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Background: Electroconvulsive therapy (ECT) is the most effective treatment for treatment-resistant depression (TRD), especially for acute suicidal ideation, but the associated cognitive adverse effects and negative stigma limit its use. Another seizure therapy under development is magnetic seizure therapy (MST), which could potentially overcome the restrictions associated with ECT with similar efficacy. The neurophysiological targets and mechanisms of seizure therapy, however, remain poorly understood.Methods/design: This neurophysiological study protocol is published as a companion to the overall Confirmatory Efficacy and Safety Trial of Magnetic Seizure Therapy for Depression (CREST-MST) protocol that describes our two-site, double-blind, randomized, non-inferiority clinical trial to develop MST as an effective and safe treatment for TRD. Our aim for the neurophysiological component of the study is to evaluate two biomarkers, one to predict remission of suicidal ideation (primary outcome) and the other to predict cognitive impairment (secondary outcome). Suicidal ideation will be assessed through cortical inhibition, which according to our preliminary studies, correlates with remission of suicidal ideation. Cortical inhibition will be measured with simultaneous transcranial magnetic stimulation (TMS) and electroencephalography (EEG), TMS-EEG, which measures TMS-evoked EEG activity. Cognitive adverse effects associated with seizure therapy, on the contrary, will be evaluated via multiscale entropy analysis reflecting the complexity of ongoing resting-state EEG activity.Discussion: ECT and MST are known to influence cortical inhibition associated with depression, suicidal ideation severity, and clinical outcome. Therefore, evaluating cortical inhibition and brain temporal dynamics will help understand the pathophysiology of depression and suicidal ideation and define new biological targets that could aid clinicians in diagnosing and selecting treatments. Resting-state EEG complexity was previously associated with the degree of cognitive side effects after a seizure therapy. This neurophysiological metric may help clinicians assess the risk for adverse effects caused by these useful and effective treatments.Trial Registration: ClinicalTrials.gov NCT03191058 . Registered on June 19, 2017. [ABSTRACT FROM AUTHOR]

Biomarkers are essential for understanding the underlying pathologies in brain disorders and for developing effective treatments. Combined transcranial magnetic stimulation and electroencephalography (TMS-EEG) is an emerging neurophysiological tool that can be used for biomarker development. This method can identify biomarkers associated with the function and dynamics of the inhibitory and excitatory neurotransmitter systems and effective connectivity between brain areas. In this review, we outline the current state of the TMS-EEG biomarker field by summarizing the existing protocols and the possibilities and challenges associated with this methodology. • TMS-EEG is an emerging neurophysiological method for searching biomarkers. • TMS-EEG can measure neurotransmitter functionality and effective connectivity. • The main challenges are various artifacts that may influence the biomarkers. [ABSTRACT FROM AUTHOR]

An individualized model that predicts trial‐by‐trial working memory performance is instrumental for personalized interventions. Here, we propose a single‐trial electroencephalography (EEG) classification process predicting individuals' responses, that is, target correct versus target non‐correct during a working memory task, N‐back. We used event‐related (de‐)synchronization (ERD and ERS) prior to an anticipatory cue as features. The proposed comprehensive process addresses single‐trial EEG classification challenges such as temporal overlap between training and testing datasets, feature selection's stability, and significance of the classification accuracy which have been often overlooked. Our model identified for the first time a few (ranged between 4 and 10) brain regions and oscillations where ERD and ERS predicted an individual's performance. Mean (SD) prediction accuracy across 50 participants (mean age [SD] = 28.56 [7.55]) was 69.51% (8.41). Accuracy was significantly above chance in 34 participants. This machine learning‐based approach provides a proof of principle for individualizing EEG targets for potential interventions. [ABSTRACT FROM AUTHOR]

Intermittent theta burst stimulation (iTBS) targeting the left dorsolateral prefrontal cortex is effective for treatment-resistant depression, but the effects of iTBS on neurophysiological markers remain unclear. Here, we indexed transcranial magnetic stimulation–electroencephalography (TMS-EEG) markers, specifically, the N45 and N100 amplitudes, at baseline and post-iTBS, comparing separated and contiguous iTBS schedules. TMS-EEG markers were also compared between iTBS responders and nonresponders. TMS-EEG was analyzed from a triple-blind 1:1 randomized trial for treatment-resistant depression, comparing a separated (54-minute interval) and contiguous (0-minute interval) schedule of 2 × 600-pulse iTBS for 30 treatments. Participants underwent TMS-EEG over the left dorsolateral prefrontal cortex at baseline and posttreatment. One hundred fourteen participants had usable TMS-EEG at baseline, and 98 at posttreatment. TMS-evoked potential components (N45, N100) were examined via global mean field analysis. The N100 amplitude decreased from baseline to posttreatment, regardless of the treatment group (F 1,106 = 5.20, p =.02). There were no changes in N45 amplitude in either treatment group. In responders, the N100 amplitude decreased after iTBS (F 1,102 = 11.30, p =.001, p corrected =.0004). Responders showed higher posttreatment N45 amplitude than nonresponders (F 1,94 = 4.11, p =.045, p corrected =.016). Higher baseline N100 amplitude predicted lower post-iTBS depression scores (F 4,106 = 6.28, p =.00014). These results provide further evidence for an association between the neurophysiological effects of iTBS and treatment efficacy in treatment-resistant depression. Future studies are needed to test the predictive potential for clinical applications of TMS-EEG markers. [ABSTRACT FROM AUTHOR]

Background: Repetitive transcranial magnetic stimulation has been employed to treat drug dependence, reduce drug use and improve cognition. The aim of the study was to analyze the effectiveness of intermittent theta-burst stimulation (iTBS) on cognition in individuals with methamphetamine use disorder (MUD). Methods: This was a secondary analysis of 40 MUD subjects receiving left dorsolateral prefrontal cortex (L-DLPFC) iTBS or sham iTBS for 20 times over 10 days (twice-daily). Changes in working memory (WM) accuracy, reaction time, and sensitivity index were analyzed before and after active and sham rTMS treatment. Resting-state EEG was also acquired to identify potential biological changes that may relate to any cognitive improvement. Results: The results showed that iTBS increased WM accuracy and discrimination ability, and improved reaction time relative to sham iTBS. iTBS also reduced resting-state delta power over the left prefrontal region. This reduction in resting-state delta power correlated with the changes in WM. Conclusions: Prefrontal iTBS may enhance WM performance in MUD subjects. iTBS induced resting EEG changes raising the possibility that such findings may represent a biological target of iTBS treatment response. [ABSTRACT FROM AUTHOR]

• TMS-EEG research on unconscious state was comprehensively reviewed. • Some TMS-EEG neurophysiological indices could be useful biomarkers for unconscious state. • Specifically, perturbational complexity index could be an applicable index for differentiating DOC. • TMS-EEG may be a promising approach to examine unconscious state non-invasively. Unconscious state has been investigated in numerous studies so far, but pathophysiology of this state is not fully understood. Recently, combined transcranial magnetic stimulation (TMS) and electroencephalography (EEG) has been developed to allow for non-invasive assessment of neurophysiology in the cerebral cortex. We conducted a systematic literature search for TMS-EEG studies on human unconscious state using PubMed with cross-reference and manual searches. The initial search yielded 137 articles, and 19 of them were identified as relevant, including one article found by manual search. This review included 10 studies for unresponsive wakefulness syndrome (UWS), 9 for minimally conscious states (MCS), 5 for medication-induced unconscious states, and 6 for natural non-rapid eye movement states. These studies analyzed TMS-evoked potential to calculate perturbational complexity index (PCI) and OFF-periods. In particular, PCI was found to be a potentially useful marker to differentiate between UWS and MCS. This review demonstrated that TMS-EEG could represent a promising neuroscientific tool to investigate various unconscious states. Further TMS-EEG research may help elucidate the neural basis of unconscious state. [ABSTRACT FROM AUTHOR]

• Interhemispheric signal propagation was elevated in schizophrenia and depression patients relative to healthy controls. • Interhemispheric signal propagation did not differ between patient groups. • There were no medication effects on interhemispheric signaling from inter-individual comparisons and no significant correlation with symptom severity. Altered interhemispheric connectivity is implicated in the pathophysiology of schizophrenia (SCZ) and major depressive disorder (MDD) and may account for deficits in lateralized cognitive processes. We measured transcranial magnetic stimulation evoked interhemispheric signal propagation (ISP), a non-invasive measure of transcallosal connectivity, and hypothesized that the SCZ and MDD groups will have increased ISP compared to healthy controls. We evaluated ISP over the dorsolateral prefrontal cortex in 34 patients with SCZ and 34 patients with MDD compared to 32 age and sex-matched healthy controls. ISP was significantly increased in patients with SCZ and patients with MDD compared to healthy controls but did not differ between patient groups. There were no effects of antidepressant, antipsychotic, and benzodiazepine medications on ISP and our results remained unchanged after re-analysis with a region of interest method. Altered ISP was found in both SCZ and MDD patient groups. This indicates that disruptions of interhemispheric signaling processes can be indexed with ISP across psychiatric populations. These findings enhance our knowledge of the physiological mechanisms of interhemispheric imbalances in SCZ and MDD, which may serve as potential treatment targets in future patients. [ABSTRACT FROM AUTHOR]

Background: Combined transcranial magnetic stimulation and electroencephalography (TMS-EEG) is emerging as a powerful technique for interrogating neural circuit dysfunction in psychiatric disorders. Here, we utilized time-frequency analyses to characterize differences in neural oscillatory dynamics between subjects with major depressive disorder (MDD) and healthy controls (HC). We further examined changes in TMS-related oscillatory power following convulsive therapy.Methods: Oscillatory power was examined following TMS over the dorsolateral prefrontal and motor cortices (DLPFC and M1) in 38 MDD subjects, and 22 HCs. We further investigated how these responses changed in the MDD group following an acute course of convulsive therapy (either magnetic seizure therapy [MST, n = 24] or electroconvulsive therapy [ECT, n = 14]).Results: Prior to treatment, MDD subjects exhibited increased oscillatory power within delta, theta, and alpha frequency bands with TMS-EEG over the DLPFC, but showed no differences to HCs with stimulation over M1. Following MST, DLPFC stimulation revealed attenuated baseline-normalized power in the delta and theta bands, with reductions in the delta, theta, and alpha power following ECT. TMS over M1 revealed reduced delta and theta power following ECT, with no changes observed following MST. An association was also observed between the treatment- induced change in alpha power and depression severity score.Limitations: Limitations include the modest sample size, open-label MST and ECT treatment designs, and lack of a placebo condition.Conclusions: These results provide evidence of alterations in TMS-related oscillatory activity in MDD, and further suggest modulation of oscillatory power following ECT and MST. [ABSTRACT FROM AUTHOR]

• Baseline resting EEG theta connectivity and alpha power predicted response to rTMS for depression in our previous research. • These measures did not differentiate responders and non-responders in a larger independent dataset. • Theta connectivity and alpha power are unlikely to be clinically useful predictors of response to rTMS for depression. Our previous research showed high predictive accuracy at differentiating responders from non-responders to repetitive transcranial magnetic stimulation (rTMS) for depression using resting electroencephalography (EEG) and clinical data from baseline and one-week following treatment onset using a machine learning algorithm. In particular, theta (4–8 Hz) connectivity and alpha power (8–13 Hz) significantly differed between responders and non-responders. Independent replication is a necessary step before the application of potential predictors in clinical practice. This study attempted to replicate the results in an independent dataset. We submitted baseline resting EEG data from an independent sample of participants who underwent rTMS treatment for depression (N = 193, 128 responders) (Krepel et al., 2018) to the same between group comparisons as our previous research (Bailey et al., 2019). Our previous results were not replicated, with no difference between responders and non-responders in theta connectivity (p = 0.250, Cohen's d = 0.1786) nor alpha power (p = 0.357, η p 2 = 0.005). These results suggest that baseline resting EEG theta connectivity or alpha power are unlikely to be generalisable predictors of response to rTMS treatment for depression. These results highlight the importance of independent replication, data sharing and using large datasets in the prediction of response research. [ABSTRACT FROM AUTHOR]

While several studies have found that neural oscillations play a key role in the functioning of working memory, the nature of aberrant oscillatory activity underlying working memory impairments in Alzheimer's disease (AD) and mild cognitive impairment (MCI) remains largely unexplored. These individuals often display structural alterations in brain regions and pathways involved in working memory processes and therefore may also display altered oscillatory activity during memory activation. Electroencephalographic (EEG) activity was recorded during the N-back working memory task in three groups: AD (n = 29), MCI (n = 100), and healthy controls (HCs; n = 40). Theta (4-7 Hz) and alpha (7.5-12 Hz) modulation was measured in response to the stimulus presentation during correct and incorrect responses. This modulation represents the change in EEG activity associated with the stimulus onset and was measured as a ratio of post stimulus power to pre stimulus power. We also assessed the relationship between change in oscillatory power and working memory performance. Compared to HCs, the AD group demonstrated the lowest working memory accuracy and a smaller theta ratio for correct responses on the 2-back condition; the MCI group demonstrated a smaller theta ratio for correct responses on the 3-back condition. Finally, we observed that the theta ratio, but not the alpha ratio, was a significant predictor of working memory performance in the three groups for all conditions. Taken together, these behavioral and electrophysiological results suggest that in addition to impairments in working memory performance, modulation of theta, but not alpha power, may be impaired in MCI and AD. [ABSTRACT FROM AUTHOR]

Objectives The first objective of this study aimed to elucidate the relationship between seizure characteristics and Magnetic Seizure Therapy (MST) treatment outcome. The second objective was to determine the effect of stimulation frequency on seizure characteristics. Methods Using a between-subjects design, we compared the seizures of patients with unipolar depression receiving MST at three separate stimulation frequencies: 25 Hz ( n  = 34), 50 Hz ( n  = 16) and 100 Hz ( n  = 11). Seizures were rated for overall seizure adequacy on a scale of 0–6, with one point given for each measure that was considered to be adequate according to the ECT literature: (1) seizure EEG duration (2) motor duration, (3) post-ictal suppression, (4) ictal EEG maximum amplitude, (5) Global Seizure Strength, and (6) Symmetry. Mixed-effect models were used to evaluate the effect of frequency on seizure characteristics and the relationships between seizure characteristics and clinical outcome. Results (1) 100 Hz induced seizures that were less adequate than seizures induced with 50 Hz and 25 Hz stimulations. Seizures induced by 50 Hz stimulations had longer slow-wave phase durations and total EEG durations than the 100 Hz and 25 Hz groups. Global seizure strength was less robust in seizures induced by 100 Hz MST compared to the other stimulation frequencies. (2) Shorter polyspike durations and smaller slow-wave amplitude predicted reductions in overall symptoms of depression as measured by the 24-item Hamilton Depression Scale. Conclusion Analysis of our first objective revealed stimulation frequency significantly influences measures of overall seizure adequacy. However, our results also revealed these descriptions of seizure adequacy based on ECT literature may not be useful for MST-induced seizures, as the characteristics of MST-induced seizure characteristics may predict clinical response in a different manner. Significance These results may help to distinguish the biological processes impacted by stimulation frequency and may suggest different mechanisms of action between convulsive therapies and challenge the current understanding of seizure adequacy for MST. [ABSTRACT FROM AUTHOR]

Background: Dysfunctional neuroplasticity may be one of the pathophysiological mechanisms underlying major depression. We have previously established methods to assess neuroplasticity from the dorsolateral prefrontal cortex (DLPFC) using a paired associative stimulation (PAS) paradigm, which pairs a preceding peripheral nerve stimulation with subsequent transcranial magnetic stimulation (TMS) combined with electroencephalography (EEG). We aimed to investigate neuroplasticity through the PAS paradigm in the DLPFC in patients with depression compared to healthy subjects.Methods: Twenty-nine patients with depression and 28 healthy controls participated in this study. There were no significant age or sex differences between the two groups. All participants received PAS paradigm in the DLPFC. We analyzed PAS induced potentiation from the DLPFC in both groups calculating the power of TMS-evoked potentials (TEP). A two-way ANOVA with PAS effect as a within-subject factor and diagnostic group as a between-subject factor was performed to examine the group differences in the PAS paradigm.Results: DLPFC-PAS induced a significant potentiation at the stimulation site in both patients and healthy subjects (mean ± SD: 1.24 ± 0.33 [μV] vs. 1.48 ± 0.28 [μV]). However, when we compared PAS potentiation between patients and healthy subjects, there were significant main effects of PAS (F1,53  = 68.63, p < 0.0001) and PAS-by-diagnostic group interaction (F1,53  = 25.05, p < 0.0001). Post hoc analysis demonstrated that patients had a significantly lower PAS potentiation compared to healthy subjects (t55  = 3.128, p = 0.003).Conclustions: Our findings provide evidence for impaired neuroplasticity in DLPFC in patients with depression compared to healthy subjects. Such findings may ultimately help us understand the pathophysiology of MDD and mechanisms involved in its treatment. [ABSTRACT FROM AUTHOR]

Background: Treatment-resistant major depressive disorder is common; repetitive transcranial magnetic stimulation (rTMS) by use of high-frequency (10 Hz) left-side dorsolateral prefrontal cortex stimulation is an evidence-based treatment for this disorder. Intermittent theta burst stimulation (iTBS) is a newer form of rTMS that can be delivered in 3 min, versus 37·5 min for a standard 10 Hz treatment session. We aimed to establish the clinical effectiveness, safety, and tolerability of iTBS compared with standard 10 Hz rTMS in adults with treatment-resistant depression.Methods: In this randomised, multicentre, non-inferiority clinical trial, we recruited patients who were referred to specialty neurostimulation centres based at three Canadian university hospitals (Centre for Addiction and Mental Health and Toronto Western Hospital, Toronto, ON, and University of British Columbia Hospital, Vancouver, BC). Participants were aged 18-65 years, were diagnosed with a current treatment-resistant major depressive episode or could not tolerate at least two antidepressants in the current episode, were receiving stable antidepressant medication doses for at least 4 weeks before baseline, and had an HRSD-17 score of at least 18. Participants were randomly allocated (1:1) to treatment groups (10 Hz rTMS or iTBS) by use of a random permuted block method, with stratification by site and number of adequate trials in which the antidepressants were unsuccessful. Treatment was delivered open-label but investigators and outcome assessors were masked to treatment groups. Participants were treated with 10 Hz rTMS or iTBS to the left dorsolateral prefrontal cortex, administered on 5 days a week for 4-6 weeks. The primary outcome measure was change in 17-item Hamilton Rating Scale for Depression (HRSD-17) score, with a non-inferiority margin of 2·25 points. For the primary outcome measure, we did a per-protocol analysis of all participants who were randomly allocated to groups and who attained the primary completion point of 4 weeks. This trial is registered with ClinicalTrials.gov, number NCT01887782.Findings: Between Sept 3, 2013, and Oct 3, 2016, we randomly allocated 205 participants to receive 10 Hz rTMS and 209 participants to receive iTBS. 192 (94%) participants in the 10 Hz rTMS group and 193 (92%) in the iTBS group were assessed for the primary outcome after 4-6 weeks of treatment. HRSD-17 scores improved from 23·5 (SD 4·4) to 13·4 (7·8) in the 10 Hz rTMS group and from 23·6 (4·3) to 13·4 (7·9) in the iTBS group (adjusted difference 0·103 [corrected], lower 95% CI -1·16; p=0·0011), which indicated non-inferiority of iTBS. Self-rated intensity of pain associated with treatment was greater in the iTBS group than in the 10 Hz rTMS group (mean score on verbal analogue scale 3·8 [SD 2·0] vs 3·4 [2·0] out of 10; p=0·011). Dropout rates did not differ between groups (10 Hz rTMS: 13 [6%] of 205 participants; iTBS: 16 [8%] of 209 participants); p=0·6004). The most common treatment-related adverse event was headache in both groups (10 Hz rTMS: 131 [64%] of 204; iTBS: 136 [65%] of 208).Interpretation: In patients with treatment-resistant depression, iTBS was non-inferior to 10 Hz rTMS for the treatment of depression. Both treatments had low numbers of dropouts and similar side-effects, safety, and tolerability profiles. By use of iTBS, the number of patients treated per day with current rTMS devices can be increased several times without compromising clinical effectiveness.Funding: Canadian Institutes of Health Research. [ABSTRACT FROM AUTHOR]

Background: Working memory deficits represent a core feature of schizophrenia. These deficits have been associated with dysfunctional dorsolateral prefrontal cortex (DLPFC) cortical oscillations. Theta-gamma coupling describes the modulation of gamma oscillations by theta phasic activity that has been directly associated with the ordering of information during working memory performance. Evaluating theta-gamma coupling may provide greater insight into the neural mechanisms mediating working memory deficits in this disorder.Methods: Thirty-eight patients diagnosed with schizophrenia or schizoaffective disorder and 38 healthy controls performed the verbal N-Back task administered at 4 levels, while EEG was recorded. Theta (4-7Hz)-gamma (30-50Hz) coupling was calculated for target and non-target correct trials for each working memory load. The relationship between theta-gamma coupling and accuracy was determined.Results: Theta-gamma coupling was significantly and selectively impaired during correct responses to target letters among schizophrenia patients compared to healthy controls. A significant and positive relationship was found between theta-gamma coupling and 3-Back accuracy in controls, while this relationship was not observed in patients.Conclusions: These findings suggest that impaired theta-gamma coupling contribute to working memory dysfunction in schizophrenia. Future work is needed to evaluate the predictive utility of theta-gamma coupling as a neurophysiological marker for functional outcomes in this disorder. [ABSTRACT FROM AUTHOR]

An overly negative self-schema is a proposed cognitive mechanism of major depressive disorder (MDD). Self-schema − one’s core conception of self, including how strongly one believes one possesses various characteristics − is part of semantic memory (SM), our knowledge about concepts and their relationships. We used the N400 event-related potential (ERP) − elicited by meaningful stimuli, and reduced by greater association of the stimulus with preceding context − to measure association strength between self-concept and positive, negative, and neutral characteristics in SM. ERPs were recorded from MDD patients ( n = 16) and controls ( n = 16) who viewed trials comprising a self-referential phrase followed by a positive, negative, or neutral adjective. Participants’ task was to indicate via button-press whether or not they felt each adjective described themselves. Controls endorsed more positive adjectives than did MDD patients, but the opposite was true for negative adjectives. Patients had smaller N400s than controls specifically for negative adjectives, suggesting that MDD is associated with stronger than normal functional neural links between self-concept and negative characteristics in SM. [ABSTRACT FROM AUTHOR]

Over 350 million people worldwide suffer from depression, a third of whom are medication-resistant. Seizure therapy remains the most effective treatment in depression, even when many treatments fail. The utility of seizure therapy is limited due to its cognitive side effects and stigma. The biological targets of seizure therapy remain unknown, hindering design of new treatments with comparable efficacy. Seizures impact the brains temporal dynamicity observed through electroencephalography. This dynamicity reflects richness of information processing across distributed brain networks subserving affective and cognitive processes. We investigated the hypothesis that seizure therapy impacts mood (depressive symptoms) and cognition by modulating brain temporal dynamicity. We obtained resting-state electroencephalography from 34 patients (age = 46.0 ± 14.0, 21 females) receiving two types of seizure treatments-electroconvulsive therapy or magnetic seizure therapy. We used multi-scale entropy to quantify the complexity of the brain's temporal dynamics before and after seizure therapy. We discovered that reduction of complexity in fine timescales underlined successful therapeutic response to both seizure treatments. Greater reduction in complexity of fine timescales in parieto-occipital and central brain regions was significantly linked with greater improvement in depressive symptoms. Greater increase in complexity of coarse timescales was associated with greater decline in cognition including the autobiographical memory. These findings were region and timescale specific. That is, change in complexity in occipital regions (e.g. O2 electrode or right occipital pole) at fine timescales was only associated with change in depressive symptoms, and not change in cognition, and change in complexity in parieto-central regions (e.g. Pz electrode or intra and transparietal sulcus) at coarser timescale was only associated with change in cognition, and not depressive symptoms. Finally, region and timescale specific changes in complexity classified both antidepressant and cognitive response to seizure therapy with good (80%) and excellent (95%) accuracy, respectively. In this study, we discovered a novel biological target of seizure therapy: complexity of the brain resting state dynamics. Region and timescale dependent changes in complexity of the brain resting state dynamics is a novel mechanistic marker of response to seizure therapy that explains both the antidepressant response and cognitive changes associated with this treatment. This marker has tremendous potential to guide design of the new generation of antidepressant treatments. [ABSTRACT FROM AUTHOR]

Objective We aimed to investigate neuromodulatory effects of high-frequency left dorsolateral prefrontal cortex repetitive transcranial magnetic stimulation (rTMS) on resting-state electroencephalography (EEG) and their clinical and cognitive correlates in patients with depression. Methods Thirty-one patients diagnosed with depression included in the present study. Resting-state gamma power and theta–gamma coupling (TGC) were calculated before and after a course of rTMS. We explored the relationship among gamma power, TGC, and clinical/cognitive outcomes as measured with the Hamilton Rating Scale for Depression (HAM-D 17 ), Beck Depression Inventory (BDI), and Wisconsin Card Sorting Test (WCST). Results Following rTMS, depressed patients demonstrated significant increases of resting gamma power at the F3 and F4 electrode sites and resting TGC at the C3 and T3 electrode sites. Furthermore, the increased gamma power at the F3 electrode site was significantly correlated with improved score on the HAM-D 17 and BDI, while the increased TGC at the C3 electrode site was significantly correlated with reduced number of errors on the WCST. Conclusion Thus, resting-state gamma power and TGC may represent potential biomarkers of depression associated with therapeutic effects of rTMS. Significance Resting-state EEG may provide potential biomarkers related to therapeutic effects of rTMS. [ABSTRACT FROM AUTHOR]

Theta-burst stimulation is an emerging protocol for repetitive transcranial magnetic stimulation that takes 1-3 min to administer, yet offers equal/superior potency to conventional protocols lasting 30-60 min. However, preclinical evidence suggests that D2 receptor blockade may abolish the acute effects of theta-burst stimulation on synaptic facilitation or inhibition. As many patients presenting for repetitive transcranial magnetic stimulation are taking antipsychotic medications as augmentation for treatment-resistant depression, this finding is potentially concerning for the implementation of theta-burst stimulation in clinical settings. Here, we examined whether treatment-resistant depression patients taking antipsychotics have worse outcomes after a course of intermittent theta-burst stimulation. A chart review identified 105 treatment-resistant depression patients who underwent dorsomedial prefrontal-intermittent theta-burst stimulation; clinical outcomes on Hamilton Depression Rating Scale and Beck Depression Inventory were compared for those taking and not taking antipsychotics. The 29 of 105 patients who were taking antipsychotics showed non-significantly better response and remission rates, and non-significantly larger percentage improvements on both scales, with a positive but non-significant correlation between higher antipsychotic dose and larger percentage improvement. Contrary to expectations, outcomes were not significantly worse, and in some analyses trended towards being better, in patients taking antipsychotics. Future randomized controlled studies of repetitive transcranial magnetic stimulation combined with standardized dopaminergic manipulations may be justified and warranted. [ABSTRACT FROM AUTHOR]

Objectives.Preclinical studies suggest that cortical alterations within the prefrontal cortex (PFC) are critical to the pathophysiology of alcohol dependence. Combined transcranial magnetic stimulation (TMS) and electroencephalography (EEG) allows direct assessment of cortical excitability and inhibition within the PFC of human subjects. We report the first application of TMS-EEG to measure these indices within the PFC of alcohol-dependent (ALD) patients post-detoxification.Methods.Cortical inhibition was assessed in 12 ALD patients and 14 healthy controls through single and paired-pulse TMS paradigms. Long-interval cortical inhibition indexed cortical inhibition in the PFC. In the motor cortex (MC), short- interval intracortical inhibition and cortical silent period determined inhibition, while intracortical facilitation measured facilitation, resting and active motor threshold indexed cortical excitability.Results.ALD patients demonstrated altered cortical inhibition across the bilateral frontal cortices relative to controls. There was evidence of altered cortical excitability in ALD patients; however, no significant differences in MC inhibition.Conclusions.Our study provides first direct evidence of reduced cortical inhibition in the PFC of ALD patients post-detoxification. Altered cortical excitability in the MC may reflect hyper-excitability within the cortex associated with chronic alcohol consumption. These findings provide initial neurophysiological evidence of disrupted cortical excitability within the PFC of ALD patients. [ABSTRACT FROM AUTHOR]

Background Recent increase in the size and complexity of electrophysiological data from multidimensional electroencephalography (EEG) and magnetoencephalography (MEG) studies has prompted the development of sophisticated statistical frameworks for data analysis. One of the main challenges for such frameworks is the multiple comparisons problem, where the large number of statistical tests performed within a high-dimensional dataset lead to an increased risk of Type I errors (false positives). A solution to this problem, cluster analysis, applies the biologically-motivated knowledge of correlation between adjacent voxels in one or more dimensions of the dataset to correct for the multiple comparisons problem and detect true neurophysiological effects. Cluster-based methods provide increased sensitivity towards detecting neurophysiological events compared to conservative methods such as Bonferroni correction, but are limited by their dependency on an initial cluster-forming statistical threshold (e.g. t-score, alpha) obstructing precise comparisons of results across studies. New method Rather than selecting a single threshold value, unbiased cluster estimation (UCE) computes a significance distribution across all possible threshold values to provide an unbiased overall significance value. Comparison to existing methods UCE functions as a novel extension to existing cluster analysis methods. Results Using data from EEG combined with brain stimulation study, we showed the impact of statistical threshold on outcome measures and introduction of bias. We showed the application of UCE for different study designs (e.g., within-group, between-group comparisons). Conclusion We propose that researchers consider employing UCE for multidimensional EEG/MEG datasets toward an unbiased comparison of results between subjects, groups, and studies. [ABSTRACT FROM AUTHOR]

Combined transcranial magnetic stimulation and electroencephalography (TMS-EEG) enables noninvasive neurophysiological investigation of the human cortex. A TMS paradigm of short-latency afferent inhibition (SAI) is characterized by attenuation of the motor-evoked potential (MEP) and modulation of N100 of the TMS-evoked potential (TEP) when TMS is delivered to motor cortex (M1) following median nerve stimulation. SAI is a marker of cholinergic activity in the motor cortex; however, the SAI has not been tested from the prefrontal cortex. We aimed to explore the effect of SAI in dorsolateral prefrontal cortex (DLPFC). SAI was examined in 12 healthy subjects with median nerve stimulation and TMS delivered to M1 and DLPFC at interstimulus intervals (ISIs) relative to the individual N20 latency. SAI in M1 was tested at the optimal ISI of N20 + 2 ms. SAI in DLPFC was investigated at a range of ISI from N20 + 2 to N20 + 20 ms to explore its temporal profile. For SAI in M1, the attenuation of MEP amplitude was correlated with an increase of TEP N100 from the left central area. A similar spatiotemporal neural signature of SAI in DLPFC was observed with a marked increase of N100 amplitude. SAI in DLPFC was maximal at ISI N20 + 4 ms at the left frontal area. These findings establish the neural signature of SAI in DLPFC. Future studies could explore whether DLPFC-SAI is neurophysiological marker of cholinergic dysfunction in cognitive disorders. [ABSTRACT FROM AUTHOR]

Using TMS and EEG, Radhu et al. reveal reductions in long-interval cortical inhibition specific to the dorsolateral prefrontal cortex in patients with schizophrenia compared to healthy subjects and individuals with obsessive-compulsive disorder (OCD). The absence of such changes in OCD confirms that reductions in inhibition are not a generalized deficit associated with severe psychopathology.Abnormal gamma-aminobutyric acid inhibitory neurotransmission is a key pathophysiological mechanism underlying schizophrenia. Transcranial magnetic stimulation can be combined with electroencephalography to index long-interval cortical inhibition, a measure of GABAergic receptor-mediated inhibitory neurotransmission from the frontal and motor cortex. In previous studies we have reported that schizophrenia is associated with inhibitory deficits in the dorsolateral prefrontal cortex compared to healthy subjects and patients with bipolar disorder. The main objective of the current study was to replicate and extend these initial findings by evaluating long-interval cortical inhibition from the dorsolateral prefrontal cortex in patients with schizophrenia compared to patients with obsessive-compulsive disorder. A total of 111 participants were assessed: 38 patients with schizophrenia (average age: 35.71 years, 25 males, 13 females), 27 patients with obsessive-compulsive disorder (average age: 36.15 years, 11 males, 16 females) and 46 healthy subjects (average age: 33.63 years, 23 females, 23 males). Long-interval cortical inhibition was measured from the dorsolateral prefrontal cortex and motor cortex through combined transcranial magnetic stimulation and electroencephalography. In the dorsolateral prefrontal cortex, long-interval cortical inhibition was significantly reduced in patients with schizophrenia compared to healthy subjects (P = 0.004) and not significantly different between patients with obsessive-compulsive disorder and healthy subjects (P = 0.5445). Long-interval cortical inhibition deficits in the dorsolateral prefrontal cortex were also significantly greater in patients with schizophrenia compared to patients with obsessive-compulsive disorder (P = 0.0465). There were no significant differences in long-interval cortical inhibition across all three groups in the motor cortex. These results demonstrate that long-interval cortical inhibition deficits in the dorsolateral prefrontal cortex are specific to patients with schizophrenia and are not a generalized deficit that is shared by disorders of severe psychopathology. [ABSTRACT FROM AUTHOR]

Background Deep brain stimulation (DBS) has treatment efficacy in neurological and psychiatric disorders such as Parkinson's disease and major depression. Electroencephalography (EEG) is a versatile neurophysiological tool that can be used to better understand DBS treatment mechanisms. DBS causes artifacts in EEG recordings that preclude meaningful neurophysiological activity from being quantified during stimulation. New method In this study, we modeled the DBS stimulation artifact and illustrated a technique for removing the artifact using matched filters. The approach was validated using a synthetically generated DBS artifact superimposed on EEG data. Mean squared error (MSE) between the recovered signal and the artifact-free signal was used to quantify the effectiveness of the approach. Results The DBS artifact was characterized by a series of narrow band components at the harmonic frequencies of DBS stimulation. The filtering approach successfully removed the DBS artifact with MSE value being less than 2% of base signal power for the typical stimulation and recording setups. General guidelines on how to setup DBS EEG studies and configure the subsequent artifact removal process are described. Comparison with previous method To avoid stimulus artifacts, a number of EEG studies with DBS subjects have resorted to turning the stimulator off during recording, while other studies have used low pass filters to remove artifacts and look at frequencies well below 50 Hz. Conclusions This study establishes a method through which DBS artifact in EEG recordings can be reliably eliminated, thereby preserving a meaningful neurophysiological signal through which to better understand DBS treatment mechanisms. [ABSTRACT FROM AUTHOR]

Introduction The combination of transcranial magnetic stimulation and electroencephalography (TMS-EEG) is emerging as a powerful tool for causally investigating cortical mechanisms and networks. However, various artefacts contaminate TMS-EEG recordings, particularly over regions such as the dorsolateral prefrontal cortex (DLPFC). The aim of this study was to substantiate removal of artefacts from TMS-EEG recordings following stimulation of the DLPFC and motor cortex using independent component analysis (ICA). Methods 36 healthy volunteers (30.8 ± 9 years, 9 female) received 75 single TMS pulses to the left DLPFC or left motor cortex while EEG was recorded from 57 electrodes. A subset of 9 volunteers also received 50 sham pulses. The large TMS artefact and early muscle activity (− 2 to ~ 15 ms) were removed using interpolation and the remaining EEG signal was processed in two separate ICA runs using the FastICA algorithm. Five sub-types of TMS-related artefacts were manually identified: remaining muscle artefacts, decay artefacts, blink artefacts, auditory-evoked potentials and other noise-related artefacts. The cause of proposed blink and auditory-evoked potentials was assessed by concatenating known artefacts (i.e. voluntary blinks or auditory-evoked potentials resulting from sham TMS) to the TMS trials before ICA and evaluating grouping of resultant independent components (ICs). Finally, we assessed the effect of removing specific artefact types on TMS-evoked potentials (TEPs) and TMS-evoked oscillations. Results Over DLPFC, ICs from proposed muscle and decay artefacts correlated with TMS-evoked muscle activity size, whereas proposed TMS-evoked blink ICs combined with voluntary blinks and auditory ICs with auditory-evoked potentials from sham TMS. Individual artefact sub-types characteristically distorted each measure of DLPFC function across the scalp. When free of artefact, TEPs and TMS-evoked oscillations could be measured following DLPFC stimulation. Importantly, characteristic TEPs following motor cortex stimulation (N15, P30, N45, P60, N100) could be recovered from artefactual data, corroborating the reliability of ICA-based artefact correction. Conclusions Various different artefacts contaminate TMS-EEG recordings over the DLPFC and motor cortex. However, these artefacts can be removed with apparent minimal impact on neural activity using ICA, allowing the study of TMS-evoked cortical network properties. [ABSTRACT FROM AUTHOR]

Magnetic seizure therapy (MST) is emerging as a safe and well-tolerated experimental intervention for major depressive disorder (MDD), with very minimal cognitive side-effects. However, the underlying mechanism of action of MST remains uncertain. Here, we used resting-state electroencephalography (RS-EEG) to characterise the physiological effects of MST for treatment resistant MDD. We recorded RS-EEG in 21 patients before and after an open label trial of MST applied over the prefrontal cortex using a bilateral twin coil. RS-EEG was analysed for changes in functional connectivity, network topology, and spectral power. We also ran further baseline comparisons between the MDD patients and a cohort of healthy controls (n = 22). Network-based connectivity analysis revealed a functional subnetwork of significantly increased theta connectivity spanning frontal and parieto-occipital channels following MST. The change in theta connectivity was further found to predict clinical response to treatment. An additional widespread subnetwork of reduced beta connectivity was also elucidated. Graph-based topological analyses showed an increase in functional network segregation and reduction in integration in the theta band, with a decline in segregation in the beta band. Finally, delta and theta power were significantly elevated following treatment, while gamma power declined. No baseline differences between MDD patients and healthy subjects were observed. These results highlight widespread changes in resting-state brain dynamics following a course of MST in MDD patients, with changes in theta connectivity providing a potential physiological marker of treatment response. Future prospective studies are required to confirm these initial findings. • We utilised rest EEG to characterise physiological changes following MST in MDD. • MST significantly altered functional connectivity, network topology, and spectral power. • Changes in theta connectivity predicted clinical response to MST. • Rest EEG is a sensitive marker of neural response to MST. [ABSTRACT FROM AUTHOR]

Schizophrenia (SCZ) is a serious mental disorder, and its pathogenesis is complex. Recently, the glutamate hypothesis and the excitatory/inhibitory (E/I) imbalance hypothesis have been proposed as new pathological hypotheses for SCZ. Combined transcranial magnetic stimulation (TMS) and electroencephalography (EEG) is a non-invasive novel method that enables us to investigate the cortical activity in humans, and this modality is a suitable approach to evaluate these hypotheses. In this study, we systematically reviewed TMS-EEG studies that investigated the cortical dysfunction of SCZ to examine the emerging hypotheses for SCZ. The following search terms were set in this systematic review: (TMS or 'transcranial magnetic stimulation') and (EEG or electroencephalog*) and (schizophrenia). We inspected the articles written in English that examined humans and were published by March 2020 via MEDLINE, Embase, PsycINFO, and PubMed. The initial search generated 379 studies, and 14 articles were finally identified. The current review noted that patients with SCZ demonstrated the E/I deficits in the prefrontal cortex, whose dysfunctions were also associated with cognitive impairment and clinical severity. Moreover, TMS-induced gamma activity in the prefrontal cortex was related to positive symptoms, while theta/delta band activities were associated with negative symptoms in SCZ. Thus, this systematic review discusses aspects of the pathophysiological neural basis of SCZ that are not explained by the traditional dopamine hypothesis exclusively, based on the findings of previous TMS-EEG research, mainly in terms of the E/I imbalance hypothesis. In conclusion, TMS-EEG neurophysiology can be applied to establish objective biomarkers for better diagnosis as well as to develop new therapeutic strategies for patients with SCZ. [ABSTRACT FROM AUTHOR]

Electroconvulsive therapy (ECT) is a highly effective neuromodulatory intervention for treatment-resistant major depressive disorder (MDD). Presently, however, understanding of its neurophysiological effects remains incomplete. In the present study, we utilised resting-state electroencephalography (RS-EEG) to explore changes in functional connectivity, network topology, and spectral power elicited by an acute open-label course of ECT in a cohort of 23 patients with treatment-resistant MDD. RS-EEG was recorded prior to commencement of ECT and again within 48 h following each patient's final treatment session. Our results show that ECT was able to enhance connectivity within lower (delta and theta) frequency bands across subnetworks largely confined to fronto-central channels, while, conversely, more widespread subnetworks of reduced connectivity emerged within faster (alpha and beta) bands following treatment. Graph-based topological analyses revealed changes in measures of functional segregation (clustering coefficient), integration (characteristic path length), and small-world architecture following ECT. Finally, post-treatment enhancement of delta and theta spectral power was observed, which showed a positive association with the number of ECT sessions received. Overall, our findings indicate that RS-EEG can provide a sensitive measure of dynamic neural activity following ECT and highlight network-based analyses as a promising avenue for furthering mechanistic understanding of the effects of convulsive therapies. [ABSTRACT FROM AUTHOR]