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BACKGROUND: Previous research has confirmed the presence of increased motor overflow in schizophrenia. There are essentially two theories regarding the cortical origins of overflow. Recent research suggests that both may be correct, and that the cortical origin of overflow is highly dependent upon the population in which it presents. Motor overflow, due to an abnormally active ipsilateral corticospinal tract, may indicate a potentially severe brain abnormality arising in early development. In contrast, bilaterally active corticospinal tracts accounting for overflow probably represent a naturally occurring response during fatiguing contractions. METHOD: The cortical origins of motor overflow in 20 participants with schizophrenia and 20 normal controls were investigated through the use of a number of transcranial magnetic stimulation (TMS) protocols. RESULTS: Each of the experimental protocols employed independently supported the contention that overflow was originating in the hemisphere contralateral to the involuntary movement. CONCLUSIONS: Results indicated that the origins of overflow in schizophrenia are the same as those seen in the normal control group, i.e. motor overflow seems to be due to the presence of bilaterally active corticospinal tracts. Potential explanations for greater motor overflow seen in schizophrenia are discussed. [ABSTRACT FROM AUTHOR]

There is growing evidence that neural network dysfunction is a likely proximate cause of cognitive impairment in Alzheimer's disease and may represent a promising therapeutic target. Here, we investigated whether a course of intermittent theta burst stimulation (iTBS) could modulate functional connectivity and cognition in mild to moderate Alzheimer's. In a double-blind parallel randomized sham-controlled trial, 58 participants were randomized to either active or sham iTBS. Stimulation was applied to the left dorsolateral prefrontal cortex, right dorsolateral prefrontal cortex, left posterior parietal cortex, and right posterior parietal cortex in every treatment session. Neurobiological (electroencephalography), cognitive, and behavioral functional assessments were undertaken at baseline and end of treatment. Cognitive and functional assessments were also conducted at 3 (blinded) and 6 month (active group only) follow-ups. Active iTBS increased resting-state gamma connectivity and improved delayed recall on an episodic memory task. Both baseline gamma connectivity and change in gamma connectivity predicted improved delayed recall following active treatment. These findings support future research into iTBS for Alzheimer's focusing on protocol optimization., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: To compare effects of transcranial direct current stimulation (tDCS) and transcranial random noise stimulation with a direct-current offset (tRNS + DC-offset) on working memory (WM) performance and task-related electroencephalography (EEG) in individuals with Major Depressive Disorder (MDD)., Methods: Using a sham-controlled, parallel-groups design, 49 participants with MDD received either anodal tDCS (N = 16), high-frequency tRNS + DC-offset (N = 16), or sham stimulation (N = 17) to the left dorsolateral prefrontal cortex (DLPFC) for 20-minutes. The Sternberg WM task was completed with concurrent EEG recording before and at 5- and 25-minutes post-stimulation. Event-related synchronisation/desynchronisation (ERS/ERD) was calculated for theta, upper alpha, and gamma oscillations during WM encoding and maintenance., Results: tDCS significantly increased parieto-occipital upper alpha ERS/ERD during WM maintenance, observed on EEG recorded 5- and 25-minutes post-stimulation. tRNS + DC-offset did not significantly alter WM-related oscillatory activity when compared to sham stimulation. Neither tDCS nor tRNS + DC-offset improved WM performance to a significantly greater degree than sham stimulation., Conclusions: Although tDCS induced persistent effects on WM-related oscillatory activity, neither tDCS nor tRNS + DC-offset enhanced WM performance in MDD., Significance: This reflects the first sham-controlled comparison of tDCS and tRNS + DC-offset in MDD. These findings directly contrast with evidence of tRNS-induced enhancements in WM in healthy individuals., 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 three years PBF has received equipment for research from Neurosoft, Nexstim and Brainsway Ltd. PBF has served on scientific advisory boards for Magstim and LivaNova and acted as a founder and board member for TMS Clinics Australia and Resonance Therapeutics. All other authors have no conflicts to report., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: The objective of this study was to investigate clinical symptoms, cognitive performance and cortical activity following mild traumatic brain injury (mTBI)., Methods: We recruited 30 individuals in the sub-acute phase post mTBI and 28 healthy controls with no history of head injury and compared these groups on clinical, cognitive and cortical activity measures. Measures of cortical activity included; resting state electroencephalography (EEG), task related EEG and combined transcranial magnetic stimulation with electroencephalography (TMS-EEG). Primary analyses investigated clinical, cognitive and cortical activity differences between groups. Exploratory analyses investigated the relationships between these measures., Results: At 4 weeks' post injury, mTBI participants exhibited significantly greater post concussive and clinical symptoms compared to controls; as well as reduced cognitive performance on verbal learning and working memory measures. mTBI participants demonstrated alterations in cortical activity while at rest and in response to stimulation with TMS., Conclusions: The present study comprehensively characterized the multidimensional effect of mTBI in the sub-acute phase post injury, showing a broad range of differences compared to non-mTBI participants. Further research is needed to explore the relationship between these pathophysiologies and clinical/cognitive symptoms in mTBI.

Objective: To find sensitive neurophysiological correlates of non-motor symptoms in Huntington's disease (HD), which are essential for the development and assessment of novel treatments., Methods: We used resting state EEG to examine differences in oscillatory activity (analysing the isolated periodic as well as the complete EEG signal) and functional connectivity in 22 late premanifest and early stage people with HD and 20 neurotypical controls. We then assessed the correlations between these neurophysiological markers and clinical measures of apathy and processing speed., Results: Significantly lower theta and greater delta resting state power was seen in the HD group, as well as significantly greater delta connectivity. There was a significant positive correlation between theta power and processing speed, however there were no associations between the neurophysiological and apathy measures., Conclusions: We speculate that these changes in oscillatory power and connectivity reflect ongoing, frontally concentrated degenerative and compensatory processes associated with HD., Significance: Our findings support the potential utility of quantitative EEG as a proximate marker of processing speed, but not apathy in HD., (Copyright © 2023 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

We investigated the effects of transcranial alternating current stimulation (tACS) targeted to the bilateral medial prefrontal cortex (mPFC) and administered at either delta or alpha frequencies, on brain activity and apathy in people with Huntington's disease (HD) (n = 17). Given the novelty of the protocol, neurotypical controls (n = 20) were also recruited. All participants underwent three 20-min sessions of tACS; one session at alpha frequency (Individualised Alpha Frequency (IAF), or 10 Hz when an IAF was not detected); one session at delta frequency (2 Hz); and a session of sham tACS. Participants completed the Monetary Incentive Delay (MID) task with simultaneous recording of EEG immediately before and after each tACS condition. The MID task presents participants with cues signalling potential monetary gains or losses that increase activity in key regions of the cortico-basal ganglia-thalamocortical networks, with dysfunction of the latter network being implicated in the pathophysiology of apathy. We used the P300 and Contingent Negative Variation (CNV) event-related potentials elicited during the MID task as markers of mPFC engagement. HD participants' CNV amplitude significantly increased in response to alpha-tACS, but not delta-tACS or sham. Neurotypical controls' P300 and CNV were not modulated by any of the tACS conditions, but they did demonstrate a significant decrease in post-target response times following alpha-tACS. We present this as preliminary evidence of the ability of alpha-tACS to modulate brain activity associated with apathy in HD., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The mechanisms that underpin recovery following mild traumatic brain injury (mTBI) remain poorly understood. Identifying neurophysiological markers and their functional significance is necessary to develop diagnostic and prognostic indicators of recovery. The current study assessed 30 participants in the subacute phase of mTBI (10-31 days post-injury) and 28 demographically matched controls. Participants also completed 3 month (mTBI: N = 21, control: N = 25) and 6 month (mTBI: N = 15, control: N = 25) follow up sessions to track recovery. At each time point, a battery of clinical, cognitive, and neurophysiological assessments was completed. Neurophysiological measures included resting-state electroencephalography (EEG) and transcranial magnetic stimulation combined with EEG (TMS-EEG). Outcome measures were analysed using mixed linear models (MLM). Group differences in mood, post-concussion symptoms and resting-state EEG resolved by 3 months, and recovery was maintained at 6 months. On TMS-EEG derived neurophysiological measures of cortical reactivity, group differences ameliorated at 3 months but re-emerged at 6 months, while on measures of fatigue, group differences persisted across all time points. Persistent neurophysiological changes and greater fatigue in the absence of measurable cognitive impairment may suggest the impact of mTBI on neuronal communication may leads to increased neural effort to maintain efficient function. Neurophysiological measures to track recovery may help identify both temporally optimal windows and therapeutic targets for the development of new treatments in mTBI., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

We investigated the effects of transcranial alternating current stimulation (tACS) targeted to the medial prefrontal cortex (mPFC) on resting electroencephalographic (EEG) indices of oscillatory power, aperiodic exponent and offset, and functional connectivity in 22 late premanifest and early manifest stage individuals with HD and 20 neurotypical controls. Participants underwent three 20-minute sessions of tACS at least 72 hours apart; one session at alpha frequency (either each participant's Individualised Alpha Frequency (IAF), or 10 Hz when an IAF was not detected); one session at delta frequency (2 Hz); and a session of sham tACS. Session order was randomised and counterbalanced across participants. EEG recordings revealed a reduction of the spectral exponent ('flattening' of the 1/f slope) of the eyes-open aperiodic signal in participants with HD following alpha-tACS, suggestive of an enhancement in excitatory tone. Contrary to expectation, there were no changes in oscillatory power or functional connectivity in response to any of the tACS conditions in the participants with HD. By contrast, alpha-tACS increased delta power in neurotypical controls, who further demonstrated significant increases in theta power and theta functional connectivity in response to delta-tACS. This study contributes to the rapidly growing literature on the potential experimental and therapeutic applications of tACS by examining neurophysiological outcome measures in people with HD as well as neurotypical controls., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective: The ability of the brain to recover following neurological insult is of interest for mild traumatic brain injury (mTBI) populations. Investigating whether non-invasive brain stimulation (NIBS) can modulate neurophysiology and cognition may lead to the development of therapeutic interventions post injury. The purpose of this study was to investigate neurobiological effects of one session of intermittent theta burst stimulation (iTBS) to the dorsolateral prefrontal cortex (DLPFC) in participants recovering from mTBI., Method: Changes to neurophysiology were assessed with electroencephalography (EEG) and transcranial magnetic stimulation combined with EEG (TMS-EEG). Digit span working memory accuracy assessed cognitive performance. 30 patients were assessed within one-month of sustaining a mTBI and 26 demographically matched controls were assessed. Participants were also assessed at 3-months (mTBI: N = 21, control: N = 26) and 6-months (mTBI: N = 15, control: N = 24)., Results: Analyses demonstrated iTBS did not reliably modulate neurophysiological activity, and no differences in cognitive performance were produced by iTBS at any assessment time-point., Conclusions: Factors responsible for our null results are unclear. Possible limitations to our experimental design are discussed., Significance: Our findings suggest additional research is required to establish the effects of iTBS on plasticity following mTBI, prior to therapeutic application., Data and Code Availability Statement: We do not have ethical approval to make this data publicly available, as our approval predated our inclusion of such approvals (which we now do routinely)., (Copyright © 2023 Elsevier B.V. All rights reserved.)

We explored the utility of the Monetary Incentive Delay (MID) task with concurrent encephalography (EEG) as a marker of apathy in people with Huntington's disease (HD) as well as neurotypical controls. Specifically, we assessed between and within-group differences in the amplitude of the P300 and Contingent Negative Variation (CNV) event-related potentials as a function of motivational salience. In contrast to neurotypical controls, HD participants' ERP amplitudes were not differentially modulated by motivationally salient cues (i.e., signalling potential 'gain' or 'loss') compared to 'neutral' cues. Difference waves isolating amplitude specific to the motivationally salient cues were calculated for the P300 and CNV. Only the difference waves for ERPs elicited by 'gain' cues differentiated the groups. The CNV difference wave was also significantly correlated with clinical measures of apathy and processing speed in the HD group. These findings provide initial support for the use of the MID with EEG as a marker of apathy in HD, and its potential as a sensitive outcome measure for novel treatment development., Competing Interests: Declaration of competing interest KEH is a founder of Resonance Therapeutics. PBF has received equipment for research from MagVenture A/S, Nexstim, Neuronetics and Brainsway Ltd and funding for research from Neuronetics. PBF is a founder of TMS Clinics Australia and Resonance Therapeutics. JCS is founder and a director of Zindametrix which provides cognitive assessment services in HD clinical trials, and Stout Neuropsych, which provides consultancy services for pharmaceutical companies. MCD and ATH have no biomedical financial interests or potential conflicts of interest to report., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Following on from the publication of the Royal Australian and New Zealand Journal of Psychiatry Mood Disorder Clinical Practice Guidelines (2020) and criticisms of how these aberrantly addressed repetitive transcranial magnetic stimulation treatment of depression, questions have continued to be raised in the journal about this treatment by a small group of authors, whose views we contend do not reflect the broad acceptance of this treatment nationally and internationally. In fact, the evidence supporting the use of repetitive transcranial magnetic stimulation treatment in depression is unambiguous and substantial, consisting of an extensive series of clinical trials supported by multiple meta-analyses, network meta-analysis and umbrella reviews. Importantly, the use of repetitive transcranial magnetic stimulation treatment in depression has also been subject to a series of health economic analyses. These indicate that repetitive transcranial magnetic stimulation is a cost-effective therapy and have been used in some jurisdictions, including Australia, in support of public funding. An argument has been made that offering repetitive transcranial magnetic stimulation treatment may delay potentially effective pharmacotherapy. In fact, there is considerably greater danger of the opposite happening. Repetitive transcranial magnetic stimulation is as, if not more effective, than antidepressant medication after two unsuccessful medication trials and should be a consideration for all patients under these circumstances where available. There is no meaningful ongoing debate about the use of repetitive transcranial magnetic stimulation treatment in depression - it is a safe, effective and cost-effective treatment.

Background: Alzheimer's disease (AD) is characterized by a progressive decline in cognitive functioning for which there is a stark lack of effective treatments. Investigating the neurophysiological markers of symptom severity in AD may aid in the identification of alternative treatment targets., Objective: In the current study we used a multimodal approach to investigate the association between functional connectivity (specifically between scalp electrodes placed over frontal and parietal regions) and symptom severity in AD, and to explore the relationship between connectivity and cortical excitability., Methods: 40 people with AD (25 mild severity, 15 moderate severity) underwent neurobiological assessment (resting state electroencephalography (EEG) and prefrontal transcranial magnetic stimulation (TMS) with EEG) and cognitive assessment. Neurobiological outcomes were resting state functional connectivity and TMS-evoked potentials. Cognitive outcomes were scores on the Alzheimer's Disease Assessment Scale-Cognitive Subscale, Mini-Mental Status Examination, and a measure of episodic verbal learning., Results: Greater contralateral functional theta connectivity between frontal scalp electrodes and parietal scalp electrodes was associated with poorer cognitive performance. In addition, significant correlations were seen between the contralateral theta connectivity and the N100 and P60 TMS-evoked potentials measured from electrodes over the left dorsolateral prefrontal cortex., Conclusion: Together these findings provide initial support for the use of multimodal neurophysiological approaches to investigate potential therapeutic targets in AD. Suggestions for future research are discussed.

How a letter addressing the lack of women invited to speak at a conference in brain stimulation encouraged researchers to take action., Competing Interests: KH, BF, AB No competing interests declared, (© 2021, Hoy et al.)

Introduction: Theta burst pattern repetitive transcranial magnetic stimulation (TBS) is increasingly applied to treat depression. TBS's brevity is well-suited to application in accelerated schedules. Sizeable trials of accelerated TBS are lacking; and optimal TBS parameters such as stimulation intensity are not established., Methods: We conducted a three arm, single blind, randomised, controlled, multi-site trial comparing accelerated bilateral TBS applied at 80 % or 120 % of the resting motor threshold and left unilateral 10 Hz rTMS. 300 patients with treatment-resistant depression (TRD) were recruited. TBS arms applied 20 bilateral prefrontal TBS sessions over 10 days, while the rTMS arm applied 20 daily sessions of 10 Hz rTMS to the left prefrontal cortex over 4 weeks. Primary outcome was depression treatment response at week 4., Results: The overall treatment response rate was 43.7 % and the remission rate was 28.2 %. There were no significant differences for response (p = 0.180) or remission (p = 0.316) across the three groups. Response rates between accelerated bilateral TBS applied at sub- and supra-threshold intensities were not significantly different (p = 0.319). Linear mixed model analysis showed a significant effect of time (p < 0.01), but not rTMS type (p = 0.680)., Conclusion: This is the largest accelerated bilateral TBS study to date and provides evidence that it is effective and safe in treating TRD. The accelerated application of TBS was not associated with more rapid antidepressant effects. Bilateral sequential TBS did not have superior antidepressant effect to unilateral 10 Hz rTMS. There was no significant difference in antidepressant efficacy between sub- and supra-threshold accelerated bilateral TBS., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Anxiety disorders are highly prevalent and cause substantial personal, social and economic burden. Altered attentional control has been shown to be present across anxiety disorders and is associated with specific changes in brain activity which can be recorded by electroencephalogram (EEG). These include changes in the EEG markers of error-related negativity (ERN) and correct-response negativity (CRN), both believed to reflect response monitoring and attentional control pathophysiology in anxiety. The aim of this review was to systematically assess the research on ERN and CRN in attentional control in individuals with clinical anxiety and healthy controls, across emotional and non-emotional attentional control., Methods: A comprehensive literature search was conducted for studies published prior to October 22 nd , 2020. Details of the protocol for this systematic review were registered on PROSPERO (CRD42019144885)., Results: 66 studies had their data extracted. All 66 studies measured ERN, with 85% finding significantly increased ERN amplitudes associated with clinical anxiety. Only 44 of the extracted studies analysed CRN and only ~20% of these found significant changes in CRN amplitude associated with individuals with clinical anxiety., Limitations: There were several anxiety disorders that had either limited literature (i.e. specific phobia, separation anxiety disorder or agoraphobia) or nil literature (i.e. selective mutism) available. No extracted studies included samples of older adults (i.e. aged 60+ years), and only six extracted studies included measures of emotional attentional control., Conclusions: Findings indicate the promising utility of ERN of attentional control as a robust, transdiagnostic trait marker of clinical anxiety., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Cognitive impairment is highly prevalent in schizophrenia and treatment options are severely limited. A greater understanding of the pathophysiology of impaired cognition would have broad implications, including for the development of effective treatments. In the current study we used a multimodal approach to identify neurophysiological markers of cognitive impairment in schizophrenia. Fifty-seven participants (30 schizophrenia, 27 controls) underwent neurobiological assessment (electroencephalography [EEG] and Transcranial Magnetic Stimulation combined with EEG [TMS-EEG]) and assessment of cognitive functioning using an n-back task and the MATRICS Consensus Cognitive Battery. Neurobiological outcome measures included oscillatory power during a 2-back task, TMS-related oscillations and TMS-evoked potentials (TEPs). Cognitive outcome measures were d prime and accurate reaction time on the 2-back and MATRICS domain scores. Compared to healthy controls, participants with schizophrenia showed significantly reduced theta oscillations in response to TMS, and trend level decreases in task-related theta and cortical reactivity (i.e. reduced N100 and N40 TEPs). Participants with schizophrenia also showed significantly impaired cognitive performance across all measures. Correlational analysis identified significant associations between cortical reactivity and TMS-related oscillations in both groups; and trend level associations between task-related oscillations and impaired cognition in schizophrenia. The current study provides experimental support for possible neurophysiological markers of cognitive impairment in schizophrenia. The potential implications of these findings, including for treatment development, are discussed., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: Considerable research has demonstrated the efficacy of repetitive transcranial magnetic stimulation treatment (rTMS) in patients with major depressive disorder (MDD) with differences in effects related to laterality of stimulation. However, no systematic research has explored whether left-handed subjects respond in the same way as right-handed subjects., Methods: Data from 6 clinical trials ( n  = 310) were pooled and we explored whether left-handed patients with MDD responded in a similar manner to rTMS, including how they responded to both high-frequency left and low-frequency right-sided forms of treatment., Results: Overall, patients with MDD who were left-handed responded to a greater degree than right-handed patients to rTMS therapy. On subgroup analysis, notably limited by small numbers in the left handed groups, this effect was seen with high-frequency left-sided treatment but not with low-frequency right-sided treatment. The overall effect of a greater response in left-handed patients was not attributable to other clinical or study variables., Conclusions: Standard forms of rTMS treatment appear to be effective in patients with MDD who are left-handed and there seems no justification for modifying the laterality of treatment application in these patients.

Background: Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for depression but a standard course can be time-consuming. Of all rTMS protocols, high-frequency rTMS (HF rTMS) is the most studied and applied in clinical settings. Little is known about applying multiple sessions of HF rTMS per day, in so-called accelerated schedules., Methods: We systematically searched electronic records up to September 2019 for studies that applied HF rTMS in accelerated schedules to treat depression to review its efficacy, efficiency and safety. Treatment effect sizes of accelerated rTMS versus standard and sham rTMS were calculated from comparison studies and pooled to derive overall treatment effect., Results: Of 1,361 records screened, 12 met review criteria. Qualitative synthesis suggested accelerated HF rTMS was equally effective as once-daily scheduling in treating depression. It is equivocal if accelerated HF rTMS results in more rapid antidepressant response. Accelerated HF rTMS was well-tolerated. The small number of studies suitable for quantitative analysis led to pooled effect sizes that did not reach statistical significance., Limitations: There was an overall paucity of studies examining the accelerated application of HF rTMS and even fewer studies comparing accelerated HF rTMS with once-daily or sham rTMS., Conclusion: Our review found comparable antidepressant efficacy between accelerated and once-daily HF rTMS. Between group differences in therapeutic effect sizes were not clinically meaningful. More studies investigating accelerated rTMS protocols are needed to validate its utility and guide clinical decision making., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Transcranial direct current stimulation (tDCS) has been shown to improve working memory (WM) performance in healthy individuals, however effects tend to be modest and variable. Transcranial random noise stimulation (tRNS) can be delivered with a direct-current offset (DC-offset) to induce equal or even greater effects on cortical excitability than tDCS. To-date, no research has directly compared the effects of these techniques on WM performance or underlying neurophysiological activity., Objective: To compare the effects of anodal tDCS, tRNS + DC-offset, or sham stimulation over the left dorsolateral prefrontal cortex (DLPFC) on WM performance and task-related EEG oscillatory activity in healthy adults., Methods: Using a between-subjects design, 49 participants were allocated to receive either anodal tDCS (N = 16), high-frequency tRNS + DC-offset (N = 16), or sham stimulation (N = 17) to the left DLPFC. Changes in WM performance were assessed using the Sternberg WM task completed before and 5- and 25-min post-stimulation. Event-related synchronisation/desynchronisation (ERS/ERD) of oscillatory activity was analysed from EEG recorded during WM encoding and maintenance., Results: tRNS induced more pronounced and consistent enhancements in WM accuracy when compared to both tDCS and sham stimulation. Improvements in WM performance following tRNS were accompanied by increased theta ERS and diminished gamma ERD during WM encoding, which were significantly greater than those observed following anodal tDCS or sham stimulation., Conclusions: These findings demonstrate the potential of tRNS + DC-offset to modulate cognitive and electrophysiological measures of WM and raise the possibility that tRNS + DC-offset may be more effective and reliable than tDCS for enhancing WM performance in healthy individuals., Competing Interests: Declaration of competing interest This work was supported by a National Health and Medical Research Council (NHMRC) fellowship held by RAS (grant number: 1036201). OWM was supported by an Australian Government Research Training Program (RTP) Scholarship. PBF is supported by an NHMRC Practitioner Fellowship (1078567). PBF has received equipment for research from MagVenture A/S, Medtronic Ltd, Neuronetics and Brainsway Ltd and funding for research from Neuronetics and Cervel Neurotech. He is on scientific advisory boards for Bionomics Ltd and LivaNova. All other authors have no conflicts to report., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Schizophrenia is characterised by delusions, hallucinations, anhedonia and apathy; while impairments in social cognition are often less recognised. Poor social cognition can lead to difficulties in obtaining and maintaining employment, academic progression, interpersonal relationships, and community functioning. Current interventions are highly intensive, require significant resources and have only modest effects on functional outcomes. Virtual reality (VR) and non-invasive brain stimulation (NIBS) may have a role in addressing these limitations. VR allows treatments that are potentially more accessible, less delivery intensive, and have higher ecological validity. While NIBS is able to directly modulate activity in social brain areas in order to promote neuroplasticity, strengthen neural connections and enhance brain function related to social cognitive behaviours. Therefore, the combination of VR and NIBS may allow for more efficient and transferrable interventions than those currently available. This review will explore the potential role of these technologies in the treatment of social cognitive impairment., Competing Interests: Declarations of Competing Interest PBF has received equipment for research from Brainsway Ltd, Medtronic Ltd and MagVenture A/S and funding for research from Neuronetics Ltd. He is on scientific advisory boards for Bionomics Ltd and LivaNova and is a founder of TMS Clinics Australia., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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: Investigating approaches for determining a functionally meaningful dorsolateral prefrontal cortex (DLPFC) stimulation site is imperative for optimising repetitive transcranial magnetic stimulation (rTMS) response rates for treatment-resistant depression. One proposed approach is neuro-cardiac-guided rTMS (NCG-TMS) in which high frequency rTMS is applied to the DLPFC to determine the site of greatest heart rate deceleration. This site is thought to index a frontal-vagal autonomic pathway that intersects a key pathway believed to underlie rTMS response., Objective: We aimed to independently replicate previous findings of high-frequency NCG-TMS and extend it to evaluate the use of low-frequency rTMS for NCG-TMS., Methods: Twenty healthy participants (13 female; aged 38.6 ± 13.9) underwent NCG-TMS on frontal, fronto-central (active) and central (control) sites. For high-frequency NCG-TMS, three 5 s trains of 10 Hz were provided at each left hemisphere site. For low-frequency NCG-TMS, 60 s trains of 1 Hz were applied to left and right hemispheres and heart rate and heart rate variability outcome measures were analysed., Results: For high-frequency NCG-TMS, heart rate deceleration was observed at the left frontal compared with the central site. For low-frequency NCG-TMS, accelerated heart rate was found at the right frontal compared with central sites. No other site differences were observed., Conclusion: Opposite patterns of heart rate activity were found for high- and low-frequency NCG-TMS. The high-frequency NCG-TMS data replicate previous findings and support further investigations on the clinical utility of NCG-TMS for optimising rTMS site localisation. Further work assessing the value of low-frequency NCG-TMS for rTMS site localisation is warranted., Competing Interests: Declaration of competing interest PBF has received equipment for research from MagVenture A/S, Medtronic Ltd, Neuronetics and Brainsway Ltd and funding for research from Neuronetics. He is on scientific advisory boards for Bionomics Ltd and LivaNova and is a founder of TMS Clinics Australia. MA reports options from Brain Resource (Sydney, Australia), is unpaid research director of the Brainclinics Foundation, a minority shareholder in neuroCare group (Munich, Germany); TAI and MA are co-inventor on a patent application covering NCG-TMS, but do not own the patent nor receive any royalties related to this patent; Research Institute Brainclinics received research funding from Brain Resource (Sydney, Australia) and neuroCare group (Munich, Germany); equipment support from Deymed, neuroConn and MagVenture, however data analyses and writing of this manuscript were unconstrained. We have no other conflicts of interest to declare., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Repetitive transcranial magnetic stimulation treatment (rTMS) is an effective treatment for depression but the optimal methods of administration have yet to be determined. In particular, it is unclear whether there is a relationship between elements of the dose of stimulation (i.e., number of pulses) and clinical response. To address one aspect of dose, we conducted a trial comparing standard and high dose versions of high frequency left sided and low frequency right sided rTMS protocols (left standard = 50 trains, left high = 125 trains, right standard = 20 min, right high = 60 min, all per day in a single session)., Method: 300 patients with treatment resistant depression were enrolled in a four arm randomized controlled trial across a four week time period. The primary outcome assessment was a comparison of response and remission rates on data from the 17-item Hamilton Rating Scale for Depression Rating Scale (HRSD-17)., Results: The rate of response exceeded 45% in all groups. There was no significant difference between groups on initial analysis of the primary or secondary outcome measures (response rates: standard left = 52.5%, high left = 47.3%, standard right = 49.1%, high right = 48.4%). There was a greater remission rate with high compared to moderate dose left sided treatment when controlling for illness duration. We also found significant improvements in quality of life across all treatment groups. Illness duration was weakly associated with response., Conclusions: There was no consistent association between the antidepressant effect of rTMS and the number of TMS pulses provided across the ranges investigated in this study. Increasing TMS pulse number in individual sessions seems unlikely to be a method to substantially improve clinical outcomes, and future research should explore alternative means of improving clinical response. The study was registered on the Australian and New Zealand Clinical Trials Register (ACTRN12612000321842) https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=362063&isReview=true., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Cognitive impairment is a prevalent non-motor feature of Parkinson's disease (PD) which can present even in early stages of the disease. Impairments in executive processing and working memory (WM) are common and have been attributed, in part, to abnormalities within the dorsolateral prefrontal cortex (DLPFC) and broader fronto-striatal circuitry. Previous studies in cognitively normal adults have suggested intermittent Theta Burst Stimulation (iTBS), an excitatory plasticity-inducing non-invasive brain stimulation technique, can enhance these cognitive functions. Fourteen participants with a diagnosis of idiopathic PD received either Active or Sham iTBS over the left DLPFC across two separate experimental sessions as part of a double-blind sham-controlled crossover experimental design. The Berg's Card Sorting Test (BCST) and N-Back tasks, which measure executive function and WM respectively, were administered prior to iTBS and again five- and 30-minutes following stimulation. Despite being well-tolerated, iTBS failed to modulate performance on any of the cognitive outcome measures. This finding was further supported by Bayes Factor analyses which indicated moderate levels of support for the null hypothesis overall. This initial pilot study therefore does not support single-session iTBS as an efficacious method for modulating either executive processes or WM in PD. We discuss potential reasons for this finding along with directions for future research., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Introduction: Accelerated or intensive forms of repetitive transcranial magnetic stimulation (rTMS) are increasingly being explored for their potential to produce more efficient and rapid treatment benefits in major depressive disorder (MDD). However, accelerated or intensive protocols using standard forms of rTMS are still quite time-consuming to apply. Theta burst stimulation (TBS) is a novel form of magnetic stimulation with the potential to produce similar anti-depressant effects but in a much abbreviated period of time. The aim of this study was to investigate the comparative efficacy of an intensive TBS protocol compared to standard rTMS treatment., Methods: 74 outpatients (36 female, mean age 44.36 ± 12.1 years) with MDD received either intensive TBS (3 intermittent TBS treatments per day for 3 days in week 1, 3 treatments a day for 2 days in week 2, and 3 treatments in 1 day in week 3 and in week 4, or standard rTMS (5 daily sessions per week for 4 weeks). Patients were assessed weekly throughout the treatment course, and at 4 weeks after treatment end., Results: There were no significant differences in the degree of reduction in depressive symptoms, the rate of reduction in depressive symptoms, remission or response rates (response rates = 27.8% for intensive group, 26.3% for the standard group, p > 0.05 for all analyses) between the intensive TBS and standard rTMS treatment groups. However, the overall response and remission rates were limited in both groups. There was no difference in rates of side effects, no serious adverse events and no alterations in cognitive performance., Conclusion: Intensively applied TBS appears to have similar efficacy to standard rTMS when these were applied as delivered in this study but does not produce more rapid clinical benefits. The overall response rates in both groups in this study were limited, most likely by the total doses provided in both study arms., Clinical Trials Registration: Australian New Zealand Clinical Trials Registry: ACTRN12616000443493., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: To investigate neural oscillatory activity supporting working memory (WM) processing in depressed individuals and healthy controls., Methods: Forty-six participants with Major Depressive Disorder (MDD) and 41 healthy controls balanced on age, gender, and WM ability completed a Sternberg verbal WM task with concurrent electroencephalography recording. Oscillatory activity was calculated for upper alpha, theta, and gamma frequency bands during WM encoding and maintenance., Results: WM performance did not differ between groups. When compared to healthy controls, depressed individuals displayed reduced frontal-midline theta power and increased occipital upper alpha power during WM encoding, and reductions in frontal-midline theta power and occipital gamma and upper alpha power during WM maintenance. Higher depression severity was associated with greater reductions upper alpha and gamma power during WM maintenance., Conclusions: Depressed individuals displayed prominent alterations in oscillatory activity during WM encoding and maintenance, indicating that the neural processes which support WM processing are altered in MDD even when no cognitive impairments are observed., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Introduction : Major depression is a common and debilitating mental disorder that can be difficult to treat. Substantive evidence over the past two decades has established repetitive transcranial magnetic stimulation (rTMS) as an effective antidepressant therapy, although scope exists to improve its efficacy and efficiency. Theta burst stimulation (TBS) is a novel rTMS pattern attracting much research interest as a tool to study neurophysiology and treat neuropsychiatric disorders. Areas covered : This article outlines rTMS' state of development and explores the physiology studies underpinning TBS development and its observable neuronal conditioning and metabolic effects. We present a systematic review of studies that applied TBS to treat depression, followed by commentary on safety and practical considerations. Expert opinion : Much experimental and clinical research have advanced our understanding of the antidepressant effects of TBS, although unanswered questions remain relating to its physiological effects, response variability and optimal parameters for therapeutic purposes. A small number of sham-controlled trials, and one large comparative trial, support the therapeutic efficacy of TBS and demonstrates its non-inferiority relative to traditional rTMS. In this light, TBS can reasonably be offered as an alternative to rTMS in treatment-resistant depression, while ongoing research is likely to inform its therapeutic potential.

Attention is vital for optimal behavioural performance in every-day life. Mindfulness meditation has been shown to enhance attention. However, the components of attention altered by meditation and the related neural activities are underexplored. In particular, the contributions of inhibitory processes and sustained attention are not well understood. To address these points, 34 meditators were compared to 28 age and gender matched controls during electroencephalography (EEG) recordings of neural activity during a Go/Nogo response inhibition task. This task generates a P3 event related potential, which is related to response inhibition processes in Nogo trials, and attention processes across both trial types. Compared with controls, meditators were more accurate at responding to Go and Nogo trials. Meditators showed a more frontally distributed P3 to both Go and Nogo trials, suggesting more frontal involvement in sustained attention rather than activity specific to response inhibition. Unexpectedly, meditators also showed increased positivity over the right parietal cortex prior to visual information reaching the occipital cortex (during the pre-C1 window). Both results were positively related to increased accuracy across both groups. The results suggest that meditators show altered engagement of neural regions related to attention, including both higher order processes generated by frontal regions, and sensory anticipation processes generated by poster regions. This activity may reflect an increased capacity to modulate a range of neural processes in order to meet task requirements. This increased capacity may underlie the improved attentional function observed in mindfulness meditators., Competing Interests: PBF has received equipment for research from MagVenture A/S, Medtronic Ltd, Cervel Neurotech and Brainsway Ltd and funding for research from Neuronetics and Cervel Neurotech. PBF is on the scientific advisory board for Bionomics Ltd. All other authors have no conflicts to report. PBF is supported by a National Health and Medical Research Council of Australia Practitioner Fellowship (6069070). KEH is supported by a National Health and Medical Research Council of Australia Career Development Fellowship (1082894). NCR is supported by a National Health and Medical Research Council of Australia Fellowship (1072057). This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Anxiety symptoms are common in major depressive disorder. Whilst therapeutic efficacy of repetitive transcranial magnetic stimulation (rTMS) in depression is well-established, minimal research has investigated rTMS's efficacy in treating anxiety symptoms in depression., Methods: This study investigates the effectiveness of rTMS in treating anxiety symptoms in depression, specifically the relative efficacy of the three rTMS protocols commonly used in clinical practice: left-sided high-frequency, right-sided low-frequency and sequential bilateral rTMS. Antidepressant efficacy of each rTMS protocol is also investigated. Treatment data for 697 patients were pooled from three studies across five sites. Changes in Beck's Anxiety Inventory (BAI) and the Hamilton Depression Rating Scale over 4-week rTMS courses were analysed using latent growth curve modelling., Results: All rTMS protocols were effective in treating anxiety symptoms (mean BAI reduction, 8.13 points; p < 0.001) and depressive symptoms. Near therapeutic equivalence was seen across the three protocols. Improvement in depressive severity positively correlated with improvement in anxiety. Both high- and low-baseline anxiety scores showed overall symptom reduction., Conclusions: This study addresses the clinical knowledge gap pertaining to rTMS's therapeutic efficacy in treating anxiety symptoms in depression and the relative efficacy of three commonly used stimulation protocols. Our findings suggest therapeutic equivalence across left-sided high-frequency, right-sided low-frequency, and sequential bilateral rTMS approaches., (© 2019 Wiley Periodicals, Inc.)

Depression following a traumatic brain injury (TBI) is common and difficult to treat using standard approaches. The current study investigated, for the first time, transcranial magnetic stimulation (TMS) for the treatment of post TBI depression. We specifically assessed the safety, tolerability, and efficacy of TMS in this patient population. We also explored cognitive outcomes. Twenty-one patients with a current episode of major depression subsequent to a TBI participated in a randomized double-blind placebo-controlled trial of repetitive TMS (rTMS). Sequential bilateral rTMS (to the left and right dorsolateral prefrontal cortex) was provided in 20 treatments over a period of 4 weeks. Patients were randomly allocated to receive either active or sham stimulation. There were no adverse effects and treatment was well tolerated. There was no significant effect of rTMS on post-TBI depression, with all patients showing a significant improvement in depressive symptoms irrespective of their treatment group ( p  = 0.002). There were significant improvements in cognition following active rTMS in the areas of working memory ( p  = 0.021) and executive function ( p  = 0.029). rTMS was shown to be safe and well tolerated in patients who had developed depression after a TBI. We did not find a therapeutic effect for post-TBI depression; however, this approach may have some utility in improving cognitive function. Future research should focus on alternative rTMS treatment approaches for post-TBI depression and the direct investigation of rTMS as a treatment for cognitive impairment in TBI.

Low-frequency and high-frequency repetitive transcranial magnetic stimulation (rTMS) are similarly efficacious for treatment-resistant depression. Low-frequency is posited to be better tolerated than high-frequency rTMS, however, this is not supported by empirical evidence to date. This study aimed to quantify and compare the tolerability of low-versus high-frequency rTMS. Twenty healthy participants (mean age 38.6 ± 13.9 years) underwent low- and high-frequency rTMS administered on left frontal, fronto-central and central sites at 100% resting motor threshold. For the low-frequency protocol, 60 s of 1 Hz stimulation was applied at each site and for the high-frequency protocol, 3 × 5 s trains of 10 Hz stimulation with a 30 s inter-train interval were applied at each site. Tolerance for each stimulation type was assessed immediately after stimulation through participant ratings of overall intensity of scalp sensations, pain, muscle twitching, discomfort and any other sensation. Low-frequency rTMS was significantly less intense than high-frequency rTMS in overall intensity, pain, muscle twitching (all p < .01) and discomfort (p < .001). Limitations of this study include the healthy participant sample and administration of a single session of rTMS. While further work is needed in clinical samples using typical rTMS treatment protocols, these data provide the first evidence that low-frequency is better tolerated than high-frequency. These findings may inform clinical practice of rTMS treatment for depression (and other illnesses) by supporting the application of low-frequency protocols., (Copyright © 2019. Published by Elsevier Ltd.)

Transcranial direct current stimulation (tDCS) provides a means of non-invasively inducing plasticity-related changes in neural circuits in vivo and is experiencing increasing use as a potential tool for modulating brain function. There is growing evidence that tDCS-related outcomes are likely to be influenced by an individual's brain state at the time of stimulation, i.e., effects show a degree of 'state-dependency'. However, few studies have examined the behavioural and physiological impact of state-dependency within cognitively salient brain regions. Here, we applied High-Definition tDCS (HD-tDCS) over the left dorsolateral prefrontal cortex (DLPFC) in 20 healthy participants, whilst they either remained at rest, or performed a cognitive task engaging working memory (WM). In a third condition sham stimulation was administered during task performance. Neurophysiological changes were probed using TMS-evoked potentials (TEPs), event-related potentials (ERPs) recorded during n-back WM tasks, and via resting-state EEG (RS-EEG). From a physiological perspective, our results indicate a degree of neuromodulation following HD-tDCS, regardless of task engagement, as evidenced by changes in TEP amplitudes following both active stimulation conditions. Changes in ERP (P3) amplitudes were also observed for the 2-Back task following stimulation delivered during task performance only. However, no changes were seen on RS-EEG for any condition, nor were any group-level effects of either stimulation condition observed on n-back performance. As such, these findings paint a complex picture of neural and behavioural responses to prefrontal stimulation in healthy subjects and provide only limited support for state-dependent effects of HD-tDCS over the DLPFC overall., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Transcranial direct current stimulation (tDCS) has been investigated as a way to improve motor and cognitive functioning, with largely variable results. Currently, relatively little is known about the neurobiological effects, and possible drivers of variability, in either healthy or clinical populations. Therefore, this study aimed to characterise the neurobiological effects to tDCS in younger adults, older adults and adults with mild cognitive impairment (MCI), and their relationship to cognitive performance. 20 healthy younger adults, 20 healthy older adults and 9 individuals with MCI participated in the study. All completed neuropsychological tasks and TMS-EEG, prior to and following delivery of 20 min of anodal tDCS to the left dorsolateral prefrontal cortex (DLPFC). EEG was also recorded during the 2-Back working memory task. Following tDCS, younger adults demonstrated alterations in early TMS-Evoked Potentials (TEPs), namely P30 and P60. Both younger and older adults exhibited a larger task-related N250 amplitude after stimulation, with contrasting relationships to cognitive performance. The MCI group showed no change in TEPs or ERPs over time. Comparisons between the groups revealed differences in the change in amplitude of early TEP (P60) and ERP (N100) peaks between younger and older adults. Our findings indicate that tDCS was able to modulate cortical activity in younger and older healthy adults, but in varying ways. These findings suggest that varied response to tDCS may be related to factors such as age and the presence/absence of cognitive impairment, and these factors should be considered when assessing the effectiveness of tDCS in healthy and pathological aging., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Recent studies have highlighted variability in response to theta burst stimulation (TBS) in humans. TBS paradigm was originally developed in rodents to mimic gamma bursts coupled with theta rhythms, and was shown to elicit long-term potentiation. The protocol was subsequently adapted for humans using standardised frequencies of stimulation. However, each individual has different rhythmic firing pattern. The present study sought to explore whether individualised intermittent TBS (Ind iTBS) could outperform the effects of two other iTBS variants. Twenty healthy volunteers received iTBS over left prefrontal cortex using 30 Hz at 6 Hz, 50 Hz at 5 Hz, or individualised frequency in separate sessions. Ind iTBS was determined using theta-gamma coupling during the 3-back task. Concurrent use of transcranial magnetic stimulation and electroencephalography (TMS-EEG) was used to track changes in cortical plasticity. We also utilised mood ratings using a visual analogue scale and assessed working memory via the 3-back task before and after stimulation. No group-level effect was observed following either 30 or 50 Hz iTBS in TMS-EEG. Ind iTBS significantly increased the amplitude of the TMS-evoked P60, and decreased N100 and P200 amplitudes. A significant positive correlation between neurophysiological change and change in mood rating was also observed. Improved accuracy in the 3-back task was observed following both 50 Hz and Ind iTBS conditions. These findings highlight the critical importance of frequency in the parameter space of iTBS. Tailored stimulation parameters appear more efficacious than standard paradigms in neurophysiological and mood changes. This novel approach presents a promising option and benefits may extend to clinical applications., (© 2018 Wiley Periodicals, Inc.)

The utility of key phenotypes of depression in predicting response to repetitive transcranial magnetic stimulation (rTMS), namely sleep-wake behaviour, cognition and illness chronicity, has been understudied and not been extended to young samples. This study aimed to determine whether sleep-wake disturbance, cognition or depression chronicity are associated with rTMS outcome in young depressed adults. Sixteen depressed young adults diagnosed with mood disorders (aged 18-29 years) completed this open-label study. Neuronavigationally targeted high-frequency rTMS was administered at 110% of motor threshold on the left dorsolateral prefrontal cortex for 20 sessions over 4 weeks. Clinical, sleep-wake and cognitive assessments were undertaken pre- and post-treatment. Repeated-measures and correlational analyses determined pre- and post-treatment changes and predictors of treatment outcome. rTMS significantly reduced depression and anxiety. Better cognitive flexibility, verbal learning, later age of onset and greater number of depressive episodes were associated with better treatment outcome. There were no other significant/trend-level associations. rTMS had no effect on sleep-wake or cognitive measures. We provide the first evidence for the utility of cognitive flexibility and verbal learning in predicting rTMS outcome in depressed young adults. This research provides preliminary support for rTMS as an early intervention for depression and supports the need for sham-controlled trials., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Previous research has typically focussed on the neuromodulatory effects of direct currents applied over single regions of the cortex. However, complex processes such as working memory (WM) strongly rely on activations across a wider neural network and therefore might benefit from stimulation administered over multiple cortical targets., Objective: We examined the neurobiological and cognitive effects of High-Definition transcranial direct current stimulation (HD-tDCS) montages that either targeted the dorsolateral prefrontal cortex (DLPFC) alone, or simultaneously stimulated the DLPFC and parietal cortex (DLPFC + PC)., Methods: In a within-subjects design, 16 healthy participants completed three experimental sessions in which they received HD-tDCS over either the DLPFC, the DLPFC + PC or sham stimulation. Changes in cortical reactivity were examined using transcranial magnetic stimulation combined with electroencephalography (TMS-EEG), while oscillatory power was measured via EEG recorded during n-back tasks. WM performance was also examined across several separate tasks., Results: Stimulation using both the DLPFC or DLPFC + PC montages modulated cortical reactivity, as indexed by potentiation of the P60 TMS-evoked potential. However, only the dual-site DLPFC + PC stimulation produced a reduction in the amplitude of the N100 component, relative to baseline. Increases in theta and gamma power were also observed following this montage, when compared to baseline, but were not present following HD-tDCS over the DLPFC alone. Despite these neurophysiological changes, WM performance was not significantly modulated by HD-tDCS, regardless of stimulation montage., Conclusion: These results provide important initial insight into the behavioural and biological effects of stimulation over key cortical regions linked to WM and attest to the sensitivity of TMS-EEG and EEG in detecting subtle neurophysiological changes induced by HD-tDCS., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The pathophysiology associated with mild traumatic brain injury (mTBI) includes neurometabolic and cytoskeletal changes that have been shown to impair structural and functional connectivity. Evidence that persistent neuropsychological impairments post injury are linked to structural and functional connectivity changes is increasing. However, to date the relationship between connectivity changes, heterogeneity of persistent symptoms and recovery post mTBI has been poorly characterised. Recent innovations in neuroimaging provide new ways of exploring connectivity changes post mTBI. Namely, combined transcranial magnetic stimulation and electroencephalography (TMS-EEG) offers several advantages over traditional approaches for studying connectivity changes post TBI. Its ability to perturb neural function in a controlled manner allows for measurement of causal interactions or effective connectivity between brain regions. We review the current literature assessing structural and functional connectivity following mTBI and outline the rationale for the use of TMS-EEG as an ideal tool for investigating the neural substrates of connectivity dysfunction and reorganisation post mTBI. The diagnostic, prognostic and potential therapeutic implications will also be explored., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Fibromyalgia is a complex chronic disorder with few effective treatments currently available. One promising treatment option is repetitive transcranial magnetic stimulation (rTMS), a non-invasive brain stimulation technique that has shown promise in disorders effecting the central nervous system., Methods: We assessed the efficacy of a course of high-frequency (10 Hz) left-hemisphere dorsolateral prefrontal cortex (DLPFC) rTMS in 26 patients (14 active; 12 sham) with a diagnosis of fibromyalgia. Participants underwent a double-blind stimulation protocol of daily (Monday-Friday) rTMS sessions over four consecutive weeks (total of 20 sessions; 75 × 4-s 10 Hz trains at 120% resting motor threshold). Assessments were conducted at baseline, 4 weeks and at 1-month follow-up., Results: Using mixed-model analysis we did not identify a group difference for our primary outcome measures. However, we found that patients in the active group compared to sham treatment group had significantly greater improvement in the Physical Fatigue (p = 0.045) and General Fatigue (p = 0.023) scales of the Multidimensional Fatigue Inventory-20 at the 1 month follow-up. In a responder analysis, we also found the active group was significantly more likely (2.84 times) to achieve a minimum 30% improvement in pain intensity ratings. (p = 0.024)., Conclusions: High-frequency rTMS applied daily for 4 weeks to the left DLPFC induces significant relief from fatigue and a greater chance of clinically meaningful improvement in pain intensity in patients with fibromyalgia. These results suggest DLPFC rTMS may be a relevant therapy for fibromyalgia., Significance: This study provides evidence that 4-weeks of daily rTMS to the left DLPFC is able to improve fatigue in fibromyalgia. This novel finding provides impetus for the further investigation of the utility of TMS approaches for the relief of fatigue, an otherwise difficult-to-treat symptom, in fibromyalgia and related disorders., (© 2018 European Pain Federation - EFIC®.)

Repetitive transcranial magnetic stimulation (rTMS) is increasingly used clinically in the treatment of patients with major depressive disorder (MDD). However, rTMS treatment response can be slow. Early research suggests that accelerated forms of rTMS may be effective but no research has directly evaluated a schedule of accelerated rTMS compared to standard rTMS. To assess the efficacy of accelerated rTMS compared to standard daily rTMS., 115 outpatients with MDD received either accelerated rTMS (n = 58) (i.e., 63,000 high frequency rTMS pulses delivered as 3 treatments per day over 3 days in week 1, 3 treatments over 2 days in week 2 and 3 treatments on a single day in week 3) or standard rTMS (n = 57) (i.e., 63,000 total high frequency rTMS pulses delivered over 5 days per week for 4 weeks) following randomization. There were no significant differences in remission or response rates (p > 0.05 for all analyses) or reduction in depression scores (Time by group interaction (F (5, 489.452) = 1.711, p = 0.130) between the accelerated and standard rTMS treatment groups. Accelerated treatment was associated with a higher rate of reported treatment discomfort. It is feasible to provide accelerated rTMS treatment for outpatients with depression and this is likely to produce meaningful antidepressant effects.

Background: With an increasing interest in the use of theta burst stimulation (TBS) as a cognitive enhancer and a potential therapeutic tool for psychiatric disorders, there is a need to identify optimal parameters of TBS in the prefrontal cortex., Objective/hypothesis: This study examined the effect of two blocks of prefrontal intermittent TBS (iTBS) on cortical reactivity and working memory performance, compared to one block of iTBS and sham stimulation. We hypothesized that greater cortical effects would be obtained with two blocks of iTBS., Methods: Eighteen healthy participants attended three experimental sessions and received either sham, one block or two blocks of iTBS with a 15-min interval. Concurrent transcranial magnetic stimulation with electroencephalography (TMS-EEG) was used to assess the change in cortical reactivity via TMS-evoked potentials. Working memory performance was assessed using the N-back task. Cluster-based permutation statistics and two-way ANOVAs were used for neurophysiological and behavioural data, respectively., Results: Both single and two blocks of iTBS resulted in a significant increase in the amplitude of TMS-evoked N100 and P200. No significant differences were observed between active conditions in either neurophysiological changes or working memory performance, and both failed to improve working memory performance relative to sham., Conclusions: Two blocks of iTBS did not result in stronger measured effects as compared to one block of iTBS. Future studies are needed to identify the optimal stimulation pattern in order to achieve a desired effect. It is also important to establish the best approach in quantifying neuromodulatory effects targeting the prefrontal cortex., (Copyright © 2018 Elsevier Inc. All rights reserved.)