Joseph J. Taylor

Resting-state functional connectivity is increasingly used to measure neural engagement following transcranial magnetic stimulation (TMS), but whether connectivity changes are specific to the stimulation target and clinically meaningful remains unclear. In a head-to-head trial, thirty-six patients with depression and anxiety were randomized to 30 TMS sessions at one of two circuit-based targets: a dorsolateral prefrontal target hypothesized to improve "dysphoric" symptoms, and a dorsomedial prefrontal target hypothesized to improve "anxiosomatic" symptoms. We tested whether: (1) TMS selectively engaged the targeted circuit; (2) baseline TMS site connectivity to the targeted circuit predicted circuit engagement; (3) either metric correlated with improvement on the Beck Depression and Beck Anxiety Inventories. Twenty-nine participants with pre- and post-treatment MRI were included. Target engagement was defined as change in average connectivity within each circuit and compared between target groups; associations were measured using Spearman's partial correlation, controlling for relevant covariates. While connectivity decreased within both circuits, the effects were not clearly target-specific and did not predict symptom improvement. In contrast, stronger baseline TMS site connectivity to the targeted circuit predicted greater connectivity change (r = -0.61, p < 0.001) and anxiety improvement (r_w = 0.47, p = 0.004). These effects were driven by the anxiosomatic target group. Negative findings in the dysphoric target group may reflect greater inter-individual variability in dysphoric circuit topography, as suggested by post-hoc analyses. Within the constraints of a modest sample size, results suggest that baseline TMS site connectivity may represent a more informative biomarker than TMS-induced connectivity changes, and that circuit architecture should be considered when defining targeting protocols.

Transcranial magnetic stimulation (TMS) is effective for major depressive disorder (MDD) and anxious depression despite imprecise scalp-based targeting. Retrospective connectomics analyses suggest that targeting one brain circuit preferentially improves “dysphoric” symptoms, while targeting a different brain circuit preferentially improves “anxiosomatic” symptoms. Here, we tested this hypothesis prospectively by randomizing adults with MDD (n = 40, age 18-65) who had moderate-to-severe symptoms of depression (Beck Depression Inventory (BDI) ≥ 20) and anxiety (Beck Anxiety Inventory (BAI) ≥ 16) to a 30-treatment TMS course at the dysphoric circuit target (MNI coordinates [-32, 44, 34], close to the conventional left dorsolateral prefrontal cortex target for MDD), or at the anxiosomatic circuit target (MNI coordinates [0, 48, 46], a dorsomedial target not routinely used). As hypothesized, dysphoric circuit targeting (n = 16) improved BDI more than BAI (ratio 1.08, IQR 0.69-2.02), while anxiosomatic circuit targeting (n = 20) improved BAI more than BDI (ratio 0.70, IQR 0.01-1.01) (Wilcoxon rank-sum test p = 0.0195). Both targets improved BDI (55 vs 54%), but BAI improved significantly more with anxiosomatic circuit targeting (58 vs 36%, p = 0.0301), even when controlling for BDI (p < 0.001). Thus, TMS targeting different connectome-derived brain circuits differentially modulates anxiety that is comorbid with major depressive disorder. Future studies could target according to baseline symptom profile, a step toward precision psychiatry. Trial Registration Number NCT04604210.

Functional connectivity (FC) is increasingly used to measure target engagement following transcranial magnetic stimulation (TMS), but whether FC changes are specific to the TMS target remains unclear. We examined FC before and after TMS in patients with depression and anxiety (N=29) enrolled in a randomized trial targeting a dysphoric vs. anxiosomatic circuit. We tested whether: 1) TMS selectively modulated FC within the targeted circuit; 2) baseline TMS site FC to the targeted circuit predicted FC changes; 3) either metric correlated with symptom improvement. We found that: 1) FC decreased in both circuits, but effects were not clearly target-specific; 2) FC to the targeted circuit correlated with FC changes; 3) FC to the targeted circuit, not FC changes, correlated with symptom improvement. Results were driven by the anxiosomatic target group, likely due to heterogeneity in dysphoric circuit properties. These results have implications for using FC to target TMS and measure engagement.

Small single-site studies found that transcranial magnetic stimulation (TMS) targets with better antidepressant response were more negatively functionally connected to the subgenual cingulate cortex (SGC). These led to “anti-subgenual” TMS targeting in recent clinical trials. We conducted a larger prospective multi-site observational study to test the robustness of this observation in more diverse clinical populations. Sixty-six treatment-seeking individuals with major depressive disorder (MDD) received 3–8 weeks of daily rTMS to the left dorsolateral prefrontal cortex using scalp-based targeting as part of standard clinical care. Stimulation sites were recorded with MRI neuronavigation on multiple days. Our primary outcome was the correlation between change in Beck Depression Inventory (BDI-II) score and connectivity of each individual’s TMS site to the SGC, computed using resting-state functional connectivity data from 1000 healthy individuals. Secondary (post hoc) analyses incorporated additional clinical covariates. No relationship was found between antidepressant response and normative connectivity of TMS site to SGC (r = 0.1, p = 0.39). This was not due to inconsistency in the location of the TMS sites, which showed smaller within- than between-individual variance (p < 0.0001). Post hoc analyses showed significant associations when adding clinical covariates (r = −0.27, p = 0.014). Baseline anxiety (p < 0.0001) and comorbid psychiatric conditions (p < 0.001) accounted for the most variance in response. Atlas-based connectivity of TMS site to the SGC accounted for minimal variance in antidepressant response in this diverse sample. The “anti-subgenual” target derived based on normative connectome may be suboptimal for MDD patients with high baseline anxiety or psychiatric comorbidities. Trial registration ClinicalTrials.gov Identifier: NCT03276793.

Transcranial magnetic stimulation (TMS) is rapidly developing as a therapeutic tool for multiple psychiatric disorders. All current US Food and Drug Administration-cleared TMS indications for psychiatric illness target the frontal lobes. Historically, TMS target selection was based on reports of brain lesion locations that cause illness or functional neuroimaging correlates within the prefrontal cortex. In addition to prefrontal targets, however, these neuroimaging studies have consistently implicated posterior brain regions in a variety of psychiatric disorders. Thus far, these posterior regions have rarely been tested in TMS clinical trials. In this Perspective, we consider the role in psychiatric disorders of posterior regions such as the occipital cortex, precuneus, inferior parietal lobules and cerebellum. We synthesize preliminary evidence across the few existing TMS trials targeting posterior regions and consider the risks and benefits of stimulating posterior targets for the treatment of psychiatric illness.

Aim: We investigated the impact of repetitive transcranial magnetic stimulation (rTMS) for treatment-resistant depression on healthcare resource utilization as well as commercial and Medicare Fee-for-Service payer costs. Materials & methods: We conducted a retrospective observational analysis of claims data using Medicare Fee-for-Service datasets and commercial (Merative MarketScan Research Databases) datasets from 1 January 2021 to 30 September 2023. We identified two cohorts, a cohort that received rTMS and a cohort not treated with rTMS over an 18-month period. We used propensity score matching to balance the baseline characteristics of the cohorts, and we calculated the total cost of care based on payer allowed amounts from Merative MarketScan Research Databases and Standard Analytical Files. Results: Relative to the non-TMS cohort, the rTMS cohort incurred 37% more hospital outpatient visits (14.00 vs 10.21; p ≤ 0.0001) with 7% higher outpatient cost ($8946 vs $8363; p = 0.3400). Simultaneously, the rTMS cohort incurred 24% fewer inpatient admissions (0.25 vs 0.33; p = 0.0003) with 19% lower inpatient admission costs ($5666 vs $6978; p = 0.0392), 48% fewer emergency room visits (0.27 vs 0.53; p ≤ 0.0001) with 34% lower emergency room costs ($322 vs $487; p ≤ 0.0001), and $893 less in episode of care costs. Conclusion: This study suggests that patients who receive rTMS for treatment-resistant depression required fewer high acuity hospital visits and incurred less expensive episode-of-care costs compared with patients who do not receive rTMS. From this perspective, rTMS is an investment that returns health and economic dividends through fewer high acuity hospital visits.

Perinatal depression affects approximately 1 in 5 women and is the leading cause of maternal mortality in the United States. In addition to evidence-based treatment with antidepressant medications, there has been a push to identify rapid-acting options for pregnant and postpartum individuals. This paper reviews the evidence behind new pharmacological agents (neurosteroids and ketamine) and non-pharmacological approaches (transcranial magnetic stimulation). The paper also highlights the risks and benefits of electroconvulsive therapy and selective serotonin reuptake inhibitors. Based on recent studies and research, the paper provides considerations when prescribing these modalities including: timing of symptom onset, severity of presentation, breastfeeding priorities, prior treatment response and treatment availability and cost.

Causal network mapping is an emerging technique that can be used to derive optimal disorder/symptom-specific brain stimulation targets. This technique exploits incidental variability in brain lesion and brain stimulation locations, which creates a natural experiment in which causal inferences can be drawn between lesions or modulation of specific circuits and specific clinical outcomes. Circuits identified by causal network mapping, referred to as symptom-networks, represent candidate disorder/symptom-specific brain stimulation targets. The library of psychiatric symptom-networks has grown rapidly in recent years, creating a need for a comprehensive synthesis. The present Resource includes an open-source atlas of 12 psychiatric symptom-networks which we appraise using an established evaluative framework. These materials are designed to guide the translation of symptom-network targets and to scaffold advancements in this quickly developing field.