Publications by authors named "Daniel M Blumberger"

241 Publications

Caution at psychiatry's psychedelic frontier.

Nat Med 2021 Oct 11;27(10):1687-1688. Epub 2021 Oct 11.

Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada.

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http://dx.doi.org/10.1038/s41591-021-01524-1DOI Listing
October 2021

Enhancing Cognition in Older Persons with Depression or Anxiety with a Combination of Mindfulness-Based Stress Reduction (MBSR) and Transcranial Direct Current Stimulation (tDCS): Results of a Pilot Randomized Clinical Trial.

Mindfulness (N Y) 2021 Oct 5:1-13. Epub 2021 Oct 5.

Centre for Addiction and Mental Health and Department of Psychiatry, University of Toronto, Toronto, ON Canada.

Objectives: Individuals with subjective memory complaints and symptoms of depression and/or anxiety are at high risk for further cognitive decline, and possible progression to dementia. Low-burden interventions to help slow or prevent cognitive decline in this high-risk group are needed. The objective of this study is to assess the feasibility of combining Mindfulness-Based Stress Reduction (MBSR) with transcranial direct current stimulation (tDCS) to increase putative benefits of MBSR for cognitive function and everyday mindfulness in depressed or anxious older adults with subjective cognitive decline.

Methods: We conducted a two-site pilot double-blind randomized sham-controlled trial, combining active MBSR with either active or sham tDCS. The intervention included weekly in-class group sessions at the local university hospital and daily at-home practice. Anodal tDCS was applied for 30 min during MBSR meditative practice, both in-class and at-home.

Results: Twenty-six individuals with subjective cognitive complaints and symptoms of depression and/or anxiety were randomized to active ( = 12) or sham tDCS ( = 14). The combination of MBSR and tDCS was safe and well tolerated, though at-home adherence and in-class attendance were variable. While they were not statistically significant, the largest effect sizes for active vs. sham tDCS were for everyday mindfulness ( = 0.6) and social functioning ( = 0.9) (  = 3.68,  = 0.07 and  = 3.9,  = 0.06, respectively).

Conclusions: Our findings suggest that it is feasible and safe to combine tDCS with MBSR in older depressed and anxious adults, including during remote, at-home use. Furthermore, tDCS may enhance MBSR via transferring its meditative learning and practice into increases in everyday mindfulness. Future studies need to improve adherence to MBSR with tDCS.

Trial Registration: ClinicalTrials.gov (NCT03653351 and NCT03680664).

Supplementary Information: The online version contains supplementary material available at 10.1007/s12671-021-01764-9.
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http://dx.doi.org/10.1007/s12671-021-01764-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8491443PMC
October 2021

Repetitive transcranial magnetic stimulation for major depressive disorder: basic principles and future directions.

Ther Adv Psychopharmacol 2021 23;11:20451253211042696. Epub 2021 Sep 23.

Institute of Medical Science and Department of Psychiatry, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.

Repetitive transcranial magnetic stimulation (rTMS) is a safe and well-tolerated intervention for major depressive disorder (MDD). Over 150 randomized controlled trials (RCTs) have been carried out, and its efficacy has been confirmed in dozens of meta-analyses. Real world data has also confirmed the effectiveness of rTMS for MDD in clinical practice, with the most recent literature indicating response rates of 40-50% and remission rates of 25-30%. In this review, we first offer an historical perspective, followed by a review of basic principles, such as putative mechanisms, procedures and protocols, stimulation targets, efficacy and durability of response, side effects, and the placebo controversy. In the second part of this review, we first discuss solutions to increase accessibility to rTMS, such as modifications to treatment equipment, protocols and setting. We continue with possible means to further increase effectiveness, such as treatment personalization and extension. We conclude by addressing the scheduling issue, with accelerated rTMS (arTMS) as a possible solution.
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http://dx.doi.org/10.1177/20451253211042696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8474312PMC
September 2021

A randomized sham controlled comparison of once vs twice-daily intermittent theta burst stimulation in depression: A Canadian rTMS treatment and biomarker network in depression (CARTBIND) study.

Brain Stimul 2021 Sep 21;14(6):1447-1455. Epub 2021 Sep 21.

Department of Psychiatry and Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, M5S 1A8, Canada; Centre for Mental Health and Krembil Research Institute, University Health Network, Toronto, M5T 0S8, Canada.

Background: Intermittent theta burst stimulation (iTBS) is a newer form of repetitive transcranial magnetic stimulation (rTMS) for patients with treatment resistant depression (TRD). Applying multiple daily iTBS sessions may enable patients to achieve remission more rapidly.

Objective: We compared the efficacy and tolerability of a twice-daily versus once-daily iTBS protocol in patients with TRD. We hypothesized that twice-daily iTBS would result in a greater improvement in depression scores compared to once-daily iTBS.

Methods: 208 participants (131 females) with TRD were randomized to receive either iTBS (600 pulses) delivered twice-daily with a 54-min interval between treatments or once-daily (1200 pulses) with 1 sham treatment with the same interval between treatments, to ensure equal levels of daily therapeutic contact and blinding of patients and raters. The primary outcome measure was change in depression scores on the Hamilton Rating Scale for Depression (HRSD-17) after 10 days of treatment and 30 days of treatments.

Results: HRSD-17 scores improved in both the twice-daily and once-daily iTBS groups; however, these improvements did not significantly differ between the two groups at either the 10-day or 30-day timepoints. Response and remission rates were low (<10%) in both groups after 10 days and consistent with prior reports at 30 days; these rates did not differ between the treatment groups.

Conclusions: These results suggest that twice-daily iTBS does not accelerate response to iTBS and is not different from once-daily treatment in terms of improving depressive symptoms in patients with TRD. Clinicaltrials.gov ID: NCT02729792 (https://clinicaltrials.gov/ct2/show/NCT02729792).
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http://dx.doi.org/10.1016/j.brs.2021.09.003DOI Listing
September 2021

Magnitude of the Placebo Response Across Treatment Modalities Used for Treatment-Resistant Depression in Adults: A Systematic Review and Meta-analysis.

JAMA Netw Open 2021 Sep 1;4(9):e2125531. Epub 2021 Sep 1.

Department of Psychiatry, University of California San Diego.

Importance: The placebo effect in depression clinical trials is a substantial factor associated with failure to establish efficacy of novel and repurposed treatments. However, the magnitude of the placebo effect and whether it differs across treatment modalities in treatment-resistant depression (TRD) is unclear.

Objective: To examine the magnitude of the placebo effect in patients with TRD across different treatment modalities and its possible moderators.

Data Sources: Searches were conducted on MEDLINE, Web of Science, and PsychInfo from inception to June 21, 2021.

Study Selection: Randomized clinical trials (RCTs) were included if they recruited patients with TRD and randomized them to a placebo or sham arm and a pharmacotherapy, brain stimulation, or psychotherapy arm.

Data Extraction And Synthesis: Independent reviewers used standard forms for data extraction and quality assessment. Random-effects analyses and standard pairwise meta-analyses were performed.

Main Outcomes And Measures: The primary outcome was the Hedges g value for the reported depression scales. Secondary outcomes included moderators assessed via meta-regression and response and remission rates. Heterogeneity was assessed with the I2 test, and publication bias was evaluated using the Egger test and a funnel plot. Cochrane Risk of Bias Tool was used to estimate risks.

Results: Fifty RCTs were included involving various types of placebo or sham interventions with a total of 3228 participants (mean [SD] age, 45.8 [6.0] years; 1769 [54.8%] female). The pooled placebo effect size for all modalities was large (g = 1.05; 95% CI, 0.91-1.1); the placebo effect size in RCTs of specific treatment modalities did not significantly differ. Similarly, response and remission rates associated with placebo were comparable across modalities. Heterogeneity was large. Three variables were associated with a larger placebo effect size: open-label prospective treatment before double-blind placebo randomization (β = 0.35; 95% CI, 0.11 to 0.59; P = .004), later year of publication (β = 0.03; 95% CI, 0.003 to 0.05; P = .03), and industry-sponsored trials (β = 0.34; 95% CI, 0.09 to 0.58; P = .007). The number of failed interventions was associated with the probability a smaller placebo effect size (β = -0.12; 95% CI, -0.23 to -0.01, P = .03). The Egger test result was not significant for small studies' effects.

Conclusions And Relevance: This analysis may provide a benchmark for past and future clinical RCTs that recruit patients with TRD standardizing an expected placebo effect size.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.25531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8463940PMC
September 2021

Insights of neurophysiology on unconscious state using combined transcranial magnetic stimulation and electroencephalography: A systematic review.

Neurosci Biobehav Rev 2021 Sep 20;131:293-312. Epub 2021 Sep 20.

Department of Neuropsychiatry, Graduate School of Medicine, Keio University School of Medicine, Tokyo, Japan. Electronic address:

Unconscious state has been investigated in numerous studies so far, but pathophysiology of this state is not fully understood. Recently, combined transcranial magnetic stimulation (TMS) and electroencephalography (EEG) has been developed to allow for non-invasive assessment of neurophysiology in the cerebral cortex. We conducted a systematic literature search for TMS-EEG studies on human unconscious state using PubMed with cross-reference and manual searches. The initial search yielded 137 articles, and 19 of them were identified as relevant, including one article found by manual search. This review included 10 studies for unresponsive wakefulness syndrome (UWS), 9 for minimally conscious states (MCS), 5 for medication-induced unconscious states, and 6 for natural non-rapid eye movement states. These studies analyzed TMS-evoked potential to calculate perturbational complexity index (PCI) and OFF-periods. In particular, PCI was found to be a potentially useful marker to differentiate between UWS and MCS. This review demonstrated that TMS-EEG could represent a promising neuroscientific tool to investigate various unconscious states. Further TMS-EEG research may help elucidate the neural basis of unconscious state.
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http://dx.doi.org/10.1016/j.neubiorev.2021.09.029DOI Listing
September 2021

Electroconvulsive Therapy in Canada During the First Wave of COVID-19: Results of the "What Happened" National Survey.

J ECT 2021 Sep 13. Epub 2021 Sep 13.

From the Interventional Psychiatry Program, Mental Health and Addictions Service, St Michael's Hospital Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health Department of Psychiatry, University of Toronto Institute of Medical Science, University of Toronto Centre for Mental Health, University Health Network Library and Information Services, University Health Network, Toronto, Ontario, Canada Department of Psychiatry, University of California San Diego, San Diego, CA Department of Anesthesia and Pain Management, University Health Network Department of Anesthesiology and Pain Medicine Institute of Health Policy, Management, and Evaluation, University of Toronto Department of Anesthesia Centre for Clinical Ethics, St Michael's Hospital Dalla Lana School of Public Health, University of Toronto Department of Infection Prevention and Control, University Health Network Department of Psychiatry, North York General Hospital, Toronto, Ontario, Canada Department of Psychiatry, University of Michigan, Ann Arbor, MI.

Objectives: The COVID-19 pandemic has disrupted the provision of essential and potentially life-saving procedural treatments such as electroconvulsive therapy (ECT). We surveyed ECT providers across Canada to understand how the first wave of the pandemic affected ECT delivery between mid-March 2020 and mid-May 2020.

Methods: The survey was administered to ECT team members and decision makers at 107 Canadian health care centers with a focus on 5 domains: operations, decision-making, hospital resources, ECT procedure, and patient impact. Responses were obtained from 72 institutions, and collected answers were used to derive representative responses reflecting the situation at each ECT center. For specific domains, responses were split into 2 databases representing the perspective of psychiatrists (n = 67 centers) and anesthesiologists (n = 24 centers).

Results: Provision of ECT decreased in 64% centers and was completely suspended in 27% of centers after the onset of the pandemic. Outpatient and maintenance ECT were more affected than inpatient and acute ECT. Programs reported a high level of collaboration between psychiatry and hospital leadership (59%) but a limited input from clinical ethicists (18%). Decisions were mostly made ad hoc leading to variability across institutions in adopted resource allocation, physical location of ECT delivery, and triaging frameworks. The majority of centers considered ECT to be aerosol-generating and incorporated changes to airway management.

Conclusions: Electroconvulsive therapy services in Canada were markedly disrupted by the COVID-19 pandemic. The variability in decision-making across centers warrants the development of a rational approach toward offering ECT in pandemic contexts.
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http://dx.doi.org/10.1097/YCT.0000000000000801DOI Listing
September 2021

Assessing the Longitudinal Relationship between Theta-Gamma Coupling and Working Memory Performance in Older Adults.

Cereb Cortex 2021 Sep 14. Epub 2021 Sep 14.

Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto M6J 1H4, Canada.

Theta-gamma coupling (TGC) is a neurophysiologic mechanism that supports working memory (WM). TGC is associated with N-back performance, a WM task. Similar to TGC, theta and alpha event-related synchronization (ERS) and desynchronization (ERD) are also associated with WM. Few studies have examined the longitudinal relationship between WM performance and TGC, ERS, or ERD. This study aimed to determine if changes in WM performance are associated with changes in TGC (primary aim), as well as theta and alpha ERS or ERD over 6 to 12 weeks. Participants included 62 individuals aged 60 and older with no neuropsychiatric conditions or with remitted Major Depressive Disorder (MDD) and no cognitive disorders. TGC, ERS, and ERD were assessed using electroencephalography (EEG) during the N-back task (3-back condition). There was an association between changes in 3-back performance and changes in TGC, alpha ERD and ERS, and theta ERS in the control group. In contrast, there was only a significant association between changes in 3-back performance and changes in TGC in the subgroup with remitted MDD. Our results suggest that the relationship between WM performance and TGC is stable over time, while this is not the case for changes in theta and alpha ERS and ERD.
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http://dx.doi.org/10.1093/cercor/bhab295DOI Listing
September 2021

The fundamental basis of palpitations: a neurocardiology approach.

Curr Cardiol Rev 2021 Sep 9. Epub 2021 Sep 9.

Faculty of Medicine, Department of Medicine Division of Cardiology University of British Columbia, Vancouver, British Columbia. Canada.

Background And Objective: Palpitations are a common symptom that may indicate cardiac arrhythmias, be a somatic complaint in anxiety disorders, and can be present in patients without either condition. The objective of this review was to explore the pathways and fundamental mechanisms through which individuals appreciate palpitations.

Observations: Cardiac afferents provide beat-to-beat sensory information on the heart to the spinal cord, brain stem, and higher brain centers. Cardioception, a subset of interoception ('the physiological sense of the condition of the body'), refers to sensing of the heartbeat. High cardioception is present in persons with lower body mass index, lower percentages of body fat, and anxiety disorders. Low cardioception (lower interoceptive awareness) is associated with psychiatric disorders, such as depression, personality disorders, and schizophrenia. CNS sites associated with heartbeat detection have been identified by functional magnetic resonance imaging studies and heartbeat-evoked electroencephalogram potentials. The right insula, cingulate gyrus, somatomotor and somatosensory cortices nucleus accumbens, left subthalamic nucleus, and left ventral capsule/striatum are implicated in both palpitations and heartbeat detection. Involvement of the brain as a primary modulator of palpitations rests on the data that various areas of the brain are activated in association with cardioception, the ability of focal brain stimulation to induce palpitations, the ability of central alpha receptor agonists and antagonists to modulate palpitations, and suppression of palpitations by transcranial repetitive magnetic stimulation (rTMS).

Conclusions: Palpitations should be viewed as a pathway extending from the heart to the brain. Palpitations are, in part, a reflection of an individual's cardioception awareness, which is modulated by body size, percentage of body fat, and psychological or psychiatric conditions. Palpitations can originate in the brain and involve central neurotransmitters. Treatment of palpitations unrelated to cardiac arrhythmias or anxiety disorders should consider the use of central alpha-2 agonists and possibly rTMS.
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http://dx.doi.org/10.2174/1573403X17666210909123930DOI Listing
September 2021

Dorsolateral prefrontal cortex excitability abnormalities in Alzheimer's Dementia: Findings from transcranial magnetic stimulation and electroencephalography study.

Int J Psychophysiol 2021 Nov 6;169:55-62. Epub 2021 Sep 6.

Centre for Addiction and Mental Health, Toronto, Canada; Temerty Faculty of Medicine, University of Toronto, Toronto, Canada; Toronto Dementia Research Alliance, Toronto, Canada. Electronic address:

There is some evidence of cortical hyper-excitability in Alzheimer's Dementia (AD) but its relationship with cognition is not clear. In this study, we assessed dorsolateral prefrontal cortex (DLPFC) excitability and its relationship with cognition in AD. Twenty-four participants with AD (mean [SD] age = 74.1 [7.2] years) and eleven elderly healthy controls (HC) (mean [SD] age = 68.8 [7.3] years) were recruited. Transcranial magnetic stimulation (TMS) combined with electroencephalography (EEG) was used to assess cortical excitability. Cortical evoked activity (CEA) between 25 and 80 ms post-TMS stimulus was calculated as the primary measure of cortical excitability. TMS-evoked potential peak (TEP) amplitudes (P30, N45 and P60) were also calculated. Cognition was assessed using Montreal Cognitive Assessment (MoCA), Executive Interview (EXIT) and Cambridge Neuropsychological Test Automated Battery Stockings of Cambridge (SOC). There was no difference in TMS stimulus intensity between the groups. DLPFC-CEA was higher in the AD (mean [SD] = 134.64 [90.22] μV) than the HC group (mean [SD] = 82.65 [40.28] μV; t = 2.357, p = 0.025). There were no differences in TEP peak amplitudes between the groups. Further, DLPFC-CEA was inversely associated with MoCA and SOC, and positively associated with EXIT scores in AD. These results suggest increased DLPFC excitability in AD, and its inverse associations with global cognition and executive function. Future studies should examine these findings in larger samples and longitudinally, and could also assess these markers of cortical excitability in relation to other established markers of AD and in response to interventions.
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http://dx.doi.org/10.1016/j.ijpsycho.2021.08.008DOI Listing
November 2021

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

J Affect Disord 2021 Aug 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.
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http://dx.doi.org/10.1016/j.jad.2021.08.046DOI Listing
August 2021

Neuromodulatory treatments for psychiatric disease: A comprehensive survey of the clinical trial landscape.

Brain Stimul 2021 Sep-Oct;14(5):1393-1403. Epub 2021 Aug 27.

Krembil Research Institute, University of Toronto, Toronto, Canada; Department of Psychiatry, University Health Network & University of Toronto, Toronto, Canada; Centre for Depression & Suicide Studies, St. Michael's Hospital & University of Toronto, Toronto, Canada. Electronic address:

Background: Numerous neuromodulatory therapies are currently under investigation or in clinical use for the treatment of psychiatric conditions.

Objective/hypothesis: We sought to catalogue past and present human research studies on psychiatric neuromodulation and identify relevant trends in this field.

Methods: ClinicalTrials.gov (https://www.clinicaltrials.gov/) and the International Clinical Trials Registry Platform (https://www.who.int/ictrp/en/) were queried in March 2020 for trials assessing the outcome of neuromodulation for psychiatric disorders. Relevant trials were categorized by variables such as neuromodulation modality, country, brain target, publication status, design, and funding source.

Results: From 72,086 initial search results, 1252 unique trials were identified. The number of trials registered annually has consistently increased. Half of all trials were active and a quarter have translated to publications. The largest proportion of trials involved depression (45%), schizophrenia (18%), and substance use disorders (14%). Trials spanned 37 countries; China, the second largest contributor (13%) after the United States (28%), has increased its output substantially in recent years. Over 75% of trials involved non-convulsive non-invasive modalities (e.g., transcranial magnetic stimulation), while convulsive (e.g., electroconvulsive therapy) and invasive modalities (e.g., deep brain stimulation) were less represented. 72% of trials featured approved or cleared interventions. Characteristic inter-modality differences were observed with respect to enrollment size, trial design/phase, and funding. Dorsolateral prefrontal cortex accounted for over half of focal neuromodulation trial targets. The proportion of trials examining biological correlates of neuromodulation has increased.

Conclusion(s): These results provide a comprehensive overview of the state of psychiatric neuromodulation research, revealing the growing scope and internationalism of this field.
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http://dx.doi.org/10.1016/j.brs.2021.08.021DOI Listing
August 2021

A patient-oriented analysis of pain side effect: A step to improve the patient's experience during rTMS?

Brain Stimul 2021 Sep-Oct;14(5):1147-1153. Epub 2021 Aug 5.

Non-Invasive Neurostimulation Therapies (NINET) Laboratory, Department of Psychiatry, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, Canada, V6T 2A1. Electronic address:

Background: Repetitive transcranial magnetic stimulation (rTMS) is an efficacious and well-tolerated intervention for treatment-resistant depression (TRD). A novel rTMS protocol, intermittent theta burst stimulation (iTBS) has been recently implemented in clinical practice, and it is essential to characterize the factors associated to pain and the trajectory of pain of iTBS compared to standard rTMS protocols.

Objective: We aimed to characterize the side effect profile and the pain trajectories of High-Frequency Left (HFL) and iTBS in TRD patients in the THREE-D trial. We also investigated factors associated to pain and the relationship between pain and clinical outcomes.

Methods: 414 patients were randomized to either HFL or iTBS. Severity of pain was measured after every treatment. General Estimating Equation was used to investigate factors associated with pain. Latent class linear mixed model was used to investigate latent classes of pain trajectories over the course of rTMS.

Results: Higher level of pain was associated with older age, higher stimulation intensity, higher anxiety, female, and non-response. The severity of pain significantly declined over the course of treatments with a steeper decrease early on in the course of the treatment in both protocols, and four latent pain trajectories were identified. The less favorable pain trajectories were associated with non-response and higher stimulation intensity.

Conclusions: HFL and iTBS were associated with similar factors and pain trajectories, although iTBS was more uncomfortable. Response to rTMS was associated with less pain and more favorable pain trajectories furthering the evince base of overlapping neurobiological underpinnings of mood and pain. We translated these results into patient-oriented information to aid in the decision-making process when considering rTMS.
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http://dx.doi.org/10.1016/j.brs.2021.07.015DOI Listing
August 2021

Repetitive transcranial magnetic stimulation in patients with borderline personality disorder: A systematic review.

Psychiatry Res 2021 Oct 29;304:114145. Epub 2021 Jul 29.

Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada; Temerty Centre for Therapeutic Brain Intervention and Campbell Family Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada. Electronic address:

The literature on the application of repetitive transcranial magnetic stimulation (rTMS) in Borderline Personality Disorder (BPD) is unclear, even though its neuromodulatory effects on underlying neural circuitry involved in BPD symptoms suggest that it could be a potential treatment option. We sought to review the evidence on rTMS as a treatment option in BPD. PubMed (for Medline database), Google Scholar, and Scopus were systematically searched following the PRISMA guidelines for studies of any design examining the application of the rTMS treatment in adult patients with precise and primary diagnosis of BPD written in the English language. The systematic review has been registered on PROSPERO (CRD42020215927). Forty one records were screened, and eight fulfilled inclusion criteria (total of 63 patients). The existing studies suggest that rTMS is a well-tolerated treatment in patients with BPD. Double-blind randomized controlled studies are necessary to help elucidate the effects of rTMS in the different symptoms in BPD and establish efficacy and the best cortical targets and stimulation protocols. Longitudinal studies that combine evidenced based psychotherapy with rTMS may be a future line of investigation that could potentially improve outcomes for this population.
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http://dx.doi.org/10.1016/j.psychres.2021.114145DOI Listing
October 2021

Transcranial Magnetic Stimulation Indices of Cortical Excitability Enhance the Prediction of Response to Pharmacotherapy in Late-Life Depression.

Biol Psychiatry Cogn Neurosci Neuroimaging 2021 Jul 23. Epub 2021 Jul 23.

Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada. Electronic address:

Background: Older adults with late-life depression (LLD) often experience incomplete or lack of response to first-line pharmacotherapy. The treatment of LLD could be improved using objective biological measures to predict response. Transcranial magnetic stimulation (TMS) can be used to measure cortical excitability, inhibition, and plasticity, which have been implicated in LLD pathophysiology and associated with brain stimulation treatment outcomes in younger adults with depression. TMS measures have not yet been investigated as predictors of treatment outcomes in LLD or pharmacotherapy outcomes in adults of any age with depression.

Methods: We assessed whether pretreatment single-pulse and paired-pulse TMS measures, combined with clinical and demographic measures, predict venlafaxine treatment response in 76 outpatients with LLD. We compared the predictive performance of machine learning models including or excluding TMS predictors.

Results: Two single-pulse TMS measures predicted venlafaxine response: cortical excitability (neuronal membrane excitability) and the variability of cortical excitability (dynamic fluctuations in excitability levels). In cross-validation, models using a combination of these TMS predictors, clinical markers of treatment resistance, and age classified patients with 73% ± 11% balanced accuracy (average correct classification rate of responders and nonresponders; permutation testing, p < .005); these models significantly outperformed (corrected t test, p = .025) models using clinical and demographic predictors alone (60% ± 10% balanced accuracy).

Conclusions: These preliminary findings suggest that single-pulse TMS measures of cortical excitability may be useful predictors of response to pharmacotherapy in LLD. Future studies are needed to confirm these findings and determine whether combining TMS predictors with other biomarkers further improves the accuracy of predicting LLD treatment outcome.
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http://dx.doi.org/10.1016/j.bpsc.2021.07.005DOI Listing
July 2021

Deep Transcranial Magnetic Stimulation Combined With Brief Exposure for Posttraumatic Stress Disorder: A Prospective Multisite Randomized Trial.

Biol Psychiatry 2021 May 4. Epub 2021 May 4.

McLean Hospital, Harvard Medical School, Belmont, Massachusetts. Electronic address:

Background: Posttraumatic stress disorder (PTSD) is both prevalent and debilitating. While deep transcranial magnetic stimulation (dTMS) has shown preliminary efficacy, exposure therapy remains the most efficacious, though limited, treatment in PTSD. The medial prefrontal cortex (mPFC) is implicated in extinction learning, suggesting that concurrent mPFC stimulation may enhance exposure therapy. In this randomized controlled multicenter trial, the efficacy and safety of mPFC dTMS combined with a brief exposure procedure were studied in patients with PTSD.

Methods: Immediately following exposure to their trauma narrative, 125 outpatients were randomly assigned to receive dTMS or sham. Twelve sessions were administered over 4 weeks, with a primary end point of change in 5-week Clinician-Administered PTSD Scale for DSM-5 score. This clinical study did not include biological markers.

Results: Clinician-Administered PTSD Scale for DSM-5 score improved significantly in both groups at 5 weeks, though the improvement was smaller in the dTMS group (16.32) compared with the sham group (20.52; p = .027). At 9 weeks, improvement continued in Clinician-Administered PTSD Scale for DSM-5 score in both groups but remained smaller in dTMS (19.0) versus sham (24.4; p = .024).

Conclusions: Both groups showed significant PTSD symptom improvement, possibly from the brief script-driven imagery exposure. While our design was unable to rule out placebo effects, the magnitude and durability of improvement suggest that repeated ultrabrief exposure therapy alone may be an effective treatment for PTSD, warranting additional study. The surprising and unexpected effect in the dTMS group also suggests that repeated mPFC stimulation with the H7 coil may interfere with trauma memory-mediated extinction. Our results provide new insight for dTMS approaches for possible future avenues to treat PTSD.
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http://dx.doi.org/10.1016/j.biopsych.2021.04.019DOI Listing
May 2021

Risk of serious medical events in patients with depression treated with electroconvulsive therapy: a propensity score-matched, retrospective cohort study.

Lancet Psychiatry 2021 08 12;8(8):686-695. Epub 2021 Jul 12.

Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada; Campbell Family Mental Health Research Institute Centre for Addiction and Mental Health, Toronto, ON, Canada.

Background: Previous studies examining the risk of medical complications from electroconvulsive therapy have been confounded and this might contribute to its underuse. This study aimed to compare the risk of serious medical events, defined as those resulting in hospitalisation or death, among patients with depression who received electroconvulsive therapy versus patients who did not receive electroconvulsive therapy.

Methods: This was a propensity score-matched, retrospective cohort study using linked population-based administrative health data for adults admitted to designated psychiatric facilities in Ontario, Canada, for more than 3 days with depression between April 1, 2007, to Feb 28, 2017. Electroconvulsive therapy exposure was defined as one or more physician billing procedure codes during hospitalisation. The unit of analysis was individual admissions and propensity score matching was used to match each exposed admission to an unexposed admission to estimate the average treatment effect of electroconvulsive therapy among those treated. The primary outcome was serious medical events, a composite of hospitalisation for medical (ie, non-psychiatric) reasons or non-suicide death within 30 days from electroconvulsive therapy exposure or matched date in the unexposed group. Effect modification was examined using tests of interaction for three clinically relevant prespecified subgroups (sex, presence of psychotic symptoms, and illness polarity). Secondary outcomes were medical hospitalisation and non-suicide death separately, suicide death, and specific serious medical events.

Findings: In propensity score matched analyses, there were 10 016 psychiatric hospitalisation records (6628 women, 3388 men) with mean age 56·6 years (SD 16·3) and no ethnicity data available. 65 818 admissions were eligible for matching and 5008 were matched (1:1) in each exposure group. In the propensity score matched cohort, the incidence of serious medical events was 0·25 per person-year in the exposed group and 0·33 per person-year in the unexposed group (cause-specific hazard ratio 0·78 [95% CI 0·61-1·00]). Suicide death as a competing risk did not alter this finding. The risk of suicide death was significantly lower in the exposed (≤5 of 5008 admissions) versus the unexposed group (11 [0·2%] of 5008 admissions; p<0·03). Bipolar depression, compared with unipolar depression, was associated with a greater reduction in the risk of serious medical events with electroconvulsive therapy. Electroconvulsive therapy was not associated with medical hospitalisation or non-suicide death separately, nor with any specific serious medical event.

Interpretation: Among individuals hospitalised with depression, we found no evidence for a clinically significant increased risk for serious medical events with exposure to electroconvulsive therapy, and the risk of suicide was found to be significantly reduced, suggesting the benefits of electroconvulsive therapy for depression outcomes might outweigh its risks in this population.

Funding: Norris Scholars Award, Department of Psychiatry, University of Toronto; the Canadian Institutes for Health Research.
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http://dx.doi.org/10.1016/S2215-0366(21)00168-1DOI Listing
August 2021

Quantitative Assessment of Cortical Excitability in Alzheimer's Dementia and Its Association with Clinical Symptoms: A Systematic Review and Meta-Analyses.

J Alzheimers Dis 2021 Jul 2. Epub 2021 Jul 2.

Centre for Addiction and Mental Health, Toronto, Canada.

Background: Alzheimer's disease (AD) is characterized by cognitive and neuropsychiatric symptoms (NPS) due to underlying neurodegenerative pathology. Some studies using electroencephalography (EEG) have shown increased epileptiform and epileptic activity in AD.

Objective: This review and meta-analyses aims to synthesize the existing evidence for quantitative abnormalities of cortical excitability in AD and their relationship with clinical symptoms.

Methods: We systematically searched and reviewed publications that quantitatively assessed cortical excitability, using transcranial magnetic stimulation (TMS) resting motor threshold (rMT), active motor threshold (aMT), motor evoked potential (MEP) or directly from the cortex using TMS-EEG via TMS-evoked potential (TEP). We meta-analyzed studies that assessed rMT and aMT using random effects model.

Results: We identified 895 publications out of which 37 were included in the qualitative review and 30 studies using rMT or aMT were included in the meta-analyses. The AD group had reduced rMT (Hedges' g = -0.99, 95%CI [-1.29, -0.68], p <  0.00001) and aMT (Hedges' g = -0.87, 95%CI [-1.50, -0.24], p <  0.00001) as compared with control groups, indicative of higher cortical excitability. Qualitative review found some evidence of increased MEP amplitude, whereas findings related to TEP were inconsistent. There was some evidence supporting an inverse association between cortical excitability and global cognition. No publications reported on the relationship between cortical excitability and NPS.

Conclusion: There is strong evidence of increased motor cortex excitability in AD and some evidence of an inverse association between excitability and cognition. Future studies should assess cortical excitability from non-motor areas using TMS-EEG and examine its relationship with cognition and NPS.
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http://dx.doi.org/10.3233/JAD-210311DOI Listing
July 2021

Neurophysiological effects of repetitive transcranial magnetic stimulation (rTMS) in treatment resistant depression.

Clin Neurophysiol 2021 Sep 1;132(9):2306-2316. Epub 2021 Jun 1.

Department of Psychiatry, University of California, San Diego, San Diego, CA, United States. Electronic address:

Objective: Repetitive transcranial magnetic stimulation (rTMS) is effective for treatment resistant depression (TRD), but little is known about rTMS' effects on neurophysiological markers. We previously identified neurophysiological markers in depression (N45 and N100) of GABA receptor mediated inhibition. Here, we indexed TMS-electroencephalographic (TMS-EEG) effects of rTMS.

Methods: TMS-EEG data was analyzed from a double blind 2:1 randomized active (10 Hz left/bilateral):sham rTMS TRD trial. Participants underwent TMS-EEG over left dorsolateral prefrontal cortex (DLPFC) before and after 6 weeks of rTMS. 30 had useable datasets. TMS-evoked potentials (TEP) and components (N45, N100, P60) were examined with global mean field analysis (GMFA) and locally in DLPFC regions of interest.

Results: The N45 amplitude differed between active and sham groups over time, N100 amplitude did not. N45 (t = 2.975, p = 0.007) and N100 amplitudes (t = 2.177, p = 0.042) decreased after active rTMS, demonstrating alterations in cortical inhibition. TEP amplitudes decreased after active rTMS in left (t = 4.887, p < 0.001) and right DLPFC (t = 4.403, p < 0.001) not sham rTMS, demonstrating alterations in cortical excitability.

Conclusions: Our results provide important new knowledge regarding rTMS effects on TMS-EEG measures in TRD, suggesting rTMS reduces neurophysiological markers of inhibition and excitability.

Significance: These findings uncover potentially important neurophysiological mechanisms of rTMS action.
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http://dx.doi.org/10.1016/j.clinph.2021.05.008DOI Listing
September 2021

Differentiating transcranial magnetic stimulation cortical and auditory responses via single pulse and paired pulse protocols: A TMS-EEG study.

Clin Neurophysiol 2021 08 30;132(8):1850-1858. Epub 2021 May 30.

Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Toronto, ON, Canada; Institute of Medical Science, University of Toronto, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada; Department of Psychiatry, Faculty of Health, University of California San Diego, La Jolla, CA, USA. Electronic address:

Objective: We measured the neurophysiological responses of both active and sham transcranial magnetic stimulation (TMS) for both single pulse (SP) and paired pulse (PP; long interval cortical inhibition (LICI)) paradigms using TMS-EEG (electroencephalography).

Methods: Nineteen healthy subjects received active and sham (coil 90° tilted and touching the scalp) SP and PP TMS over the left dorsolateral prefrontal cortex (DLPFC). We measured excitability through SP TMS and inhibition (i.e., cortical inhibition (CI)) through PP TMS.

Results: Cortical excitability indexed by area under the curve (AUC) was significantly higher in the active compared to sham stimulation (F(1,18) = 43.737, p < 0.001, η = 0.708). Moreover, the amplitude of N100-P200 complex was significantly larger (F(1,18) = 9.118, p < 0.01, η = 0.336) with active stimulation (10.38 ± 9.576 µV) compared to sham (4.295 ± 2.323 µV). Significant interaction effects were also observed between active and sham stimulation for both the SP and PP (i.e., LICI) cortical responses. Finally, only active stimulation (CI = 0.64 ± 0.23, p < 0.001) resulted in significant cortical inhibition.

Conclusion: The significant differences between active and sham stimulation in both excitatory and inhibitory neurophysiological responses showed that active stimulation elicits responses from the cortex that are different from the non-specific effects of sham stimulation.

Significance: Our study reaffirms that TMS-EEG represents an effective tool to evaluate cortical neurophysiology with high fidelity.
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http://dx.doi.org/10.1016/j.clinph.2021.05.009DOI Listing
August 2021

Altered interhemispheric signal propagation in schizophrenia and depression.

Clin Neurophysiol 2021 07 26;132(7):1604-1611. Epub 2021 Apr 26.

Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Toronto, ON M6J 1H4, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario M5S 1A1, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario M5S 1A1, Canada. Electronic address:

Objective: Altered interhemispheric connectivity is implicated in the pathophysiology of schizophrenia (SCZ) and major depressive disorder (MDD) and may account for deficits in lateralized cognitive processes. We measured transcranial magnetic stimulation evoked interhemispheric signal propagation (ISP), a non-invasive measure of transcallosal connectivity, and hypothesized that the SCZ and MDD groups will have increased ISP compared to healthy controls.

Methods: We evaluated ISP over the dorsolateral prefrontal cortex in 34 patients with SCZ and 34 patients with MDD compared to 32 age and sex-matched healthy controls.

Results: ISP was significantly increased in patients with SCZ and patients with MDD compared to healthy controls but did not differ between patient groups. There were no effects of antidepressant, antipsychotic, and benzodiazepine medications on ISP and our results remained unchanged after re-analysis with a region of interest method.

Conclusion: Altered ISP was found in both SCZ and MDD patient groups. This indicates that disruptions of interhemispheric signaling processes can be indexed with ISP across psychiatric populations.

Significance: These findings enhance our knowledge of the physiological mechanisms of interhemispheric imbalances in SCZ and MDD, which may serve as potential treatment targets in future patients.
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http://dx.doi.org/10.1016/j.clinph.2021.03.039DOI Listing
July 2021

Assessing and stabilizing atypical plasticity in autism spectrum disorder using rTMS: Results from a proof-of-principle study.

Clin Neurophysiol 2021 May 5. Epub 2021 May 5.

Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada; Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Toronto, ON, Canada; Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry, University of California San Diego, San Diego, CA, USA.

Objectives: Emerging evidence implicates atypical plasticity in the neurophysiology of autism spectrum disorder (ASD). Specifically, autistic people demonstrated hyperplasticity in response to theta-burst stimulation (TBS). We hypothesized that autistic adults would display hyperplasticity to TBS and that repetitive transcranial magnetic stimulation (rTMS) - which potentiates brain inhibitory mechanisms - would 'stabilize' hyperplasticity.

Methods: Using a randomized, cross-over design, plasticity was assessed using TBS in the left motor cortex (M1) in 31 autistic adults and 30 sex-, intelligence quotient-, and age-matched controls. Autistic adults (n = 29) were further randomized (1:1) to receive a single session of active (n = 14) or sham (n = 15) rTMS (6000 pulses at 20 Hz) over left M1 and plasticity was reassessed on the next day following rTMS.

Results: Both long-term potentiation (LTP) and long-term depression (LTD) were significantly increased in the ASD group, indicating hyperplasticity. Active, but not sham rTMS, attenuated LTD in autistic adults.

Conclusions: We provided further evidence for the presence of brain hyperplasticity in ASD. To our knowledge, this is the first study to show preliminary evidence that an excessive LTD in ASD can be 'stabilized' using rTMS. Such 'stabilizing' effect of rTMS on LTP was not observed, likely due to small sample size or a more specific 'attenuating' effect of rTMS on LTD, compared to LTP.

Significance: These findings indicate atypical brain inhibitory mechanisms behind hyperplasticity in ASD. Utilizing a larger sample, future replication studies could investigate therapeutic opportunities of 'mechanism-driven' rTMS.
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http://dx.doi.org/10.1016/j.clinph.2021.03.046DOI Listing
May 2021

Repetitive transcranial magnetic stimulation (rTMS) in bipolar disorder: A systematic review.

Bipolar Disord 2021 May 4. Epub 2021 May 4.

Department of Psychiatry, University of Toronto, Toronto, ON, Canada.

Objectives: Repetitive transcranial magnetic stimulation (rTMS) is commonly used in unipolar depression; yet, its evidence in bipolar disorder (BD) is limited. We sought to review the evidence on the use of rTMS across the different stages of BD.

Methods: MEDLINE database was systematically searched using the PubMed interface following the PRISMA guidelines. Inclusion criteria were as follows: (i) randomized clinical trials (RCTs), open-label studies, and case series; (ii) specific evaluation of the treatment outcomes using psychometric scales; (iii) clinical studies in adults; and (iv) articles in the English language. The systematic review has been registered on PROSPERO (CRD42020192788).

Results: Thirty-one papers were included in the review. Most studies included participants diagnosed with a bipolar depressive episode (N = 24), have yielded mixed findings, and have yet to reach a consensus on the most effective rTMS protocol. Few studies examined the effect of rTMS during manic (N = 5) or mixed episode (N = 1), or as maintenance treatment (N = 1). The limited data thus far suggest rTMS to be relatively safe and well tolerated. Small sample sizes, heterogeneity among study designs, patients and control groups recruited, rTMS parameters, and outcome measures are among the most significant limitations to these studies.

Conclusion: The current data regarding the application of rTMS in BD patients remain limited. More adequately powered sham-controlled studies are required to verify its efficacy. Large-scale clinical trials are needed to also determine whether its effects extend to manic and mixed episodes, as well as its role in mood stabilization and amelioration of suicidal behavior.
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http://dx.doi.org/10.1111/bdi.13099DOI Listing
May 2021

An update on antidepressant pharmacotherapy in late-life depression.

Expert Opin Pharmacother 2021 Oct 19;22(14):1909-1917. Epub 2021 Jun 19.

Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Toronto, Canada.

: Clinically important depressive symptoms that occur in adults over age 60 are often termed late-life depression (LLD). LLD poses challenges for treating clinicians in both detection and treatment. Antidepressants are the most common first-line treatment approach. Older adults are at an increased risk of adverse effects because of polypharmacy.: This article summarizes the challenges and approaches when using pharmacotherapy in LLD with a focus on newer data that have become available during the last five years. While no new antidepressants have become available during this period, a review of the literature summarizes advances in the knowledge of the adverse effects associated with various antidepressants and on the potential contribution of pharmacogenetic tools when prescribing antidepressants to older patients.: During the past 5 years, most of the literature relevant to the pharmacotherapy of MDD in older patients has focused on adverse effects. In particular, the effects of antidepressants on cognition and bone are emerging as important areas for clinical attention and further investigation. There is also an emerging literature on the potential role of pharmacogenetic testing in patients with MDD, though recommendations for use in older adults await larger studies that demonstrate its efficacy and cost-effectiveness.
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http://dx.doi.org/10.1080/14656566.2021.1921736DOI Listing
October 2021

Electroconvulsive therapy with a memory reactivation intervention for post-traumatic stress disorder: A randomized controlled trial.

Brain Stimul 2021 May-Jun;14(3):635-642. Epub 2021 Mar 27.

Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Ontario, Canada; Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada; Department of Pharmacology & Toxicology, University of Toronto, Ontario, Canada. Electronic address:

Background: Post-traumatic Stress Disorder (PTSD) often does not respond to available treatments. Memories are vulnerable to disruption during reconsolidation, and electroconvulsive therapy (ECT) has amnestic effects OBJECTIVE/HYPOTHESIS: To test the use of ECT to disrupt the reconsolidation of traumatic memories as a potential treatment for PTSD METHODS: Participants were adults from the civilian population and were referred for ECT treatment for severe depression with comorbid PTSD symptoms. Twenty-eight participants were randomly assigned to reactivation of a traumatic or non-traumatic memory using audio script driven imagery prior to each ECT treatment. Primary outcomes were change in scores on the Modified PTSD Symptom Scale - Self Report (MPSS-SR) and the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5). Secondary outcomes included a comparison of the change in heart rate while listening to the script RESULTS: Twenty-five female patients who completed a post-ECT assessment were included in the analysis. No significant group differences were found in the MPSS-SR or CAPS-5 scores from pre-ECT to post-ECT or 3-month follow-ups. However, both groups improved at post-ECT and 3-month follow up. Partial eta squared estimates of effect size showed large effect sizes for all outcomes (η > 0.13). Changes in heart rate were not significantly different between groups or over time CONCLUSIONS: ECT paired with pre-treatment traumatic memory reactivation was not more effective for treating PTSD symptoms than ECT with non-traumatic memory reactivation. While our primary hypothesis was not supported, our data provides further support for the efficacy of ECT for improving symptoms of PTSD with comorbid depression. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04027452.

Identifier: NCT04027452.
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http://dx.doi.org/10.1016/j.brs.2021.03.015DOI Listing
March 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.
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http://dx.doi.org/10.1016/j.jad.2021.03.010DOI Listing
May 2021

A practical overview and decision tool for analyzing recurrent events in mental illness: A review.

J Psychiatr Res 2021 05 16;137:7-13. Epub 2021 Feb 16.

Institute of Health Policy Management and Evaluation, University of Toronto, Toronto, ON, Canada; ICES, Toronto, ON, Canada.

Mental illnesses are chronic conditions in which an individual will often experience recurrent outcomes such as hospitalization, symptomatic relapse or self-harm behaviours. Most clinical research in psychiatry considers only the first event, and does not analyze subsequent recurrent events. Methods exist to analyze recurrent events; however, these methods are underused in the psychiatric research literature. This review identifies that recurrent events can be analyzed using a time homogenous or time-to-recurrent-event (TTRE) framework. The TTRE framework is underutilized in psychiatric research; however, this framework allows for longitudinal observations that are more congruent with the chronic nature of psychiatric illness than typical first event analyses. There are several readily available statistical models using the TTRE framework extending the standard Cox proportional hazards model. Our decision tool outlines four aspects of a research question to consider when selecting a TTRE model: (1) importance of event timing, (2) explanatory vs predictive, (3) common vs event-specific hazard, and (4) correlation of events within an individual. Analyzing recurrent events in psychiatric research provides an opportunity to address research questions aimed at understanding the longitudinal course of a chronic condition. These approaches may provide novel insights into risk factors or interventions for psychiatric illness, and ultimately improved outcomes for these chronic conditions.
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http://dx.doi.org/10.1016/j.jpsychires.2021.02.031DOI Listing
May 2021

Genome-wide analysis suggests the importance of vascular processes and neuroinflammation in late-life antidepressant response.

Transl Psychiatry 2021 02 15;11(1):127. Epub 2021 Feb 15.

Institute of Medical Science, University of Toronto, Toronto, ON, Canada.

Antidepressant outcomes in older adults with depression is poor, possibly because of comorbidities such as cerebrovascular disease. Therefore, we leveraged multiple genome-wide approaches to understand the genetic architecture of antidepressant response. Our sample included 307 older adults (≥60 years) with current major depression, treated with venlafaxine extended-release for 12 weeks. A standard genome-wide association study (GWAS) was conducted for post-treatment remission status, followed by in silico biological characterization of associated genes, as well as polygenic risk scoring for depression, neurodegenerative and cerebrovascular disease. The top-associated variants for remission status and percentage symptom improvement were PIEZO1 rs12597726 (OR = 0.33 [0.21, 0.51], p = 1.42 × 10) and intergenic rs6916777 (Beta = 14.03 [8.47, 19.59], p = 1.25 × 10), respectively. Pathway analysis revealed significant contributions from genes involved in the ubiquitin-proteasome system, which regulates intracellular protein degradation with has implications for inflammation, as well as atherosclerotic cardiovascular disease (n = 25 of 190 genes, p = 8.03 × 10, FDR-corrected p = 0.01). Given the polygenicity of complex outcomes such as antidepressant response, we also explored 11 polygenic risk scores associated with risk for Alzheimer's disease and stroke. Of the 11 scores, risk for cardioembolic stroke was the second-best predictor of non-remission, after being male (Accuracy = 0.70 [0.59, 0.79], Sensitivity = 0.72, Specificity = 0.67; p = 2.45 × 10). Although our findings did not reach genome-wide significance, they point to previously-implicated mechanisms and provide support for the roles of vascular and inflammatory pathways in LLD. Overall, significant enrichment of genes involved in protein degradation pathways that may be impaired, as well as the predictive capacity of risk for cardioembolic stroke, support a link between late-life depression remission and risk for vascular dysfunction.
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http://dx.doi.org/10.1038/s41398-021-01248-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884410PMC
February 2021

Optimized repetitive transcranial magnetic stimulation techniques for the treatment of major depression: A proof of concept study.

Psychiatry Res 2021 04 7;298:113790. Epub 2021 Feb 7.

Krembil Research Institute, University Health Network, Toronto, ON, Canada; Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON, Canada; Department of Psychiatry, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.

Although effective in major depressive disorder (MDD), repetitive transcranial magnetic stimulation (rTMS) is costly and complex, limiting accessibility. To address this, we tested the feasibility of novel rTMS techniques with cost-saving opportunities, such as an open-room setting, large non-focal parabolic coils, and custom-built coil arms. We employed a low-frequency (LF) 1 Hz stimulation protocol (360 pulses per session), delivered on the most affordable FDA-approved device. MDD participants received an initial accelerated rTMS course (arTMS) of 6 sessions/day over 5 days (30 total), followed by a tapering course of daily sessions (up to 25) to decrease the odds of relapse. The self-reported Beck Depression Inventory II (BDI-II) was used to measure severity of depression. Forty-eight (48) patients completed the arTMS course. No serious adverse events occurred, and all patients reported manageable pain levels. Response and remission rates were 35.4% and 27.1% on the BDI-II, respectively, at the end of the tapering course. Repeated measures ANOVA showed significant changes of BDI-II scores over time. Even though our protocol will require further improvements, some of the concepts we introduced here could help guide the design of future trials aiming at increasing accessibility to rTMS.
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http://dx.doi.org/10.1016/j.psychres.2021.113790DOI Listing
April 2021

Effects of Repetitive Transcranial Magnetic Stimulation on Working Memory Performance and Brain Structure in People With Schizophrenia Spectrum Disorders: A Double-Blind, Randomized, Sham-Controlled Trial.

Biol Psychiatry Cogn Neurosci Neuroimaging 2021 04 28;6(4):449-458. Epub 2020 Nov 28.

Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada; Department of Psychiatry, University of California San Diego School of Medicine, La Jolla, California.

Background: There are currently no approved treatments for working memory deficits in schizophrenia spectrum disorders (SSDs). The objective of the present study was to assess whether repetitive transcranial magnetic stimulation (rTMS) to the bilateral dorsolateral prefrontal cortex (DLPFC) in people with SSDs 1) improves working memory deficits and 2) changes brain structure.

Methods: We conducted a double-blind, parallel, randomized, sham-controlled study at the Centre for Addiction and Mental Health in Toronto, Canada. We randomized 83 participants with SSDs to receive either active 20 Hz rTMS applied to the bilateral DLPFC or sham rTMS for 4 weeks. The participants also completed pre/posttreatment magnetic resonance imaging. Clinical and cognitive assessments were performed at baseline, treatment end, and 1 month later. The primary outcome was change in verbal n-back working memory performance accuracy (d-prime). The secondary outcome measures were change in DLPFC thickness and fractional anisotropy of white matter tracts connecting to the DLPFC. Prespecified exploratory outcome measures were changes in general cognition; positive, negative, and depressive symptoms.

Results: Compared with sham treatment, active rTMS did not lead to significant change in working memory performance; it was associated with an increase in right DLPFC thickness but not fractional anisotropy. Prespecified exploratory analysis showed a significant decrease in depressive symptoms in the active group; the decrease in depressive symptoms was correlated with an increase in right DLPFC thickness.

Conclusions: Although rTMS applied to the bilateral DLPFC was not efficacious in treating working memory deficits in SSDs, it did increase right DLPFC thickness and decrease depressive symptoms. These findings deserve further study given the lack of efficacy of antidepressant medications in SSDs.
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http://dx.doi.org/10.1016/j.bpsc.2020.11.011DOI Listing
April 2021
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