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Background: Intermittent theta burst stimulation (iTBS) is a form of repetitive transcranial magnetic stimulation (rTMS) that can be administered in a fraction of the time of standard rTMS. Applying multiple daily iTBS sessions (ie, accelerated iTBS) may enable patients to achieve remission more rapidly. However, questions remain regarding the optimal time interval between treatment sessions., Objective: The overall aim of this study was to compare the efficacy and tolerability of two accelerated bilateral iTBS protocols (ie, 30-min or 60-min intervals) and a once-daily bilateral iTBS protocol (ie, 0-min interval) while the number of pulses was held constant, in patients with treatment-resistant depression (TRD)., Methods: 182 patients with TRD were randomised to receive two sessions per day of bilateral iTBS of the dorsomedial prefrontal cortex (DMPFC) at 60-min, 30-min or 0-min intervals. Sham treatments were delivered using a shielded 'sham coil' which produced the auditory and tactile sensations of stimulation. The primary outcome measure was a change in depression scores on the 17-item Hamilton Rating Scale for Depression (HRSD-17) after 20 days of treatment., Results: HRSD-17 scores improved across all groups; however, these improvements did not significantly differ between the three groups after 20 days of treatment. Similarly, response and remission rates did not differ between the treatment groups., Conclusions: These results suggest that contrary to our original hypothesis, implementing a 30-min or 60-min interval between two treatment sessions of DMPFC-iTBS does not lead to a more rapid improvement in symptoms, than once-daily iTBS administration., Trial Registration Number: NCT02778035., Competing Interests: Competing interests: FM reports grants from Mitacs, outside the submitted work. LS reports grants from Ontario Mental Health Foundation, outside the submitted work. TSK has received research support from CIHR and the AFP Innovation Fund. JD has received research and equipment in-kind support for an investigator-initiated study through Brainsway and Magventure. He is also on the scientific advisory board for Brainsway. His work has been supported by the National Institutes of Mental Health (NIMH), the Canadian Institutes of Health Research (CIHR), Brain Canada and the Temerty Family and Grant Family Foundations. JD has received research support from NIH, CIHR, Brain Canada, Ontario Brain Institute, the Klarman Family Foundation, the Krembil Foundation, Arrell Family Foundation and the Buchan Family Foundation, in-kind equipment support for investigator-initiated trials from MagVenture, is an advisor for BrainCheck, Arc Health Partners and Salience Neuro Health, and is a co-founder of Ampa Health. DMB receives research support from CIHR, NIMH (R01MH112815;R21MH128815; R01MH1192850), Brain Canada and the Temerty Family through the CAMH Foundation and the Campbell Family Research Institute. He received research support and in-kind equipment support for an investigator-initiated study from Brainsway. He was the site principal investigator for three sponsor-initiated studies for Brainsway. He also received in-kind equipment support from Magventure for two investigator-initiated studies. He received medication supplies for an investigator-initiated trial from Indivior. He is a scientific advisor for Sooma Medical. He is the Co-Chair of the Clinical Standards Committee of the Clinical TMS Society (unpaid). APT, GK and MG declares no conflicts of interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. Published by BMJ.)

Understanding how spontaneous brain activity influences the response to neurostimulation is crucial for the development of neurotherapeutics and brain-computer interfaces. Localized brain activity is suggested to influence the response to neurostimulation, but whether fast-fluctuating (i.e., tens of milliseconds) large-scale brain dynamics also have any such influence is unknown. By stimulating the prefrontal cortex using combined transcranial magnetic stimulation (TMS) and electroencephalography, we examined how dynamic global brain state patterns, as defined by microstates, influence the magnitude of the evoked brain response. TMS applied during what resembled the canonical Microstate C was found to induce a greater evoked response for up to 80 ms compared with other microstates. This effect was found in a repeated experimental session, was absent during sham stimulation, and was replicated in an independent dataset. Ultimately, ongoing and fast-fluctuating global brain states, as probed by microstates, may be associated with intrinsic fluctuations in connectivity and excitation-inhibition balance and influence the neurostimulation outcome. We suggest that the fast-fluctuating global brain states be considered when developing any related paradigms., Competing Interests: D.M.B. has received in-kind equipment support for investigator-initiated studies from MagVenture; he has received research support and in-kind equipment support for an investigator-initiated study from BrainsWay and is the site principal investigator for three sponsor-initiated studies for BrainsWay; he has received medication supplies for an investigator-initiated trial from Indivior; and he has participated on an advisory board for Janssen. Z.J.D. has received research and equipment in-kind support for an investigator-initiated study through BrainsWay and MagVenture. A.K., P.D., M.D.G., S.M., and F.F. report no biomedical financial interests or potential competing financial interests., (Copyright © 2024 the authors.)

Background: Repetitive transcranial magnetic stimulation (rTMS) is entering wider use as a therapeutic intervention for many psychiatric illnesses. The efficacy of this therapeutic intervention may depend on accurately localizing target brain regions. Recent work investigating whole-brain maps of circuits associated with depression and its successful treatment has identified foci of interest within the dorsolateral prefrontal cortex (DLPFC)., Objective: To create an updated scalp heuristic for localizing the DLPFC based on convergent evidence of lesion and brain stimulation studies in depression., Methods: Using the standard MNI ICBM152 anatomical template, we localized the scalp sites at minimum Euclidean distance from target MNI coordinates and performed nasion-inion, tragus-tragus, and head-circumference measurements on the anatomical template. We then derived equations to localize these scalp sites., Results: The derived equations to calculate the arc length X and Y for these new targets are as follows: [Y=((NI+TrTr)/2)×0.3167 ; X=HC×0.1359] for the left anterior DLPFC[ Y=((NI+TrTr)/2)×0.2884; X=HC×0.1352] for the right anterior DLPFC[ Y=((NI+TrTr)/2)×0.2480; X=HC×0.1847] for the left posterior DLPFC[ Y=((NI+TrTr)/2)×0.2316 ; X=HC×0.1968] for the right posterior DLPFC CONCLUSIONS: This heuristic may help localize DLPFC targets identified in previous lesion-/stimulation-mapping work. A spreadsheet calculation tool is offered to support use of this heuristic., Competing Interests: Declaration of competing interest DMB reports research grants from the Canadian Institutes of Health Research (CIHR), US National Institutes of Health, Weston Brain Institute, Brain Canada, the Temerty Family Foundation (through the Centre for Addiction and Mental Health Foundation and the Campbell Research Institute), and Brainsway; reports receiving in-kind equipment support for investigator-initiated studies (including this study) MagVenture; is the site principal investigator for three sponsor-initiated studies for Brainsway; and has been on an advisory board for Janssen Pharmaceutical. FVR receives research support from CIHR, Brain Canada, Michael Smith Foundation for Health Research, Vancouver Coastal Health Research Institute, and Weston Brain Institute for investigator-initiated research. Philanthropic support from Seedlings Foundation. In-kind equipment support for this investigator-initiated trial from MagVenture. He has received honoraria for participation in an advisory board for Janssen. JD reports research grants from CIHR, the National Institute for Mental Health, Brain Canada, the Canadian Biomarker Integration Network in Depression, the Ontario Brain Institute, the Klarman Family Foundation, the Arrell Family Foundation, and the Edgestone Foundation; reports travel stipends from Lundbeck and ANT Neuro; reports in-kind equipment support for this investigator-initiated trial from MagVenture; and is an advisor for BrainCheck. S.H.S. serves as a clinical consultant for Kaizen Brain Center. S.H.S. and M.D.F. have jointly received investigator-initiated research support from Neuronetics. None of these organizations were involved in the present work. S.H.S. and M.D.F. each own independent intellectual property on the use of brain network mapping to target neuromodulation. The present work did not utilize any of this intellectual property. ZJD has received research and equipment in-kind support for an investigator-initiated study through Brainsway Inc and Magventure Inc. His work has been supported by the Canadian Institutes of Health Research (CIHR), the National Institutes of Mental Health (NIMH), Brain Canada and the Temerty Family and Grant Family and through the Centre for Addiction and Mental Health (CAMH) Foundation and the Campbell Institute. AM and KM report no conflicts of interest or significant financial support associated with this publication., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Here we bring a neurophysiological diagnostic tool, based on pathophysiologically-relevant brain region, that is critical for reducing the variability between clinicians, and necessary for quantitative measures of ADHD severity., Methods: 54 healthy and 57 ADHD adults participated in the study. Electroencephalography (EEG) was recorded when combined with transcranial magnetic stimulation (TMS) over the right prefrontal cortex and also recorded during the Stop Signal task., Results: TMS evoked potentials (TEPs) and the event related potential (ERP) components in the Stop Signal task were found to be significantly reduced in ADHD relative to the matched healthy controls. Stop signal reaction time (SSRT) and stopping accuracy was found to correlate with the ERP signal, and ADHD severity correlated with the TEP signal. Cortical activity (early TEP and Stop Signal ERP) diagnostic model yielded accuracy of 72%., Conclusion: TEPs and ERPs reveal that right PFC excitability was associated with ADHD severity, and with behavioral impulsivity - as a hallmark of ADHD pathology. This electrophysiological biomarker supports the potential of objective diagnosis for ADHD., Significance: Such tools would allow better assessment of treatment efficacy and prognosis, may advance understanding of the pathophysiology of the disease and better the public's attitudes and stigma towards ADHD., Trial Registration: Trial to Evaluate the Efficacy of the HLPFC Coil Deep Transcranial Magnetic Stimulation System in Treating Attention Deficit and Hyperactivity Disorder (ADHD) in Adults, https://clinicaltrials.gov/ct2/show/NCT01737476, ClinicalTrials.govnumberNCT01737476., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: We measured the neurophysiological responses of both active and sham transcranial magnetic stimulation (TMS) for both single pulse (SP) and paired pulse (PP; long interval cortical inhibition (LICI)) paradigms using TMS-EEG (electroencephalography)., Methods: Nineteen healthy subjects received active and sham (coil 90° tilted and touching the scalp) SP and PP TMS over the left dorsolateral prefrontal cortex (DLPFC). We measured excitability through SP TMS and inhibition (i.e., cortical inhibition (CI)) through PP TMS., Results: Cortical excitability indexed by area under the curve (AUC (25-275ms) ) was significantly higher in the active compared to sham stimulation (F(1,18) = 43.737, p < 0.001, η 2  = 0.708). Moreover, the amplitude of N100-P200 complex was significantly larger (F(1,18) = 9.118, p < 0.01, η 2  = 0.336) with active stimulation (10.38 ± 9.576 µV) compared to sham (4.295 ± 2.323 µV). Significant interaction effects were also observed between active and sham stimulation for both the SP and PP (i.e., LICI) cortical responses. Finally, only active stimulation (CI = 0.64 ± 0.23, p < 0.001) resulted in significant cortical inhibition., Conclusion: The significant differences between active and sham stimulation in both excitatory and inhibitory neurophysiological responses showed that active stimulation elicits responses from the cortex that are different from the non-specific effects of sham stimulation., Significance: Our study reaffirms that TMS-EEG represents an effective tool to evaluate cortical neurophysiology with high fidelity., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: In the last 5 years, ZJD has received research and equipment in-kind support for an investigator-initiated study through Brainsway Inc and Magventure Inc. His work is supported by the Canadian Institutes of Health Research (CIHR), the Natural Sciences and Engineering Research Council (NSERC) of Canada, the National Institutes of Mental Health (NIMH), Brain Canada and the Temerty Family and Grant Family and through the Centre for Addiction and Mental Health (CAMH) Foundation and the Campbell Institute. DMB receives research support from CIHR, NIH, Brain Canada and the Temerty Family through the CAMH Foundation and the CampbellFamilyResearch Institute. He receivedresearch support and in-kind equipment support for an investigator-initiated study from Brainsway Ltd. He is the site principal investigator for three sponsor-initiated studies for Brainsway Ltd. He also receives in-kind equipment support from Magventure for investigator-initiated research. He received medication supplies for an investigator-initiated trial from Indivior. TKR has received research support from Brain Canada, Brain and Behavior Research Foundation, BrightFocus Foundation, Canada Foundation for Innovation, Canada Research Chair, Canadian Institutes of Health Research, Centre for Aging and Brain Health Innovation, National Institutes of Health, Ontario Ministry of Health and Long-Term Care, Ontario Ministry of Research and Innovation, and the Weston Brain Institute. Dr. Rajji also received in-kind equipment support for an investigator-initiated study from Magstim, and in-kind research accounts from Scientific Brain Training Pro. DV has received research training fellowship funding from the Ontario Mental Health Foundation, an American Psychiatric Association/Eli Lilly research fellowship, and a CAMH postdoctoral fellowship and support from the Innovation Fund of the Alternative Funding Plan for the Academic Health Sciences Centres of Ontario.DV declares no biomedical interests or conflicts. MP, RZ, CH, ATH, IH, RC, and AAD have nothing to disclose., (Copyright © 2021. Published by Elsevier B.V.)

Objective: 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., Methods: 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., Results: 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., Conclusion: 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., Significance: 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., Competing Interests: Declaration of Competing Interest This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. None of the authors have potential conflicts of interest to be disclosed., (Copyright © 2021. Published by Elsevier B.V.)

Background: To determine if an accelerated rTMS protocol results in distinct depressive symptom response trajectories, compared to a standard rTMS protocol. We also sought to validate previous analyses that identified distinct depressive symptom response trajectories with rTMS treatment using an external dataset., Method: Data from two recent clinical trials comparing accelerated rTMS protocol delivered to the left dorsolateral prefrontal cortex (DLPFC) with standard once-daily rTMS protocol were used to identify depressive symptom response trajectories. The accelerated protocol in Trial 1 was conventional 10-Hz rTMS, while Trial 2 employed intermittent theta burst stimulation (iTBS). Participants were adult outpatients (18-70 years old) with bipolar or unipolar depression and moderate-severe depression (Montgomery Asberg Depression Rating Scale score >19) who had failed to respond to adequate courses of two different antidepressants. We used group-based trajectory modeling to identify MADRS response trajectories, and regression techniques adjusting for baseline depressive symptom severity to determine the association between treatment protocol and depressive symptom response trajectory., Results: Treatment outcomes of 189 participants were analysed. We identified four distinct response trajectories: "nonresponse" (N = 59; 30.7%), "minimal response" (N = 65; 34.1%), "higher symptoms, response" (N = 26; 14.6%), "lower symptoms, response" (N = 39; 20.6%). We failed to find an association between rTMS protocol (accelerated vs standard) with depressive symptom response trajectory even after adjusting for baseline depressive symptom severity., Conclusion: The accelerated rTMS protocol in this study did not impact depressive symptom response trajectories. This work provides further confirmatory evidence that there are distinct depressive symptom response trajectories with rTMS delivered to the left DLPFC., Australian New Zealand Clinical Trials Registry: ACTRN12616000443493 and ACTRN12613000044729., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Conventional treatments for youth depression, such as antidepressants, have modest efficacy, side effects, and ongoing controversies regarding safety. Repetitive transcranial magnetic stimulation (rTMS), specifically theta burst stimulation (TBS), applied to the dorsolateral prefrontal cortex (DLPFC) has demonstrated efficacy for the treatment of depression in adults. However, the feasibility and clinical response to TBS for youth depression has yet to be explored., Methods: Twenty participants between the ages of 16 to 24 years old with MDD were recruited. The intervention consisted of 10 treatment sessions over the course of two weeks, in which participants received intermittent TBS and continuous TBS stimulation to the left and right DLPFC, respectively. Change in the Hamilton Rating Scale for Depression (HRSD-17) score was the primary outcome. Clinical assessments occurred at baseline, after the fifth treatment session, and within a week after treatment completion., Results: Of the twenty participants, eighteen received all TBS sessions, and seventeen completed all clinical assessments. There was a significant reduction in depressive symptoms following treatment completion (p < 0.001). Four of the twenty patients had more than 50% reduction in their depressive symptoms, two of whom achieved remission. All participants received and tolerated at least six daily TBS treatments with no major adverse events., Limitations: Study was an uncontrolled, open-label design., Conclusion: Ten sessions of TBS was feasible, well tolerated, and appeared to have clinical effects for the treatment of depressed youth. Future sham-controlled randomized trials are warranted to validate these findings in a larger cohort of youth depression., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Importance: Hyperactivity in the subgenual cingulate cortex (SGC) is associated with major depressive disorder (MDD) and anticorrelated with activity in the dorsolateral prefrontal cortex (DLPFC). This association was found to be predictive of responsiveness to repetitive transcranial magnetic stimulation (rTMS) treatment. Such findings suggest that DLPFC-SGC connectivity is important for understanding both the therapeutic mechanism of rTMS in patients with MDD and the underlying pathophysiology of MDD., Objective: To evaluate SGC hyperactivity in patients with MDD before and after rTMS treatment., Design, Setting, and Participants: In this diagnostic study, among participants recruited from the adult and geriatric mood and anxiety services at the Centre for Addiction and Mental Health, Toronto, Ontario, Canada, who had participated in a randomized clinical trial, baseline SGC activity of patients with MDD was compared with healthy controls. In patients with MDD, SGC activity was compared before and after active or sham high-frequency rTMS treatment. Data collection started in July 2008 and concluded in March 2012. Neurophysiological data analysis started in January 2017 and ended in May 2018., Main Outcomes and Measures: Hyperactivity in the SGC before and after rTMS treatment was measured. Subgenual cingulate cortex hyperactivity activity was quantified using significant current density (SCD), and effective connectivity between the left DLPFC and SGC was computed using significant current scattering (SCS). Both measures were computed around TMS evoked potentials standard peak latencies prior to rTMS and after rTMS treatment, comparing patients with MMD treated with active and sham rTMS. Patients with MDD were assessed with the 17-item Hamilton Rating Scale for Depression., Results: Of 121 patients with MDD in the initial trial, 30 (15 [50.0%] women) were compared with 30 healthy controls (15 [50.0%] women) at rTMS treatment baseline. The mean (SD) age of the cohort with MDD was 39.1 (10.9) years, and the mean (SD) age of healthy controls was 37.0 (11.0) years. Following rTMS treatment, 26 patients with MDD who had active rTMS treatment (21.5%) were compared with 17 patients with MDD who had sham treatment (14.0%). At baseline, the SGC mean (SD) SCD and mean (SD) SCS at 200 milliseconds after TMS pulse were higher in participants with MDD compared with healthy controls (SCD: 1.04 × 10-6 [1.41 × 10-6] μA/mm2 vs 3.8 × 10-7 [7.8 × 10-7] μA/mm2; z = -2.95; P = .004; SCS: 0.87 [0.86] mm vs 0.54 [0.87] mm; z = -2.27; P = .02). Baseline source current density was able to classify MDD with 77% accuracy. Scores on the 17-item Hamilton Rating Scale for Depression were correlated with current density at the SGC (ρ = 0.41; P = .03). After rTMS treatment, SGC mean (SD) SCD and mean (SD) SCS at 200 milliseconds after rTMS pulse were attenuated to approximately the standard TMS-evoked potential latencies in the active rTMS group compared with the sham rTMS group (SCD: 1.57 × 10-7 [3.67 × 10-7] μA/mm2 vs 7.00 × 10-7 [7.51 × 10-7] μA/mm2; z = -2.91; P = .004; SCS: 0.20 [0.44] mm vs 0.74 [0.73] mm; z = -2.78; P = .006). Additionally, the SGC SCS change was correlated with symptom improvement on the 17-item Hamilton Rating Scale for Depression in the active rTMS group (ρ = 0.58; P = .047)., Conclusions and Relevance: The findings of this study further implicate left DLPFC-SGC effective connectivity and SGC excitability in the pathophysiology of MDD and treatment with rTMS. These findings suggest that DLPFC-SGC connectivity may be a marker of rTMS treatment responsiveness., Trial Registration: ClinicalTrials.gov identifier: NCT01515215.

Objective: Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for refractory major depressive disorder, yet no studies have characterized trajectories of rTMS response. The aim of this study was to characterize response trajectories for patients with major depression undergoing left dorsolateral prefrontal cortex rTMS and to determine associated baseline clinical characteristics., Methods: This was a secondary analysis of a randomized noninferiority trial (N=388) comparing conventional 10-Hz rTMS and intermittent theta burst stimulation (iTBS) rTMS. Participants were adult outpatients who had a primary diagnosis of major depressive disorder, had a score ≥18 on the 17-item Hamilton Depression Rating Scale (HAM-D), and did not respond to one to three adequate antidepressant trials. Treatment was either conventional 10-Hz rTMS or iTBS rTMS applied to the dorsolateral prefrontal cortex, 5 days/week over 4-6 weeks (20-30 sessions). Group-based trajectory modeling was applied to identify HAM-D response trajectories, and regression techniques were used to identify associated characteristics., Results: Four trajectories were identified: nonresponse (N=43, 11%); rapid response (N=73, 19%); higher baseline symptoms, linear response (N=118, 30%); and lower baseline symptoms, linear response (N=154, 40%). Significant differences in response and remission rates between trajectories were detectable by week 1. There was no association between treatment protocol and response trajectory. Higher baseline scores on the HAM-D and the Quick Inventory of Depression Symptomatology-Self-Report (QIDS-SR) were associated with the nonresponse trajectory, and older age, lower QIDS-SR score, and lack of benzodiazepine use were associated with the rapid response trajectory., Conclusions: Major depression shows distinct response trajectories to rTMS, which are associated with baseline clinical characteristics but not treatment protocol. These response trajectories with differential response to rTMS raise the possibility of developing individualized treatment protocols.

Background: The 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., Methods: In 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., Results: MDD 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., Conclusions: As 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., (Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Repetitive transcranial magnetic stimulation (rTMS) is an effective clinical intervention for various neuropsychiatric diseases. However, it is still unclear whether rTMS has an effect on cognitive functioning. In this review, we aimed to systematically evaluate the cognitive effects of rTMS in depression, schizophrenia, and Alzheimer's disease. We searched PubMed (1996-2018) under the set terms to review randomized controlled trials (RCT) to examine the effectiveness of rTMS administered to the dorsolateral prefrontal cortex (DLPFC) and evaluated cognitive functions in patients with depression, schizophrenia, and Alzheimer's disease. Two authors reviewed each article and came to consensus on the inclusion and exclusion criteria. All eligible studies were reviewed, duplicates were removed, and data were extracted individually. The search identified 579 articles, 31 of which met inclusion and exclusion criteria. Among them, 15 were conducted in patients with depression, 11 in patients with schizophrenia, and 5 in patients with Alzheimer's disease. Specifically, 6 studies demonstrated a significant improvement of executive function across these diseases. Further, no evidence for cognitive adverse effects was found in these included rTMS studies. Although the heterogeneity between studies in terms of cognitive measures applied, stimulation parameters, and participants limits the ability to generalize conclusions, this review demonstrated that prefrontal rTMS could exert pro-cognitive effects on executive function and attention in some patients with depression but inconsistent cognitive impacts in any of the examined domains especially in patients with schizophrenia and Alzheimer's disease. The results warrant further rTMS studies that include systematic assessment of cognition across various neuropsychiatric diseases., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Therapeutic seizures may work for treatment-resistant depression (TRD) by producing neuroplasticity. We evaluated whether magnetic seizure therapy (MST) produces changes in suicidal ideation and neuroplasticity as indexed through transcranial magnetic stimulation and electroencephalography (TMS-EEG) of the dorsolateral prefrontal cortex (DLPFC). Twenty-three patients with TRD were treated with MST. Changes in suicidal ideation was assessed through the Scale for Suicidal Ideation (SSI). Before and after the treatment course, neuroplasticity in excitatory and inhibitory circuits was assessed with TMS-EEG measures of cortical-evoked activity (CEA) and long-interval cortical inhibition (LICI) from the left DLPFC, and the left motor cortex as a control condition. As in our previous report, the relationship between TMS-EEG measures and suicidal ideation was examined with the SSI. Results show that 44.4% of patients experienced resolution of suicidal ideation. Based on DLPFC assessment, MST produced significant CEA increase over the frontal central electrodes (cluster p < 0.05), but did not change LICI on a group level. MST also reduced the SSI scores (p < 0.005) and the amount of reduction correlated with the decrease in LICI over the right frontal central electrodes (cluster p < 0.05; rho = 0.73 for Cz). LICI change identified patients who were resolved of suicidal ideation with 90% sensitivity and 88% specificity (AUC = 0.9, p = 0.004). There was no significant finding with motor cortex assessment. Overall, MST produced significant rates of resolution of suicidal ideation. MST also produced neuroplasticity in the frontal cortex, likely through long-term potentiation (LTP)-like mechanisms. The largest reduction in suicidal ideation was demonstrated in patients showing concomitant decreases in cortical inhibition-a mechanism linked to enhanced LTP-like plasticity. These findings provide insights into the mechanisms through which patients experience resolution of suicidal ideation following seizure treatments in depression.

Transcranial magnetic stimulation (TMS) modulates activity at local and regions distal to the site of simulation. TMS has also been found to modulate brain networks, and it has been hypothesized that functional connectivity may predict the neuronal changes at local and distal sites in response to a TMS pulse. However, a direct relationship between resting connectivity and change in TMS-induced brain activation has yet to be demonstrated. Concurrent TMS-fMRI is a technique to directly measure this spread activity following TMS in real time. In twenty-two participants, resting-state fMRI scans were acquired, followed by four ten minute sessions of concurrent TMS-fMRI over the left dorsolateral prefrontal cortex (DLPFC). Seed-based functional connectivity to the individualized TMS target was examined using the baseline resting fMRI scan data, and the change of activity resulting from TMS was determined using a general linear model (High vs Low intensity TMS). While at the group level the spatial pattern of resting connectivity related to the pattern of TMS-induced cortical changes, there was substantial variability across individuals. This variability was further probed by examining individual's connectivity from the TMS target to six resting state networks. Only connectivity between the salience network (SN) and the TMS target site correlated with the RSC-TMS score. This suggests that resting state connectivity is correlated with TMS-induced changes in activity following DLPFC stimulation, particularly when the DLPFC target interacts with the SN. These results highlight the importance of examining such relationships at the individual level and may help to guide individual treatment in clinical populations., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The underlying mechanism of repetitive transcranial magnetic stimulation (rTMS) effects on cognition has not been fully examined. Previously, we have reported the left hippocampal volume increase and theta-gamma coupling (TGC) enhancement associated with working memory improvement following rTMS in depression. This study was aimed to examine whether there is a structure-function relationship in hippocampal neuroplasticity induced by prefrontal rTMS. Thirty-one patients with major depression underwent longitudinal MRI scans and resting-state EEG recordings with the 10-20 system using averaged ear-lobes reference, following 10 sessions of high-frequency rTMS over the left dorsolateral prefrontal cortex. Pearson's correlation analyses were applied for the longitudinal changes among the left and right hippocampal volumes as measured by manual volumetry, theta and gamma spectral powers, and TGC as measured by resting-state EEG. The analyses demonstrated that the left hippocampus volume increases correlated with TGC increases at the left central area (r = 0.576, p = 0.001, N = 31), whereas no significant correlations were observed among changes of right hippocampal volume, right central TGC, bilateral gamma or theta powers. These finding suggests structure-function relationship in rTMS-induced neuroplastic changes mediated through the hippocampus and prefrontal network at the stimulated side. Therefore, high-frequency prefrontal rTMS may exert its cognitive effect through the hippocampal structural-functional neuroplasticity., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Transcranial magnetic stimulation (TMS) is a non-invasive method that produces neural excitation in the cortex by means of brief, time-varying magnetic field pulses. The initiation of cortical activation or its modulation depends on the background activation of the neurons of the cortical region activated, the characteristics of the coil, its position and its orientation with respect to the head. TMS combined with simultaneous electrocephalography (EEG) and neuronavigation (nTMS-EEG) allows for the assessment of cortico-cortical excitability and connectivity in almost all cortical areas in a reproducible manner. This advance makes nTMS-EEG a powerful tool that can accurately assess brain dynamics and neurophysiology in test-retest paradigms that are required for clinical trials. Limitations of this method include artifacts that cover the initial brain reactivity to stimulation. Thus, the process of removing artifacts may also extract valuable information. Moreover, the optimal parameters for dorsolateral prefrontal (DLPFC) stimulation are not fully known and current protocols utilize variations from the motor cortex (M1) stimulation paradigms. However, evolving nTMS-EEG designs hope to address these issues. The protocol presented here introduces some standard practices for assessing neurophysiological functioning from stimulation to the DLPFC that can be applied in patients with treatment resistant psychiatric disorders that receive treatment such as transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS), magnetic seizure therapy (MST) or electroconvulsive therapy (ECT).

Objective: The purpose of this study was to evaluate the effects of repetitive transcranial magnetic stimulation (rTMS) on suicidal ideation in patients with treatment-resistant major depression (TRD) (patients who failed to clinically respond to at least 2 medication trials)., Methods: We pooled data from 2 published prospective randomized controlled trials of rTMS applied to the dorsolateral prefrontal cortex in patients with TRD. We compared the effect of bilateral, left unilateral, and sham rTMS on suicidal ideation as measured by the suicide item of the 17-item Hamilton Depression Rating Scale (HDRS) (N = 156)., Results: Suicidal ideation resolved in 40.4%, 26.8%, and 18.8% of participants randomized to bilateral, left unilateral, and sham rTMS, respectively. The difference between bilateral and sham was significant (OR = 3.03; 95% CI, 1.19-7.71; P = .02), unlike the difference between left unilateral and sham (OR = 1.59; 95% CI, 0.61-4.12; P = .33). There was a modest correlation between change in suicidal ideation and change in depression severity (Pearson r = 0.38; P < .001) and no difference in change of HDRS-16 score between suicide remitters and nonremitters (P = .32)., Conclusions: Bilateral rTMS was superior to sham rTMS in reducing suicidal ideation in patients with TRD. Only a small portion of the reduction in suicidal ideation was attributable to the reduction in depressive symptoms. These data suggest that suicidal ideation could be a specific target symptom construct for rTMS., Trial Registration: ClinicalTrials.gov identifiers: NCT01515215 and NCT00305045., (© Copyright 2018 Physicians Postgraduate Press, Inc.)

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 (F 1,53  = 68.63, p < 0.0001) and PAS-by-diagnostic group interaction (F 1,53  = 25.05, p < 0.0001). Post hoc analysis demonstrated that patients had a significantly lower PAS potentiation compared to healthy subjects (t 55  = 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., (© 2018 Wiley Periodicals, Inc.)

Alcohol is thought to exert its effect by acting on gamma-aminobutyric (GABA) inhibitory neurotransmission. The N100, the negative peak on electroencephalography (EEG) that occurs approximately 100 ms following the transcranial magnetic stimulation (TMS) pulse, is believed to represent GABA B receptor mediated neurotransmission. However, no studies have examined the effect of alcohol on the N100 response to TMS stimulation of the dorsolateral prefrontal cortex (DLPFC). In the present study, we aimed to explore the effect of alcohol on the DLPFC TMS-evoked N100 response. The study was a within-subject cross-over design study. Fifteen healthy alcohol drinkers were administered TMS to the DLPFC before (PreBev) and after consumption (PostBev) of an alcohol or placebo beverage. The amplitude of the N100 before and after beverage was compared for both the alcohol and placebo beverage. Alcohol produced a significant decrease in N100 amplitude (t = 4.316, df = 14, p = 0.001). The placebo beverage had no effect on the N100 amplitude (t = -1.856, df = 14, p = 0.085). Acute alcohol consumption produces a decrease in N100 amplitude to TMS stimulation of the DLPFC, suggesting a decrease in GABA B receptor mediated neurotransmission. Findings suggest that the N100 may represent a marker of alcohol's effects on inhibitory neurotransmission.

Background: Cholinergic dysfunction is increasingly assumed to be involved in the pathophysiology of schizophrenia. Short-latency afferent inhibition (SAI) is a transcranial magnetic stimulation (TMS) paradigm that has been shown to assay central cholinergic activity from the motor cortex (M1). Recently, we established a method to index SAI from the dorsolateral prefrontal cortex (DLPFC), an area implicated in the pathophysiology of schizophrenia. We investigated SAI in M1 and DLPFC in schizophrenia. We hypothesized that modulation of N100 on TMS-evoked potentials (TEPs) from the DLPFC would be attenuated in patients with schizophrenia compared to healthy controls., Methods: SAI was examined in 12 patients, whose age was matched to controls, using TMS combined with electroencephalography (EEG). SAI was recorded with TMS applied to left M1 (M1-SAI) and DLPFC (DLPFC-SAI). For group comparison, we used the SAI data of healthy participants in our previous study., Results: In patients, N100 TEP was significantly attenuated with DLPFC-SAI, whereas P180 TEP was significantly increased with M1-SAI. Between patients and controls, there were significant differences in modulation of P180 TEP by M1-SAI (t22 = -2.748, P = .012; patients > controls) and N100 TEP by DLPFC-SAI (t22 = 5.456, P < .0001; patients < controls). Further, modulation of N100 TEP by DLPFC-SAI significantly correlated with executive function (r = -.740, P = .006, N = 12)., Conclusion: Our findings suggest that DLPFC-SAI but not M1-SAI were reduced in patients with schizophrenia and this was linked to deficits in cognition. This may reflect prefrontal cholinergic deficits and represent a biomarker for cholinergic and executive dysfunction in patients with schizophrenia., (© The Author(s) 2017. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Conventional rTMS in major depressive disorder (MDD) targets the dorsolateral prefrontal cortex (DLPFC). However, many patients do not respond to DLPFC-rTMS. Recent evidence suggests that the right lateral orbitofrontal cortex (OFC) plays a key role in 'non-reward' functions and shows hyperconnectivity in MDD. OFC-rTMS has been used successfully in obsessive-compulsive disorder, and achieved remission in an MDD case nonresponsive to DLPFC- and DMPFC-rTMS. Here, we assess the safety and tolerability of right OFC-rTMS, and examine the effectiveness of inhibitory right OFC-rTMS in MDD, particularly among patients with previous nonresponse to DMPFC-rTMS. We performed a chart review to retrieve data on clinical characteristics, stimulation parameters, adverse events, and clinical symptom outcomes for a series of 42 patients with medication-resistant and/or DMPFC-rTMS-nonresponsive MDD, who underwent 20-30 sessions of 1Hz right OFC-rTMS at a single Canadian clinic from 2015 to 2017. Over 882 sessions of treatment, there were no seizures, visual/ocular complications, or other serious or treatment-limiting adverse events. Pain ratings averaged 6-7/10 (10=maximum tolerable); no patient discontinued treatment prematurely due to pain. 15/42 patients (35.7%) achieved response (≥50% symptom reduction) and 10/42 (23.8%) achieved remission. Among the 30/42 patients who were previous nonresponders to DMPFC-rTMS, 9/30 (30.0%) achieved response and 7/30 (23.8%) achieved remission. Response distribution was sharply bimodal. 1Hz right OFC-rTMS appears safe and tolerable, and may achieve remission in MDD patients even when conventional rTMS has failed. Sham-controlled follow-up studies may be warranted., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Cortical inhibition (CI) occurs largely through GABA receptor-mediated inhibitory neurotransmission, which can be modulated by cholinergic, dopaminergic, and glutamatergic inputs. Transcranial magnetic stimulation (TMS) can be used to index CI through a paradigm known as long-interval CI (LICI). When TMS is combined with electroencephalography (EEG), LICI can index GABA receptor-mediated inhibitory neurotransmission in the dorsolateral prefrontal cortex (DLPFC). We conducted a hypothesis-driven pharmacological study to assess the role of cholinergic, dopaminergic, GABAergic, and glutamatergic neurotransmission on LICI from the DLPFC using TMS-EEG. In this randomized controlled, double-blind crossover within-subject study, 12 healthy participants received five sessions of LICI to the DLPFC in a random order, each preceded by the administration of placebo or one of the four active drugs. LICI was assessed after each drug administration and compared to LICI after placebo. Relative to placebo, baclofen resulted in a significant increase in LICI, while rivastigmine resulted in a significant decrease in LICI. Dextromethorphan and L-DOPA did not result in a significant change in LICI relative to placebo. Our study confirms that LICI in the DLPFC is largely mediated by GABA B receptor-mediated inhibitory neurotransmission and also suggests that cholinergic modulation decreases LICI in the DLPFC. Such findings may help guide future work examining the neurophysiological impact of these neurotransmitters in healthy and diseased states.

GABAergic and glutamatergic dysfunction in the dorsolateral prefrontal cortex (DLPFC) are thought to be the core pathophysiological mechanisms of schizophrenia. Recently, we have established a method to index these functions from the DLPFC using the paired transcranial magnetic stimulation (TMS) paradigms of short interval intracortical inhibition (SICI) and facilitation (ICF) combined with electroencephalography (EEG). In this study, we aimed to evaluate neurophysiological indicators related to GABA A and glutamate receptor-mediated functions respectively from the DLPFC in patients with schizophrenia using these paradigms, compared to healthy controls. Given that these activities contribute to cognitive functions, the relationship between the TMS-evoked potential (TEP) modulations by SICI/ICF and cognitive/clinical measures were explored. Compared to controls, patients showed reduced inhibition in P60 (t 22  = -4.961, p < 0.0001) by SICI and reduced facilitation in P60 (t 22  = 5.174, p < 0.0001) and N100 (t 22  = 3.273, p = 0.003) by ICF. In patients, the modulation of P60 by SICI was correlated with the longest span of the Letter-Number Span Test (r = -0.775, p = 0.003), while the modulation of N100 by ICF was correlated with the total score of the Positive and Negative. Syndrome Scale (r = 0.817, p = 0.002). These findings may represent the pathophysiology, which may be associated with prefrontal GABA A and glutamatergic dysfunctions, in the expression of symptoms of schizophrenia.

Importance: The extent of dorsolateral prefrontal cortex (DLPFC) plasticity in Alzheimer disease (AD) and its association with working memory are not known., Objectives: To determine whether participants with AD had impaired DLPFC plasticity compared with healthy control participants, to compare working memory between participants with AD and controls, and to determine whether DLPFC plasticity was associated with working memory., Design, Setting, and Participants: This cross-sectional study included 32 participants with AD who were 65 years or older and met diagnostic criteria for dementia due to probable AD with a score of at least 17 on the Mini-Mental State Examination and 16 age-matched control participants. Participants were recruited from a university teaching hospital from May 2013 to October 2016., Main Outcomes and Measures: Plasticity of the DLPFC measured as potentiation of cortical-evoked activity using paired associative stimulation (a combination of peripheral nerve electrical stimulation and transcranial magnetic stimulation) combined with electroencephalography. Working memory was assessed with the n-back task (1- and 2-back) and measured using the A' statistic., Results: Among the 32 participants with AD, 17 were women and 15 were men (mean [SD] age, 76.3 [6.3] years); among the 16 controls, 8 were men and 8 were women (mean [SD] age, 76.4 [5.1] years). Participants with AD had impaired DLPFC plasticity (mean [SD] potentiation, 1.18 [0.25]) compared with controls (mean [SD] potentiation, 1.40 [0.35]; F1,44 = 5.90; P = .02; between-group comparison, Cohen d = 0.77; P = .01). Participants with AD also had impaired performances on the 1-back condition (mean [SD] A' = 0.47 [0.30]) compared with controls (mean [SD] A' = 0.96 [0.01]; Cohen d = 1.86; P < .001), with similar findings for participants with AD on the 2-back condition (mean [SD] A' = 0.29 [0.2]) compared with controls (mean [SD], A' = 0.85 [0.18]; Cohen d = 2.83; P < .001). Plasticity of DLPFC was positively associated with working memory performance on the 1-back A' (parameter estimate B [SE] = 0.32 [0.13]; standardized β = 0.29; P = .02) and 2-back A' (B [SE] = 0.43 [0.15]; β = 0.39; P = .006) across both groups after controlling for age, education, and attention., Conclusions and Relevance: This study demonstrated impaired in vivo DLPFC plasticity in patients with AD. The findings support the use of DLPFC plasticity as a measure of DLPFC function and a potential treatment target to enhance DLPFC function and working memory in patients with AD.

Previous studies have demonstrated that alcohol consumption impairs neuroplasticity in the motor cortex. However, it is unknown whether alcohol produces a similar impairment of neuroplasticity in the dorsolateral prefrontal cortex (DLPFC), a brain region that plays an important role in cognitive functioning. The aim of the current study was to evaluate the effect of alcohol intoxication on neuroplasticity in the DLPFC. Paired associative stimulation (PAS) combined with electroencephalography (EEG) was used for the induction and measurement of associative LTP-like neuroplasticity in the DLPFC. Fifteen healthy subjects were administered PAS to the DLPFC following consumption of an alcohol (1.5 g/l of body water) or placebo beverage in a within-subject cross-over design. PAS induced neuroplasticity was indexed up to 60 minutes following PAS. Additionally, the effect of alcohol on PAS-induced potentiation of theta-gamma coupling (an index associated with learning and memory) was examined prior to and following PAS. Alcohol consumption resulted in a significant impairment of mean (t = 2.456, df = 13, p = 0.029) and maximum potentiation (t = -2.945, df = 13, p = 0.011) compared to the placebo beverage in the DLPFC and globally. Alcohol also suppressed the potentiation of theta-gamma coupling by PAS. Findings from the present study provide a potential neurophysiological mechanism for impairment of cognitive functioning by alcohol.

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., (Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Gamma-aminobutyric acid (GABA)ergic and glutamatergic neurotransmissions in the prefrontal cortex decreases with age. Further, cognitive function mediated through the dorsolateral prefrontal cortex (DLPFC) also declines with age. Although neuroimaging studies have demonstrated decreased levels of these substances, direct neurophysiological data investigating the effect of aging in the DLPFC in human subjects is lacking. The advent of transcranial magnetic stimulation (TMS) combined with electroencephalography (EEG) has allowed for the assessment of functional neurotransmission in vivo. In the present study, we examined short interval intracortical inhibition (SICI) and intracortical facilitation (ICF) in a group of older adults (> 60 yrs) to evaluate the strength of GABA A and glutamate-mediated neurotransmission in the DLPFC, compared to younger adults (18-59 yrs). Older adults showed an increase of amplitude of N100 by the SICI paradigm, while N45 amplitude was increased and N100 amplitude was decreased by ICF. Moreover, these modulations significantly correlated with age. Our findings provide evidence for age-related alterations of excitatory and inhibitory functions in the prefrontal cortex in healthy adults. Future studies may aim to explore these neurophysiological relationships in the DLPFC in pathological forms of aging that affect cortical functioning such as mild cognitive impairment and Alzheimer's disease.

Short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) are noninvasive transcranial magnetic stimulation (TMS) measures of GABA A receptor-mediated inhibition and glutamatergic excitatory transmission, respectively. Conventionally these measures have been restricted to the motor cortex. We investigated whether SICI and ICF could be recorded from the dorsolateral prefrontal cortex (DLPFC) using combined TMS and electroencephalography (TMS-EEG). We first characterized the neural signature of SICI and ICF in M1 in terms of TMS-evoked potentials (TEPs) and spectral power modulation. Subsequently, these paradigms were applied in the DLPFC to determine whether similar neural signatures were evident. With TMS at M1, SICI and ICF led to bidirectional modulation (inhibition and facilitation, respectively) of P30 and P60 TEP amplitude, which correlated with MEP amplitude changes. With DLPFC stimulation, P60 was bidirectionally modulated by SICI and ICF in the same manner as for M1 stimulation, whereas P30 was absent. The sole modulation of early TEP components is in contradistinction to other measures such as long-interval intracortical inhibition and may reflect modulation of short latency excitatory and inhibitory postsynaptic potentials (EPSPs and IPSPs). Overall, the data suggest that SICI and ICF can be recorded using TMS-EEG in DLPFC providing noninvasive measures of glutamatergic and GABA A receptor-mediated neurotransmission. This may facilitate future research attempting to ascertain the role of these neurotransmitters in the pathophysiology and treatment of neurological and psychiatric disorders.

Repetitive transcranial magnetic stimulation (rTMS) is a relatively recent addition to the neurostimulation armamentarium for treating individuals suffering from treatment refractory depression and has demonstrated efficacy in clinical trials. One of the proposed mechanisms of action underlying the therapeutic effects of rTMS for depression involves the modulation of depression-associated dysfunctional activity in distributed brain networks involving frontal cortical and subcortical limbic regions, via changes to aberrant functional and structural connectivity. Although there is currently a paucity of published data, we review changes to functional and structural connectivity following rTMS for depression. Current evidence suggests an rTMS-induced normalisation of depression-associated dysfunction within and between large scale functional networks, including the default mode, central executive and salience networks, associated with an amelioration of depressive symptoms. Additionally, changes to measures of white matter microstructure, primarily in the dorsolateral prefrontal cortex, have also been reported following rTMS for depression, possibly reversing depression-associated abnormalities. We argue that measures of functional and structural connectivity can be used to optimise rTMS targeting within the dorsolateral prefrontal cortex and also to explore novel rTMS targets for depression. Finally, we discuss the utility of measures of brain connectivity as predictive biomarkers of rTMS treatment response in guiding therapeutic decisions., (Copyright © 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

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., (Copyright © 2016 the American Physiological Society.)

The glutamic acid decarboxylase 1 (GAD1) gene is a major determinant of γ-aminobutyric acid (GABA), the most abundant inhibitory neurotransmitter modulating local neuronal circuitry. GABAergic dysfunction and expression of GAD1 have been implicated in the pathophysiology of schizophrenia, and in working memory impairment. We examined the influence of the functional GAD1 rs3749034 variant on white matter fractional anisotropy (FA), cortical thickness, and working memory performance in schizophrenia patients and healthy controls (N=197). Using transcranial magnetic stimulation with electroencephalography (TMS-EEG), we subsequently examined the effect of rs3749034 on long-interval cortical inhibition (LICI) in the dorsolateral prefrontal cortex (DLPFC) in schizophrenia patients and healthy controls (N=66). We found that the rs3749034 T-allele carrier risk group had lower voxel-wise FA in the prefrontal cortex region (PFWE-corrected<0.05) but not cortical thickness. Mixed-model regression revealed a significant effect on attentional processing and working memory across four performance measures (F1,182=11.5, P=8 × 10(-4)). FA in the prefrontal cortex was associated with digit-span performance. Voxel-wise mediation analysis revealed that the effect GAD1 on poorer digit-span performance statistically predicted the lower white matter FA (PFWE-corrected<0.05). In exploratory analysis, we found a prominent GAD1 genotype-by-diagnosis interaction on DLPFC LICI (F1,56=14.3, P=4.1 × 10(-4)). Our findings converge on variation in GAD1 gene predicting a susceptibility mechanism that affects white matter FA, GABAergic inhibitory neurotransmission in the DLPFC, and working memory performance. Furthermore, via voxel mediation of FA and TMS-EEG intervention, we provide evidence for a potentially causal mechanism through which aberrant DLPFC GABA signaling may contribute to working memory dysfunction.

Depression is one of the most prevalent mental illnesses worldwide and a leading cause of disability, especially in the setting of treatment resistance. In recent years, repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising alternative strategy for treatment-resistant depression and its clinical efficacy has been investigated intensively across the world. However, the underlying neurobiological mechanisms of the antidepressant effect of rTMS are still not fully understood. This review aims to systematically synthesize the literature on the neurobiological mechanisms of treatment response to rTMS in patients with depression. Medline (1996-2014), Embase (1980-2014) and PsycINFO (1806-2014) were searched under set terms. Three authors reviewed each article and came to consensus on the inclusion and exclusion criteria. All eligible studies were reviewed, duplicates were removed, and data were extracted individually. Of 1647 articles identified, 66 studies met both inclusion and exclusion criteria. rTMS affects various biological factors that can be measured by current biological techniques. Although a number of studies have explored the neurobiological mechanisms of rTMS, a large variety of rTMS protocols and parameters limits the ability to synthesize these findings into a coherent understanding. However, a convergence of findings suggest that rTMS exerts its therapeutic effects by altering levels of various neurochemicals, electrophysiology as well as blood flow and activity in the brain in a frequency-dependent manner. More research is needed to delineate the neurobiological mechanisms of the antidepressant effect of rTMS. The incorporation of biological assessments into future rTMS clinical trials will help in this regard.

Background: A significant proportion of patients with depression fail to respond to psychotherapy and standard pharmacotherapy, leading to treatment-resistant depression (TRD). Due to the significant prevalence of TRD, alternative therapies for depression have emerged as viable treatments in the armamentarium for this disorder. Repetitive transcranial magnetic stimulation (rTMS) is now being offered in clinical practice in broader numbers. Many studies have investigated various different neurobiological predictors of response of rTMS. However, a synthesis of this literature and an understanding of what biological targets predict response is lacking. This review aims to systematically synthesize the literature on the neurobiological predictors of rTMS in patients with depression., Methods: Medline (1996-2014), Embase (1980-2014), and PsycINFO (1806-2014) were searched under set terms. Two authors reviewed each article and came to consensus on the inclusion and exclusion criteria. All eligible studies were reviewed, duplicates were removed, and data were extracted individually., Results: The search identified 1,673 articles, 41 of which met both inclusion and exclusion criteria. Various biological factors at baseline appear to predict response to rTMS, including levels of certain molecular factors, blood flow in brain regions implicated in depression, electrophysiological findings, and specific genetic polymorphisms., Conclusions: Significant methodological variability in rTMS treatment protocols limits the ability to generalize conclusions. However, response to treatment may be predicted by baseline frontal lobe blood flow, and presence of polymorphisms of the 5-hydroxytryptamine (5-HT) -1a gene, the LL genotype of the serotonin transporter linked polymorphic region (5-HTTLPR) gene, and Val/Val homozygotes of the brain-derived neurotrophic factor (BDNF) gene., (© 2015 Wiley Periodicals, Inc.)

Background: The dorsolateral prefrontal cortex (DLPFC) is a common target for repetitive transcranial magnetic stimulation (rTMS) in major depression, but the conventional "5 cm rule" misses DLPFC in >1/3 cases. Another heuristic, BeamF3, locates the F3 EEG site from scalp measurements. MRI-guided neuronavigation is more onerous, but can target a specific DLPFC stereotaxic coordinate directly. The concordance between these two approaches has not previously been assessed., Objective: To quantify the discrepancy in scalp site between BeamF3 versus MRI-guided neuronavigation for left DLPFC., Methods: Using 100 pre-treatment MRIs from subjects undergoing left DLPFC-rTMS, we localized the scalp site at minimum Euclidean distance from a target MNI coordinate (X - 38 Y + 44 Z + 26) derived from our previous work. We performed nasion-inion, tragus-tragus, and head-circumference measurements on the same subjects' MRIs, and applied the BeamF3 heuristic. We then compared the distance between BeamF3 and MRI-guided scalp sites., Results: BeamF3-to-MRI-guided discrepancies were <0.65 cm in 50% of subjects, <0.99 cm in 75% of subjects, and <1.36 cm in 95% of subjects. The angle from midline to the scalp site did not differ significantly using MRI-guided versus BeamF3 methods. However, the length of the radial arc from vertex to target site was slightly but significantly longer (mean 0.35 cm) with MRI-guidance versus BeamF3., Conclusions: The BeamF3 heuristic may provide a reasonable approximation to MRI-guided neuronavigation for locating left DLPFC in a majority of subjects. A minor optimization of the heuristic may yield additional concordance., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Here we outline the protocol for magnetic resonance imaging (MRI) guided repetitive transcranial magnetic stimulation (rTMS) to the dorsal medial prefrontal cortex (dmPFC) in patients with major depressive disorder (MDD). Technicians used a neuronavigation system to process patient MRIs to generate a 3-dimensional head model. The head model was subsequently used to identify patient-specific stimulatory targets. The dmPFC was stimulated daily for 20 sessions. Stimulation intensity was titrated to address scalp pain associated with rTMS. Weekly assessments were conducted on the patients using the Hamilton Rating Scale for Depression (HamD17) and Beck Depression Index II (BDI-II). Treatment-resistant MDD patients achieved significant improvements on both HAMD and BDI-II. Of note, angled, double-cone coil rTMS at 120% resting motor threshold allows for optimal stimulation of deeper midline prefrontal regions, which results in a possible therapeutic application for MDD. One major limitation of the rTMS field is the heterogeneity of treatment parameters across studies, including duty cycle, number of pulses per session and intensity. Further work should be done to clarify the effect of stimulation parameters on outcome. Future dmPFC-rTMS work should include sham-controlled studies to confirm its clinical efficacy in MDD.

Background: Conventional rTMS protocols for major depression commonly employ stimulation sessions lasting >30 min. However, recent studies have sought to improve costs, capacities, and outcomes by employing briefer protocols such as theta burst stimulation (iTBS)., Objective: To compare safety, effectiveness, and outcome predictors for DMPFC-rTMS with 10 Hz (30 min) versus iTBS (6 min) protocols, in a large, naturalistic, retrospective case series., Methods: A chart review identified 185 patients with a medication-resistant major depressive episode who underwent 20-30 sessions of DMPFC-rTMS (10 Hz, n = 98; iTBS, n = 87) at a single Canadian clinic from 2011 to 2014., Results: Clinical characteristics of 10 Hz and iTBS patients did not differ prior to treatment, aside from significantly higher age in iTBS patients. A total 7912 runs of DMPFC-rTMS (10 Hz, 4274; iTBS, 3638) were administered, without any seizures or other serious adverse events, and no significant differences in rates of premature discontinuation between groups. Dichotomous outcomes did not differ significantly between groups (Response/remission rates: Beck Depression Inventory-II: 10 Hz, 40.6%/29.2%; iTBS, 43.0%/31.0%. 17-item Hamilton Rating Scale for Depression: 10 Hz, 50.6%/38.5%; iTBS, 48.5%/27.9%). On continuous outcomes, there was no significant difference between groups in pre-treatment or post-treatment scores, or percent improvement on either measure. Mixed-effects modeling revealed no significant group-by-time interaction on either measure., Conclusions: Both 10 Hz and iTBS DMPFC-rTMS appear safe and tolerable at 120% resting motor threshold. The effectiveness of 6 min iTBS and 30 min 10 Hz protocols appears comparable. Randomized trials comparing 10 Hz to iTBS may be warranted., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Paired-pulse transcranial magnetic stimulation combined with electroencephalography (TMS-EEG) is a method for studying cortical inhibition from the dorsolateral prefrontal cortex (DLPFC). However, little is known about the mechanisms underlying TMS-evoked cortical potentials (TEPs) from this region, let alone inhibition of these components. The aim of this study was to assess cortical inhibition of distinct TEPs and oscillations in the DLPFC using TMS-EEG and to investigate the relationship of these mechanisms to working memory. 30 healthy volunteers received single and paired (interstimulus interval = 100 msec) TMS to the left DLPFC. Variations in long-interval cortical inhibition (LICI) of different TEP peaks (N40, P60, N100) and different TMS-evoked oscillations (alpha, lower beta, upper beta, gamma) were compared between individuals. Variation in N100 slope following single pulse TMS, another putative marker of inhibition, was also compared with LICI of each measure. Finally, these measures were correlated with performance of a working memory task. LICI resulted in significant suppression of all TEP peaks and TMS-evoked oscillations (all p < .05). There were no significant correlations between LICI of different TEP peaks or TMS-evoked oscillations with the exception of P60 and N100. Variation in N100 slope correlated with LICI of N40 and beta oscillations. In addition, LICI of P60 and N100 were differentially correlated with working memory performance. The results suggest that both the LICI paradigm and N100 following single pulse TMS reflect complementary methods for assessing GABAB-mediated cortical inhibition in the DLPFC. Furthermore, these measures demonstrate the importance of prefrontal GABAB-mediated inhibitory control for working memory performance., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

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., (© The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Generally, rewards that are received sooner are often preferred over future rewards, and the time between the choice and the reception of the reward is an important factor that influences our decisions, a phenomenon called delay discounting (DD). In DD, the medial prefrontal cortex (MePFC) and striatal dopamine neurotransmission both play an important role. We used repetitive transcranial magnetic stimulation (rTMS) to transiently activate the MePFC to evaluate its behavioral effect on the DD paradigm, and subsequently to measure its effect on striatal dopamine. Twenty-four right-handed young healthy subjects (11 females; age: 22.1±2.9 years) underwent DD following 10 Hz-rTMS of the MePFC and vertex stimulation (control condition). Thereafter, 11 subjects (5 females; age: 22.2±2.87 years) completed the PET study at rest using [(11)C]-(+)-PHNO following 10 Hz-rTMS of the MePFC and vertex. Modulation of the MePFC excitability influenced the subjective level of DD for delayed rewards and interfered with synaptic dopamine level in the striatum. The present study yielded findings that might reconcile the role of these areas in inter-temporal decision making and dopamine modulation, suggesting that the subjective sense of time and value of reward are critically controlled by these important regions.

Background: A small number of studies conducted to date have suggested that transcranial direct current stimulation (tDCS) applied to the temporoparietal cortex may reduce auditory hallucinations in patients with schizophrenia. Prefrontal brain stimulation with other methods, has also been shown to potentially improve the negative symptoms of this disorder., Objective: To investigate the therapeutic potential of daily bimodal tDCS: anodal stimulation to the prefrontal cortex and cathodal stimulation to the temporoparietal junction in patients with persistent hallucinations and negative symptoms of schizophrenia., Methods: We conducted two small randomized double-blind controlled trials comparing bimodal tDCS to sham stimulation. In one study, stimulation was provided unilaterally, in the second study it was provided bilaterally., Results: Neither unilateral nor bilateral tDCS resulted in a substantial change in either hallucinations or negative symptoms. Stimulation was well tolerated without side-effects., Conclusion: Daily tDCS does not appear to have substantial potential in the treatment of hallucinations or negative symptoms and further research should investigate higher doses of stimulation or more frequently applied treatment schedules., (Copyright © 2014 Elsevier Inc. All rights reserved.)

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., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Depression is a heterogeneous mental illness. Neurostimulation treatments, by targeting specific nodes within the brain's emotion-regulation network, may be useful both as therapies and as probes for identifying clinically relevant depression subtypes., Methods: Here, we applied 20 sessions of magnetic resonance imaging-guided repetitive transcranial magnetic stimulation (rTMS) to the dorsomedial prefrontal cortex in 47 unipolar or bipolar patients with a medication-resistant major depressive episode., Results: Treatment response was strongly bimodal, with individual patients showing either minimal or marked improvement. Compared with responders, nonresponders showed markedly higher baseline anhedonia symptomatology (including pessimism, loss of pleasure, and loss of interest in previously enjoyed activities) on item-by-item examination of Beck Depression Inventory-II and Quick Inventory of Depressive Symptomatology ratings. Congruently, on baseline functional magnetic resonance imaging, nonresponders showed significantly lower connectivity through a classical reward pathway comprising ventral tegmental area, striatum, and a region in ventromedial prefrontal cortex. Responders and nonresponders also showed opposite patterns of hemispheric lateralization in the connectivity of dorsomedial and dorsolateral regions to this same ventromedial region., Conclusions: The results suggest distinct depression subtypes, one with preserved hedonic function and responsive to dorsomedial rTMS and another with disrupted hedonic function, abnormally lateralized connectivity through ventromedial prefrontal cortex, and unresponsive to dorsomedial rTMS. Future research directly comparing the effects of rTMS at different targets, guided by neuroimaging and clinical presentation, may clarify whether hedonia/reward circuit integrity is a reliable marker for optimizing rTMS target selection., (© 2013 Society of Biological Psychiatry Published by Society of Biological Psychiatry All rights reserved.)

Background: Prominent regional cortical thickness reductions have been shown in schizophrenia. In contrast, little is known regarding alterations of structural coupling between regions in schizophrenia and how these alterations may be related to cognitive impairments in this disorder., Methods: T1-weighted magnetic resonance images were acquired in 54 patients with schizophrenia and 68 healthy control subjects aged 18-55 years. Cortical thickness was compared between groups using a vertex-wise approach. To assess structural coupling, seeds were selected within regions of reduced thickness, and brain-wide cortical thickness correlations were compared between groups. The relationships between identified patterns of circuit structure disruption and cognitive task performance were then explored., Results: Prominent cortical thickness reductions were found in patients compared with controls at a 5% false discovery rate in a predominantly frontal and temporal pattern. Correlations of the left dorsolateral prefrontal cortex (DLPFC) with right prefrontal regions were significantly different in patients and controls. The difference remained significant in a subset of 20 first-episode patients. Participants with stronger frontal interhemispheric thickness correlations had poorer working memory performance., Conclusions: We identified structural impairment in a left-right DLPFC circuit in patients with schizophrenia independent of illness stage or medication exposure. The relationship between left-right DLPFC thickness correlations and working memory performance implicates prefrontal interhemispheric circuit impairment as a vulnerability pathway for poor working memory performance. Our findings could guide the development of novel therapeutic interventions aimed at improving working memory performance in patients with schizophrenia., (© The Author 2013. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: Long-interval cortical inhibition (LICI) can be recorded from motor and non-motor regions of the cortex through combined transcranial magnetic stimulation (TMS) with electroencephalography (EEG). This study aimed to evaluate additional dimensions of LICI characteristics over an extended time-frequency and spatial domain. This was done by introducing two alternative measures of LICI signal amplitude: the Discrete Fourier Transform (DFT) and the Hilbert transform (HT). Both approaches estimate signal amplitude not taking into account the phase. In both cases LICI was measured as the difference between the unconditioned and conditioned activity evoked by the test pulse. Finally, we evaluated whether the topographical patterns of single and paired responses differed beyond the expected variations in amplitude., Materials and Methods: LICI was delivered as single and paired pulses to the motor cortex (MC) and dorsolateral prefrontal cortex (DLPFC) in 33 healthy subjects with TMS-EEG., Results: Significant differences (p<0.0001) between the unconditioned and conditioned evoked activity were found for both the DLPFC and MC using both methods (i.e., DFT and HT) after correcting for multiple comparisons in the time-frequency domain. The influence of inhibition was found to be significantly larger in space and time than previously considered. Single and paired conditions differ in intensity, but also in their topographic pattern (i.e., the specific spatiotemporal configuration of active sources)., Conclusion: Similar results were found by both DFT and HT. The effect of inhibition across the cortex was also found to be complex and extended. In particular, it was found that LICI may be measured with high sensitivity in areas that were relatively distant from the stimulation site, which may have important practical applications. The analysis presented in this study overcomes some limitations of previous studies and could serve as a key reference for future studies examining TMS-indices of inhibition/excitation in healthy and diseased states.

Neuroplasticity and long-term potentiation (LTP) in the dorsolateral prefrontal cortex (DLPFC) are considered important mechanisms in learning and memory, and their disruption may be related to the pathophysiology of several neuropsychiatric disorders. Paired associative stimulation (PAS) is a brain stimulation paradigm that produces enhanced activity in the human motor cortex that may be related to LTP. In a group of 15 healthy participants, we report on the potentiation of cortical-evoked activity in the human DLPFC using the combination of PAS and electroencephalography. In contrast, a PAS control condition did not result in potentiation in another group of nine healthy participants. We also demonstrate that PAS-induced potentiation of cortical-evoked activity is characterized by anatomical specificity that is largely confined to the site of stimulation. Finally, we show that PAS results in potentiation of θ- and γ-activity and θ-phase-γ-amplitude coupling. These neurophysiological indices may be related to working memory, an important function of the DLPFC. To our knowledge, this is the first report of potentiation of cortical-evoked activity in the DLPFC. As this potentiation may be related to LTP, our findings provide a model through which neuroplasticity in health and disease states in the frontal cortex can be studied.

High and low frequency repetitive transcranial magnetic stimulation (rTMS) are both used to treat major depressive disorder(MDD). However, the physiological mechanisms underlying the therapeutic benefit and the effect of the stimulation frequency are unclear. Twelve healthy participants received 1Hz, 2Hz, and 5Hz active rTMS. Twenty 5 second trains were delivered at left dorsolateral prefrontal cortex at 110% of resting motor threshold with a 25 second inter-train interval. Blood oxygenation (HbO) was significantly reduced following the 1Hz trains compared to the HbO increases observed in both the 2Hz and 5Hz conditions. There was no significant inter-hemispheric difference in response. These results suggest that short trains of high and low frequency rTMS delivered to prefrontal cortex evoke a differential HbO response and provide additional evidence that high frequency trains result in increased neural activity. The findings may provide further explanation for the improved symptoms observed in MDD patients treated with high frequency rTMS., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Repetitive transcranial magnetic stimulation treatment (rTMS) is an effective treatment for depression but the optimal methods of administration have yet to be determined. Recent studies have produced conflicting results as to whether unilateral rTMS is more or less effective than sequentially applied bilateral rTMS. To address this we conducted a trial comparing sequential bilateral rTMS to right-sided unilateral rTMS using a priming protocol. Patients with treatment-resistant depression (n = 179) were enrolled in a two-arm randomized controlled trial across a 4-wk time period. The primary outcome assessment was the Hamilton Depression Rating Scale. Overall, there was a substantial response rate of >50% (and a 40% remission rate); however, there were no significant differences in clinical response between the two treatment groups. rTMS was well tolerated with a very low discontinuation rate. There was no relationship between response in the current trial and previous response, or non-response, to electroconvulsive therapy. We found no significant differences in clinical response between sequential bilateral rTMS and right-sided unilateral rTMS applied with a priming protocol. The results of this study do not support superior efficacy of bilateral rTMS and instead suggest that other approaches should be explored to increase treatment efficacy.

Transcranial Direct Current Stimulation (tDCS) is a non-invasive form of brain stimulation which has been shown to induce changes in brain activity and subsequent functioning. In particular, there is a rapidly growing evidence base showing that anodal tDCS applied to the left prefrontal cortex (PFC) is able to enhance aspects of cognitive functioning, in particular working memory (WM). This has led to both excitement and concerns regarding the possibility of 'electrodoping' in order to greatly improve one's cognitive performance. We investigated the behavioural and neurophysiological effects of increasing the current (or 'dose') of tDCS on the degree of WM improvement in healthy controls. Single sessions of 1 mA, 2 mA and sham anodal tDCS to the left PFC were undertaken over a period of three weeks. Participants underwent a WM task at three time points post-stimulation (0, 20 and 40 min) with concurrent electrophysiological (EEG) recordings. Our results showed that while active tDCS can enhance behavioural performance, with neurophysiological findings indicating improve efficiency of cognitive processing; we showed that 1 mA produced the most significant effects. These findings are somewhat unexpected as tDCS dose effects in cognitive enhancement have been shown previously in patient populations. Our results provide valuable information regarding the potential limits of tDCS induced cognitive enhancement in healthy controls, as well as providing additional insights into the possible mechanisms of action of tDCS., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Prefrontal transcranial magnetic stimulation (TMS) is being investigated as a treatment for several neurological and psychiatric disorders. The direction of the cortical current induced by TMS can be modulated by the coil orientation and this influences the extent of neural depolarization. Although the optimal coil orientation has previously been established for motor cortex, identifying an optimal coil orientation for prefrontal areas is more challenging due to the absence of a motor response. The current study used near infra-red spectroscopy (NIRS) to investigate the impact of coil orientation on TMS induced changes in prefrontal blood oxygenation (HbO). It was hypothesized that a greater change in HbO would be observed when current was induced in a posterior to anterior direction., Methods: Single pulse and trains of 1 Hz repetitive TMS (rTMS) were administered to the left prefrontal cortex while simultaneously recording HbO response bilaterally. The effect of coil orientation was examined at 45°, 135°, and 225° counterclockwise from midline., Results: Greatest changes in HbO were observed at a 45° orientation when both single and rTMS were applied, and only minor changes were observed at 135° and 225°. Application of short trains of rTMS at 45° resulted in transient increases in HbO that were significantly greater in magnitude than when the coil orientation was reversed., Conclusions: The utility of NIRS for examining the TMS evoked physiological response at non-motor areas is highlighted in this study. Prefrontal HbO response evoked by TMS is sensitive to the direction of induced cortical current and it appears that the de facto 45° angle utilized in most clinical studies may prove to be optimal., (Copyright © 2013 Elsevier Inc. All rights reserved.)