Electroconvulsive therapy-induced volumetric brain changes converge on a common causal circuit in depression.

Neurostimulation is a mainstream treatment option for major depression. Neuromodulation techniques apply repetitive magnetic or electrical stimulation to some neural target but significantly differ in their invasiveness, spatial selectivity, mechanism of action, and efficacy. Despite these differences, recent analyses of transcranial magnetic stimulation (TMS) and deep brain stimulation (DBS)-treated individuals converged on a common neural network that might have a causal role in treatment response. We set out to investigate if the neuronal underpinnings of electroconvulsive therapy (ECT) are similarly associated with this causal depression network (CDN). Our aim here is to provide a comprehensive analysis in three cohorts of patients segregated by electrode placement (N = 246 with right unilateral, 79 with bitemporal, and 61 with mixed) who underwent ECT. We conducted a data-driven, unsupervised multivariate neuroimaging analysis Principal Component Analysis (PCA) of the cortical and subcortical volume changes and electric field (EF) distribution to explore changes within the CDN associated with antidepressant outcomes. Despite the different treatment modalities (ECT vs TMS and DBS) and methodological approaches (structural vs functional networks), we found a highly similar pattern of change within the CDN in the three cohorts of patients (spatial similarity across 85 regions: r = 0.65, 0.58, 0.40, df = 83). Most importantly, the expression of this pattern correlated with clinical outcomes (t = -2.35, p = 0.019). This evidence further supports that treatment interventions converge on a CDN in depression. Optimizing modulation of this network could serve to improve the outcome of neurostimulation in depression.

Telemedicine-Based Cognitive Examinations During COVID-19 and Beyond: Perspective of the Massachusetts General Hospital Behavioral Neurology & Neuropsychiatry Group.

Telehealth and telemedicine have encountered explosive growth since the beginning of the COVID-19 pandemic, resulting in increased access to care for patients located far from medical centers and clinics. Subspecialty clinicians in behavioral neurology & neuropsychiatry (BNNP) have implemented the use of telemedicine platforms to perform cognitive examinations that were previously office based. In this perspective article, BNNP clinicians at Massachusetts General Hospital (MGH) describe their experience performing cognitive examinations via telemedicine. The article reviews the goals, prerequisites, advantages, and potential limitations of performing a video- or telephone-based telemedicine cognitive examination. The article shares the approaches used by MGH BNNP clinicians to examine cognitive and behavioral areas, such as orientation, attention and executive functions, language, verbal learning and memory, visual learning and memory, visuospatial function, praxis, and abstract abilities, as well as to survey for neuropsychiatric symptoms and assess activities of daily living. Limitations of telemedicine-based cognitive examinations include limited access to and familiarity with telecommunication technologies on the patient side, limitations of the technology itself on the clinician side, and the limited psychometric validation of virtual assessments. Therefore, an in-person examination with a BNNP clinician or a formal in-person neuropsychological examination with a neuropsychologist may be recommended. Overall, this article emphasizes the use of standardized cognitive and behavioral assessment instruments that are either in the public domain or, if copyrighted, are nonproprietary and do not require a fee to be used by the practicing BNNP clinician.

Transcranial Magnetic Stimulation for the Neurological Patient: Scientific Principles and Applications.

Non-invasive brain stimulation has been increasingly recognized for its potential as an investigational, diagnostic and therapeutic tool across the clinical neurosciences. Transcranial magnetic stimulation (TMS) is a non-invasive method of focal neuromodulation. Diagnostically, TMS can be used to probe cortical excitability and plasticity, as well as for functional mapping. Therapeutically, depending on the pattern employed, TMS can either facilitate or inhibit stimulated cortex potentially modulating maladaptive physiology through its effects on neuroplasticity. Despite this potential, applications of TMS in neurology have only been approved for diagnostic clinical neurophysiology, pre-surgical mapping of motor and language cortex, and the treatment of migraines. In this article, we discuss the principles of TMS and its clinical applications in neurology, including experimental applications in stroke rehabilitation, seizures, autism spectrum disorder, neurodegenerative disorders, movement disorders, tinnitus, chronic pain and functional neurological disorder. To promote increased cross-talk across neurology and psychiatry, we also succinctly review the TMS literature for the treatment of major depression and obsessive compulsive disorder. Overall, we argue that larger clinical trials that are better informed by circuit-level biomarkers and pathophysiological models will lead to an expansion of the application of TMS for patients cared for by neurologists.

Perturbing fMRI brain dynamics using transcranial direct current stimulation.

The dynamic nature of resting-state functional magnetic resonance imaging (fMRI) brain activity and connectivity has drawn great interest in the past decade. Specific temporal properties of fMRI brain dynamics, including metrics such as occurrence rate and transitions, have been associated with cognition and behaviors, indicating the existence of mechanism distruption in neuropsychiatric disorders. The development of new methods to manipulate fMRI brain dynamics will advance our understanding of these pathophysiological mechanisms from native observation to experimental mechanistic manipulation. In the present study, we applied repeated transcranial direct current stimulation (tDCS) to the right dorsolateral prefrontal cortex (rDLPFC) and the left orbitofrontal cortex (lOFC), during multiple simultaneous tDCS-fMRI sessions from 81 healthy participants to assess the modulatory effects of stimulating target brain regions on fMRI brain dynamics. Using the rDLPFC and the lOFC as seeds, respectively, we first identified two reoccurring co-activation patterns (CAPs) and calculated their temporal properties (e.g., occurrence rate and transitions) before administering tDCS. The spatial maps of CAPs were associated with different cognitive and disease domains using meta-analytical decoding analysis. We then investigated how active tDCS compared to sham tDCS in the modulation of the occurrence rates of these different CAPs and perturbations of transitions between CAPs. We found that by enhancing neuronal excitability of the rDLPFC and the lOFC, the occurrence rate of one CAP was significantly decreased while that of another CAP was significantly increased during the first 6 min of stimulation. Furthermore, these tDCS-associated changes persisted over subsequent testing sessions (both during and before/after tDCS) across three consecutive days. Active tDCS could perturb transitions between CAPs and a non-CAP state (when the rDLPFC and the lOFC were not activated), but not the transitions within CAPs. These results demonstrate the feasibility of modulating fMRI brain dynamics, and open new possibilities for discovering stimulation targets and dynamic connectivity patterns that can ensure the propagation of tDCS-induced neuronal excitability, which may facilitate the development of new treatments for disorders with altered dynamics.

Telemedicine in Behavioral Neurology-Neuropsychiatry: Opportunities and Challenges Catalyzed by COVID-19.

Coronavirus 2019 (COVID-19) has profoundly impacted the well-being of society and the practice of medicine across health care systems worldwide. As with many other subspecialties, the clinical paradigm in behavioral neurology and neuropsychiatry (BN-NP) was transformed abruptly, transitioning to real-time telemedicine for the assessment and management of the vast majorities of patient populations served by our subspecialty. In this commentary, we outline themes from the BN-NP perspective that reflect the emerging lessons we learned using telemedicine during the COVID-19 pandemic. Positive developments include the ability to extend consultations and management to patients in our high-demand field, maintenance of continuity of care, enhanced ecological validity, greater access to a variety of well-reimbursed telemedicine options (telephone and video) that help bridge the digital divide, and educational and research opportunities. Challenges include the need to adapt the mental state examination to the telemedicine environment, the ability to perform detailed motor neurologic examinations in patients where motor features are important diagnostic considerations, appreciating nonverbal cues, managing acute safety and behavioral concerns in less controlled environments, and navigating intervention-based (neuromodulation) clinics requiring in-person contact. We hope that our reflections help to catalyze discussions that should take place within the Society for Behavioral and Cognitive Neurology, the American Neuropsychiatric Association, and allied organizations regarding how to optimize real-time telemedicine practices for our subspecialty now and into the future.

Brain Volumetric Correlates of Right Unilateral Versus Bitemporal Electroconvulsive Therapy for Treatment-Resistant Depression.

OBJECTIVE: The selection of a bitemporal (BT) or right unilateral (RUL) electrode placement affects the efficacy and side effects of ECT. Previous studies have not entirely described the neurobiological underpinnings of such differential effects. Recent neuroimaging research on gray matter volumes is contributing to our understanding of the mechanism of action of ECT and could clarify the differential mechanisms of BT and RUL ECT. METHODS: To assess the whole-brain gray matter volumetric changes observed after treating patients with treatment-resistant depression with BT or RUL ECT, the authors used MRI to assess 24 study subjects with treatment-resistant depression (bifrontotemporal ECT, N=12; RUL ECT, N=12) at two time points (before the first ECT session and after ECT completion). RESULTS: Study subjects receiving BT ECT showed gray matter volume increases in the bilateral limbic system, but subjects treated with RUL ECT showed gray matter volume increases limited to the right hemisphere. The authors observed significant differences between the two groups in midtemporal and subcortical limbic structures in the left hemisphere. CONCLUSIONS: These findings highlight that ECT-induced gray matter volume increases may be specifically observed in the stimulated hemispheres. The authors suggest that electrode placement may relevantly contribute to the development of personalized ECT protocols.

Predictors of Hypomania During Ventral Capsule/Ventral Striatum Deep Brain Stimulation.

Deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VC/VS) is a novel therapy for neuropsychiatric disorders. Hypomania is a known complication of VC/VS DBS, but who is at risk is less understood. Factors such as family history, combined with details of DBS programming, might quantify that risk. The authors performed an iterative modeling procedure on a VC/VS DBS patient registry to identify key predictors. Hypomania was less common for men and for patients stimulated on the ventral right contact. It was more common with right monopolar stimulation. These findings may help to establish decision rules to reduce complications of VC/VS DBS.

Device-based brain stimulation to augment fear extinction: implications for PTSD treatment and beyond.

Conditioned fear acquisition and extinction paradigms have been widely used both in animals and humans to examine the neurobiology of emotional memory. Studies have also shown that patients suffering from posttraumatic stress disorder (PTSD) exhibit deficient extinction recall along with dysfunctional activation of the fear extinction network, including the ventromedial prefrontal cortex, amygdala, and hippocampus. A great deal of overlap exists between this fear extinction network and brain regions associated with symptom severity in PTSD. This suggests that the neural nodes of fear extinction could be targeted to reduce behavioral deficits that may subsequently translate into symptom improvement. In this article, we discuss potential applications of brain stimulation and neuromodulation methods, which, combined with a mechanistic understanding of the neurobiology of fear extinction, could be used to further our understanding of the pathophysiology of anxiety disorders and develop novel therapeutic tools. To this end, we discuss the following stimulation approaches: deep-brain stimulation, vagus nerve stimulation, transcranial direct current stimulation, and transcranial magnetic stimulation. We propose new translational research avenues that, from a systems neuroscience perspective, aim to expand our understanding of circuit dynamics and fear processing toward the practical development of clinical tools, to be used alone or in combination with behavioral therapies.

Multimodal 7T imaging reveals enhanced functional coupling between salience and frontoparietal networks in young adult tobacco cigarette smokers.

Tobacco cigarette smoking is associated with disrupted brain network dynamics in resting brain networks including the Salience (SN) and Fronto parietal (FPN). Unified multimodal methods [Resting state connectivity analysis, Diffusion Tensor Imaging (DTI), neurite orientation dispersion and density imaging (NODDI), and cortical thickness analysis] were employed to test the hypothesis that the impact of cigarette smoking on the balance among these networks is due to alterations in white matter connectivity, microstructural architecture, functional connectivity and cortical thickness (CT) and that these metrics define fundamental differences between people who smoke and nonsmokers. Multimodal analyses of previously collected 7 Tesla MRI data via the Human Connectome Project were performed on 22 people who smoke (average number of daily cigarettes was 10 ± 5) and 22 age- and sex-matched nonsmoking controls. First, functional connectivity analysis was used to examine SN-FPN-DMN interactions between people who smoke and nonsmokers. The anatomy of these networks was then assessed using DTI and CT analyses while microstructural architecture of WM was analyzed using the NODDI toolbox. Seed-based connectivity analysis revealed significantly enhanced within network [p = 0.001 FDR corrected] and between network functional coupling of the salience and R-frontoparietal networks in people who smoke [p = 0.004 FDR corrected]. The network connectivity was lateralized to the right hemisphere. Whole brain diffusion analysis revealed no significant differences between people who smoke and nonsmokers in Fractional Anisotropy, Mean diffusivity and in neurite orienting and density. There were also no significant differences in CT in the hubs of these networks. Our results demonstrate that tobacco cigarette smoking is associated with enhanced functional connectivity, but anatomy is largely intact in young adults. Whether this enhanced connectivity is pre-existing, transient or permanent is not known. The observed enhanced connectivity in resting state networks may contribute to the maintenance of smoking frequency.

Multichannel tDCS with Advanced Targeting for Major Depressive Disorder: A Tele-Supervised At-Home Pilot Study.

Introduction: Proof-of-principle human studies suggest that transcranial direct current stimulation (tDCS) over the dorsolateral prefrontal cortex (DLPFC) may improve depression severity. This open-label multicenter study tested remotely supervised multichannel tDCS delivered at home in patients (N=35) with major depressive disorder (MDD). The primary aim was to assess the feasibility and safety of our protocol. As an exploratory aim, we evaluated therapeutic efficacy: the primary efficacy measure was the median percent change from baseline to the end of the 4-week post-treatment follow-up period in the observer-rated Montgomery-Asberg Depression Mood Rating Scale (MADRS). Methods: Participants received 37 at-home stimulation sessions (30 minutes each) of specifically designed multichannel tDCS targeting the left DLPFC administered over eight weeks (4 weeks of daily treatments plus 4 weeks of taper), with a follow-up period of 4 weeks following the final stimulation session. The stimulation montage (electrode positions and currents) was optimized by employing computational models of the electric field generated by multichannel tDCS using available structural data from a similar population (group optimization). Conducted entirely remotely, the study employed the MADRS for assessment at baseline, at weeks 4 and 8 during treatment, and at 4-week follow-up visits. Results: 34 patients (85.3% women) with a mean age of 59 years, a diagnosis of MDD according to DSM-5 criteria, and a MADRS score ≥20 at the time of study enrolment completed all study visits. At baseline, the mean time since MDD diagnosis was 24.0 (SD 19.1) months. Concerning compliance, 85% of the participants (n=29) completed the complete course of 37 stimulation sessions at home, while 97% completed at least 36 sessions. No detrimental effects were observed, including suicidal ideation and/or behavior. The study observed a median MADRS score reduction of 64.5% (48.6, 72.4) 4 weeks post-treatment (Hedge's g = -3.1). We observed a response rate (≥ 50% improvement in MADRS scores) of 72.7% (n=24) from baseline to the last visit 4 weeks post-treatment. Secondary measures reflected similar improvements. Conclusions: These results suggest that remotely supervised and supported multichannel home-based tDCS is safe and feasible, and antidepressant efficacy motivates further appropriately controlled clinical studies.

The clinical significance of bilateral basal ganglia calcification presenting with mania and delusions.

The authors present the case of a 37-year-old man who developed a psychotic manic episode and was found to have bilateral basal ganglia calcification (BGC). The authors present this case report along with a discussion of the literature on the neuropsychiatry of BGC.

Electroconvulsive Therapy: Mechanisms of Action, Clinical Considerations, and Future Directions.

LEARNING OBJECTIVES: • Outline and discuss the fundamental physiologic, cellular, and molecular mechanisms of ECT to devise strategies to optimize therapeutic outcomes• Summarize the overview of ECT, its efficacy in treating depression, the known effects on cognition, evidence of mechanisms, and future directions. ABSTRACT: Electroconvulsive therapy (ECT) is the most effective treatment for a variety of psychiatric illnesses, including treatment-resistant depression, bipolar depression, mania, catatonia, and clozapine-resistant schizophrenia. ECT is a medical and psychiatric procedure whereby electrical current is delivered to the brain under general anesthesia to induce a generalized seizure. ECT has evolved a great deal since the 1930s. Though it has been optimized for safety and to reduce adverse effects on cognition, issues persist. There is a need to understand fundamental physiologic, cellular, and molecular mechanisms of ECT to devise strategies to optimize therapeutic outcomes. Clinical trials that set out to adjust parameters, electrode placement, adjunctive medications, and patient selection are critical steps towards the goal of improving outcomes with ECT. This narrative review provides an overview of ECT, its efficacy in treating depression, its known effects on cognition, evidence of its mechanisms, and future directions.

Functional hyperconnectivity between corticocerebellar networks and altered decision making in young adult cannabis users: Evidence from 7T and multivariate pattern analysis.

Decision-making (DM) impairments are important predictors of cannabis initiation and continued use. In cannabis users, how decision-making abnormalities related to structural and functional connectivity in the brain are not fully understood. We employed a three-method multimodal image analysis and multivariate pattern analysis (MVPA) on high dimensional 7 tesla MRI images examining functional connectivity, white matter microstructure and gray matter volume in a group of cannabis users and non-users. Neuroimaging and cognitive analyses were performed on 92 CU and 92 age- matched NU from a total of 187 7T scans. CU were selected on the basis of their scores on the Semi-Structured Assessment for the Genetics of Alcoholism. The groups were first compared on a decision-making test and then on ICA based functional connectivity between corticocerebellar networks. An MVPA was done as a confirmatory analysis. The anatomy of these networks was then assessed using Diffusion Tensor imaging (DTI) and cortical volume analyses. Cannabis Users had significantly higher scores on the Iowa Gambling task (IGT) [Gambling task Percentage larger] and significantly lower scores on the [Gambling task reward Percentage smaller]. Left accumbens (L NAc) volume was significantly larger in cannabis users. DTI analysis between the groups yielded no significant (FWE corrected) differences. Resting state FC analysis of the left Cerebellum region 9 showed enhanced functional connectivity with the right nucleus accumbens and left pallidum and left putamen in CU. In addition, posterior cerebellum showed enhanced functional connectivity (FWE corrected) with 2 nodes of the DMN and left and right paracingulate (sub genual ACC) and the sub callosal cortex in CU. IGT percentage larger scores correlated with posterior cerebellar functional connectivity in non-user women. A multivariate pattern analysis confirmed this cerebellar hyperconnectivity in both groups. Our results demonstrate for the first time that deficits in DM observed in cannabis users are mirrored in hyper connectivity in corticocerebellar networks. Cortical volumes of some of the nodes of these networks showed increases in users. However, the underlying white matter was largely intact in CU. The observed DM deficits and hyper connectivity in resting networks may contribute to difficulties in quitting and/or facilitating relapse.

Extension of transcranial magnetic stimulation treatment for depression in non-responders: Results of a naturalistic study.

BACKGROUND: Repetitive Transcranial Magnetic Stimulation (rTMS) shows efficacy in the treatment of major depressive disorder using a standard course of 20-36 treatment sessions. However, research efforts are being made to improve overall response and remission rates. Evidence from open-label extension studies of randomized control trials suggests that extending the rTMS treatment course beyond 36 treatments may improve outcomes, however, little has been published on the benefit of extended TMS treatment courses in clinical practice. OBJECTIVE: In this retrospective naturalistic observational study, we studied response rates on continuation of rTMS following failure of the first round of 36 treatments. METHODS: From 142 patients who received conventional rTMS and 29 who underwent theta-burst stimulation (TBS) at Massachusetts General Hospital TMS clinical service, 28 non-responders (23 to rTMS and 5 to TBS) opted to continue their treatment beyond session 36. The treatment protocol allowed personalization in target, TMS protocol, as well as number of pulses and sessions as clinically indicated. Sustained response and remission using Hamilton Rating Scale for Depression, 17-items (HAMD-17) was the primary outcome. RESULTS: The average number of overall treatment sessions was 70.54 ± 16.73 for the sample. Overall, there was a 53.57% response rate and a 32.14% remission rate. Response and remission rates rose as the number of sessions increased and there did not appear to be a plateau in response over time. CONCLUSION: Our results support the idea that subpopulation of TMS patients are late responders. Continuation of TMS up to 72 treatments among those patients who do not meet response criteria by session 36 may improve overall response rates. While the number of subjects and study design limit generalization, given the fact that these patients were medication refractory and had failed initial course of TMS, the result of this study is encouraging.

The Impact of Sex Hormones on Transcranial Magnetic Stimulation Measures of Cortical Excitability: A Systematic Review and Considerations for Clinical Practice.

ABSTRACT: Repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising alternative for the treatment of major depressive disorder (MDD), although its clinical effectiveness varies substantially. The effects of sex hormone fluctuations on cortical excitability have been identified as potential factors that can explain this variability. However, data on how sex hormone changes affect clinical response to rTMS is limited. To address this gap, we reviewed the literature examining the effects of sex hormones and hormonal treatments on transcranial magnetic stimulation (TMS) measures of cortical excitability. Results show that variations of endogenous estrogen, testosterone, and progesterone have modulatory effects on TMS-derived measures of cortical excitability. Specifically, higher levels of estrogen and testosterone were associated with greater cortical excitability, while higher progesterone was associated with lower cortical excitability. This highlights the importance of additional investigation into the effects of hormonal changes on rTMS outcomes and circuit-specific physiological variables. These results call for TMS clinicians to consider performing more frequent motor threshold (MT) assessments in patients receiving high doses of estrogen, testosterone, and progesterone in cases such as in vitro fertilization, hormone replacement therapy, and gender-affirming hormonal treatments. It may also be important to consider physiological hormonal fluctuations and their impact on depressive symptoms and the MT when treating female patients with rTMS.

Neuroticism modulates the qualitative effects of inferior parietal tDCS on negatively-valenced memories.

For individuals with increased levels of neuroticism, experiencing criticism or receiving negative feedback has been associated with worse psychological and cognitive outcomes. Transcranial direct current stimulation (tDCS) can change cognitive processes in clinical populations. We bilaterally stimulated the posterior inferior parietal lobule (pIPL), a critical superficial node of the default model network. We investigated how baseline neuroticism modulates the impact of bilateral tDCS to pIPL on qualitative measures of memory after hearing criticism, hypothesizing that cathodal stimulation of the IPL would offer qualitative memory improvements for individuals with higher levels of neuroticism. Ninety individuals from the community were randomly assigned to receive anodal, cathodal, or sham stimulation while they were exposed to critical comments before and after stimulation. Participants then recalled the critical comments, and their linguistic responses were analyzed using Pennebaker's Linguistic Inquiry and Word Count software, a quantitative analysis software for linguistic data. Results showed that for individuals receiving cathodal tDCS, higher neuroticism scores corresponded with greater proportions of non-personal language (i.e., words such as "us," "they," or "other" instead of "I" or "me") when recalling negative feedback. For individuals with higher neuroticism, cathodal tDCS stimulation, rather than anodal or sham, of the pIPL prompted increased emotional distancing and perspective taking strategies when recalling criticism. These results further highlight the state-dependent nature of tDCS effects and the role of the IPL in interpersonal processing - a clinically meaningful outcome that current tDCS studies solely examining quantitative measures of memory (e.g., task-based accuracy or speed) do not reveal.

Cerebellar transcranial magnetic stimulation in psychotic disorders: intermittent, continuous, and sham theta-burst stimulation on time perception and symptom severity.

Background: The cerebellum contributes to the precise timing of non-motor and motor functions, and cerebellum abnormalities have been implicated in psychosis pathophysiology. In this study, we explored the effects of cerebellar theta burst stimulation (TBS), an efficient transcranial magnetic stimulation protocol, on temporal discrimination and self-reported mood and psychotic symptoms. Methods: We conducted a case-crossover study in which patients with psychosis (schizophrenias, schizoaffective disorders, or bipolar disorders with psychotic features) were assigned to three sessions of TBS to the cerebellar vermis: one session each of intermittent (iTBS), continuous (cTBS), and sham TBS. Of 28 enrolled patients, 26 underwent at least one TBS session, and 20 completed all three. Before and immediately following TBS, participants rated their mood and psychotic symptoms and performed a time interval discrimination task (IDT). We hypothesized that cerebellar iTBS and cTBS would modulate these measures in opposing directions, with iTBS being adaptive and cTBS maladaptive. Results: Reaction time (RT) in the IDT decreased significantly after iTBS vs. Sham (LS-mean difference = -73.3, p = 0.0001, Cohen's d = 1.62), after iTBS vs. cTBS (LS-mean difference = -137.6, p < 0.0001, d = 2.03), and after Sham vs. cTBS (LS-mean difference = -64.4, p < 0.0001, d = 1.33). We found no effect on IDT accuracy. We did not observe any effects on symptom severity after correcting for multiple comparisons. Conclusion: We observed a frequency-dependent dissociation between the effects of iTBS vs. cTBS to the cerebellar midline on the reaction time of interval discrimination in patients with psychosis. iTBS showed improved (adaptive) while cTBS led to worsening (maladaptive) speed of response. These results demonstrate behavioral target engagement in a cognitive dimension of relevance to patients with psychosis and generate testable hypotheses about the potential therapeutic role of cerebellar iTBS in this clinical population. Clinical Trial Registration: clinicaltrials.gov, identifier NCT02642029.

Brain volumetric correlates of electroconvulsive therapy versus transcranial magnetic stimulation for treatment-resistant depression.

BACKGROUND: Electroconvulsive therapy (ECT) and repetitive transcranial magnetic stimulation (rTMS) are effective neuromodulation therapies for treatment-resistant depression (TRD). While ECT is generally considered the most effective antidepressant, rTMS is less invasive, better tolerated and leads to more durable therapeutic benefits. Both interventions are established device antidepressants, but it remains unknown if they share a common mechanism of action. Here we aimed to compare the brain volumetric changes in patients with TRD after right unilateral (RUL) ECT versus left dorsolateral prefrontal cortex (lDLPFC) rTMS. METHODS: We assessed 32 patients with TRD before the first treatment session and after treatment completion using structural magnetic resonance imaging. Fifteen patients were treated with RUL ECT and seventeen patients received lDLPFC rTMS. RESULTS: Patients receiving RUL ECT, in comparison with patients treated with lDLPFC rTMS, showed a greater volumetric increase in the right striatum, pallidum, medial temporal lobe, anterior insular cortex, anterior midbrain, and subgenual anterior cingulate cortex. However, ECT- or rTMS-induced brain volumetric changes were not associated with the clinical improvement. LIMITATIONS: We evaluated a modest sample size with concurrent pharmacological treatment and without neuromodulation therapies randomization. CONCLUSIONS: Our findings suggest that despite comparable clinical outcomes, only RUL ECT is associated with structural change, while rTMS is not. We hypothesize that structural neuroplasticity and/or neuroinflammation may explain the larger structural changes observed after ECT, whereas neurophysiological plasticity may underlie the rTMS effects. More broadly, our results support the notion that there are multiple therapeutic strategies to move patients from depression to euthymia.

White matter markers and predictors for subject-specific rTMS response in major depressive disorder.

Repetitive transcranial magnetic stimulation (rTMS) has established therapeutic efficacy for major depressive disorder (MDD). While translational research has focused primarily on understanding the mechanism of action of TMS on functional activation and connectivity, the effects on structural connectivity remain largely unknown especially when rTMS is applied using subject-specific brain targets. This study aims to use novel diffusion magnetic resonance imaging (dMRI) analysis to examine microstructural changes related to rTMS treatment response using a unique cohort of 21 patients with MDD treated using rTMS with subject-specific targets. White matter dMRI microstructural measures and clinical scores were captured before and after the full course of treatment. We defined disease-relevant fiber bundles connected to different subregions of the left prefrontal cortex and analyzed changes in diffusion properties as well as correlations between the changes of dMRI measures and the changes in Hamilton Depression Rating Scale (HAMD). No significant changes were observed in tracts connected to the TMS targets. rTMS significantly increased the extra-axonal free-water volume, fractional anisotropy and decreased the radial diffusivity in anterior-medial prefrontal fiber bundles but did not lead to raw changes in lateral prefrontal tracts. That said, the microstructural changes in the lateral prefrontal white matter were significantly correlated with treatment response. Moreover, pre-rTMS dMRI measures of the dorsal anterior cingulate cortex and lateral prefrontal cortex connections are correlated with changes in HAMD scores. Microstructural changes in the anterior-medial and lateral prefrontal white matter are potentially involved in treatment response to TMS, though further investigation is needed using larger datasets.