Search

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

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

Background: Repetitive transcranial magnetic stimulation (rTMS) has become increasingly popular during the last decades mainly driven by the antidepressant effects of dorsolateral prefrontal cortex stimulation with "butterfly" coils. Only recently, alternative targets such as the dorsomedial prefrontal cortex (dmPFC) have been brought into focus and innovative coil designs such as the angled geometry of the double cone coil (DCC) have raised hope to reach even deeper located targets., Objective: To provide a systematic and comprehensive review on the application of rTMS stimulation of the dmPFC using the DCC in neuropathological and healthy samples., Methods: We systematically searched the MEDLINE® database (http://www.ncbi.nlm.nih.gov/pubmed/). Due to the heterogeneous naming of DCC stimulation over the dmPFC a variety of search terms was applied resulting in a numeral quantity of 340 hits., Results: DCC stimulation over the dmPFC has been proven to be safe and feasible in various neuropsychiatric disorders and in healthy subjects. Clinical results are encouraging, but have to be considered as preliminary as data from sham-controlled clinical trials and knowledge about the neurobiological underpinnings are still scarce., Conclusion: DCC stimulation over the dmPFC represents a promising approach in the fast evolving noninvasive brain stimulation techniques aiming at the functional modulation of brain areas vitally involved in affect, sensory autonomic, cognitive, and salience regulation. This may hold potential for both neuroscientific research and clinical applications in the treatment of psychiatric disorders., (© 2018 International Neuromodulation Society.)

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

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

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

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

Background: Accurate neuronavigation is essential for optimal outcomes in therapeutic brain stimulation. MRI-guided neuronavigation, the current gold standard, requires access to MRI and frameless stereotaxic equipment, which is not available in all settings. Scalp-based heuristics depend on operator skill, with variable reproducibility across operators and sessions. An intermediate solution would offer superior reproducibility and ease-of-use to scalp measurements, without requiring MRI and frameless stereotaxy., Objective: We present and assess a novel neuronavigation method using commercially-available, inexpensive 3D head scanning, computer-aided design, and 3D-printing tools to fabricate form-fitted headsets for individuals that hold a stimulator, such as an rTMS coil, in the desired position over the scalp., Methods: 20 individuals underwent scanning for fabrication of individualized headsets designed for rTMS of the left dorsolateral prefrontal cortex (DLPFC). An experienced operator then performed three trials per participant of three neuronavigation methods: MRI-guided, scalp-measurement (BeamF3 method), and headset placement, and marked the sites obtained. Accuracy (versus MRI-guidance) and reproducibility were measured for each trial of each method., Results: Within-subject accuracy (against a gold-standard centroid of three MRI-guided localizations) for MRI-guided, scalp-measurement, and headset methods was 3.7  ±  1.6 mm, 14.8  ±  7.1 mm, and 9.7  ±  5.2 mm respectively, with headsets significantly more accurate (M  =  5.1, p  =  0.008) than scalp-measurement methods. Within-subject reproducibility (against the centroid of 3 localizations in the same modality) was 3.7  ±  1.6 mm (MRI), 4.2  ±  1.4 (scalp-measurement), and 1.4  ±  0.7 mm (headset), with headsets achieving significantly better reproducibility than either other method (p  <  0.0001)., Conclusions: 3D-printed headsets may offer good accuracy, superior reproducibility and greater ease-of-use for stimulator placement over DLPFC, in settings where MRI-guidance is impractical.

Background: Dysfunctional neuroplasticity may be one of the pathophysiological mechanisms underlying major depression. We have previously established methods to assess neuroplasticity from the dorsolateral prefrontal cortex (DLPFC) using a paired associative stimulation (PAS) paradigm, which pairs a preceding peripheral nerve stimulation with subsequent transcranial magnetic stimulation (TMS) combined with electroencephalography (EEG). We aimed to investigate neuroplasticity through the PAS paradigm in the DLPFC in patients with depression compared to healthy subjects., Methods: Twenty-nine patients with depression and 28 healthy controls participated in this study. There were no significant age or sex differences between the two groups. All participants received PAS paradigm in the DLPFC. We analyzed PAS induced potentiation from the DLPFC in both groups calculating the power of TMS-evoked potentials (TEP). A two-way ANOVA with PAS effect as a within-subject factor and diagnostic group as a between-subject factor was performed to examine the group differences in the PAS paradigm., Results: DLPFC-PAS induced a significant potentiation at the stimulation site in both patients and healthy subjects (mean ± SD: 1.24 ± 0.33 [μV] vs. 1.48 ± 0.28 [μV]). However, when we compared PAS potentiation between patients and healthy subjects, there were significant main effects of PAS (F 1,53  = 68.63, p < 0.0001) and PAS-by-diagnostic group interaction (F 1,53  = 25.05, p < 0.0001). Post hoc analysis demonstrated that patients had a significantly lower PAS potentiation compared to healthy subjects (t 55  = 3.128, p = 0.003)., Conclustions: Our findings provide evidence for impaired neuroplasticity in DLPFC in patients with depression compared to healthy subjects. Such findings may ultimately help us understand the pathophysiology of MDD and mechanisms involved in its treatment., (© 2018 Wiley Periodicals, Inc.)

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

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

Posttraumatic stress disorder (PTSD) is a common comorbid condition in anorexia nervosa (AN) and bulimia nervosa (BN), and may be associated with reduced response to treatment. We report on a case series employing repetitive transcranial magnetic stimulation (rTMS) with a novel target, the dorsomedial prefrontal cortex (DMPFC). Fourteen subjects with eating disorders and comorbid PTSD received 20-30 neuronavigated DMPFC-rTMS treatments on an open-label basis. PTSD symptoms were assessed pretreatment and posttreatment with the PTSD checklist-Civilian (PCL-C) and the Difficulties in Emotional Regulation Scale (DERS). PCL-C scores were reduced by 51.99% ± 27.24% overall, from a mean of 54.29 ± 19.34 pretreatment to 24.86 ± 17.43 posttreatment (p < .001). Of the 14, 8 showed an improvement of >50%. DERS scores improved by 36.02% ± 24.24% overall, from 140.00 ± 22.09 at pretreatment to 89.29 ± 38.31 at posttreatment (p < .001). OF the 14 subjects, 5 achieved >50% improvement. These data may suggest that DMPFC-rTMS could be helpful in the treatment of PTSD in some ED patients., (© 2017 Wiley Periodicals, Inc.)

Obsessive-compulsive disorder (OCD) is a disabling illness with high rates of nonresponse to conventional treatments. OCD pathophysiology is believed to involve abnormalities in cortico-striatal-thalamic-cortical circuits through regions such as dorsomedial prefrontal cortex (dmPFC) and ventral striatum. These regions may constitute therapeutic targets for neuromodulation treatments, such as repetitive transcranial magnetic stimulation (rTMS). However, the neurobiological predictors and correlates of successful rTMS treatment for OCD are unclear. Here, we used resting-state functional magnetic resonance imaging (fMRI) to identify neural predictors and correlates of response to 20-30 sessions of bilateral 10 Hz dmPFC-rTMS in 20 treatment-resistant OCD patients, with 40 healthy controls as baseline comparators. A region of interest in the dmPFC was used to generate whole-brain functional connectivity maps pre-treatment and post treatment. Ten of 20 patients met the response criteria (⩾50% improvement on Yale-Brown Obsessive-Compulsive Scale, YBOCS); response to dmPFC-rTMS was sharply bimodal. dmPFC-rTMS responders had higher dmPFC-ventral striatal connectivity at baseline. The degree of reduction in this connectivity, from pre- to post-treatment, correlated to the degree of YBOCS symptomatic improvement. Baseline clinical and psychometric data did not predict treatment response. In summary, reductions in fronto-striatal hyperconnectivity were associated with treatment response to dmPFC-rTMS in OCD. This finding is consistent with previous fMRI studies of deep brain stimulation in OCD, but opposite to previous reports on mechanisms of dmPFC-rTMS in major depression. fMRI could prove useful in predicting the response to dmPFC-rTMS in OCD.

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

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

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

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

Background: Conventional treatments for eating disorders are associated with poor response rates and frequent relapse. Novel treatments are needed, in combination with markers to characterize and predict treatment response. Here, resting-state functional magnetic resonance imaging (rs-fMRI) was used to identify predictors and correlates of response to repetitive transcranial magnetic stimulation (rTMS) of the dorsomedial prefrontal cortex (dmPFC) at 10 Hz for eating disorders with refractory binge/purge symptomatology., Methods: 28 subjects with anorexia nervosa, binge-purge subtype or bulimia nervosa underwent 20-30 sessions of 10 Hz dmPFC rTMS. rs-fMRI data were collected before and after rTMS. Subjects were stratified into responder and nonresponder groups using a criterion of ≥50% reduction in weekly binge/purge frequency. Neural predictors and correlates of response were identified using seed-based functional connectivity (FC), using the dmPFC and adjacent dorsal anterior cingulate cortex (dACC) as regions of interest., Results: 16 of 28 subjects met response criteria. Treatment responders had lower baseline FC from dmPFC to lateral orbitofrontal cortex and right posterior insula, and from dACC to right posterior insula and hippocampus. Responders had low baseline FC from the dACC to the ventral striatum and anterior insula; this connectivity increased over treatment. However, in nonresponders, frontostriatal FC was high at baseline, and dmPFC-rTMS suppressed FC in association with symptomatic worsening., Conclusions: Enhanced frontostriatal connectivity was associated with responders to dmPFC-rTMS for binge/purge behavior. rTMS caused paradoxical suppression of frontostriatal connectivity in nonresponders. rs-fMRI could prove critical for optimizing stimulation parameters in a future sham-controlled trial of rTMS in disordered eating.

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

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

Despite its high toll on society, there has been little recent improvement in treatment efficacy for major depressive disorder (MDD). The identification of biological markers of successful treatment response may allow for more personalized and effective treatment. Here we investigate whether resting-state functional connectivity predicted response to treatment with repetitive transcranial magnetic stimulation (rTMS) to dorsomedial prefrontal cortex (dmPFC). Twenty-five individuals with treatment-refractory MDD underwent a 4-week course of dmPFC-rTMS. Before and after treatment, subjects received resting-state functional MRI scans and assessments of depressive symptoms using the Hamilton Depresssion Rating Scale (HAMD17). We found that higher baseline cortico-cortical connectivity (dmPFC-subgenual cingulate and subgenual cingulate to dorsolateral PFC) and lower cortico-thalamic, cortico-striatal, and cortico-limbic connectivity were associated with better treatment outcomes. We also investigated how changes in connectivity over the course of treatment related to improvements in HAMD17 scores. We found that successful treatment was associated with increased dmPFC-thalamic connectivity and decreased subgenual cingulate cortex-caudate connectivity, Our findings provide insight into which individuals might respond to rTMS treatment and the mechanisms through which these treatments work.

Although rTMS is moving steadily into the mainstream as a treatment for medically refractory depression, its efficacy continues to lag behind that of more invasive neuromodulation treatments such as ECT or DBS. Here we review evidence to suggest that a fruitful, but neglected, strategy for improving rTMS efficacy may be to explore alternatives to the conventional stimulation target in the dorsolateral prefrontal cortex (DLPFC). The convergent evidence of lesion, stimulation, connectivity, and correlative neuroimaging studies suggests that the DLPFC may have a relatively peripheral role in mood regulation, at least compared to several alternative areas within the prefrontal cortex. In particular, we consider the evidence base in support of four new potential targets for rTMS in depression: dorsomedial prefrontal cortex (DMPFC), frontopolar cortex (FPC), ventromedial prefrontal cortex (VMPFC), and ventrolateral prefrontal cortex (VLPFC). Each of these regions enjoys broader support, from a more diverse evidence base, than the DLPFC in terms of its role in emotion regulation in major depression. We discuss the relative merits of each of these novel targets, including potential obstacles to stimulation using currently available technologies, and potential strategies for overcoming these obstacles. It is hoped that this detailed review will spur a more vigorous exploration of new targets for rTMS in depression. The use of new targets may help to propel rTMS across the threshold of efficacy required of a first-line treatment, to assume a more widespread role in the treatment of depressed mood., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Patients with Obsessive-Compulsive Disorder (OCD) often show minimal response to either pharmacotherapy or psychotherapy. Repetitive transcranial magnetic stimulation (rTMS) is being explored as a new treatment for OCD. rTMS targeting the dorsolateral prefrontal cortex (DLPFC) has not shown robust efficacy; however, neuroimaging studies of OCD have shown more consistent volumetric grey matter reductions along the medial rather than the lateral prefrontal cortex, specifically in the dorsomedial prefrontal cortex (DMPFC). rTMS targeting medial motor areas such as the supplementary motor area (SMA) and pre-SMA has shown some efficacy in OCD. However, the DMPFC proper, just anterior to the pre-SMA, has not previously been targeted. We have previously used a novel rTMS technique to target DMPFC with robust effects in refractory depression. Here we apply this technique in an open-label series of 10 consecutive patients with refractory OCD. Under MRI-guidance, patients received bilateral DMPFC-rTMS at 10 Hz, 120% resting motor threshold, 6000 pulses per day for 20 - 30 sessions over 4-6 weeks. Robust improvements were achieved, with YBOCS scores dropping by more than half in the large majority of cases and full remission achieved in several cases. Scores continued dropping after treatment in some cases, suggesting durable improvements in capacity to suppress intrusive thoughts and behaviours. Improvements were durable at 3-6 months. Pre- and post-treatment functional MRI revealed changes in resting-state connectivity to DMPFC following treatment. A sham-controlled trial may be warranted as a next step. If successful, DMPFC-rTMS may represent a new, effective therapeutic option in refractory OCD. [Copyright &y& Elsevier]