OBJECTIVE:To quantify dose-response associations of total pulse dose and intersession interval with antidepressant outcomes in accelerated repetitive transcranial magnetic stimulation (rTMS), with more than one treatment session per day, for major depressive episodes. METHODS:A systematic review and dose-response meta-analysis of total pulses and intersession interval was conducted, stratified by sham-controlled randomized controlled trials (RCTs) versus non-sham-controlled trials/observational studies, using linear, quadratic, and restricted cubic spline models. Fifty-nine studies (2908 participants) were included. Outcomes were symptom change (standardized mean difference; Hedges' g), response, and remission. RESULTS:Among the included accelerated rTMS protocols, total pulses ranged from 10,800 to 120,000 (median 36,000), and intersession intervals ranged from 10 to 480 min (median 50). Across sham-controlled RCTs, higher total pulses showed a consistent positive association with efficacy, response, and remission. In non-sham-controlled trials and observational studies, the association was clearer for response and remission than for continuous symptom improvement. In sham-controlled RCTs, intersession interval showed a non-linear (bell-shaped) association, with intermediate spacing (roughly 30-75 min) generally outperforming shorter or longer intervals; findings in non-sham-controlled evidence were mixed. Compared with session number or pulses per session, total pulses appeared to be a more informative dose metric. CONCLUSIONS:Total pulse count generally appears to follow a "more is better" pattern, and intersession interval may show a non-linear association with outcomes. This meta-analysis offers a quantitative framework that may help inform parameter optimization and guide future trials aimed at refining and standardizing accelerated protocols for clinical implementation.

Repetitive Transcranial Magnetic Stimulation (rTMS) is a widely used noninvasive brain stimulation technique that has been approved for treatment-resistant depression (TRD) in many countries. A growing divergence in national health authority positions has reignited debate over the role of rTMS in the treatment of treatment-resistant depression (TRD). While numerous countries—including the United States, Canada, and Australia—have endorsed and reimbursed rTMS based on robust meta-analytic evidence, other jurisdictions have issued more restrictive or inconclusive recommendations. These contrasting stances reflect significant variability in how health authorities interpret the clinical and cost-effectiveness data, leading to inconsistent access and coverage worldwide. This heterogeneity has sparked ongoing controversies in multiple countries, including recent policy discussions in Australia and Europe, highlighting the need for clearer, evidence-aligned guidance at the international level. The striking contrast between the evidence for efficacy of rTMS in TRD and the lack of recommendation from some national health authorities raises particularly important questions since it leads to many serious consequences from public health and medico-economic standpoints. In this article, we argue that health authority endorsement of rTMS for TRD is justified on clinical, safety, and economic grounds. We further propose that such endorsement should be linked to three prerequisites—training certification, defined therapeutic positioning, and standardized clinical protocols. Training and accreditation frameworks should be implemented at scale to facilitate the approval of rTMS by health authorities, enabling widespread, high-quality delivery, optimizing outcomes, and generating health economic returns.

Recently, novel regimens for transcranial magnetic stimulation (TMS) have been reported, combining multiple sessions per day with pharmacological augmentation of neuroplasticity, to enable delivery of an entire treatment course in a single day. Here we report outcomes for a single-day, optimized neuroplasticity-enhanced regimen in bipolar depression (ONE-BD). 30 TMS-eligible adults with bipolar disorder, type I, and a current depressive episode underwent 20 sessions of TMS (q 20min, iTBS, 600 pulses, dorsomedial prefrontal target Fz) with 125mg D-cycloserine given 1h pre-treatment. All patients completed treatment, with no serious adverse events or switch to mania/hypomania. Response trajectories showed progressive improvement over 6 weeks post-treatment. On HDRS-17, scores improved from 24.0±SD4.3 (baseline) to 9.1±SD6.4 at week 6 and 9.9±SD5.2 at week 12. On BDI-II, scores improved from 35.2±SD10.6 (baseline) to 13.2±SD11.9 at week 6 and 12.7±SD11.2 at week 12. On PHQ9, scores improved from 17.0±SD5.5 (baseline) to 6.3±SD6.2 at week 6 and 7.3±SD5.8 at week 12. On GAD-7, scores improved from 13.2±SD4.7 (baseline) to 5.9±SD5.6 at week 6 and 5.4±SD5.9 at week 12. Response/remission rates at week 6 were 73.3% and 43.3% (HDRS-17), 70.0% and 46.7% (BDI-II), 73.3% and 46.7% (PHQ-9), and 76.7% and 50.0% (GAD-7). YMRS scores remained low and stable from 6.0±SD5.5 at baseline to 3.9±SD5.0 at week 6. This preliminary report suggests that single-day TMS regimens appear safe and well-tolerated, with clinically meaningful response and remission rates. Randomized controlled studies would allow further validation of the approach, and optimization of augmentation regimen, stimulation target, and inter-session interval.

Precision functional mapping (PFM) enables the individual-level characterization of brain network organization but requires substantially more and higher-quality fMRI data than is standard. Despite the growing use of PFM, the objective criteria for data sufficiency and the quality needed to ensure interpretable and replicable individual-level results remain unclear. Here, we introduce the network similarity index (NSI), an objective measure of the extent to which functional connectivity (FC) patterns express the large-scale network structure required for PFM. The NSI captures low-spatial-frequency, coherent network organization and denoising fidelity, and it aligns closely with blinded expert assessments of PFM usability. The NSI also accounts for the variability in the rate at which FC becomes reliable across individuals. This NeuroResource provides an open source framework for NSI-based data quality evaluation and models linking NSI values with expert-judged PFM suitability. This framework can inform expected returns from additional data collection, thus enabling principled decisions about data sufficiency and replication in precision fMRI research.

BACKGROUND:Targeting methods for repetitive transcranial magnetic stimulation (rTMS) in patients with depression now include individual functional magnetic resonance imaging (fMRI) scans to target specific functional connectivity (FC) patterns. Potential biomarkers of rTMS response include target FC with the subgenual anterior cingulate cortex (SGC) or the causal depression circuit (CDC), each of which may be candidates for individualized functional targets (iFTs). We retrospectively assessed the relationship of these two approaches to outcomes in secondary analyses of two large rTMS clinical trials. METHODS:501 subjects with moderate to severe depression underwent 4-6 weeks of daily rTMS to the left dorsolateral prefrontal cortex (DLPFC), targeted using neuronavigation to an optimized DLPFC-SGC-FC group-based functional target. Baseline resting-state scans were used to retrospectively compute iFTs using either SGC-DLPFC or CDC-DLPFC FC. Proximity (Euclidean distance) of the stimulated target to iFTs were correlated with outcomes. Electric field magnitude at iFTs was computed to capture non-linear stimulation propagation. RESULTS:Most iFTs were within 2 cm of their group-target. Proximity to either an SGC- or CDC-iFT was not associated with better outcomes. Sensitivity analyses accounting for treatment target FC, methodology, data quality, or treatment parameters did not change results. Electric field-based measures were highly similar to Euclidean distance and likewise showed no association with outcomes. CONCLUSIONS:Under the specific fMRI acquisition parameters used, proximity to optimized DLPFC-SGC-iFTs was not associated with better outcomes in patients receiving neuronavigated rTMS to an optimized DLPFC-SGC group-target. Prospective randomized clinical trials definitively assessing the clinical utility of iFTs are warranted.

Recently, accelerated, pharmacologically augmented regimens for transcranial magnetic stimulation (TMS) have been described, allowing treatment completion in a single day. However, comparisons of outcomes versus once-daily treatment regimens are lacking. Here, we performed a propensity-matched retrospective analysis of individual patient data from a naturalistic sample of patients with major depression who received either a 36-day course of once-daily TMS or single-day of pharmacologically augmented TMS, at a large community practice. Following exclusions, the initial set of 879 patient records yielded a preliminary sample of 114 individuals who received one-day TMS and 330 individuals who underwent 36-day TMS. Propensity-score matching yielded a final analytic sample of N=191 36-day TMS patients, matched to N=106 one-day TMS patients. Remission (PHQ9<5) was defined as the primary outcome measure, with response (≥50% PHQ9 improvement from baseline) as the secondary outcome measure; similar analyses were performed for anxiety symptoms using the GAD7. PHQ9 remission was achieved in 49.1% (52/106) of the single-day TMS patients, versus 25.1% (48/191) of the 36-day patients (χ²=17.473, p <0.0001). PHQ9 response was achieved in 71.7% (76/106) of the single-day TMS patients, versus 56.0% (107/191) of the 36-day patients (χ²=7.084, p =0.0078). Regarding anxiety symptoms, remission (GAD7<5) was achieved in 62.3% (66/106) of the single-day TMS patients, versus 33.0% (63/191) of the 36-day patients(χ²=23.79, p<0.0001). Response was achieved in 72.6% (77/106) of the single-day versus 51.9% (98/189) of the 36-day TMS patients (χ²=12.16, p =0.0005). As previously observed, single-day TMS improvements were not immediate, but instead developed in a delayed fashion over the 6 weeks following treatment, and reaching a plateau at 6-12 weeks post-treatment. This pattern was well-modeled with an exponential-decay function, which yielded superior fits versus linear models in both groups, with the single-day TMS group showing a significantly greater magnitude of effect and rapidity of onset. Observed effects were robust across four slightly different versions of the single-day protocol, varying in target set (dorsolateral ± dorsomedial ± orbitofrontal stimulation), inter-session interval (20 versus 30 min), NMDA agonist (D-cycloserine versus D-serine), and presence/absence of lisdexamfetamine augmentation. Randomized controlled studies will be required for definitive comparisons of single-day to once-daily TMS and for optimization of the regimen. However, the present study suggests that single-day TMS regimens may be capable of achieving outcomes that are not only non-inferior, but indeed superior, to typical 36-day TMS regimens, when delivered under naturalistic conditions in the community.

Abstract The primary motor cortex has a prominent role in transcranial magnetic stimulation (TMS). It is one of few locations that provide directly observable responses, and its physiology serves as model or reference for almost all other TMS targets, e.g., through the motor threshold and spatial targeting relative to its position. It furthermore sets the safety limits for the entire brain. Its easily detectable responses have led to closed-loop methods for a range of aspects, e.g., for automated thresholding, amplitude tracking, and targeting. The high variability of brain stimulation methods would substantially benefit from fast unbiased closed-loop methods. However, the development of more potent methods would early on in the design phase require proper models that allowed tuning and testing with sufficient conditions but without a high number of experiments, which are time-consuming and expensive or even impossible at the needed scale. On the one hand, theoretical researchers without access to experiments miss realistic spatial response models of brain stimulation to develop better methods. On the other hand, subjects should potentially not be exposed to early closed-loop-methods without sufficient prior testing. After all, initial, poorly tuned feed-back as needed for closed-loop operation is known to demonstrate erratic behavior. To bridge this gap, we developed a digital-twin-style population model that generates motor evoked potentials in response to virtual stimuli and includes statistical information on spatial (coil position and orientation) as well as pulse-strength-dependent neural recruitment in the population to represent inter- and intra-individual variability. The population data were extracted from a combination of datasets of healthy and depressed subjects to reach large numbers and wide coverage. The model allows users to simulate different subjects and millions of runs for software-in-the loop testing. The model provides all code open-source to stimulate further development.

OBJECTIVE:Transcranial magnetic stimulation (TMS) and deep brain stimulation (DBS) can modulate brain circuits, and certain stimulation targets may relieve or exacerbate anxiety. The objective of this study was to localize circuit-based stimulation targets that modify anxiety by integrating causal sources of information, including lesion, TMS, and DBS datasets. METHODS:The authors leveraged a series of natural experiments across multiple datasets (N=936). First, patients with incidental brain lesions (N=451) and TMS-treated individuals with incidental variability in stimulation location for depression (N=111) were analyzed. Functional connectivity of these sites was estimated using a normative connectome. Next, a TMS dataset (N=300) with a common set of stimulation coordinates but individual variability in brain connectivity was analyzed. Finally, the authors examined subthalamic DBS locations in patients with Parkinson's disease (N=74). RESULTS:Similar brain circuits were derived from lesions associated with greater anxiety and TMS sites that decreased anxiety (spatial r=0.68). In an independent TMS dataset (N=300), individualized TMS site connectivity to this circuit was significantly correlated with treatment-induced anxiety change. In Parkinson's disease, overlap of subthalamic DBS (N=74) sites with the anxiety circuit significantly predicted greater anxiety increases, confirming network involvement despite the circuit being derived independently of DBS. The circuit was associated significantly with trait anxiety versus state anxiety in two datasets that measured both. The peak proposed TMS target for anxiety was in the right superior frontal gyrus. CONCLUSIONS:This study identified a convergent anxiety circuit across lesions, TMS, and DBS. This provides a potential therapeutic target for brain stimulation and represents a generalizable approach for identifying stimulation targets across neuropsychiatric conditions.

BACKGROUND:Late-life depression (LLD) is commonly accompanied by cognitive impairment and poor response to first-line antidepressants. Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for treatment-resistant LLD, yet neurobiological predictors of cognitive and clinical outcomes remain unclear. Brain aging, quantified via magnetic resonance imaging (MRI)-derived centile scores from normative brain charts, may capture individual variability in neurostructural aging relevant to rTMS treatment response. METHODS:We examined relationships between centile scores, cognition, and antidepressant outcomes in older adults with LLD (n=112) and healthy controls (HC; n=41) who participated in a noninferiority clinical trial of bilateral dorsolateral prefrontal cortex (DLPFC) rTMS versus theta burst stimulation. Structural MRI was obtained before and after treatment. Centile scores leveraging cortical and subcortical tissue volumes were generated using BrainChart.io. Cognitive outcomes were assessed using standardized neuropsychological measures, including verbal learning and executive function. RESULTS:Baseline centile scores did not differ between the LLD cohort and HCs and were unrelated to depression severity or antidepressant response. However, participants in a cognitively-diminished LLD subtype exhibited significantly lower centile scores driven by reduced white-matter volume. Across LLD participants, higher baseline centile scores predicted greater improvement in verbal learning following rTMS, but not global cognition or executive function, independent of antidepressant response. Centile scores remained stable post-treatment. CONCLUSIONS:Brain age measures reflect cognitive, but not antidepressant, outcomes following rTMS in LLD. Structural-MRI based centile scores may serve as biomarkers of cognitive function and predictors of rTMS-related cognitive improvement in individuals with LLD.

Background:Repetitive transcranial magnetic stimulation (rTMS) and intranasal esketamine are effective treatment options for treatment-resistant depression (TRD) that have not been directly compared. We aimed to compare the effectiveness of rTMS, intranasal esketamine, and pharmacotherapy for TRD using data from two randomised clinical trials (RCTs). Methods:This secondary analysis of individual patient data (IPD) included data from two large clinical trials for rTMS (THREE-D; non-inferiority RCT, four sites in Canada from Sept 2013 to Oct 2016, n = 388 eligible) and intranasal esketamine (TRANSFORM-2; superiority RCT, 39 sites across five countries from Aug 2015 to Nov 2017, n = 227 eligible) to compare efficacy for TRD (defined as non-response to at least one evidence-based treatment). A third group included participants who received standard of care (new antidepressant medications) plus placebo nasal spray (TRANSFORM-2). rTMS was delivered in a once daily format, while intranasal esketamine was delivered twice weekly. Restriction, propensity-score matching, and regression adjustments were used to minimise confounding factors between studies. The primary outcome for this analysis was the severity of depressive symptoms using the 17-item Hamilton Depression Rating scale (HDRS), assessed as a continuous measure, after 4 weeks of treatment. THREE-D and TRANSFORM-2 are registered with ClinicalTrials.gov as NCT01887782 and NCT02418585, respectively. Findings:After restriction and propensity-score matching, the analytic sample consisted of 282 participants in three arms: rTMS (n = 94), intranasal esketamine (n = 94), and new antidepressant medication (n = 94). Both rTMS (β: -5.35 [95% CI, -8.77, -1.93]) and intranasal esketamine (-2.89 [-5.38, -0.40]) were superior at reducing depression severity when compared with initiating a new antidepressant medication. rTMS resulted in a non-statistically significant greater symptom reduction compared with intranasal esketamine (-2.46 [-5.82, 0.89]). The upper confidence limit interval for the rTMS and intranasal esketamine comparison provide preliminary evidence that intranasal esketamine is not superior to rTMS by a minimal clinically important difference. Interpretation:This analysis showed rTMS and intranasal esketamine are superior to initiation of a new antidepressant medication, which is consistent with prior randomised clinical trials. Acknowledging its limitations and exploratory nature, our work indicates that rTMS may be superior, or at least similarly effective, to intranasal esketamine and highlights the need for large, prospective, comparative effectiveness trials directly comparing these interventions. Funding:Support for this work was provided by the Delaney Family Foundation. THREE-D was funded by the Canadian Institutes of Health Research and TRANSFORM-2 was funded by Johnson and Johnson Pharmaceuticals.

BACKGROUND:Previous studies have shown that repetitive transcranial magnetic stimulation (rTMS) can treat suicidal symptoms; however, the effects of rTMS on suicidal ideation (SI) in late-life depression (LLD) have not been well-characterized, particularly with theta burst stimulation (TBS). METHODS:Data were analyzed from 84 older adults with depression from the FOUR-D trial (ClinicalTrials.gov identifier: NCT02998580), who received either bilateral standard rTMS or bilateral TBS targeting the dorsolateral prefrontal cortex. The primary outcome was change in the Beck Scale for Suicide Ideation (SSI). The secondary outcome was remission of SI. Demographic, cognitive, and clinical characteristics that may moderate the effects of rTMS or TBS on SI were explored. RESULTS:There was a statistically significant change in the total SSI score over time [χ2(7) = 136.018, p < 0.001], with no difference between the two treatment groups. Remission of SI was 55.8% in the standard rTMS group and 53.7% in the TBS group. In the standard rTMS group, there was no difference in remission of SI between males and females, whereas remission was higher in females in the TBS group (χ2(1) =6.87, p = 0.009). There was a significant correlation between time to remission of SI and RCI z-score for D-KEFS inhibition/switching [rs = -0.389, p = 0.012]. CONCLUSIONS:Both bilateral rTMS and bilateral TBS were effective in reducing SI in LLD. There may be sex differences in response to TBS, with females having more favorable response in reducing SI. There may be an association between improvement in cognitive flexibility and inhibition and reduction of SI.