Background Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive neuromodulation intervention investigated as a treatment for substance use disorder (SUD) and its co-occurring disorders. As the number of rTMS SUD clinical trials increase, the safety and tolerability profile should be assessed. In this systematic review, we investigate adverse events (AEs) of rTMS in individuals with SUD and factors that may influence their occurrence. Methods We performed a systematic PubMed search to identify all controlled trials of rTMS in SUD published up to January 2025. Eligible studies were assessed, and safety information was extracted for analysis. Results A total of 141 clinical trials with 4299 participants were included in their active arms. rTMS trials recruited participants who were engaged in active substance use, were in the pre-treatment phase, in early recovery, or in sustained recovery. Twenty-two studies explicitly reported no AEs. Sixty-nine studies reported only mild AEs, while only six studies reported moderate AEs. Thirty-five studies did not report safety-outcomes/AEs. As expected, participants reported mild and temporary AEs such as headaches, pain or discomfort under the coil, or dizziness. Only nine studies reported serious AEs (7 studies in active TMS and 2 in sham TMS). Importantly, no seizures attributable to active rTMS were reported in these SUD samples. Conclusion Overall, rTMS in SUD samples is safe and well-tolerated regardless of recovery stage and substance. Most reported side effects were mild, self-limiting, and tolerable. However, AE reporting was incomplete, as 35 of 141 trials reported no safety data, limiting conclusions to reported outcomes. This evidence supports the safety of rTMS as a potential stand-alone or adjunctive treatment for SUD.

BACKGROUND:Novel therapies are needed to improve smoking cessation outcomes in people with opioid use disorder (OUD), as they are far more likely to smoke cigarettes (70-90%) compared to the general population (11.6%) and demonstrate a poorer response to smoking cessation interventions. METHODS:This pilot study, intended to be a hypothesis-generating mechanistic investigation, is the first to explore the impact of a single day (four sessions) of accelerated intermittent theta burst stimulation (iTBS) (1800 pulses/session) versus sham iTBS applied to the left dorsolateral prefrontal cortex (L-dlPFC) in people with OUD who smoke tobacco cigarettes (n = 8 received iTBS, n = 7 received sham iTBS). Resting-state functional connectivity was acquired at baseline and after the fourth session. Attentional bias for cigarette and opioid cues, and craving assessments, were completed at baseline, and after the first and fourth sessions. RESULTS:Connectivity between the L-dlPFC seed and a cluster comprising the left anterior supramarginal gyrus showed a significant group × time interaction, with planned comparisons showing a greater increase at follow-up in the iTBS compared with sham iTBS group (t12 = 6.37, β = 0.40, p < 0.001). Cigarette cue attentional bias showed a significant group × session interaction (t80 = 2.34, p = 0.02), with planned comparisons showing a decrease after iTBS and an increase following sham iTBS. No effect of iTBS was observed for opioid cue attentional bias. Cigarette craving decreased in both iTBS and sham groups but did not show a significant group × session interaction. CONCLUSIONS:These results are promising but should be interpreted with caution, given the limited sample size, which precluded analyses adjusting for sex or medications for OUD. This pilot study aims to identify neural and behavioral targets for future studies of accelerated iTBS in people with OUD who smoke cigarettes. Future trials could examine the effects of increased doses of iTBS (e.g., more days of accelerated iTBS) to identify dosing to promote smoking cessation among individuals with OUD effectively.

Cigarette smoking after a cancer diagnosis is associated with increased mortality, cancer recurrence, treatment-related toxicity, and diminished quality of life, yet sustained cessation remains a challenge. Transcranial magnetic stimulation (TMS), an FDA-approved noninvasive neuromodulation treatment for both major depressive disorder and smoking cessation, represents a promising intervention for cancer survivors due to its unique multitarget effects. Cancer survivors experience high rates of comorbid psychopathology, including depression, anxiety, suicidal ideation, and pain-conditions that interact with smoking behaviors and for which TMS has demonstrated efficacy. However, the current standardized TMS protocol for smoking cessation requires adaptation for cancer populations, given their unique clinical needs. This paper proposes a stakeholder-engaged adaptation framework involving cancer survivors, oncology clinicians, tobacco treatment specialists, TMS psychiatrists, and other key stakeholders to systematically adapt TMS protocols for cancer survivors. We discuss a roadmap for procedural adaptation prior to efficacy trials, including flexible dosing schedules and accelerated protocols, secondary outcome measures beyond smoking behaviors, implementation considerations for integration into oncology care settings, and anticipated barriers and potential solutions. This framework provides a roadmap for developing an optimized, equitable TMS intervention to improve smoking cessation outcomes in cancer survivors.

Novel interventions are urgently needed to treat methamphetamine use disorder (MUD), for which there are no FDA-approved treatments. Previous studies in patients with MUD suggest transcranial magnetic stimulation (TMS) over the left dorsolateral prefrontal cortex (L. dlPFC) decreases craving for methamphetamine. Theta burst stimulation (TBS), which includes intermittent TBS and continuous TBS (cTBS), is increasingly being used for substance use disorders, including MUD. Previous reviews of TMS in MUD performed sub-group meta-analyses of studies that delivered TBS in MUD. However, these meta-analyses included studies with overlapping participant cohorts. Given the absence of prior meta-analyses or reviews examining TBS in MUD using unique participant cohorts, we reviewed randomized controlled trials (RCTs) from three databases (PubMed/Medline, EMBASE, Google Scholar) until September 1, 2024, comparing the impact of TBS versus sham TBS on cue-induced methamphetamine cravings in patients with MUD. We performed a meta-analysis with four eligible RCTs that delivered iTBS. Results suggest iTBS was more effective in reducing cue-induced methamphetamine cravings than sham iTBS (standardized mean difference [SMD] in change = 1.04; 95% CI [0.16, 1.92]). Our systematic review included two additional RCTs that did not have sham comparator arms; one of these demonstrated a significant reduction in methamphetamine craving with accelerated iTBS. Future studies should examine if iTBS can impact clinical outcome measures other than craving, such as methamphetamine use, by measuring return to drug use. It is also pertinent to explore accelerated iTBS and cTBS for MUD and study their effects on relevant biomarkers for MUD.

BACKGROUND:Previous investigations of whole thalamus and thalamic nuclei volumes in posttrauma psychopathology have been sparse and limited in scope and have yielded inconsistent results. To address this, volumetric estimates of whole thalamus and thalamic nuclei were obtained from structural brain magnetic resonance imaging scans from 2058 participants across 20 worldwide sites in the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Posttraumatic Stress Disorder (PTSD) working group. METHODS:Thalamic volumes were compared in trauma-exposed participants with PTSD (n = 238), major depressive disorder (MDD) (n = 184), and comorbid PTSD+MDD (n = 618) and in trauma-exposed control participants (n = 1018). PTSD and MDD symptom severity, PTSD symptom clusters, and childhood trauma were similarly examined for associations with thalamic volume. RESULTS:Participants with PTSD had smaller sensorimotor thalamic nuclei, while participants with MDD or comorbid PTSD+MDD had smaller mediodorsal (MD) thalamus volumes relative to control participants. Severity of PTSD and MDD symptoms negatively correlated with MD volume. A significant interaction between PTSD and MDD severity was found, such that MDD severity was positively associated with whole thalamus volume only among individuals with high PTSD severity. We observed both positive and negative volumetric associations for specific PTSD symptom clusters and childhood trauma subtypes. CONCLUSIONS:Whole thalamus volume and volumes of the sensorimotor and limbic thalamus may play an important role in the development of PTSD and MDD in the aftermath of trauma exposure. The interaction between PTSD and MDD symptoms and contrasting effects across PTSD symptom clusters and types of childhood adversity suggest that multiple neurobiological mechanisms are involved in shaping thalamic volume posttrauma.

BACKGROUND: Posttraumatic stress disorder (PTSD) is accompanied by disrupted cortical neuroanatomy. We investigated alteration in covariance of structural networks associated with PTSD in regions that demonstrate the case-control differences in cortical thickness (CT) and surface area (SA). METHODS: Neuroimaging and clinical data were aggregated from 29 research sites in >1300 PTSD cases and >2000 trauma-exposed control subjects (ages 6.2-85.2 years) by the ENIGMA-PGC (Enhancing Neuro Imaging Genetics through Meta Analysis-Psychiatric Genomics Consortium) PTSD working group. Cortical regions in the network were rank ordered by the effect size of PTSD-related cortical differences in CT and SA. The top-n (n = 2-148) regions with the largest effect size for PTSD > non-PTSD formed hypertrophic networks, the largest effect size for PTSD < non-PTSD formed atrophic networks, and the smallest effect size of between-group differences formed stable networks. The mean structural covariance (SC) of a given n-region network was the average of all positive pairwise correlations and was compared with the mean SC of 5000 randomly generated n-region networks. RESULTS: Patients with PTSD, relative to non-PTSD control subjects, exhibited lower mean SC in CT-based and SA-based atrophic networks. Comorbid depression, sex, and age modulated covariance differences of PTSD-related structural networks. CONCLUSIONS: Covariance of structural networks based on CT and cortical SA are affected by PTSD and further modulated by comorbid depression, sex, and age. The SC networks that are perturbed in PTSD comport with converging evidence from resting-state functional connectivity networks and networks affected by inflammatory processes and stress hormones in PTSD.

Methamphetamine use disorder (MUD) currently lacks FDA-approved treatments. Previous studies involving transcranial magnetic stimulation (TMS) over the left dorsolateral prefrontal cortex (L.dlPFC) have shown promise in TMS's effectiveness at decreasing craving for methamphetamine. Theta burst stimulation (TBS), which includes intermittent (iTBS) and continuous (cTBS) protocols, is increasingly being used for substance use disorders, including MUD. Previous reviews of TMS in MUD performed subgroup meta-analyses of studies that delivered TBS in MUD. However, these meta-analyses included studies with overlapping participant cohorts, limiting their validity. To address this limitation, we reviewed randomized controlled trials (RCTs) using unique patient cohorts from PubMed/Medline, EMBASE, and Google Scholar until September 1, 2024, comparing the impact of TBS versus sham on cue-induced methamphetamine craving in patients with MUD. We performed a meta-analysis with four eligible RCTs that delivered iTBS. Results suggest iTBS was more effective in reducing cue-induced methamphetamine craving than sham iTBS (standardized mean difference [SMD] in change = 1.04; 95% CI [0.16, 1.92]). Two additional RCTs without sham control arms were reviewed, and one demonstrated a significant reduction in craving following accelerated iTBS. Future studies should examine whether neuroimaging-targeted iTBS can impact outcome measures other than craving, such as methamphetamine use, by measuring return to use. Exploring accelerated iTBS and cTBS for MUD, targeting alternative cortical sites such as the frontal pole, and studying their effects on relevant MUD biomarkers is also pertinent. This review demonstrates the effectiveness of TBS for MUD, emphasizing its potential to advance treatment options for MUD.

There is a critical knowledge gap in optimally combining transcranial magnetic stimulation (TMS) and antidepressants to treat patients with major depressive disorder (MDD). TMS is effective in treating MDD in patients who have failed at least one antidepressant trial, with accelerated protocols showing faster remission in treatment-resistant depression (TRD). Although clinicians routinely augment antidepressants with TMS, there is a knowledge gap in stopping versus continuing antidepressants or the dosing strategies when starting or tapering TMS. These considerations are important when considering maintenance TMS (delivered alone or in combination with suitable antidepressants) to maintain remission in MDD after the index course of TMS. As the first step towards filling this knowledge gap, we reviewed randomized controlled trials (RCTs) and open-label trials from 2 databases (PubMed/Medline and EMBASE) that compared active TMS combined with a pre-specified antidepressant dosed in the same manner for adults with MDD versus sham TMS combined with the same antidepressant as in the active arm. All studies were published between January 1, 2000, and December 31, 2023. We excluded case reports, case series, and clinical studies that augmented TMS with antidepressants and vice versa. We found 10 RCTs (n = 654 participants) and performed a meta-analysis. This showed active TMS combined with pre-specified antidepressants had greater efficacy for MDD treatment than sham TMS combined with the same antidepressants as in the active arm (Hedge's g = 1; 95 % CI [0.27, 1.73]). The review and meta-analysis indicate greater short-term efficacy in combining antidepressants with TMS from the get-go in MDD. Given the increasing role of accelerated TMS protocols in expediting remission in MDD and the results of our meta-analysis, we advocate for RCTs examining the short-term and long-term effects of various antidepressant classes on these TMS protocols in MDD. This can also optimize and individualize maintenance TMS protocols to prevent relapse in MDD.

BackgroundPeople living with HIV (PLWHA) smoke at three times the rate of the general population and respond poorly to cessation strategies. Previous studies examined repetitive transcranial magnetic stimulation (rTMS) over left dorsolateral prefrontal cortex (L. dlPFC) to reduce craving, but no studies have explored rTMS among PLWHA who smoke. The current pilot study compared the effects of active and sham intermittent theta-burst stimulation (iTBS) on resting state functional connectivity (rsFC), cigarette cue attentional bias, and cigarette craving in PLWHA who smoke.MethodsEight PLWHA were recruited (single-blind, within-subject design) to receive one session of iTBS (n=8) over the L. dlPFC using neuronavigation and, four weeks later, sham iTBS (n=5). Cigarette craving and attentional bias assessments were completed before and after both iTBS and sham iTBS. rsFC was assessed before iTBS (baseline) and after iTBS and sham iTBS.ResultsCompared to sham iTBS, iTBS enhanced rsFC between the L. dlPFC and bilateral medial prefrontal cortex and pons. iTBS also enhanced rsFC between the right insula and right occipital cortex compared to sham iTBS. iTBS also decreased cigarette craving and cigarette cue attentional bias.ConclusioniTBS could potentially offer a therapeutic option for smoking cessation in PLWHA.

Rakesh, Gopalkumar MD; Naeem, Suniya MBBS; Elias, Madona MS, MSW; Himelhoch, Seth S. MD, MPH; Rush, Craig R. PhD Author Information

The findings based on datasets aggregated from multiple sites may be biased by site-specific profiles in the demographic and clinical characteristics of subjects, as well as the acquisition protocols. There are four commonly used methods to harmonize data from different sources: (1) linear mixed-effects model (LME) that models site-specific random intercepts (LME-INT), (2) LME that models both site-specific random intercepts and age-related random slopes (LME-INT+SLP), (3) ComBat, and (4) ComBat with a generalized additive model (ComBat-GAM). Here, in the domain of neuroimaging studies, we compared the impact of four different harmonization methods on results obtained from analyses of cortical thickness data as a case.