Examining the neural mechanisms of rTMS: a naturalistic pilot study of acute and serial effects in pharmacoresistant depression.

Introduction: Previous studies have demonstrated the effectiveness of therapeutic repetitive transcranial magnetic stimulation (rTMS) to treat pharmacoresistant depression. Nevertheless, these trials have primarily focused on the therapeutic and neurophysiological effects of rTMS following a long-term treatment course. Identifying brain-based biomarkers of early rTMS therapeutic response remains an important unanswered question. In this pilot study, we examined the effects of rTMS on individuals with pharmacoresistant depression using a graph-based method, called Functional Cortical Networks (FCN), and serial electroencephalography (EEG). We hypothesized that changes in brain activity would occur early in treatment course. Methods: A total of 15 patients with pharmacoresistant depression underwent five rTMS sessions (5Hz over the left dorsolateral prefrontal cortex, 120%MT, up to 4,000 pulses/session). Five participants received additional rTMS treatment, up to 40 sessions. Resting EEG activity was measured at baseline and following every five sessions, using 64-channel EEG, for 10 minutes with eyes closed. An FCN model was constructed using time-varying graphs and motif synchronization. The primary outcome was acute changes in weighted-node degree. Secondary outcomes included serial FFT-based power spectral analysis and changes in depressive symptoms measured by the 9-Item Patient Health Questionnaire (PHQ-9) and the 30-item Inventory of Depressive Symptoms-Self Report (IDS-SR). Results: We found a significant acute effect over the left posterior area after five sessions, as evidenced by an increase in weighted-node degree of 37,824.59 (95% CI, 468.20 to 75,180.98) and a marginal enhancement in the left frontal region (t (14) = 2.0820, p = 0.056). One-way repeated measures ANOVA indicated a significant decrease in absolute beta power over the left prefrontal cortex (F (7, 28) = 2.37, p = 0.048) following ten rTMS sessions. Furthermore, a significant clinical improvement was observed following five rTMS sessions on both PHQ-9 (t (14) = 2.7093, p = 0.017) and IDS-SR (t (14) = 2.5278, p = 0.024) and progressed along the treatment course. Discussion: Our findings suggest that FCN models and serial EEG may contribute to a deeper understanding of mechanisms underlying rTMS treatment. Additional research is required to investigate the acute and serial effects of rTMS in pharmacoresistant depression and assess whether early EEG changes could serve as predictors of therapeutic rTMS response.

Transcranial magnetic stimulation for post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) is a debilitating psychiatric disorder. While current treatment options are effective for some, many individuals fail to respond to first-line psychotherapies and pharmacotherapy. Transcranial magnetic stimulation (TMS) has emerged over the past several decades as a noninvasive neuromodulatory intervention for psychiatric disorders including depression, with mounting evidence for its safety, tolerability, and efficacy in treating PTSD. While several meta-analyses of TMS for PTSD have been published to date showing large effect sizes on PTSD overall, there is marked variability between studies, making it difficult to draw simple conclusions about how best to treat patients. The following review summarizes over 20 years of the existing literature on TMS as a PTSD treatment, and includes nine randomized controlled trials and many other prospective studies of TMS monotherapy, as well as five randomized controlled trials investigating TMS combined with psychotherapy. While the majority of studies utilize repetitive TMS targeted to the right dorsolateral prefrontal cortex (DLPFC) at low frequency (1 Hz) or high frequency (10 or 20 Hz), others have used alternative frequencies, targeted other regions (most commonly the left DLPFC), or trialed different stimulation protocols utilizing newer TMS modalities such as synchronized TMS and theta-burst TMS (TBS). Although it is encouraging that positive outcomes have been shown, there is a paucity of studies directly comparing available approaches. Biomarkers, such as functional imaging and electroencephalography, were seldomly incorporated yet remain crucial for advancing our knowledge of how to predict and monitor treatment response and for understanding mechanism of action of TMS in this population. Effects on PTSD are often sustained for up to 2-3 months, but more long-term studies are needed in order to understand and predict duration of response. In short, while TMS appears safe and effective for PTSD, important steps are needed to operationalize optimal approaches for patients suffering from this disorder.

Repetitive Transcranial Magnetic Stimulation for Treatment-Resistant Depression: Recent Critical Advances in Patient Care.

PURPOSE: Transcranial magnetic stimulation (TMS) is an evidence-based treatment for pharmacoresistant major depressive disorder (MDD). In the last decade, the field has seen significant advances in the understanding and use of this new technology. This review aims to describe the large, randomized controlled studies leading to the modern use of rTMS for MDD. It also includes a special section briefly discussing the use of these technologies during the COVID-19 pandemic. RECENT FINDINGS: Several new approaches and technologies are emerging in this field, including novel approaches to reduce treatment time and potentially yield new approaches to optimize and maximize clinical outcomes. Of these, theta burst TMS now has evidence indicating it is non-inferior to standard TMS and provides significant advantages in administration. Recent studies also indicate that neuroimaging and related approaches may be able to improve TMS targeting methods and potentially identify those patients most likely to respond to stimulation. SUMMARY: While new data is promising, significant research remains to be done to individualize and optimize TMS procedures. Emerging new approaches, such as accelerated TMS and advanced targeting methods, require additional replication and demonstration of real-world clinical utility. Cautious administration of TMS during the pandemic is possible with careful attention to safety procedures.

One-year clinical outcomes following theta burst stimulation for post-traumatic stress disorder.

Theta burst transcranial magnetic stimulation (TBS) is a potential new treatment for post-traumatic stress disorder (PTSD). We previously reported active intermittent TBS (iTBS) was associated with superior clinical outcomes for up to 1-month, in a sample of fifty veterans with PTSD, using a crossover design. In that study, participants randomized to the active group received a total of 4-weeks of active iTBS, or 2-weeks if randomized to sham. Results were superior with greater exposure to active iTBS, which raised the question of whether observed effects persisted over the longer-term. This study reviewed naturalistic outcomes up to 1-year from study endpoint, to test the hypothesis that greater exposure to active iTBS would be associated with superior outcomes. The primary outcome measure was clinical relapse, defined as any serious adverse event (e.g., suicide, psychiatric hospitalization, etc.,) or need for retreatment with repetitive transcranial magnetic stimulation (rTMS). Forty-six (92%) of the initial study's intent-to-treat participants were included. Mean age was 51.0 ± 12.3 years and seven (15.2%) were female. The group originally randomized to active iTBS (4-weeks active iTBS) demonstrated superior outcomes at one year compared to those originally randomized to sham (2-weeks active iTBS); log-rank ChiSq = 5.871, df = 1, p = 0.015; OR = 3.50, 95% CI = 1.04-11.79. Mean days to relapse were 296.0 ± 22.1 in the 4-week group, and 182.0 ± 31.9 in the 2-week group. When used, rTMS retreatment was generally effective. Exploratory neuroimaging revealed default mode network connectivity was predictive of 1-year outcomes (corrected p < 0.05). In summary, greater accumulated exposure to active iTBS demonstrated clinically meaningful improvements in the year following stimulation, and default mode connectivity could be used to predict longer-term outcomes.

Pilot Testing of Peak Alpha Frequency Stability During Repetitive Transcranial Magnetic Stimulation.

Over half of those diagnosed with post-traumatic stress disorder (PTSD) have comorbid major depressive disorder (MDD), and rates are even higher among military veterans. Transcranial magnetic stimulation (TMS) may be a safe and efficacious treatment for PTSD, both with and without comorbid MDD. Still, the mechanism of action of TMS is not fully understood, and it remains unclear which stimulation techniques (e.g., target regions, pulse strength/frequency, waveform) optimize treatment for these patients. Recent research indicated that a patient's unique individualized alpha frequency (IAF) may be used to guide brain stimulation treatment, and emerging data suggests that stimulation synchronized to the IAF may be efficacious for MDD. However, to our knowledge there are no studies to date that evaluate the stability of IAF over time in patients with comorbid PTSD and MDD. To this end, we used an eight-lead electroencephalography (EEG) system to record IAF before and after a course of TMS. Stimulation parameters were informed by prior studies of TMS for comorbid PTSD and MDD and included 5 Hz TMS to the left dorsolateral prefrontal cortex, at 120% of motor threshold, 3,000-4,000 pulses per session for up to 40 sessions. We tested whether IAF was changed with a course of TMS therapy and evaluated whether IAF predicted clinical outcomes. We observed no significant changes in IAF from baseline to post-treatment, and there was no relationship between IAF and clinical symptom change. These data demonstrate the stability of IAF with TMS and indicate its utility as a trait marker for future brain stimulation studies. This work does not support the use of IAF as predictor of clinical response to TMS as administered.