Linda L. Carpenter

Although 10-Hz repetitive transcranial magnetic stimulation (rTMS) is an FDA-approved treatment for depression, we do not understand the mechanisms through which rTMS induces therapeutic change. Two competing theories suggest that 10-Hz rTMS induces N-methyl-D-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP), and/or removal of inhibitory gamma-aminobutyric acid receptors (GABARs). We examined these two proposed mechanisms of action in the human motor cortex in a double-blind, randomized, four-arm crossover study in six healthy subjects. We tested plasticity with motor-evoked potentials (MEPs) and learning with serial reaction time task (SRTT) before and after 10-Hz rTMS in the presence of four drugs separated by 1 week each: placebo, d-cycloserine (DCS 100 mg), DCS 100 mg + NMDAR partial antagonist dextromethorphan (DXM 150 mg), and lorazepam (LZP 2.5 mg). NMDAR agonism by DCS enhanced rTMS-induced cortical excitability relative to placebo. This facilitation was specifically blocked by combining DCS with DXM. LZP administration resulted in a significant reduction of MEP amplitudes after rTMS. Results suggest that 10-Hz rTMS-induced plasticity works primarily through NMDAR dependent modulation with LTP-like mechanisms as opposed to GABAergic reduction. Our pilot study is the first to compare NMDAR v. GABAR in rTMS-induced plasticity and found the safety and feasibility of a 4-arm crossover protocol with each drug combined with the full 3000 pulse 10-Hz rTMS protocol. Our results may guide future clinical translation leveraging mechanistic understanding to improve therapeutic efficacy.

Brain criticality and complexity are increasingly recognized as promising biomarkers for psychiatric disorders. In Major Depressive Disorder (MDD), disordered neural dynamics have been reported, but their nature and consistency remain incompletely understood. Here, we study brain criticality, excitation–inhibition (E/I) balance, combined excitation– inhibition strength (E+I), and complexity of brain dynamics associated with MDD. Using resting-state EEG from 183 patients with MDD and 133 healthy controls (HC), we identified disruptions of critical dynamics and excitation–inhibition balance which discriminate groups. We found that amplitude bistability is lower, and long-range temporal correlations are weaker in MDD, implying deviation from criticality. Excitation-inhibition metrics show frequency-specific alterations in MDD. Estimates of excitation-inhibition ratios (E/I) derived from the statistical properties of amplitude fluctuations show higher values in HC than MDD in the θ band, indicating relative over-excitation, and lower values in the γ band, indicating relative over-inhibition. An excitation– inhibition strength index reflecting combined excitatory and inhibitory drive (E+I), was decreased in θ through β bands and increased in γ in MDD. Collectively, excitation-inhibition measures suggest decreased inhibitory drive in the mechanisms underlying θ oscillations in MDD and increased inhibitory drive in the mechanisms underlying γ oscillations. Classification using least absolute shrinkage and selection operator (LASSO) regression achieved high accuracy and the predictive feature set includes measures of criticality, E/I ratios, and combined E+I strength. These findings elucidate pathological alterations of brain dynamics in MDD and define a complex system fingerprint, supporting the development of biomarkers for diagnosis and treatment.

Background: Neurofeedback shows promise as an adjunctive therapy for post-traumatic stress disorder (PTSD), but its cost effectiveness has not been studied. Objectives: To assess the cost and effectiveness of neurofeedback plus other therapies (NF + OT) vs. guideline therapies alone. Methods: TreeAge software was used to develop Markov models comparing NF + OT therapy to psychotherapy and pharmacotherapy over 1–3 years. Costs were derived from Medicare rates and literature. Effectiveness was measured using CAPS-5 score reductions converted to quality-adjusted life years (QALYs) using regression analysis. Dropout and relapse rates were derived from systematic reviews and meta-analysis. Results: NF + OT resulted in greater improvements in CAPS-5 scores and was less costly than OT. In the base case, NF + OT was less expensive (on average) for years 1–3 by USD 2568−USD 4140 (vs. psychotherapy) and USD 2282−USD 7217 (vs. pharmacotherapy). QALYs improved by 0.04 compared to psychotherapy and 0.24 compared to pharmacotherapy. NF + OT dominated (lower cost, better outcomes) psychotherapy 12% of the time and pharmacotherapy 26.5% of the time in Monte Carlo simulation. Further, Monte Carlo simulation did not demonstrate dominance at any point in time for either pharmacotherapy or psychotherapy over NF + OT. Conclusions: Based on lower costs and improved effectiveness, NF + OT should be considered for treating PTSD.

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) applies electromagnetic pulses to stimulate cortical neurons. The antidepressant effect of the repetitive application of TMS (rTMS) was first shown nearly three decades ago. The therapeutic potential of TMS has been extensively investigated, mostly in treatment-resistant depression (TRD). Studies have extensively evaluated stimulation parameters, treatment schedules, methods to localize the stimulation target, and different magnetic coil designs engineered for desired stimulation breadth and depth. Several of these stimulation protocols and coils/devices have received U.S. Food and Drug Administration (FDA) clearance for application in TRD and other neuropsychiatric disorders, such as obsessive-compulsive disorder. Some stimulation protocols, while not FDA-cleared, have substantial clinical trial-derived evidence to support their safety and antidepressant efficacy. The proliferation of rTMS translational and clinical research has resulted in the field's advancement. This clinician-oriented review contains an overview of fundamental TMS principles, physiological effects, and studies of rTMS in TRD. Also discussed are two innovations that are increasingly applied in the clinic: theta burst stimulation and accelerated scheduling. A synthesis of the key clinical considerations given to patient assessment and safety, treatment setup, and the minimization and management of adverse effects is provided.