Transcranial Magnetic Stimulation Combined With Electroencephalography Research Articles

Abnormal Global Cortical Responses in Drug-Naïve Patients With Schizophrenia Following Orbitofrontal Cortex Stimulation: A Concurrent Transcranial Magnetic Stimulation–Electroencephalography Study

BackgroundAbnormalities in cortical excitability and plasticity have been considered to underlie the pathophysiology of schizophrenia. Transcranial magnetic stimulation combined with electroencephalography (TMS-EEG) can provide a direct evaluation of cortical responses to TMS. Here, we employed TMS-EEG to investigate cortical responses to orbitofrontal cortex (OFC) stimulation in schizophrenia. MethodsIn total, we recruited 92 drug-naïve patients with first-episode schizophrenia and 51 age- and sex-matched healthy individuals. For each participant, one session of 1-Hz repetitive TMS (rTMS) was delivered to the right OFC, and TMS-EEG data were obtained to explore the change in cortical-evoked activities before and immediately after rTMS during the eyes-closed state. The MATRICS Consensus Cognitive Battery was used to assess neurocognitive performance. ResultsThe cortical responses indexed by global mean field amplitudes (i.e., P30, N45, and P60) were larger in patients with schizophrenia than in healthy control participants at baseline. Furthermore, after one session of 1-Hz rTMS over the right OFC, the N100 amplitude was significantly reduced in the healthy control group but not in the schizophrenia group. In the healthy control participants, there was a significant correlation between modulation of P60 amplitude by rTMS and working memory; however, this correlation was absent in patients with schizophrenia. ConclusionsAberrant global cortical responses following right OFC stimulation were found in patients with drug-naïve first-episode schizophrenia, supporting its significance in the primary pathophysiology of schizophrenia.

Neurophysiological impact of theta burst stimulation followed by cognitive exercise in treatment of youth depression

• Changes in cortical reactivity following bilateral DLPFC TBS combined with cognitive exercise treatment were assessed in youth with depression. • Cortical reactivity was modulated at cortical sites both local and distal to the site of TBS application. • Modulation of cortical reactivity at different sites was associated with improvement in both depression and rumination scores. • TBS combined with cognitive exercise may exert its therapeutic effect by modulating the neurophysiology of sites both local and distal to the stimulation sites. Targeting the dorsolateral prefrontal cortex (DLPFC) with repeated sessions of theta-burst stimulation (TBS) is a promising treatment for youth depression. However, it remains unclear whether TBS selectively acts upon inhibitory and/or excitatory measures. Such insight could aid with the development of biomarker driven approaches to delivering TBS in depressed youth. Transcranial magnetic stimulation combined with electroencephalography (TMS-EEG) was used to assess the neurophysiological impact of a 4-week bilateral DLPFC-targeted TBS trial followed by a cognitive exercise for the treatment of depression in youth. In 26 youth with depression (aged 16 – 24 years old), TMS-evoked potentials (TEPs) were assessed at baseline and after treatment completion from the bilateral DLPFC and intraparietal lobules (IPL). Following treatment, there were significant changes in TEPs both local and distal to the stimulated treatment sites. The amplitude of the left DLPFC N100 response was significantly reduced. Also, there was a significant association between changes in the right DLPFC N45 response and reduction in depressive and rumination scores. Additionally, the amplitude of the right IPL N100 response was reduced. Moreover, the modulation of the right IPL N100 response was significantly associated with a reduction in depressive scores. The primary limitation was the lack of a sham treatment arm. Bilateral DLPFC TBS may exert its therapeutic impact by modulating the neurophysiology of regions and networks both local and distal to the treatment site. Collectively, our findings offer novel insight into the potential therapeutic mechanisms of TBS for the treatment of youth depression.

Local Prefrontal Cortex TMS-Induced Reactivity Is Related to Working Memory and Reasoning in Middle-Aged Adults.

IntroductionThe prefrontal cortex (PFC) plays a crucial role in cognition, particularly in executive functions. Cortical reactivity measured with Transcranial Magnetic Stimulation combined with Electroencephalography (TMS-EEG) is altered in pathological conditions, and it may also be a marker of cognitive status in middle-aged adults. In this study, we investigated the associations between cognitive measures and TMS evoked EEG reactivity and explored whether the effects of this relationship were related to neurofilament light chain levels (NfL), a marker of neuroaxonal damage.MethodsFifty two healthy middle-aged adults (41–65 years) from the Barcelona Brain Health Initiative cohort underwent TMS-EEG, a comprehensive neuropsychological assessment, and a blood test for NfL levels. Global and Local Mean-Field Power (GMFP/LMFP), two measures of cortical reactivity, were quantified after left prefrontal cortex (L-PFC) stimulation, and cognition was set as the outcome of the regression analysis. The left inferior parietal lobe (L-IPL) was used as a control stimulation condition.ResultsLocal reactivity was significantly associated with working memory and reasoning only after L-PFC stimulation. No associations were found between NfL and cognition. These specific associations were independent of the status of neuroaxonal damage indexed by the NfL biomarker and remained after adjusting for age, biological sex, and education.ConclusionOur results demonstrate that TMS evoked EEG reactivity at the L-PFC, but not the L-IPL, is related to the cognitive status of middle-aged individuals and independent of NfL levels, and may become a valuable biomarker of frontal lobe-associated cognitive function.

Application of Fast Perturbational Complexity Index to the Diagnosis and Prognosis for Disorders of Consciousness.

Diagnosis and prognosis of patients with disorders of consciousness (DOC) is a challenge for neuroscience and clinical practice. Transcranial magnetic stimulation combined with electroencephalography (TMS-EEG) is an effective tool to measure the level of consciousness. However, a scientific and accurate method to quantify TMS-evoked activity is still lacking. This study applied fast perturbational complexity index (PCIst) to the diagnosis and prognosis of DOC patients. TMS-EEG data of 30 normal healthy participants (NOR) and 181 DOC patients were collected. The PCIst was used to assess the time-space complexity of TMS-evoked potentials (TEP). We selected parameters of PCIst in terms of data length, data delay, sampling rate and frequency band. In addition, we collected Coma Recovery Scale-Revised (CRS-R) values for 114 DOC patients after one year. Finally, we trained the classification and regression model. 1) PCIst shows the differences among NOR, minimally consciousness state (MCS) and unresponsive wakefulness syndrome (UWS) and has low computational cost. 2) Optimal parameters of data length and delay after TMS are 300 ms and 101-300 ms. Significant differences of PCIst at 5-8 Hz and 9-12 Hz bands are found among NOR, MCS and UWS groups. PCIst still works when TEP is down-sampled to 250 Hz. 3) PCIst at 9-12 Hz shows the highest performance in diagnosis and prognosis of DOC. This study confirms that PCIst can quantify the level of consciousness. PCIst is a potential measure for the diagnosis and prognosis of DOC patients.

Evaluation of algorithms for correction of transcranial magnetic stimulation-induced artifacts in electroencephalograms.

Transcranial magnetic stimulation combined with electroencephalography (TMS-EEG) is widely used to study the reactivity and connectivity of brain regions for clinical or research purposes. The electromagnetic pulse of the TMS device generates at the instant of administration an artifact of large amplitude and a duration up to tens of milliseconds that overlaps with brain activity. Methods for TMS artifact correction have been developed to remove the artifact and recover the underlying, immediate response of the cerebral cortex to the magnetic stimulus. In this study, four such algorithms are evaluated. Since there is no ground truth for the masked brain activity, pilot data formed from the superposition of the isolated TMS artifact on EEG brain activity are used to evaluate the performance of the algorithms. Different scenarios of TMS-EEG experiments are considered for the evaluation: TMS at resting state, TMS inducing epileptiform discharges, and TMS administered during epileptiform discharges. We show that a proposed gap filling method is able to reproduce qualitative characteristics and, in many cases, closely resemble the hidden EEG signal. Finally, shortcomings of the TMS correction algorithms as well as the pilot data approach are discussed. Graphical abstract The transcranial magnetic stimulation (TMS) artifact on the electroencephalogram (EEG) and its correction.

Sleep-like bistability, loss of causality and complexity in the cerebral cortex of unresponsive wakefulness syndrome patients

Unresponsiveness Wakefulness Syndrome (UWS) patients may retain intact portions of the thalamocortical system that are spontaneously active and responsive to sensory stimuli. In most of these patients, Transcranial Magnetic Stimulation combined with electroencephalography (TMS/EEG) shows that structurally preserved cortical areas react to TMS, but fail to engage complex patterns of effective interactions, as assessed by the perturbational complexity index (PCI). Another condition during which thalamocortical circuits are intact, active and reactive, yet unable to generate complex responses, is non-rapid eye movement (NREM) sleep, in which cortical neurons become bistable and tend to fall into a silent state (OFF-period) upon receiving an input. Here we tested whether a pathological form of bistability may be responsible for the loss of cortical complexity in UWS patients. In eyes-open UWS patients (n=16) TMS evoked a slow wave-like EEG response that was associated with a suppression of high-frequency (above 20Hz) oscillations suggesting the occurrence of OFF-periods similar to the ones observed in healthy subjects (n=8) during NREM sleep. Crucially, this phenomenon was never detected in healthy awake subjects (n=20). In all targeted cortical areas (Brodmann areas 6 and 7, bilaterally) of UWS patients, pathological OFF-periods significantly impaired local causal interactions (as measured by the phase-locking factor) and prevented the build-up of global complexity (as measured by PCI). Our results draw a first link between neuronal events (OFF-periods) and global brain dynamics (complexity) in UWS patients. Detecting the presence of sleep-like bistability and tracking its evolution over time, may offer a valuable read-out to devise, guide and titrate therapeutic strategies aimed at restoring consciousness.

Altered Transcranial Magnetic Stimulation–Electroencephalographic Markers of Inhibition and Excitation in the Dorsolateral Prefrontal Cortex in Major Depressive Disorder

BackgroundThe neurophysiology of major depressive disorder (MDD) has become a particular focus of transcranial magnetic stimulation (TMS) investigational studies. TMS combined with electroencephalography (TMS-EEG) affords a window to directly measure evoked activity from the dorsolateral prefrontal cortex (DLPFC), which is of considerable interest in MDD. Our study examined TMS-EEG responses from the DLPFC in persons with MDD compared with those in healthy participants. Specifically, we examined TMS-EEG markers linked to inhibitory and excitatory neurophysiological processes and their balance. MethodsIn all, 30 participants with MDD and 30 age- and sex-matched healthy participants underwent single-pulse TMS-EEG to assess inhibition and excitation from DLPFC. TMS-EEG waveforms were analyzed through global mean field amplitude. ResultsMDD participants demonstrated abnormalities in TMS-EEG markers in the DLPFC. Inhibitory measures—N45 and N100—were larger in the MDD group than in healthy participants (N45 [t = −4.894, p < .001] and N100 [t = −3.496, p = .001]). In a receiver operating characteristic analysis, N45 amplitude predicted depression illness state with 80% sensitivity, 73.3% specificity, and 76.6% accuracy (area under the curve = 0.829, p < .001). The global mean field amplitude area under the curve, a neurophysiological measure of cortical reactivity, was significantly larger in persons with MDD (t = −3.114, p = .003), as was P60 (t = −3.260, p = .002). In healthy participants, there was a positive correlation between inhibitory N45 and excitatory global mean field amplitude area under the curve (r = .711, p < .001) that was not present in persons with MDD (r = .149, p = .43), demonstrating a potential imbalance between inhibition and excitation in MDD. ConclusionsAs the TMS-EEG waveform and its components index inhibitory and excitatory activity from the cortex, our results suggest abnormalities in these neurophysiological processes of DLPFC in persons with MDD.

Effects of single versus dual-site High-Definition transcranial direct current stimulation (HD-tDCS) on cortical reactivity and working memory performance in healthy subjects

BackgroundPrevious research has typically focussed on the neuromodulatory effects of direct currents applied over single regions of the cortex. However, complex processes such as working memory (WM) strongly rely on activations across a wider neural network and therefore might benefit from stimulation administered over multiple cortical targets. ObjectiveWe examined the neurobiological and cognitive effects of High-Definition transcranial direct current stimulation (HD-tDCS) montages that either targeted the dorsolateral prefrontal cortex (DLPFC) alone, or simultaneously stimulated the DLPFC and parietal cortex (DLPFC + PC). MethodsIn a within-subjects design, 16 healthy participants completed three experimental sessions in which they received HD-tDCS over either the DLPFC, the DLPFC + PC or sham stimulation. Changes in cortical reactivity were examined using transcranial magnetic stimulation combined with electroencephalography (TMS-EEG), while oscillatory power was measured via EEG recorded during n-back tasks. WM performance was also examined across several separate tasks. ResultsStimulation using both the DLPFC or DLPFC + PC montages modulated cortical reactivity, as indexed by potentiation of the P60 TMS-evoked potential. However, only the dual-site DLPFC + PC stimulation produced a reduction in the amplitude of the N100 component, relative to baseline. Increases in theta and gamma power were also observed following this montage, when compared to baseline, but were not present following HD-tDCS over the DLPFC alone. Despite these neurophysiological changes, WM performance was not significantly modulated by HD-tDCS, regardless of stimulation montage. ConclusionThese results provide important initial insight into the behavioural and biological effects of stimulation over key cortical regions linked to WM and attest to the sensitivity of TMS-EEG and EEG in detecting subtle neurophysiological changes induced by HD-tDCS.

Cortical dynamics underpinning the self-other distinction of touch: A TMS-EEG study

Touch supports processes crucial to human social behaviour, adding a bodily dimension to the perception and understanding of others' feelings. Mirror cortical activity was proposed to underpin the interpersonal sharing of touch, allowing an automatic and unconscious simulation of others' somatic states. However, recent evidence questioned the existence of a tactile shared representation in the primary somatosensory cortex (S1), and the neural correlates of self-other distinction in the somatosensory system remains unknown. We address these issues by exploring S1 reactivity, and the associated neural network oscillations and connectivity, to self and others' touch. Transcranial Magnetic Stimulation combined with Electroencephalography (TMS-EEG) recordings were performed during tactile perception and observation, looking for differences in cortical activation and connectivity between felt and seen touch. The sight of a touch directed to a human body part, but not to an object, triggered an early activation of S1 as a felt touch did, which, in both conditions, propagated to fronto-parietal regions. Critically, touch perception and observation shared an effective connectivity network generated in the beta band, which is typically associated to unconscious tactile processing. Conversely, alpha band connectivity, a marker of conscious tactile processing, was detected only for real tactile stimulation. Alpha connectivity within a fronto-parietal pathway seems to underpin the ability to distinguish self and others' somatosensory states, controlling and distinguishing shared tactile representations in S1.

Effects of prefrontal bipolar and high-definition transcranial direct current stimulation on cortical reactivity and working memory in healthy adults

Transcranial direct current stimulation (tDCS) is a well-recognised neuromodulatory technology which has been shown to induce short-lasting changes in motor-cortical excitability. The recent and rapid expansion of tDCS into the cognitive domain, however, necessitates deeper mechanistic understanding of its neurophysiological effects over non-motor brain regions. The present study utilised transcranial magnetic stimulation combined with electroencephalography (TMS-EEG) to probe the immediate and longer-term effects of both a bipolar (BP-tDCS) and more focal 4×1 High-Definition tDCS (HD-tDCS) montage applied over the left DLPFC on TMS-evoked potentials (TEPs) and oscillations in 19 healthy adult participants. 2-back working memory (WM) performance was also assessed as a marker of cognitive function. Region of interest (ROI) analyses taken from the F1 electrode directly adjacent to the stimulation site revealed increased P60 TEP amplitudes at this location 5min following BP-tDCS and 30min following HD-tDCS. Further global cluster based analyses of all scalp electrodes revealed widespread neuromodulatory changes following HD-tDCS, but not BP-tDCS, both five and 30min after stimulation, with reductions also detected in both beta and gamma oscillatory power over parieto-occipital channels 30min after stimulation. No significant changes in WM performance were observed following either HD-tDCS or BP-tDCS. This study highlights the capacity for single-session prefrontal anodal tDCS montages to modulate neurophysiological processes, as assessed with TMS-EEG.

Cognitive Enhancement Induced by Anodal tDCS Drives Circuit-Specific Cortical Plasticity.

Increasing evidence shows that anodal transcranial direct current stimulation (tDCS) enhances cognitive performance in healthy and clinical population. Such facilitation is supposed to be linked to plastic changes at relevant cortical sites. However, direct electrophysiological evidence for this causal relationship is still missing. Here, we show that cognitive enhancement occurring in healthy human subjects during anodal tDCS is affected by ongoing brain activity, increasing cortical excitability of task-related brain networks only, as directly measured by Transcranial Magnetic Stimulation combined with electroencephalography (TMS-EEG). Specifically, TMS-EEG recordings were performed before and after anodal tDCS coupled with a verbal fluency task. To control for effects of tDCS protocol and TMS target location, 3 conditions were assessed: anodal/sham tDCS with TMS over left premotor cortex, anodal tDCS with TMS over left posterior parietal cortex. Modulation of cortical excitability occurred only at left Brodmann's areas 6, 44, and 45, a key network for language production, after anodal tDCS and TMS over the premotor cortex, and was positively correlated to the degree of cognitive enhancement. Our results suggest that anodal tDCS specifically affects task-related functional networks active while delivering stimulation, and this boost of specific cortical circuits is correlated to the observed cognitive enhancement.

Timing of emotion representation in right and left occipital region: Evidence from combined TMS-EEG

Neuroimaging and electrophysiological studies provide evidence of hemispheric differences in processing faces and, in particular, emotional expressions. However, the timing of emotion representation in the right and left hemisphere is still unclear. Transcranial magnetic stimulation combined with electroencephalography (TMS-EEG) was used to explore cortical responsiveness during behavioural tasks requiring processing of either identity or expression of faces. Single-pulse TMS was delivered 100ms after face onset over the medial prefrontal cortex (mPFC) while continuous EEG was recorded using a 60-channel TMS-compatible amplifier; right premotor cortex (rPMC) was also stimulated as control site. The same face stimuli with neutral, happy and fearful expressions were presented in separate blocks and participants were asked to complete either a facial identity or facial emotion matching task. Analyses performed on posterior face specific EEG components revealed that mPFC-TMS reduced the P1–N1 component. In particular, only when an explicit expression processing was required, mPFC-TMS interacted with emotion type in relation to hemispheric side at different timing; the first P1–N1 component was affected in the right hemisphere whereas the later N1–P2 component was modulated in the left hemisphere. These findings support the hypothesis that the frontal cortex exerts an early influence on the occipital cortex during face processing and suggest a different timing of the right and left hemisphere involvement in emotion discrimination.

4. Reliability of the perturbational complexity index in discriminating chronic patients with disorders of consciousness

The level of consciousness is normally assessed based on the ability of an individual to interact with the surrounding environment and communicate. Theoretically, consciousness is thought to rely on brain complexity (i.e., joint presence of functional integration and functional differentiation). Transcranial magnetic stimulation combined with electroencephalography (TMS/EEG) has been recently proposed as a neurophysiological tool able to gauge the conjoint presence of integration and information in physiological and pathological conditions. Here we tested the reliability of the algorithmic complexity of TMS-evoked potentials (Perturbational Complexity Index, PCI) by comparing PCI with the Coma Recovery Scale-Revised (CRS-R) in sixty chronic brain-injured patients (22 vegetative state-VS, 25 minimally conscious state-MCS, 13 conscious state-CS) with a stable clinical diagnosis. CRS-R was significantly lower in VS as compared to MCS and CS groups. Interestingly, PCI invariably discriminated between VS and MCS/CS conditions at the single-patient level. Although preliminary, our results suggest that PCI may serve as a valuable tool to discriminate VS and MCS/CS conditions also when the behavioral evaluation gives ambiguous indications. Future studies should further validate PCI in discriminating VS from MCS/CS by involving larger samples and by comparing it with other brain functional assessments, e.g., event-related potentials and/or functional magnetic resonance imaging.

On the cerebral origin of EEG responses to TMS: insights from severe cortical lesions.

Transcranial magnetic stimulation combined with electroencephalography (TMS/EEG) represents a valuable tool to probe cortical excitability and connectivity. Although several procedures have been devised to abolish TMS-related artifacts, direct evidence that it is possible to record TMS-evoked potentials (TEPs) that purely reflect cortical responses to TMS are still lacking. To demonstrate that when TMS is delivered on a human head with intact nerves, scalp and ocular muscles, TEPs are present only if a functional portion of cortex is targeted and is absent otherwise. We performed extensive navigated TMS/EEG mappings in three vegetative state patients and in eight healthy controls. Patients were selected based on the extension of their cortical lesions as revealed by structural/functional imaging: the cerebral cortex was globally damaged in Patient 1 due to cerebral anoxia, Patient 2 showed a traumatic damage affecting one cerebral hemisphere, while Patient 3 was characterized by one left sided and one right-sided focal ischemic lesion. In Patient 1, TMS performed at any targeted cortical site did not elicit statistically significant TEPs. In Patient 2, TEPs were absent when the damaged hemisphere was targeted, while were present over the healthy side. In Patient 3, significant TEPs were absent when cortical lesions were targeted and present otherwise. Significant TEPs were always present in healthy controls. These findings suggest that, provided that appropriate experimental procedures are employed, TEPs are genuine cortical responses detectable only when preserved cortical tissue is stimulated. Hence, a dependable assessment of cortical excitability and connectivity in brain-injured patients requires the use of neuronavigated TMS.

Quantifying Cortical EEG Responses to TMS in (Un)consciousness

We normally assess another individual's level of consciousness based on her or his ability to interact with the surrounding environment and communicate. Usually, if we observe purposeful behavior, appropriate responses to sensory inputs, and, above all, appropriate answers to questions, we can be reasonably sure that the person is conscious. However, we know that consciousness can be entirely within the brain, even in the absence of any interaction with the external world; this happens almost every night, while we dream. Yet, to this day, we lack an objective, dependable measure of the level of consciousness that is independent of processing sensory inputs and producing appropriate motor outputs. Theoretically, consciousness is thought to require the joint presence of functional integration and functional differentiation, otherwise defined as brain complexity. Here we review a series of recent studies in which Transcranial Magnetic Stimulation combined with electroencephalography (TMS/EEG) has been employed to quantify brain complexity in wakefulness and during physiological (sleep), pharmacological (anesthesia) and pathological (brain injury) loss of consciousness. These studies invariably show that the complexity of the cortical response to TMS collapses when consciousness is lost during deep sleep, anesthesia and vegetative state following severe brain injury, while it recovers when consciousness resurges in wakefulness, during dreaming, in the minimally conscious state or locked-in syndrome. The present paper will also focus on how this approach may contribute to unveiling the pathophysiology of disorders of consciousness affecting brain-injured patients. Finally, we will underline some crucial methodological aspects concerning TMS/EEG measurements of brain complexity.

Top-down interference and cortical responsiveness in face processing: A TMS-EEG study

Neuroimaging and electrophysiological studies have shown the involvement of a fronto-temporo-occipital network in face processing, but the functional relation among these areas remains unclear. We used transcranial magnetic stimulation combined with electroencephalography (TMS-EEG) to explore the local and global cortical excitability at rest and during two different face processing behavioral tasks. Single-pulse TMS was delivered (100 ms after face stimulus onset) over the right medial prefrontal cortex (mPFC) during a face identity or a face expression matching task, while continuous EEG was recorded using a 60-channel TMS-compatible amplifier. We examined TMS effects on the occipital face-specific ERP component and compared TMS-evoked potentials (TEPs) recorded during task performance and a passive point fixation control task. TMS reduced the P1-N1 component recorded at the occipital electrodes. Moreover, performing face tasks significantly modulated TEPs recorded at the occipital and temporal electrodes within the first 30 ms after right mPFC stimulation, with a specific increase of temporal TEPs in the right hemisphere for the facial expression task. Furthermore, in order to test the site-specificity of the reported effects, TMS was applied over the right premotor cortex (PMC) as a control site using the same experimental paradigm. Results showed that TMS over the right PMC did not affect ERP components in posterior regions during the face tasks and TEP amplitude did not change between task and no task condition, either at fronto-central electrodes near the stimulation or at temporal and occipital electrodes. These findings support the notion that the prefrontal cortex exerts a very early influence over the occipital cortex during face processing tasks and that excitability across right fronto-temporal cortical regions is significantly modulated during explicit facial expression processing.