Effects of repetitive transcranial magnetic stimulation on individual variability of resting-state functional connectivity in major depressive disorder.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for major depressive disorder (MDD), but substantial heterogeneity in outcomes remains. We examined a potential mechanism of action of rTMS to normalize individual variability in resting-state functional connectivity (rs-fc) before and after a course of treatment. METHODS: Variability in rs-fc was examined in healthy controls (baseline) and individuals with MDD (baseline and after 4-6 weeks of rTMS). Seed-based connectivity was calculated to 4 regions associated with MDD: left dorsolateral prefrontal cortex (DLPFC), right subgenual anterior cingulate cortex (sgACC), bilateral insula, and bilateral precuneus. Individual variability was quantified for each region by calculating the mean correlational distance of connectivity maps relative to the healthy controls; a higher variability score indicated a more atypical/idiosyncratic connectivity pattern. RESULTS: We included data from 66 healthy controls and 252 individuals with MDD in our analyses. Patients with MDD did not show significant differences in baseline variability of rs-fc compared with controls. Treatment with rTMS increased rs-fc variability from the right sgACC and precuneus, but the increased variability was not associated with clinical outcomes. Interestingly, higher baseline variability of the right sgACC was significantly associated with less clinical improvement (p = 0.037, uncorrected; did not survive false discovery rate correction).Limitations: The linear model was constructed separately for each region of interest. CONCLUSION: This was, to our knowledge, the first study to examine individual variability of rs-fc related to rTMS in individuals with MDD. In contrast to our hypotheses, we found that rTMS increased the individual variability of rs-fc. Our results suggest that individual variability of the right sgACC and bilateral precuneus connectivity may be a potential mechanism of rTMS.

Depressive symptom trajectories with prolonged rTMS treatment.

BACKGROUND: A prolonged repetitive transcranial magnetic stimulation (rTMS) treatment course could be beneficial for some patients experiencing major depressive episodes (MDE). We identified trajectories of rTMS response in depressive patients who received an extended rTMS treatment course and sought to determine which trajectories achieved the greatest benefit with a prolonged treatment course. METHOD: We applied group-based trajectory modeling to a naturalistic dataset of depressive patients receiving a prolonged course of sequential bilateral rTMS (up to 51 treatment sessions) to the dorsolateral prefrontal cortex. Trajectories of the PHQ-9 with extended treatment courses were characterized, and we explored the association between baseline clinical characteristics and group membership using multinomial logistic regression. RESULTS: Among the 324 study participants, four trajectories were identified: "linear response, extended course" (N = 73; 22.5 %); "nonresponse" (N = 23; 7.1 %); "slowed response" (N = 159; 49.1 %); "rapid response, standard treatment length" (N = 69; 21.3 %). Only the "linear response, extended course" group showed considerable clinical improvement after receiving additional rTMS treatments. Greater baseline depressive symptoms were associated with linear response and non-response. CONCLUSION: Our results confirmed the distinctive response trajectories in depressive patients receiving rTMS and further highlighted that prolonged rTMS treatment courses may be beneficial for a subset of patients with higher initial symptom levels and linear early treatment response.

Causal network localization of brain stimulation targets for trait anxiety.

Transcranial magnetic stimulation (TMS) and deep brain stimulation (DBS) can treat some neuropsychiatric disorders, but there is no consensus approach for identifying new targets. We localized causal circuit-based targets for anxiety that converged across multiple natural experiments. Lesions (n=451) and TMS sites (n=111) that modify anxiety mapped to a common normative brain circuit (r=0.68, p=0.01). In an independent dataset (n=300), individualized TMS site connectivity to this circuit predicted anxiety change (p=0.02). Subthalamic DBS sites overlapping the circuit caused more anxiety (n=74, p=0.006), thus demonstrating a network-level effect, as the circuit was derived without any subthalamic sites. The circuit was specific to trait versus state anxiety in datasets that measured both (p=0.003). Broadly, this illustrates a pathway for discovering novel circuit-based targets across neuropsychiatric disorders.

Accelerated transcranial magnetic stimulation for psychological distress in advanced cancer: A phase 2a feasibility and preliminary efficacy clinical trial.

BACKGROUND: Psychological and existential suffering affects many people with advanced illness, and current therapeutic options have limited effectiveness. Repetitive transcranial magnetic stimulation (rTMS) is a safe and effective therapy for refractory depression, but no previous study has used rTMS to treat psychological or existential distress in the palliative setting. AIM: To determine whether a 5-day course of "accelerated" rTMS is feasible and can improve psychological and/or existential distress in a palliative care setting. DESIGN: Open-label, single arm, feasibility, and preliminary efficacy study of intermittent theta-burst stimulation to the left dorsolateral prefrontal cortex, 600 pulses/session, 8 sessions/day (once per hour) for 5 days. The outcomes were the rates of recruitment, completion of intervention, and follow-up (Feasibility); and the proportion of participants achieving 50% improvement on the Hamilton Depression Rating Scale (HDRS) or Hospital Anxiety and Depression Scale (HADS) 2 weeks post-treatment (Preliminary Efficacy). SETTING/PARTICIPANTS: Adults admitted to our academic Palliative Care Unit with advanced illness, life expectancy >1 month and psychological distress. RESULTS: Due to COVID-19 pandemic-related interruptions, a total of nine participants were enrolled between August 2021 and April 2023. Two withdrew before starting rTMS, one stopped due to clinical deterioration unrelated to rTMS, and six completed the rTMS treatment. Five of six participants had a >50% improvement in HDRS, HADS-Anxiety, or both between baseline and the 2 week follow up; the sixth died prior to the 2-week follow-up. In this small sample, mean depression scores decreased from baseline to 2 weeks post-treatment (HDRS 18 vs 7, p = 0.03). Side effects of rTMS included transient mild scalp discomfort. CONCLUSIONS: Accelerated rTMS improved symptoms of depression, anxiety, or both in this small feasibility and preliminary efficacy study. A larger, sham-controlled study is warranted to determine whether rTMS could be an effective, acceptable, and scalable treatment in the palliative setting. TRIAL REGISTRATION: NCT04257227.

Predictors of remission after repetitive transcranial magnetic stimulation for the treatment of late-life depression.

Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment in patients with depression, yet treatment response remains variable. While previous work has identified predictors of remission in younger adults, relatively little data exists in late-life depression (LLD). To address this gap, data from 164 participants with LLD from a randomized non-inferiority treatment trial comparing standard bilateral rTMS to bilateral theta burst stimulation (TBS) (ClinicalTrials.gov identifier: NCT02998580) were analyzed using binary logistic regression and conditional inference tree (CIT) modeling. Lower baseline depression symptom severity, fewer prior antidepressant treatment failures, and higher global cognition predicted remission following rTMS treatment. The CIT predicted a higher likelihood of achieving remission for patients with a total score of 19 or lower on the Montgomery-Åsberg Depression Rating Scale, 1 or fewer prior antidepressant treatment failures, and a total score of 23 or higher on the Montreal Cognitive Assessment. Our results indicate that older adults with lower severity of depression, fewer antidepressant treatment failures, and higher global cognition benefit more from current forms of rTMS. The results suggest that there is potentially higher value in using rTMS earlier in the treatment pathway for depression in older adults.

A randomized sham-controlled trial of high-dosage accelerated intermittent theta burst rTMS in major depression: study protocol.

BACKGROUND: Intermittent theta burst stimulation (iTBS), a novel form of repetitive transcranial magnetic stimulation (rTMS), can be administered in 1/10th of the time of standard rTMS (~ 3 min vs. 37.5 min) yet achieves similar outcomes in depression. The brief nature of the iTBS protocol allows for the administration of multiple iTBS sessions per day, thus reducing the overall course length to days rather than weeks. This study aims to compare the efficacy and tolerability of active versus sham iTBS using an accelerated regimen in patients with treatment-resistant depression (TRD). As a secondary objective, we aim to assess the safety, tolerability, and treatment response to open-label low-frequency right-sided (1 Hz) stimulation using an accelerated regimen in those who do not respond to the initial week of treatment. METHODS: Over three years, approximately 230 outpatients at the Centre for Addiction and Mental Health and University of British Columbia Hospital, meeting diagnostic criteria for unipolar MDD, will be recruited and randomized to a triple blind sham-controlled trial. Patients will receive five consecutive days of active or sham iTBS, administered eight times daily at 1-hour intervals, with each session delivering 600 pulses of iTBS. Those who have not achieved response by the week four follow-up visit will be offered a second course of treatment, regardless of whether they initially received active or sham stimulation. DISCUSSION: Broader implementation of conventional iTBS is limited by the logistical demands of the current standard course consisting of 4-6 weeks of daily treatment. If our proposed accelerated iTBS protocol enables patients to achieve remission more rapidly, this would offer major benefits in terms of cost and capacity as well as the time required to achieve clinical response. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04255784.

Dimensional and Categorical Solutions to Parsing Depression Heterogeneity in a Large Single-Site Sample.

BACKGROUND: Recent studies have reported significant advances in modeling the biological basis of heterogeneity in major depressive disorder, but investigators have also identified important technical challenges, including scanner-related artifacts, a propensity for multivariate models to overfit, and a need for larger samples with more extensive clinical phenotyping. The goals of the current study were to evaluate dimensional and categorical solutions to parsing heterogeneity in depression that are stable and generalizable in a large, single-site sample. METHODS: We used regularized canonical correlation analysis to identify data-driven brain-behavior dimensions that explain individual differences in depression symptom domains in a large, single-site dataset comprising clinical assessments and resting-state functional magnetic resonance imaging data for 328 patients with major depressive disorder and 461 healthy control participants. We examined the stability of clinical loadings and model performance in held-out data. Finally, hierarchical clustering on these dimensions was used to identify categorical depression subtypes. RESULTS: The optimal regularized canonical correlation analysis model yielded 3 robust and generalizable brain-behavior dimensions that explained individual differences in depressed mood and anxiety, anhedonia, and insomnia. Hierarchical clustering identified 4 depression subtypes, each with distinct clinical symptom profiles, abnormal resting-state functional connectivity patterns, and antidepressant responsiveness to repetitive transcranial magnetic stimulation. CONCLUSIONS: Our results define dimensional and categorical solutions to parsing neurobiological heterogeneity in major depressive disorder that are stable, generalizable, and capable of predicting treatment outcomes, each with distinct advantages in different contexts. They also provide additional evidence that regularized canonical correlation analysis and hierarchical clustering are effective tools for investigating associations between functional connectivity and clinical symptoms.

Transcranial Magnetic Stimulation-Induced Heart-Brain Coupling: Implications for Site Selection and Frontal Thresholding-Preliminary Findings.

Background: Neurocardiac-guided transcranial magnetic stimulation (TMS) uses repetitive TMS (rTMS)-induced heart rate deceleration to confirm activation of the frontal-vagal pathway. Here, we test a novel neurocardiac-guided TMS method that utilizes heart-brain coupling (HBC) to quantify rTMS-induced entrainment of the interbeat interval as a function of TMS cycle time. Because prior neurocardiac-guided TMS studies indicated no association between motor and frontal excitability threshold, we also introduce the approach of using HBC to establish individualized frontal excitability thresholds for optimally dosing frontal TMS. Methods: In studies 1A and 1B, we validated intermittent theta burst stimulation (iTBS)-induced HBC (2 seconds iTBS on; 8 seconds off: HBC = 0.1 Hz) in 15 (1A) and 22 (1B) patients with major depressive disorder from 2 double-blind placebo-controlled studies. In study 2, HBC was measured in 10 healthy subjects during the 10-Hz "Dash" protocol (5 seconds 10-Hz on; 11 seconds off: HBC = 0.0625 Hz) applied with 15 increasing intensities to 4 evidence-based TMS locations. Results: Using blinded electrocardiogram-based HBC analysis, we successfully identified sham from real iTBS sessions (accuracy: study 1A = 83%, study 1B = 89.5%) and found a significantly stronger HBC at 0.1 Hz in active compared with sham iTBS (d = 1.37) (study 1A). In study 2, clear dose-dependent entrainment (p = .002) was observed at 0.0625 Hz in a site-specific manner. Conclusions: We demonstrated rTMS-induced HBC as a function of TMS cycle time for 2 commonly used clinical protocols (iTBS and 10-Hz Dash). These preliminary results supported individual site specificity and dose-response effects, indicating that this is a potentially valuable method for clinical rTMS site stratification and frontal thresholding. Further research should control for TMS side effects, such as pain of stimulation, to confirm these findings.

Expansion of a frontostriatal salience network in individuals with depression.

Hundreds of neuroimaging studies spanning two decades have revealed differences in brain structure and functional connectivity in depression, but with modest effect sizes, complicating efforts to derive mechanistic pathophysiologic insights or develop biomarkers. 1 Furthermore, although depression is a fundamentally episodic condition, few neuroimaging studies have taken a longitudinal approach, which is critical for understanding cause and effect and delineating mechanisms that drive mood state transitions over time. The emerging field of precision functional mapping using densely-sampled longitudinal neuroimaging data has revealed unexpected, functionally meaningful individual differences in brain network topology in healthy individuals, 2-5 but these approaches have never been applied to individuals with depression. Here, using precision functional mapping techniques and 11 datasets comprising n=187 repeatedly sampled individuals and >21,000 minutes of fMRI data, we show that the frontostriatal salience network is expanded two-fold in most individuals with depression. This effect was replicable in multiple samples, including large-scale, group-average data (N=1,231 subjects), and caused primarily by network border shifts affecting specific functional systems, with three distinct modes of encroachment occurring in different individuals. Salience network expansion was unexpectedly stable over time, unaffected by changes in mood state, and detectable in children before the subsequent onset of depressive symptoms in adolescence. Longitudinal analyses of individuals scanned up to 62 times over 1.5 years identified connectivity changes in specific frontostriatal circuits that tracked fluctuations in specific symptom domains and predicted future anhedonia symptoms before they emerged. Together, these findings identify a stable trait-like brain network topology that may confer risk for depression and mood-state dependent connectivity changes in frontostriatal circuits that predict the emergence and remission of depressive symptoms over time.

A century of research on neuromodulation interventions: A scientometric analysis of trends and knowledge maps.

Interest in neurostimulation interventions has significantly grown in recent decades, yet a scientometric analysis objectively mapping scientific knowledge and recent trends remains unpublished. Using relevant keywords, we conducted a search in the Web of Science Core Collection on September 23, 2022, retrieving a total of 47,681 documents with 987,979 references. We identified two prominent research trends: 'noninvasive brain stimulation' and 'invasive brain stimulation.' These methods have interconnected over time, forming a cluster focused on evidence synthesis. Noteworthy emerging research trends encompassed 'transcutaneous auricular vagus nerve stimulation,' 'DBS/epilepsy in the pediatric population,' 'spinal cord stimulation,' and 'brain-machine interface.' While progress has been made for various neurostimulation interventions, their approval as adjuvant treatments remains limited, and optimal stimulation parameters lack consensus. Enhancing communication between experts of both neurostimulation types and encouraging novel translational research could foster further development. These findings offer valuable insights for funding agencies and research groups, guiding future directions in the field.

Effect of prior pharmacotherapy on remission with sequential bilateral theta-burst versus standard bilateral repetitive transcranial magnetic stimulation in treatment-resistant late-life depression.

Repetitive transcranial magnetic stimulation (rTMS) is used for treatment of late-life depression. In the FOUR-D study, sequential bilateral theta-burst stimulation (TBS) had comparable remission rates to standard bilateral rTMS. Data were analysed from the FOUR-D trial to compare remission rates between two types of rTMS based on the number and class of prior medication trials. The remission rate was higher in participants with ≤1 previous trial (43.9%) than in participants with 2 previous trials (26.5%) or ≥3 previous trials (24.6%; χ² = 6.36, d.f. = 2, P = 0.04). Utilising rTMS earlier in late-life depression may lead to better outcomes.

Accelerated Repetitive Transcranial Magnetic Stimulation to Treat Major Depression: The Past, Present, and Future.

Repetitive transcranial magnetic stimulation (rTMS) is an effective and evidence-based therapy for treatment-resistant major depressive disorder. A conventional course of rTMS applies 20-30 daily sessions over 4-6 weeks. The schedule of rTMS delivery can be accelerated by applying multiple stimulation sessions per day, which reduces the duration of a treatment course with a predefined number of sessions. Accelerated rTMS reduces time demands, improves clinical efficiency, and potentially induces faster onset of antidepressant effects. However, considerable heterogeneity exists across study designs. Stimulation protocols vary in parameters such as the stimulation target, frequency, intensity, number of pulses applied per session or over a course of treatment, and duration of intersession intervals. In this article, clinician-researchers and neuroscientists who have extensive research experience in accelerated rTMS synthesize a consensus based on two decades of investigation and development, from early studies ("Past") to contemporaneous theta burst stimulation, a time-efficient form of rTMS gaining acceptance in clinical settings ("Present"). We propose descriptive nomenclature for accelerated rTMS, recommend avenues to optimize therapeutic and efficiency potential, and suggest using neuroimaging and electrophysiological biomarkers to individualize treatment protocols ("Future"). Overall, empirical studies show that accelerated rTMS protocols are well tolerated and not associated with serious adverse effects. Importantly, the antidepressant efficacy of accelerated rTMS appears comparable to conventional, once daily rTMS protocols. Whether accelerated rTMS induces antidepressant effects more quickly remains uncertain. On present evidence, treatment protocols incorporating high pulse dose and multiple treatments per day show promise and improved efficacy.

Identifying Neurophysiological Markers of Intermittent Theta Burst Stimulation in Treatment-Resistant Depression Using Transcranial Magnetic Stimulation-Electroencephalography.

BACKGROUND: Intermittent theta burst stimulation (iTBS) targeting the left dorsolateral prefrontal cortex is effective for treatment-resistant depression, but the effects of iTBS on neurophysiological markers remain unclear. Here, we indexed transcranial magnetic stimulation-electroencephalography (TMS-EEG) markers, specifically, the N45 and N100 amplitudes, at baseline and post-iTBS, comparing separated and contiguous iTBS schedules. TMS-EEG markers were also compared between iTBS responders and nonresponders. METHODS: TMS-EEG was analyzed from a triple-blind 1:1 randomized trial for treatment-resistant depression, comparing a separated (54-minute interval) and contiguous (0-minute interval) schedule of 2 × 600-pulse iTBS for 30 treatments. Participants underwent TMS-EEG over the left dorsolateral prefrontal cortex at baseline and posttreatment. One hundred fourteen participants had usable TMS-EEG at baseline, and 98 at posttreatment. TMS-evoked potential components (N45, N100) were examined via global mean field analysis. RESULTS: The N100 amplitude decreased from baseline to posttreatment, regardless of the treatment group (F1,106 = 5.20, p = .02). There were no changes in N45 amplitude in either treatment group. In responders, the N100 amplitude decreased after iTBS (F1,102 = 11.30, p = .001, pcorrected = .0004). Responders showed higher posttreatment N45 amplitude than nonresponders (F1,94 = 4.11, p = .045, pcorrected = .016). Higher baseline N100 amplitude predicted lower post-iTBS depression scores (F4,106 = 6.28, p = .00014). CONCLUSIONS: These results provide further evidence for an association between the neurophysiological effects of iTBS and treatment efficacy in treatment-resistant depression. Future studies are needed to test the predictive potential for clinical applications of TMS-EEG markers.

Functional Connectivity Mapping for rTMS Target Selection in Depression.

OBJECTIVE: Repetitive transcranial magnetic stimulation (rTMS) protocols increasingly use subgenual anterior cingulate cortex (sgACC) functional connectivity to individualize treatment targets. However, the efficacy of this approach is unclear, with conflicting findings and varying effect sizes across studies. Here, the authors investigated the effect of the stimulation site's functional connectivity with the sgACC (sgACC-StimFC) on treatment outcome to rTMS in 295 patients with major depression. METHODS: The reliability and accuracy of estimating sgACC functional connectivity were validated with data from individuals who underwent extensive functional MRI testing. Electric field modeling was used to analyze associations between sgACC-StimFC and clinical improvement using standardized assessments and to evaluate sources of heterogeneity. RESULTS: An imputation-based method provided reliable and accurate sgACC functional connectivity estimates. Treatment responses weakly but robustly correlated with sgACC-StimFC (r=-0.16), but only when the stimulated cortex was identified using electric field modeling. Surprisingly, this association was driven by patients with strong global signal fluctuations stemming from a specific periodic respiratory pattern (r=-0.49). CONCLUSIONS: Functional connectivity between the sgACC and the stimulated cortex was correlated with individual differences in treatment outcomes, but the association was weaker than those observed in previous studies and was accentuated in a subgroup of patients with distinct, respiration-related signal patterns in their scans. These findings indicate that in a large representative sample of patients with major depressive disorder, individual differences in sgACC-StimFC explained only ∼3% of the variance in outcomes, which may limit the utility of existing sgACC-based targeting protocols. However, these data also provide strong evidence for a true-albeit small-effect and highlight opportunities for incorporating additional functional connectivity measures to generate models of rTMS response with enhanced predictive power.

Differential symptom cluster responses to repetitive transcranial magnetic stimulation treatment in depression.

Background: Repetitive transcranial magnetic stimulation (rTMS) can target specific neural circuits, which may allow for personalized treatment of depression. Treatment outcome is typically determined using sum scores from validated measurement scales; however, this may obscure differential improvements within distinct symptom domains. The objectives for this work were to determine: (1) whether a standard depression measure can be represented using a four symptom cluster model and (2) whether these symptom clusters had a differential response to rTMS treatment. Methods: Data were obtained from two multi-centre randomized controlled trials of rTMS delivered to the left dorsolateral prefrontal cortex (DLPFC) for participants with treatment-resistant depression (TRD) conducted in Canada (THREE-D [Conducted between Sept 2013, and Oct 2016] and CARTBIND [Conducted between Apr 2016 and Feb 2018]). The first objective used confirmatory factor analytic techniques, and the second objective used a linear mixed effects model. Trial Registration: NCT01887782, NCT02729792. Findings: In the total sample of 596 participants with TRD, we found a model consisting of four symptom clusters adequately fit the data. The primary analysis using the THREE-D treatment trial found that symptom clusters demonstrated a differential response to rTMS treatment (F(3,5984) = 31.92, p < 0.001). The anxiety symptom cluster was significantly less responsive to treatment than other symptom clusters (t(6001) = -8.02, p < 0.001). These findings were replicated using data from the CARTBIND trial. Interpretation: There are distinct symptom clusters experienced by individuals with TRD that have a differential response to rTMS. Future work will determine whether differing rTMS treatment targets have distinct patterns of symptom cluster responses with the eventual goal of personalizing rTMS protocols based on an individual's clinical presentation. Funding: Canadian Institutes of Health Research, Brain Canada.