Publications by authors named "Paul B Fitzgerald"

415 Publications

Investigating Neurophysiological Markers of Symptom Severity in Alzheimer's Disease.

J Alzheimers Dis 2021 Nov 18. Epub 2021 Nov 18.

Epworth Centre for Innovation in Mental Health, Epworth Healthcare and Monash University Department of Psychiatry, Camberwell, Victoria, Australia.

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 a multimodal neurophysiological approaches to investigate potential therapeutic targets in AD. Suggestions for future research are discussed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JAD-210401DOI Listing
November 2021

Translating Psychedelic Therapies From Clinical Trials to Community Clinics: Building Bridges and Addressing Potential Challenges Ahead.

Front Psychiatry 2021 4;12:737738. Epub 2021 Nov 4.

University Centre for Rural Health, The University of Sydney, Lismore, NSW, Australia.

Research exploring the potential of psychedelic-assisted therapies to treat a range of mental illnesses is flourishing, after the problematic sociopolitical history of psychedelics led to the shutdown of clinical research for almost 40 years. Encouraged by positive results, clinicians and patients are now hopeful that further interruptions to research will be avoided, so that the early promise of these therapies might be fulfilled. At this early stage of renewed interest, researchers are understandably focusing more on clinical trials to investigate safety and efficacy, than on longer-term goals such as progression to community practice. Looking to identify and avoid potential pitfalls on the path to community clinics, the authors, a group of Australian clinicians and researchers, met to discuss possible obstacles. Five broad categories of challenge were identified: 1) inherent risks; 2) poor clinical practice; 3) inadequate infrastructure; 4) problematic perceptions; and 5) divisive relationships and fractionation of the field. Our analysis led us to propose some strategies, including public sector support of research and training to establish best practice and optimize translation, and funding to address issues of equitable access to treatment. Above all, we believe that strategic planning and professional cohesion will be crucial for success. Accordingly, our key recommendation is the establishment of a multidisciplinary advisory body, broadly endorsed and representing all major stakeholders, to guide policy and implementation of psychedelic-assisted therapies in Australia. Although these challenges and strategies are framed within the Australian context, we sense that they may generalize to other parts of the world. Wherever they apply, we believe that anticipation of potential difficulties, and creative responses to address them, will be important to avoid roadblocks in the future and keep the "psychedelic renaissance" on track.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fpsyt.2021.737738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8599345PMC
November 2021

EEG-connectivity: A fundamental guide and checklist for optimal study design and evaluation.

Biol Psychiatry Cogn Neurosci Neuroimaging 2021 Nov 2. Epub 2021 Nov 2.

Epworth Centre for Innovation in Mental Health, Department of Psychiatry, Central Clinical School, Monash University, Epworth HealthCare, 888 Toorak Rd, Camberwell, Victoria 3124, Australia.

Brain connectivity can be estimated through many analyses applied to electroencephalographic (EEG) data. However, substantial heterogeneity in the implementation of connectivity methods exist. Heterogeneity in conceptualization of connectivity measures, data collection, or data pre-processing may be associated with variability in robustness of measurement. While it is difficult to compare the results of studies using different EEG connectivity measures, standardization of processing and reporting may facilitate the task. We discuss how factors such as referencing, epoch length and number, controls for volume conduction, artefact removal, and statistical control of multiple comparisons influence the EEG connectivity estimate for connectivity measures, and what can be done to control for potential confounds associated with these factors. Based on the results reported in previous literature, this article presents recommendations and a novel checklist developed for quality assessment of EEG connectivity studies. This checklist and its recommendations are made in an effort to draw attention to factors that may influence connectivity estimates and factors that need to be improved in future research. Standardization of procedures and reporting in EEG connectivity may lead to EEG connectivity studies to be made more synthesisable and comparable despite variations in the methodology underlying connectivity estimates.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bpsc.2021.10.017DOI Listing
November 2021

Continuation Magnetic Seizure Therapy for Treatment-Resistant Unipolar or Bipolar Depression.

J Clin Psychiatry 2021 Oct 19;82(6). Epub 2021 Oct 19.

Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.

Electroconvulsive therapy (ECT) is highly effective for treatment-resistant depression (TRD) but may be associated with adverse cognitive effects. Magnetic seizure therapy (MST) is a promising alternative convulsive treatment with a safer cognitive profile. Although there is emerging evidence for the efficacy of MST for TRD as an acute treatment, there are no published studies of continuation MST for the prevention of relapse.

Patients with TRD with a diagnosis of major depressive disorder or bipolar disorder who met response criteria after acute MST were offered continuation MST in a prospective, open-label trial between February 2012 and June 2019. They received 12 continuation MST sessions with decreasing frequency over the course of 6 months, with additional booster sessions if their depression symptoms started to worsen. The primary outcome was relapse of depression or psychiatric hospitalization. Secondary outcomes included relapse of suicidal ideation and neurocognitive outcomes.

Thirty participants completing at least one assessment during continuation MST were included in the analysis; 10 (33.3%) relapsed, with no significant differences in survival distributions between unipolar and bipolar groups (χ = 0.3,  = .58). Mean (SD) survival time was 18.6 (1.6) weeks. All 17 participants who achieved resolution of baseline suicidality after acute MST remained free of suicidality during the continuation phase. Except for improvement in verbal fluency, neurocognitive test scores did not change during continuation MST.

During 6 months of continuation MST, two-thirds of participants sustained improvements in depressive symptoms without any adverse cognitive effects. Future studies of continuation MST are warranted, particularly in comparison to ECT.

ClinicalTrials.gov identifier: NCT01596608.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4088/JCP.20m13677DOI Listing
October 2021

"Nothing to Lose, Absolutely Everything to Gain": Patient and Caregiver Expectations and Subjective Outcomes of Deep Brain Stimulation for Treatment-Resistant Depression.

Front Hum Neurosci 2021 29;15:755276. Epub 2021 Sep 29.

School of Psychological Sciences, Turner Institute for Brain and Mental Health, Monash University, Clayton, VIC, Australia.

How "success" is defined in clinical trials of deep brain stimulation (DBS) for refractory psychiatric conditions has come into question. Standard quantitative psychopathology measures are unable to capture all changes experienced by patients and may not reflect subjective beliefs about the benefit derived. The decision to undergo DBS for treatment-resistant depression (TRD) is often made in the context of high desperation and hopelessness that can challenge the informed consent process. Partners and family can observe important changes in DBS patients and play a key role in the recovery process. Their perspectives, however, have not been investigated in research to-date. The aim of this study was to qualitatively examine patient and caregivers' understanding of DBS for TRD, their expectations of life with DBS, and how these compare with actual experiences and outcomes. A prospective qualitative design was adopted. Semi-structured interviews were conducted with participants (six patients, five caregivers) before DBS-implantation and 9-months after stimulation initiation. All patients were enrolled in a clinical trial of DBS of the bed nucleus of the stria terminalis. Interviews were thematically analyzed with data saturation achieved at both timepoints. Two primary themes identified were: (1) , and (2) . The decision to undergo DBS was driven by the intolerability of life with severe depression coupled with the exhaustion of all available treatment options. Participants had greater awareness of surgical risks compared with stimulation-related risks. With DBS, patients described cognitive, emotional, behavioral and physical experiences associated with the stimulation, some of which were unexpected. Participants felt life with DBS was like "a roller coaster ride"-with positive, yet unsustained, mood states experienced. Many were surprised by the lengthy process of establishing optimum stimulation settings and felt the intervention was still a "work in progress." These findings support existing recommendations for iterative informed consent procedures in clinical trials involving long-term implantation of neurotechnology. These rich and descriptive findings hold value for researchers, clinicians, and individuals and families considering DBS. Narrative accounts capture patient and family needs and should routinely be collected to guide patient-centered approaches to DBS interventions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnhum.2021.755276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8511461PMC
September 2021

Reply to Hudaib.

Brain Stimul 2021 Nov-Dec;14(6):1587-1588. Epub 2021 Oct 2.

Epworth Centre for Innovation in Mental Health, Epworth Healthcare and Department of Psychiatry, Monash University, Camberwell, Victoria, Australia.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.brs.2021.09.013DOI Listing
October 2021

Antidepressant treatment outcomes in patients with and without comorbid physical or psychiatric disorders: A systematic review and meta-analysis.

J Affect Disord 2021 12 26;295:225-234. Epub 2021 Aug 26.

Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Department of Psychiatry, University of California San Diego School of Medicine, Biomedical Sciences Building, School of Medicine 9500 Gilman Drive, San Diego, California 92093-0603, United States. Electronic address:

Background: Many patients with major depressive disorder (MDD) experience substantial impairment despite the availability of efficacious treatments. We performed a systematic review and meta-analysis to compare antidepressant outcomes in MDD with or without physical or psychiatric comorbidities.

Methods: Pubmed, EMBASE, and PsycInfo were searched up to May 14th, 2020 using keywords including MDD, antidepressant, medication, and comorbid. 1915 studies were reviewed. Studies that performed a direct and quantitative comparison of antidepressant effect in patients with MDD with or without comorbidities were included. Study characteristics and primary outcomes were extracted. Continuous and dichotomous variables were considered using standardized mean difference (SMD). Heterogeneity was measured using χ and I tests. Risk of bias was assessed using Cochrane Risk of Bias tool and NIH Quality Assessment Tool.

Results: 26 studies met selection criteria. Studies of physical (6 studies; I = 57.69%, p = 0.04) and psychiatric comorbidities (20 studies; I = 75.75%, p < 0.001) were heterogeneous. When compared to patients with MDD without comorbidities, those with physical (SMD = -0.19, 95% CI: -0.30 to -0.08, p = 0.001; 1910 and 2905 patients with or without comorbidities) or psychiatric comorbidities (SMD = -0.20, 95% CI: -0.31 to -0.095, p < 0.001; 4308 and 6867 patients with or without comorbidities) had worse antidepressant outcomes.

Limitations: Our limitations included aggregating the comorbidities into physical and psychiatric comorbidities and the high heterogeneity of the studies.

Conclusions: Our review provides updated evidence demonstrating that patients with MDD and physical or psychiatric comorbidities experience worse antidepressant outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jad.2021.08.046DOI Listing
December 2021

The evidence is in: Repetitive transcranial magnetic stimulation is an effective, safe and well-tolerated treatment for patients with major depressive disorder.

Aust N Z J Psychiatry 2021 Aug 28:48674211043047. Epub 2021 Aug 28.

Discipline of Psychiatry, College of Health and Medicine, University of Tasmania, Hobart, TAS, Australia.

Despite more than 25 years of research establishing the antidepressant efficacy of repetitive transcranial magnetic stimulation, there remains uncertainty about the depth and breadth of this evidence base, resulting in confusion as to where repetitive transcranial magnetic stimulation fits in the therapeutic armamentarium in the management of patients with mood disorders. The purpose of this article is to provide a concise description of the evidence base supporting the use of repetitive transcranial magnetic stimulation in the context of the stages of research that typically accompanies the development of evidence for a new therapy. The antidepressant efficacy for the use of repetitive transcranial magnetic stimulation in the treatment of depression has been established through a relatively traditional pathway beginning with small case series, progressing to single-site clinical trials and then to larger multisite randomised double-blind controlled trials. Antidepressant effects have been confirmed in numerous meta-analyses followed more recently by large network meta-analysis and umbrella reviews, with evidence that repetitive transcranial magnetic stimulation may have greater efficacy than alternatives for patients with treatment-resistant depression. Finally, repetitive transcranial magnetic stimulation has been shown to produce meaningful response and remission rates in real-world samples of greater than 5000 patients. The evidence for the antidepressant efficacy of repetitive transcranial magnetic stimulation therapy is overwhelming, and it should be considered a routine part of clinical care wherever available.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/00048674211043047DOI Listing
August 2021

Repeated Transcranial Magnetic Stimulation for Improving Cognition in Alzheimer Disease: Protocol for an Interim Analysis of a Randomized Controlled Trial.

JMIR Res Protoc 2021 Aug 9;10(8):e31183. Epub 2021 Aug 9.

Warren Center for Actuarial Studies and Research, The Asper School of Business, University of Manitoba, Winnipeg, MB, Canada.

Background: Many clinical trials investigating treatment efficacy require an interim analysis. Recently we have been running a large, multisite, randomized, placebo-controlled, double-blind clinical trial investigating the effect of repetitive transcranial magnetic stimulation (rTMS) treatment for improving or stabilizing the cognition of patients diagnosed with Alzheimer disease.

Objective: The objectives of this paper are to report on recruitment, adherence, and adverse events (AEs) to date, and to describe in detail the protocol for interim analysis of the clinical trial data. The protocol will investigate whether the trial is likely to reach its objectives if continued to the planned maximum sample size.

Methods: The specific requirements of the analytic protocol are to (1) ensure the double-blind nature of the data while doing the analysis, (2) estimate the predictive probabilities of success (PPoSs), (3) estimate the numbers needed to treat, (4) re-estimate the initial required sample size. The initial estimate of sample size was 208. The interim analysis will be based on 150 patients who will be enrolled in the study and finish at least 8 weeks of the study. Our protocol for interim analysis, at the very first stage, is to determine the response rate for each participant to the treatment (either sham or active), while ensuring the double-blind nature of the data. The blinded data will be analyzed by a statistician to investigate the treatment efficacy. We will use Bayesian PPoS to predict the success rate and determine whether the study should continue.

Results: The enrollment has been slowed significantly due to the COVID-19 pandemic and lockdown. Nevertheless, so far 133 participants have been enrolled, while 22 of these have been withdrawn or dropped out for various reasons. In general, rTMS has been found tolerable with no serious AE. Only 2 patients dropped out of the study due to their intolerability to rTMS pulses.

Conclusions: Overall, the study with the same protocol is going as expected with no serious AE or any major protocol deviation.

Trial Registration: ClinicalTrials.gov NCT02908815; https://clinicaltrials.gov/ct2/show/NCT02908815.

International Registered Report Identifier (irrid): DERR1-10.2196/31183.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2196/31183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8386362PMC
August 2021

Examining resting-state functional connectivity in key hubs of the default mode network in chronic low back pain.

Scand J Pain 2021 10 10;21(4):839-846. Epub 2021 Aug 10.

Epworth Centre for Innovation in Mental Health, Epworth HealthCare and Central Clinical School Monash University, Melbourne, VIC, Australia.

Objectives: Changes in brain connectivity have been observed within the default mode network (DMN) in chronic low back pain (CLBP), however the extent of these disruptions and how they may be related to CLBP requires further examination. While studies using seed-based analysis have found disrupted functional connectivity in the medial prefrontal cortex (mPFC), a major hub of the DMN, limited studies have investigated other equally important hubs, such as the posterior cingulate cortex (PCC) in CLBP.

Methods: This preliminary study comprised 12 individuals with CLBP and 12 healthy controls who completed a resting-state functional magnetic resonance imaging (fMRI) scan. The mPFC and PCC were used as seeds to assess functional connectivity.

Results: Both groups displayed similar patterns of DMN connectivity, however group comparisons showed that CLBP group had reduced connectivity between the PCC and angular gyrus compared to healthy controls. An exploratory analysis examined whether the alterations observed in mPFC and PCC connectivity were related to pain catastrophizing in CLBP, but no significant associations were observed.

Conclusions: These results may suggest alterations in the PCC are apparent in CLBP, however, the impact and functional role of these disruptions require further investigation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1515/sjpain-2020-0184DOI Listing
October 2021

Large-scale analysis of interindividual variability in single and paired-pulse TMS data.

Clin Neurophysiol 2021 10 6;132(10):2639-2653. Epub 2021 Jul 6.

Cognitive Neuroscience Unit, School of Psychology, Deakin University, Geelong, Australia.

Objective: This study brought together over 60 transcranial magnetic stimulation (TMS) researchers to create the largest known sample of individual participant single and paired-pulse TMS data to date, enabling a more comprehensive evaluation of factors driving response variability.

Methods: Authors of previously published studies were contacted and asked to share deidentified individual TMS data. Mixed-effects regression investigated a range of individual and study level variables for their contribution to variability in response to single and paired-pulse TMS data.

Results: 687 healthy participant's data were pooled across 35 studies. Target muscle, pulse waveform, neuronavigation use, and TMS machine significantly predicted an individual's single-pulse TMS amplitude. Baseline motor evoked potential amplitude, motor cortex hemisphere, and motor threshold (MT) significantly predicted short-interval intracortical inhibition response. Baseline motor evoked potential amplitude, test stimulus intensity, interstimulus interval, and MT significantly predicted intracortical facilitation response. Age, hemisphere, and TMS machine significantly predicted MT.

Conclusions: This large-scale analysis has identified a number of factors influencing participants' responses to single and paired-pulse TMS. We provide specific recommendations to minimise interindividual variability in single and paired-pulse TMS data.

Significance: This study has used large-scale analyses to give clarity to factors driving variance in TMS data. We hope that this ongoing collaborative approach will increase standardisation of methods and thus the utility of single and paired-pulse TMS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clinph.2021.06.014DOI Listing
October 2021

Accelerated theta burst stimulation for the treatment of depression: A randomised controlled trial.

Brain Stimul 2021 Sep-Oct;14(5):1095-1105. Epub 2021 Jul 29.

Epworth Centre for Innovation in Mental Health, Epworth Healthcare and Department of Psychiatry, Monash University, Camberwell, Victoria, Australia.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.brs.2021.07.018DOI Listing
November 2021

High-frequency rTMS over the dorsolateral prefrontal cortex on chronic and provoked pain: A systematic review and meta-analysis.

Brain Stimul 2021 Sep-Oct;14(5):1135-1146. Epub 2021 Jul 16.

Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Australia.

Background: High-frequency rTMS over the dorsolateral prefrontal cortex (DLPFC) has demonstrated mixed effects on chronic and provoked pain.

Objectives/methods: In this study, a meta-analysis was conducted to characterise the potential analgesic effects of high-frequency rTMS over the DLPFC on both chronic and provoked pain.

Results: A total of 626 studies were identified in a systematic search. Twenty-six eligible studies were included for the quantitative review, among which 17 modulated chronic pain and the remaining investigated the influence on provoked pain. The left side DLPFC was uniformly targeted in the chronic pain studies. While our data identified no overall effect of TMS across chronic pain conditions, there was a significant short-term analgesia in neuropathic pain conditions only (SMD = -0.87). In terms of long-lasting analgesia, there was an overall pain reduction in the midterm (SMD = -0.53, 24.6 days average) and long term (SMD = -0.63, 3 months average) post DLPFC stimulation, although these effects were not observed within specific chronic pain conditions. Surprisingly, the number of sessions was demonstrated to have no impact on rTMS analgesia. In the analysis of provoked pain, our data also indicated a significant analgesic effect following HF-rTMS over the DLPFC (SMD = -0.73). Importantly, we identified a publication bias in the studies of provoked pain but not for chronic pain conditions.

Conclusions: Overall, our findings support that HF-DLPFC stimulation is able to induce an analgesic effect in chronic pain and in response to provoked pain. These results highlight the potential of DLPFC-rTMS in the management of certain chronic pain conditions and future directions are discussed to enhance the potential long-term analgesic effects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.brs.2021.07.004DOI Listing
November 2021

Brain stimulation and brain lesions converge on common causal circuits in neuropsychiatric disease.

Nat Hum Behav 2021 Jul 8. Epub 2021 Jul 8.

Center for Brain Circuit Therapeutics, Brigham and Women's Hospital, Boston, MA, USA.

Damage to specific brain circuits can cause specific neuropsychiatric symptoms. Therapeutic stimulation to these same circuits may modulate these symptoms. To determine whether these circuits converge, we studied depression severity after brain lesions (n = 461, five datasets), transcranial magnetic stimulation (n = 151, four datasets) and deep brain stimulation (n = 101, five datasets). Lesions and stimulation sites most associated with depression severity were connected to a similar brain circuit across all 14 datasets (P < 0.001). Circuits derived from lesions, deep brain stimulation and transcranial magnetic stimulation were similar (P < 0.0005), as were circuits derived from patients with major depression versus other diagnoses (P < 0.001). Connectivity to this circuit predicted out-of-sample antidepressant efficacy of transcranial magnetic stimulation and deep brain stimulation sites (P < 0.0001). In an independent analysis, 29 lesions and 95 stimulation sites converged on a distinct circuit for motor symptoms of Parkinson's disease (P < 0.05). We conclude that lesions, transcranial magnetic stimulation and DBS converge on common brain circuitry that may represent improved neurostimulation targets for depression and other disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41562-021-01161-1DOI Listing
July 2021

Repetitive transcranial magnetic stimulation (rTMS) in autism spectrum disorder: protocol for a multicentre randomised controlled clinical trial.

BMJ Open 2021 07 7;11(7):e046830. Epub 2021 Jul 7.

Central Clinical School, Monash University, Melbourne, Victoria, Australia.

Introduction: There are no well-established biomedical treatments for the core symptoms of autism spectrum disorder (ASD). A small number of studies suggest that repetitive transcranial magnetic stimulation (rTMS), a non-invasive brain stimulation technique, may improve clinical and cognitive outcomes in ASD. We describe here the protocol for a funded multicentre randomised controlled clinical trial to investigate whether a course of rTMS to the right temporoparietal junction (rTPJ), which has demonstrated abnormal brain activation in ASD, can improve social communication in adolescents and young adults with ASD.

Methods And Analysis: This study will evaluate the safety and efficacy of a 4-week course of intermittent theta burst stimulation (iTBS, a variant of rTMS) in ASD. Participants meeting criteria for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition ASD (n=150, aged 14-40 years) will receive 20 sessions of either active iTBS (600 pulses) or sham iTBS (in which a sham coil mimics the sensation of iTBS, but no active stimulation is delivered) to the rTPJ. Participants will undergo a range of clinical, cognitive, epi/genetic, and neurophysiological assessments before and at multiple time points up to 6 months after iTBS. Safety will be assessed via a structured questionnaire and adverse event reporting. The study will be conducted from November 2020 to October 2024.

Ethics And Dissemination: The study was approved by the Human Research Ethics Committee of Monash Health (Melbourne, Australia) under Australia's National Mutual Acceptance scheme. The trial will be conducted according to Good Clinical Practice, and findings will be written up for scholarly publication.

Trial Registration Number: Australian New Zealand Clinical Trials Registry (ACTRN12620000890932).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmjopen-2020-046830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8264904PMC
July 2021

Investigating neurophysiological markers of impaired cognition in schizophrenia.

Schizophr Res 2021 07 2;233:34-43. Epub 2021 Jul 2.

Epworth Centre for Innovation in Mental Health, Epworth Healthcare and Monash University Department of Psychiatry, Camberwell, Victoria, Australia.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.schres.2021.06.025DOI Listing
July 2021

Characterising the optimal pulse number and frequency for inducing analgesic effects with motor cortex rTMS.

Brain Stimul 2021 Sep-Oct;14(5):1081-1083. Epub 2021 Jul 2.

Melbourne Neuropsychiatry Centre, The University of Melbourne, Victoria, Australia, Department of Biomedical Engineering, The University of Melbourne, Victoria, Australia.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.brs.2021.06.015DOI Listing
November 2021

EEG correlates of attentional control in anxiety disorders: A systematic review of error-related negativity and correct-response negativity findings.

J Affect Disord 2021 08 24;291:140-153. Epub 2021 May 24.

Epworth Centre for Innovation in Mental Health, Epworth Healthcare and Department of Psychiatry, Monash University, 888 Toorak Rd, Camberwell, Victoria, Australia.

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, 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jad.2021.04.049DOI Listing
August 2021

Targeting repetitive transcranial magnetic stimulation in depression: do we really know what we are stimulating and how best to do it?

Brain Stimul 2021 May-Jun;14(3):730-736. Epub 2021 Apr 30.

Background: Repetitive transcranial magnetic stimulation (rTMS) is an established treatment for patients with depression who have not achieved optimal outcomes with one or more trials of antidepressant medication. It is an effective antidepressant treatment but there remains considerable scope for improving clinical outcomes. One method to potentially enhance the efficacy of rTMS is through the improvement of methods of stimulation localization.

Objective: The purpose of this paper is to review the literature pertaining to rTMS localization methods and approaches relevant to the treatment of major depressive disorder (MDD) and provide specific opinions on the state of the art in regards to targeting of rTMS treatment in depression.

Methods: A targeted review of the literature on rTMS targeting in depression.

Results: There is emerging evidence that optimal rTMS treatment outcomes are likely to be achieved with stimulation at a relatively anterior stimulation site in the left dorsolateral prefrontal cortex (DLPFC). However, some lines of research suggest that there may be two effective stimulation sites: one quite posterior, and one more anterior, in the DLPFC. The 'Beam F3' method provides reasonable localization to the anterior stimulation site and the posterior stimulation site corresponds to that typically used in studies using the '5 cm method'. Neuro-navigational methods are generally most likely to consistently ensure placement of the TMS coil such that it results in stimulation of a selected cortical site. fMRI - connectivity based approaches to targeting specific circuits in the DLPFC are intellectually attractive but it may not be possible to demonstrate differential effectiveness of these over the methods most commonly been used in clinical practice.

Conclusions: There is an emerging literature helping to improve our understanding of the optimal methods for targeting rTMS treatment for depression. However, we lack substantive prospective clinical trials demonstrating improved clinical outcomes with these techniques.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.brs.2021.04.018DOI Listing
November 2021

Neural activity during cognitive reappraisal in chronic low back pain: a preliminary study.

Scand J Pain 2021 07 12;21(3):586-596. Epub 2021 Apr 12.

Monash Alfred Psychiatry Research Centre, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia.

Objectives: Chronic pain patients often report higher levels of negative emotions, suggesting reduced ability to regulate emotions effectively, however, little is known of the underlying neural cognitive mechanisms. Therefore, the aim of this study was to explore brain activity and connectivity during cognitive reappraisal in chronic low back pain (CLBP).

Methods: This study recruited 24 female participants; 12 with CLBP and 12 healthy controls. Participants completed an emotion regulation task that involved cognitive reappraisal of negative images during functional magnetic resonance imaging. The negative affect following each image and perceived success of the task were reported. Region of interest and seed-to-voxel analyses were conducted using key regions involved in cognitive reappraisal (i.e., amygdalae and dorsomedial prefrontal cortex) as seed regions.

Results: During the task, there were no group differences in the behavioural measures and blood oxygen level-dependent (BOLD) brain activation in the seed regions. Functional connectivity analysis showed reduced coupling between the amygdalae and dorsolateral prefrontal cortex, orbitofrontal cortex and inferior parietal cortex in the CLBP group compared to controls. Connectivity between the amygdala and inferior parietal cortex positively correlated with the percent of reduced negative affect during reappraisal in the CLBP group.

Conclusions: These preliminary findings demonstrate that individuals with CLBP exhibit similar emotion regulation abilities to healthy controls at the behavioural and BOLD level. However, altered functional connectivity observed in the CLBP group may reduce effective cognitive reappraisal. These results provide evidence for the potential clinical impact of network changes in CLBP.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1515/sjpain-2020-0146DOI Listing
July 2021

The place of non-invasive brain stimulation in the RANZCP clinical practice guidelines for mood disorders.

Aust N Z J Psychiatry 2021 04;55(4):349-354

Psychiatry, University of NSW and Black Dog Institute, Sydney, NSW, Australia.

Clinical practice guidelines are important documents as they have the capacity to significantly influence and shape clinical practice in important areas of therapeutics. As such, they need to be developed informed by comprehensive and quality-based systematic reviews, involve consensus deliberations representative of the appropriate experts in the field and be subject to thorough critical review. A revised clinical practice guideline for the management of patients with mood disorders was recently published under the auspices of the Royal Australian and New Zealand College of Psychiatrists. However, this clinical practice guideline was not developed in a manner that reflects the appropriate standards that should apply to clinical practice guideline development and it has critical flaws, especially as it pertains to the use of repetitive transcranial magnetic stimulation treatment for patients with depression. The revision of the college clinical practice guideline has explicitly removed clear and unequivocal evidence-based recommendations that were found in a previous version of the clinical practice guideline and replaced these with consensus-based recommendations. However, the consensus-based recommendations were developed without consultation of the appropriate expert body within the college and contradict the scientific literature. There is substantive and unequivocal evidence supporting the antidepressant use of repetitive transcranial magnetic stimulation in the treatment of patients with depression and its use after a patient with depression has failed a limited number (typically around two) of antidepressant medication trials. Readers should refer to the college Professional Practice Guidelines for repetitive transcranial magnetic stimulation published in 2018 for thorough information about the use of this important new treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/00048674211004344DOI Listing
April 2021

Personalising transcranial magnetic stimulation for depression using neuroimaging: A systematic review.

World J Biol Psychiatry 2021 11 21;22(9):647-669. Epub 2021 Apr 21.

Epworth Centre for Innovation in Mental Health, Epworth Healthcare and Department of Psychiatry, Monash University, Melbourne, Australia.

Objectives: Transcranial magnetic stimulation (TMS) is a well-established and effective treatment for depression, though response rates are suboptimal. Personalising TMS for depression with neuroimaging can take into account inter-individual differences in anatomical and electrophysiological characteristics; and thereby provide a potentially more efficacious form of treatment. The current systematic review aimed to critically appraise the literature relating to personalising TMS for depression with neuroimaging.

Methods: PubMed, PsycINFO and Embase databases were used to identify relevant literature published up to November 2020.

Results: A total of 37 studies were included in the review. Across these studies, a total of 1451 patients with depression received TMS that was personalised using neuroimaging. The majority of the studies used structural or functional neuroimaging to personalise treatment target ( = 30), primarily through neuronavigation methodologies. Fewer studies used electroencephalography to personalise treatment frequency or stimulus timing ( = 7). Only 6 studies directly compared neuroimaging-personalised TMS to standard TMS.

Conclusions: The findings from this review suggest that personalising TMS with neuroimaging may be more effective in the treatment of depression compared to standard TMS. Further research is required to directly compare neuroimaging-personalised TMS with standard TMS, and to identify the optimal parameters for treatment personalisation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/15622975.2021.1907710DOI Listing
November 2021

Repetitive Transcranial Magnetic Stimulation for Obsessive-Compulsive Disorder: A Meta-analysis of Randomized, Sham-Controlled Trials.

Biol Psychiatry Cogn Neurosci Neuroimaging 2021 10 26;6(10):947-960. Epub 2021 Mar 26.

Epworth Centre for Innovation in Mental Health, Department of Psychiatry, Central Clinical School, Monash University, Epworth HealthCare, Melbourne, Victoria, Australia.

Background: Obsessive-compulsive disorder (OCD) is a chronic, disabling mental health condition with limited treatment options available to date. Numerous randomized controlled trials have explored the efficacy of repetitive transcranial magnetic stimulation (rTMS) in OCD. This meta-analysis synthesized data from selected randomized controlled trials and examined the impact of different treatment parameters to generate hypotheses that would direct future randomized controlled trials.

Methods: A database search was performed to identify studies published in English up to October 2020. Randomized, sham-controlled studies that used rTMS to treat OCD were included. Effect sizes were calculated using Hedges' g for pre- to post-treatment Yale-Brown Obsessive Compulsive Scale scores. Subgroup analyses were conducted to assess the effects of variations in rTMS treatment parameters.

Results: A total of 26 studies with 781 participants were included. Overall, rTMS demonstrated a modest effect on reduction of Yale-Brown Obsessive Compulsive Scale scores (Hedges' g = 0.64, 95% confidence interval = 0.39-0.89; p < .0001). The largest significant effect size was obtained by targeting the bilateral dorsolateral prefrontal cortex. High- and low-frequency rTMS showed comparable effects. Studies with follow-up data suggested that the effects of active rTMS remain significantly superior to those of sham 4 weeks after treatment.

Conclusions: The therapeutic effects of rTMS are superior to those of sham in the treatment of OCD. Targeting the bilateral dorsolateral prefrontal cortex was the most favorable approach in administering rTMS. Further research is required to determine the optimal frequency, total pulses per session, and duration of treatment with rTMS for OCD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bpsc.2021.03.010DOI Listing
October 2021

Characterizing Cortical Oscillatory Responses in Major Depressive Disorder Before and After Convulsive Therapy: A TMS-EEG Study.

J Affect Disord 2021 05 8;287:78-88. Epub 2021 Mar 8.

Department of Psychiatry, Faculty of Health, University of California San Diego, La Jolla, CA 92093-0603, United States. Electronic address:

Background: Combined transcranial magnetic stimulation and electroencephalography (TMS-EEG) is emerging as a powerful technique for interrogating neural circuit dysfunction in psychiatric disorders. Here, we utilized time-frequency analyses to characterize differences in neural oscillatory dynamics between subjects with major depressive disorder (MDD) and healthy controls (HC). We further examined changes in TMS-related oscillatory power following convulsive therapy.

Methods: Oscillatory power was examined following TMS over the dorsolateral prefrontal and motor cortices (DLPFC and M1) in 38 MDD subjects, and 22 HCs. We further investigated how these responses changed in the MDD group following an acute course of convulsive therapy (either magnetic seizure therapy [MST, n = 24] or electroconvulsive therapy [ECT, n = 14]).

Results: Prior to treatment, MDD subjects exhibited increased oscillatory power within delta, theta, and alpha frequency bands with TMS-EEG over the DLPFC, but showed no differences to HCs with stimulation over M1. Following MST, DLPFC stimulation revealed attenuated baseline-normalized power in the delta and theta bands, with reductions in the delta, theta, and alpha power following ECT. TMS over M1 revealed reduced delta and theta power following ECT, with no changes observed following MST. An association was also observed between the treatment- induced change in alpha power and depression severity score.

Limitations: Limitations include the modest sample size, open-label MST and ECT treatment designs, and lack of a placebo condition.

Conclusions: These results provide evidence of alterations in TMS-related oscillatory activity in MDD, and further suggest modulation of oscillatory power following ECT and MST.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jad.2021.03.010DOI Listing
May 2021

Advancing the use of non-invasive brain stimulation through systematic data review.

Braz J Psychiatry 2021 Sep-Oct;43(5):458-459

Epworth Centre for Innovation in Mental Health, Epworth Healthcare and Monash University Department of Psychiatry, Camberwell, VIC, Australia.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1590/1516-4446-2021-1742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8555637PMC
January 2021

Personalized connectivity-guided DLPFC-TMS for depression: Advancing computational feasibility, precision and reproducibility.

Hum Brain Mapp 2021 Sep 5;42(13):4155-4172. Epub 2021 Feb 5.

Melbourne Neuropsychiatry Centre, The University of Melbourne, Melbourne, Victoria, Australia.

Repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex (DLPFC) is an established treatment for refractory depression, however, therapeutic outcomes vary. Mounting evidence suggests that clinical response relates to functional connectivity with the subgenual cingulate cortex (SGC) at the precise DLPFC stimulation site. Critically, SGC-related network architecture shows considerable interindividual variation across the spatial extent of the DLPFC, indicating that connectivity-based target personalization could potentially be necessary to improve treatment outcomes. However, to date accurate personalization has not appeared feasible, with recent work indicating that the intraindividual reproducibility of optimal targets is limited to 3.5 cm. Here we developed reliable and accurate methodologies to compute individualized connectivity-guided stimulation targets. In resting-state functional MRI scans acquired across 1,000 healthy adults, we demonstrate that, using this approach, personalized targets can be reliably and robustly pinpointed, with a median accuracy of ~2 mm between scans repeated across separate days. These targets remained highly stable, even after 1 year, with a median intraindividual distance between coordinates of only 2.7 mm. Interindividual spatial variation in personalized targets exceeded intraindividual variation by a factor of up to 6.85, suggesting that personalized targets did not trivially converge to a group-average site. Moreover, personalized targets were heritable, suggesting that connectivity-guided rTMS personalization is stable over time and under genetic control. This computational framework provides capacity for personalized connectivity-guided TMS targets to be robustly computed with high precision and has the flexibly to advance research in other basic research and clinical applications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hbm.25330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357003PMC
September 2021

Effects of aspirin on the long-term management of depression in older people: a double-blind randomised placebo-controlled trial.

Mol Psychiatry 2021 Sep 27;26(9):5161-5170. Epub 2021 Jan 27.

School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, 3004, Australia.

Late-life depression is common and often inadequately managed using existing therapies. Depression is also associated with increased markers of inflammation, suggesting a potential role for anti-inflammatory agents. ASPREE-D is a sub-study of ASPREE, a large multi-centre, population-based, double-blind, placebo-controlled trial of aspirin vs placebo in older Australian and American adults (median follow-up: 4.7 years) of whom 1879 were depressed at baseline. Participants were given 100 mg daily dose of aspirin or placebo. Depressive symptoms were assessed annually using the validated, self-rated short version of the Center for Epidemiological Studies Depression scale. There was a significant increase in depressive scores (0.6; 95% CI 0.2 to 0.9; χ (1) = 10.37; p = 0.001) and a decreased score in the mental health component of a quality of life scale (-0.7; 95% CI -1.4 to -0.1; χ (1) = 4.74; p = 0.029) in the aspirin group compared to the placebo group. These effects were greater in the first year of follow-up and persisted throughout the study, albeit with small to very small effect sizes. This study failed to demonstrate any benefit of aspirin in the long-term course of depression in this community-dwelling sample of older adults over a 5-year period, and identified an adverse effect of aspirin in the course of depression in those with pre-existing depressive symptoms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41380-021-01020-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8313623PMC
September 2021

Individual alpha frequency proximity associated with repetitive transcranial magnetic stimulation outcome: An independent replication study from the ICON-DB consortium.

Clin Neurophysiol 2021 02 10;132(2):643-649. Epub 2020 Nov 10.

Research Institute Brainclinics, Brainclinics Foundation, Nijmegen, the Netherlands; Dept. of Cognitive Neuroscience, Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, the Netherlands; Amsterdam UMC, University of Amsterdam, Department of Psychiatry, Location AMC, Amsterdam Neuroscience, Amsterdam, the Netherlands. Electronic address:

Objective: The aim of the current study was to attempt to replicate the finding that the individual alpha frequency (IAF) as well as the absolute difference between IAF and 10 Hz stimulation frequency (IAF-prox) is related to treatment outcome.

Methods: Correlations were performed to investigate the relationship between IAF-prox and percentage symptom improvement in a sample of 153 patients with major depressive disorder treated with 10 Hz (N = 59) to the left dorsolateral prefrontal cortex (DLPFC) or 1 Hz (N = 94) to the right DLPFC repetitive Transcranial Magnetic Stimulation (rTMS).

Results: There was a significant negative correlation between IAF-prox and the percentage of symptom improvement only for the 10 Hz group. Curve fitting models revealed that there was a quadratic association between IAF and treatment response in the 10 Hz group, with a peak at 10 Hz IAF.

Conclusion: The main result of Corlier and colleagues was replicated, and the findings suggest that the distance between 10 Hz stimulation frequency and the IAF may influence clinical outcome in a non-linear manner.

Significance: rTMS is often administered at a frequency of 10 Hz, which is the center of the EEG alpha frequency band. The results can make a significant contribution to optimizing the clinical application of rTMS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clinph.2020.10.017DOI Listing
February 2021
-->