theoretical measures, we also observed modulated pre-stimulus network level integration. Specifically, the right primary somatosensory cortex contralateral to stimulation showed an increased integration in the theta band, and additionally, a decreased integration in the beta band. Overall, these results underline the importance of network states for enabling conscious perception. Moreover, they indicate that also a reduction of irrelevant functional connections contributes to the window to consciousness by tuning pre-stimulus pathways of information flow.

19. Cortical hyperexcitability in ALS: A heterogeneous process

Objective Cortical hyperexcitability, as heralded by reduced short interval intracortical inhibition (SICI) has been identified as an intrinsic feature of amyotrophic lateral sclerosis (ALS). However, in approximately 20% of patients cortical excitability may be normal, suggesting the presence of pathophysiological heterogeneity. Consequently, the present study assessed for the presence of clinical, functional and neurophysiological differences in ALS phenotypes, as defined by cortical hyperexcitability. Methods Cortical excitability was assessed in 62 ALS patients. Clinical, functional and neurophysiological parameters were compared between ALS patients with cortical hyperexcitability (SICI 5.5%) versus those with a “normal” level of cortical excitability (SICI > 5.5%). Results In ALS patients with features of cortical hyperexcitability, there appeared to be an absence of SICI in the early phase (interstimulus interval [ISI] 1–3 ms) with a transition to facilitation at later ISIs (3.5–7 ms). In contrast, ALS patients with normal SICI demonstrated similar levels of inhibition across early and late SICI phases. Of further relevance, ALS patients with abnormal SICI exhibited increased mortality in follow-up. Conclusion Dysfunction in cortical inter-neuronal circuits probed by short latency paired-pulse TMS appears to capture some of the pathophysiological heterogeneity in ALS and may have direct implications for survival.

Monitoring transcranial direct current stimulation induced changes in cortical excitability during the serial reaction time task

The measurement of the motor evoked potential (MEP) amplitudes using single pulse transcranial magnetic stimulation (TMS) is a common method to observe changes in motor cortical excitability. The level of cortical excitability has been shown to change during motor learning. Conversely, motor learning can be improved by using anodal transcranial direct current stimulation (tDCS). In the present study, we aimed to monitor cortical excitability changes during an implicit motor learning paradigm, a version of the serial reaction time task (SRTT). Responses from the first dorsal interosseous (FDI) and forearm flexor (FLEX) muscles were recorded before, during and after the performance of the SRTT. Online measurements were combined with anodal, cathodal or sham tDCS for the duration of the SRTT.Negative correlations between the amplitude of online FDI MEPs and SRTT reaction times (RTs) were observed across the learning blocks in the cathodal condition (higher average MEP amplitudes associated with lower RTs) but no significant differences in the anodal and sham conditions. tDCS did not have an impact on SRTT performance, as would be predicted based on previous studies. The offline before-after SRTT MEP amplitudes showed an increase after anodal and a tendency to decrease after cathodal stimulation, but these changes were not significant.The combination of different interventions during tDCS might result in reduced efficacy of the stimulation that in future studies need further attention.