tDCS for the treatment of negative symptoms in youth at clinical-high-risk for psychosis: A feasibility study.

Negative symptoms are often found in youth at clinical high risk (CHR) for psychosis. The present study explored the feasibility of using tDCS in conjunction with CBT in the treatment of negative symptoms in 5 youths at CHR. We sought to determine whether the protocol was feasible given the requirement for repeated visits over a three-week period, and to determine if measures of neurobiological change could be included, both acutely and following three weeks of stimulation. The results from this study suggest that the protocol is feasible for these youth, and the inclusion of MRI scanning sessions yielded good quality data.

Macrostructural Brain Morphology as Moderator of the Relationship Between Pandemic-Related Stress and Internalizing Symptomology During COVID-19 in High-Risk Adolescents.

BACKGROUND: According to person-by-environment models, individual differences in traits may moderate the association between stressors and the development of psychopathology; however, findings in the literature have been inconsistent and little literature has examined adolescent brain structure as a moderator of the effects of stress on adolescent internalizing symptoms. The COVID-19 pandemic presented a unique opportunity to examine the associations between stress, brain structure, and psychopathology. Given links of cortical morphology with adolescent depression and anxiety, the present study investigated whether cortical morphology moderates the relationship between stress from the COVID-19 pandemic on the development of internalizing symptoms in familial high-risk adolescents. METHODS: Prior to the COVID-19 pandemic, 72 adolescents (27M) completed a measure of depressive and anxiety symptoms and underwent magnetic resonance imaging. T1-weighted images were acquired to assess cortical thickness and surface area. Approximately 6-8 months after COVID-19 was declared a global pandemic, adolescents reported their depressive and anxiety symptoms and pandemic-related stress. RESULTS: Adjusting for pre-pandemic depressive and anxiety symptoms and stress, increased pandemic-related stress was associated with increased depressive but not anxiety symptoms. This relationship was moderated by cortical thickness and surface area in the anterior cingulate and cortical thickness in the medial orbitofrontal cortex such that increased stress was only associated with increased depressive and anxiety symptoms among adolescents with lower cortical surface area and higher cortical thickness in these regions. CONCLUSIONS: Results further our understanding of neural vulnerabilities to the associations between stress and internalizing symptoms in general, and during the COVID-19 pandemic in particular.

Adverse event monitoring and reporting in pediatric neuromodulatory studies: A systematic review.

Neuromodulatory interventions are relatively novel and approaches to studying harms and tolerability have varied. Using a checklist based on guidelines from Good Clinical Practice and the Harms Extension of the CONSORT (Consolidated Standards of Reporting Trials) Statement, we identified how adverse events are measured, assessed, and reported in studies evaluating neuromodulation for the treatment of mental and neurodevelopmental disorders among children and adolescents. A systematic literature review identified 56 experimental and quasi-experimental studies evaluating transcranial magnetic stimulation (TMS), transcranial alternating (tACS) or direct (tDCS) current stimulation, transcranial pulse stimulation (TPS), and vagus or trigeminal nerve stimulation (VNS or TNS). For 22 studies (39%), the types of adverse events to be monitored were identified, and for 31 studies (55%), methods for collecting adverse event data were described. Methods for assessing adverse events were less commonly described with 23 studies (41%) having details on assessing event severity, and 11 studies (20%) having details on assessing event causality. Among 31 studies with reported results, headache, skin irritation, and general pain or discomfort were the most reported across studies. Seizure, untoward medical occurrences, and intracranial bleeding, edema, or other intracranial pathology were considered serious events, but these events were not reported as occurring in any results-based papers. Taken together, the findings from this review indicate that most studies of pediatric neuromodulatory interventions did not include descriptions of adverse event monitoring and evaluation. Comprehensive event monitoring and reporting across studies can significantly augment the current knowledge base.

Cannabis legalization and hospitalizations in Alberta: Interrupted time series analysis by age and sex.

OBJECTIVES: Recent research has focused on the effects of legalization on cannabis-related emergency department visits, but the considerable healthcare costs of cannabis-related hospitalizations merit attention. We will examine the association between recreational cannabis legalization and cannabis-related hospitalizations. METHODS: A cohort of 3,493,864 adults from Alberta was examined (October 2015-May 2021) over three periods: pre-legalization, post-legalization of flowers and herbs (phase one), and post-legalization of edibles, extracts, and topicals (phase two). Interrupted time series analyses were used to detect changes. RESULTS: The study found an increase in hospitalization rates among younger adults (18-24) before legalization, yet no increased risk was associated with cannabis legalization, for either younger (18-24) or older adults (25+). CONCLUSIONS: Clinicians should be aware of the increased risk in younger groups and may benefit from early identification and intervention strategies, including screening and brief interventions in primary care settings.

Multi-site benchmark classification of major depressive disorder using machine learning on cortical and subcortical measures.

Machine learning (ML) techniques have gained popularity in the neuroimaging field due to their potential for classifying neuropsychiatric disorders. However, the diagnostic predictive power of the existing algorithms has been limited by small sample sizes, lack of representativeness, data leakage, and/or overfitting. Here, we overcome these limitations with the largest multi-site sample size to date (N = 5365) to provide a generalizable ML classification benchmark of major depressive disorder (MDD) using shallow linear and non-linear models. Leveraging brain measures from standardized ENIGMA analysis pipelines in FreeSurfer, we were able to classify MDD versus healthy controls (HC) with a balanced accuracy of around 62%. But after harmonizing the data, e.g., using ComBat, the balanced accuracy dropped to approximately 52%. Accuracy results close to random chance levels were also observed in stratified groups according to age of onset, antidepressant use, number of episodes and sex. Future studies incorporating higher dimensional brain imaging/phenotype features, and/or using more advanced machine and deep learning methods may yield more encouraging prospects.

Associations between parental depression and anxiety symptom severity and their Offspring's cortical thickness and subcortical volume.

Depression and anxiety are associated with grey matter changes in subcortical regions in adults and adolescents. Parent psychopathology is associated with offspring brain structure, but it's unclear whether altered brain structure in children is associated with severity of parental depression and anxiety symptoms. We examined 123 youth (Mean age = 13.64; 62% female) with no clinically significant history of depression or anxiety and one parent diagnosed with current or past depressive or anxiety disorders. Parents completed the Mini International Neuropsychiatric Interview to assess diagnostic status and the Beck Depression Inventory-II, and the Generalized Anxiety Disorder-7 to assess current symptom severity. Youth underwent T1 weighted structural Magnetic Resonance Imaging scans. Bivariate analyses revealed higher parental depressive severity was not significantly associated with offspring grey matter. Parental anxiety severity was significantly associated with less left global surface area. When controlling for offspring age, sex and intracranial volume (ICV), offspring right surface area was negatively associated with parental depressive severity at a trend level. In previously depressed parents, greater parental depressive severity was significantly associated with offspring decreased left and right surface area. There were no significant associations between parental anxiety severity in previously depressed parents and offspring subcortical or cortical brain regions. These results highlight associations between parental depressive symptom severity and offspring brain structure and suggest that even within an already high-risk group of adolescents, there may be altered cortical surface area depending on parent symptom severity. This may help identify youth most at risk for developing a mood disorder and could help further early intervention and identification efforts.

Disparities in cannabis-related emergency department visits across depressed and non-depressed individuals and the impact of recreational cannabis policy in Ontario, Canada.

BACKGROUND: Recreational cannabis policies are being considered in many jurisdictions internationally. Given that cannabis use is more prevalent among people with depression, legalisation may lead to more adverse events in this population. Cannabis legalisation in Canada included the legalisation of flower and herbs (phase 1) in October 2018, and the deregulation of cannabis edibles one year later (phase 2). This study investigated disparities in cannabis-related emergency department (ED) visits in depressed and non-depressed individuals in each phase. METHODS: Using administrative data, we identified all adults diagnosed with depression 60 months prior to legalisation (n = 929 844). A non-depressed comparison group was identified using propensity score matching. We compared the pre-post policy differences in cannabis-related ED-visits in depressed individuals v. matched (and unmatched) non-depressed individuals. RESULTS: In the matched sample (i.e. comparison with non-depressed people similar to the depressed group), people with depression had approximately four times higher risk of cannabis-related ED-visits relative to the non-depressed over the entire period. Phases 1 and 2 were not associated with any changes in the matched depressed and non-depressed groups. In the unmatched sample (i.e. comparison with the non-depressed general population), the disparity between individuals with and without depression is greater. While phase 1 was associated with an immediate increase in ED-visits among the general population, phase 2 was not associated with any changes in the unmatched depressed and non-depressed groups. CONCLUSIONS: Depression is a risk factor for cannabis-related ED-visits. Cannabis legalisation did not further elevate the risk among individuals diagnosed with depression.

Efficacy of a Therapist-Assisted Self-Help Internet-Based Intervention Targeting PTSD, Depression, and Insomnia Symptoms After a Disaster: A Randomized Controlled Trial.

This study aimed at evaluating the efficacy of an online CBT intervention with limited therapist contact targeting a range of posttraumatic symptoms among evacuees from the 2016 Fort McMurray wildfires. One hundred and thirty-six residents of Fort McMurray who reported either moderate PTSD symptoms (PCL-5 ≥ 23) or mild PTSD symptoms (PCL-5 ≥ 10) with moderate depression (PHQ-9 ≥ 10) or subthreshold insomnia symptoms (ISI ≥ 8) were randomized either to a treatment (n = 69) or a waitlist condition (n = 67). Participants were on average 45 years old, and mostly identified as White (82%) and as women (76%). Primary outcomes were PTSD, depression, and insomnia symptoms. Secondary outcomes were anxiety symptoms and disability. Significant Assessment Time × Treatment Condition interactions were observed on all outcomes, indicating that access to the treatment led to a decrease in posttraumatic stress (F[1,117.04] = 12.128, p = .001; d = .519, 95% CI = .142-.895), depression (F[1,118.29] = 9.978, p = .002; d = .519, 95% CI = .141-.898) insomnia (F[1,117.60] = 4.574, p = .035; d = .512, 95% CI = .132-.892), and anxiety (F[1,119.64] = 5.465, p = .021; d = .421, 95% CI = .044-.797) symptom severity and disability (F[1,111.55] = 7.015, p = .009; d = .582, 95% CI = .200-.963). Larger effect sizes (d = 0.823-1.075) were observed in participants who completed at least half of the treatment. The RESILIENT online treatment platform was successful to provide access to specialized evidence-based mental health care after a disaster.

The Tourette OCD Alberta Network: Development of a Continuing Professional Development Program for Community Based Mental Health Therapists.

The Tourette OCD Alberta Network (TOAN) supports mental health therapists to improve the delivery of care to patients with Tourette syndrome (TS) and OCD in Alberta. We evaluated the professional development needs of health care workers to develop a continuing professional development (CPD) webinar series. Health care workers demonstrated an urgent need to access a CPD program grounded in evidenced based knowledge about TS and OCD. While 80% of health care workers treated children with TS and OCD, 50% had no formal training. A curriculum consisting of a series of twelve live, online webinars was developed and delivered between September 2020 and June 2021, covering a range of clinical topics. The webinars were attended on average by 63 attendees, with the outcome of a positive knowledge gain. In future, the educational program will need to reflect the ongoing developing clinical understanding of TS and OCD.

Consistency of frontal cortex metabolites quantified by magnetic resonance spectroscopy within overlapping small and large voxels.

Single voxel magnetic resonance spectroscopy (MRS) quantifies metabolites within a specified volume of interest. MRS voxels are constrained to rectangular prism shapes. Therefore, they must define a small voxel contained within the anatomy of interest or include not of interest neighbouring tissue. When studying cortical regions without clearly demarcated boundaries, e.g. the dorsolateral prefrontal cortex (DLPFC), it is unclear how representative a larger voxel is of a smaller volume within it. To determine if a large voxel is representative of a small voxel placed within it, this study quantified total N-Acetylaspartate (tNAA), choline, glutamate, Glx (glutamate and glutamine combined), myo-inositol, and creatine in two overlapping MRS voxels in the DLPFC, a large (30×30x30 mm) and small (15×15x15 mm) voxel. Signal-to-noise ratio (SNR) and tissue type factors were specifically investigated. With water-referencing, only myo-inositol was significantly correlated between the two voxels, while all metabolites showed significant correlations with creatine-referencing. SNR had a minimal effect on the correspondence between voxels, while tissue type showed substantial influence. This study demonstrates substantial variability of metabolite estimates within the DLPFC. It suggests that when small anatomical structures are of interest, it may be valuable to spend additional acquisition time to obtain specific, localized data.

Structural brain network lateralization across childhood and adolescence.

Developmental lateralization of brain function is imperative for behavioral specialization, yet few studies have investigated differences between hemispheres in structural connectivity patterns, especially over the course of development. The present study compares the lateralization of structural connectivity patterns, or topology, across children, adolescents, and young adults. We applied a graph theory approach to quantify key topological metrics in each hemisphere including efficiency of information transfer between regions (global efficiency), clustering of connections between regions (clustering coefficient [CC]), presence of hub-nodes (betweenness centrality [BC]), and connectivity between nodes of high and low complexity (hierarchical complexity [HC]) and investigated changes in these metrics during development. Further, we investigated BC and CC in seven functionally defined networks. Our cross-sectional study consisted of 211 participants between the ages of 6 and 21 years with 93% being right-handed and 51% female. Global efficiency, HC, and CC demonstrated a leftward lateralization, compared to a rightward lateralization of BC. The sensorimotor, default mode, salience, and language networks showed a leftward asymmetry of CC. BC was only lateralized in the salience (right lateralized) and dorsal attention (left lateralized) networks. Only a small number of metrics were associated with age, suggesting that topological organization may stay relatively constant throughout school-age development, despite known underlying changes in white matter properties. Unlike many other imaging biomarkers of brain development, our study suggests topological lateralization is consistent across age, highlighting potential nonlinear mechanisms underlying developmental specialization.

Reliability of active robotic neuro-navigated transcranial magnetic stimulation motor maps.

Transcranial magnetic stimulation (TMS) motor mapping is a safe, non-invasive method used to study corticomotor organization and intervention-induced plasticity. Reliability of resting maps is well established, but understudied for active maps and unestablished for active maps obtained using robotic TMS techniques. The objective of  this study was to determine the reliability of robotic neuro-navigated TMS motor map measures during active muscle contraction. We hypothesized that map area and volume would show excellent short- and medium-term reliability. Twenty healthy adults were tested on 3 days. Active maps of the first dorsal interosseous muscle were created using a 12 × 12 grid (7 mm spacing). Short- (24 h) and medium-term (3-5 weeks) relative (intra-class correlation coefficient) and absolute (minimal detectable change (MDC); standard error of measure) reliabilities were evaluated for map area, volume, center of gravity (CoG), and hotspot magnitude (peak-to-peak MEP amplitude at the hotspot), along with active motor threshold (AMT) and maximum voluntary contraction (MVC). This study found that AMT and MVC had good-to-excellent short- and medium-term reliability. Map CoG (x and y) were the most reliable map measures across sessions with excellent short- and medium-term reliability (p < 0.001). Map area, hotspot magnitude, and map volume followed with better reliability medium-term than short-term, with a change of 28%, 62%, and 78% needed to detect a true medium-term change, respectively. Therefore, robot-guided neuro-navigated TMS active mapping is relatively reliable but varies across measures. This, and MDC, should be considered in interventional study designs.

Development of an Open Face Home Cage Running Wheel for Testing Activity-Based Anorexia and Other Applications.

Running wheels for mice residing in the home cage are useful for the continuous measurement of locomotor activity for studies testing exercise interventions or exercise-induced effects on brain and metabolism. Here, we have developed an open source, printable, open-faced running wheel that is automated to collect locomotor information such as distance traveled, wheel direction, and velocity that can be binned into epochs over 24 h or multiple days. This system allows for remote data collection to avoid human interference in mouse behavioral experiments. We tested this system in an activity-based anorexia procedure. Using these wheels, we replicate previous findings that food restriction augments wheel-running activity.

Associations between recreational cannabis legalization and cannabis-related emergency department visits by age, gender, and geographic status in Ontario, Canada: An interrupted time series study.

Legalization of recreational cannabis in Ontario included the legalization of flower and herbs (Phase 1, October 2018), and was followed by the deregulation of cannabis retailers and sales of edibles (Phase 2, February 2020). Research on the impact of cannabis legalization on acute care utilization is nascet; no research has investigated potential age, gender, and geographically vulnerable subgroup effects. Residents living in Northern Ontario not only have higher levels of substance use problems, but also have inadequate access to primary healthcare. Our study investigated the impact of Ontario's recreational cannabis policy (including Phase 1 and 2) on cannabis-attributable emergency department (ED) visits, and estimated the impact separately for different age and gender groups, with additional analyses focused on Northern Ontarians. We created a cohort of adults (18 and over) eligible for provincial universal health insurance with continuous coverage from 2015-2021 (n = 14,900,820). An interrupted time series was used to examine the immediate impact and month-to-month changes in cannabis-related ED visits associated with Phase 1 & 2 for each subgroup. While Northern Ontario has higher rates of cannabis-related ED visits, both Northern and Southern Ontario show similar patterns of changes. Phase 1 was associated with significant increases in adults 25-64, with the strongest increases seen in women 45-64. Month-to-month trends were flattened in most groups compared to pre-legalization. Phase 2 was associated with significant immediate increases for adults aged 18-44 in both genders, but the increases were larger in women than men. No significant month-to-month changes were detected in this period. While current preventive efforts are largely focused on reducing cannabis-related harms in youths and younger adults, our results show that adults 25-64, particularly women, have been significantly impacted by cannabis policies. Further research on gender-specific cannabis dosage and targeted interventions for adult women should be investigated. Legalization did not appear to have a differential impact on Northern versus Southern Ontario, but higher rates of ED visits in the North should be addressed.

Trainee Therapists' Perceptions of a Blended Intervention to Promote Resilience after a Natural Disaster: A Qualitative Case Study.

BACKGROUND: Natural disasters happen in an increased frequency, and telemental health interventions could offer easily accessible help to reduce mental health symptoms experienced by survivors. However, there are very few programs offered to natural disaster survivors, and no research exists on therapists' experiences with providing blended interventions for natural disaster survivors. AIMS: Our qualitative case study aims to describe psychologists' experiences with an online, therapist-assisted blended intervention for survivors of the Fort McMurray wildfires in Alberta, Canada. METHOD: The RESILIENT intervention was developed in the frames of a randomized controlled trial to promote resilience after the Fort McMurray wildfires by providing survivors free access to a 12-module, therapist-assisted intervention, aiming to improve post-traumatic stress, insomnia, and depression symptoms. A focus group design was used to collect data from the therapists, and emerging common themes were identified by thematic analysis. RESULTS: Therapists felt they could build strong alliances and communicate emotions and empathy effectively, although the lack of nonverbal cues posed some challenges. The intervention, according to participating therapists, was less suitable for participants in high-stress situations and in case of discrepancy between client expectations and the intervention content. Moreover, the therapists perceived specific interventions as easy-to-use or as more challenging based on their complexity and on the therapist support needed for executing them. Client engagement in the program emerged as an underlying theme that had fundamental impact on alliance, communication, and ultimately, treatment efficiency. Therapist training and supervision was perceived as crucial for the success of the program delivery. CONCLUSIONS: Our findings provided several implications for the optimalization of blended interventions for natural disaster survivors from our therapists' perspective.

Right Superior Frontal Gyrus Cortical Thickness in Pediatric ADHD.

OBJECTIVE: We investigated the right Superior Frontal Gyrus (right-SFG) and Anterior Cingulate Cortex (ACC) in children with ADHD and their clinical relevance with Executive Function (EF) and ADHD symptom severity. METHODS: About 26 children with ADHD and 24 typically developing children (TDC; 7‒16 years) underwent Magnetic Resonance Imaging (MRI) and completed an EF assessment battery. RESULTS: Significantly thinner right-SFG in the ADHD group was found compared to the TDC group (t (48) = 2.81, p = .007, Cohen's d = 0.84). Linear regression models showed that 12.5% of inattention, 13.6% of hyperactivity, and 9.0% of EF variance was accounted for by the right-SFG thickness. CONCLUSIONS: Differences in the right-SFG thickness were found in our ADHD group and were associated with parent ratings of inattentive and hyperactive symptoms as well with EF ratings. These results replicate previous findings of thinner right-SFG and are consistent with the delayed cortical maturation theory of ADHD.

Differences in neurometabolites and transcranial magnetic stimulation motor maps in children with attention-deficit/hyperactivity disorder.

BACKGROUND: Although much is known about cognitive dysfunction in attention-deficit/hyperactivity disorder (ADHD), few studies have examined the pathophysiology of disordered motor circuitry. We explored differences in neurometabolite levels and transcranial magnetic stimulation (TMS)-derived corticomotor representations among children with ADHD and typically developing children. METHODS: We used magnetic resonance spectroscopy (MRS) protocols to measure excitatory (glutamate + glutamine [Glx]) and inhibitory (γ-aminobutyric acid [GABA]) neurometabolite levels in the dominant primary motor cortex (M1) and the supplementary motor area (SMA) in children with ADHD and typically developing children. We used robotic neuronavigated TMS to measure corticospinal excitability and create corticomotor maps. RESULTS: We collected data from 26 medication-free children with ADHD (aged 7-16 years) and 25 typically developing children (11-16 years). Children with ADHD had lower M1 Glx (p = 0.044, d = 0.6); their mean resting motor threshold was lower (p = 0.029, d = 0.8); their map area was smaller (p = 0.044, d = 0.7); and their hotspot density was higher (p = 0.008, d = 0.9). M1 GABA levels were associated with motor map area (p = 0.036).Limitations: Some TMS data were lost because the threshold of some children exceeded 100% of the machine output. The relatively large MRS voxel required to obtain sufficient signal-to-noise ratio and reliably measure GABA levels encompassed tissue beyond the M1, making this measure less anatomically specific. CONCLUSION: The neurochemistry and neurophysiology of key nodes in the motor network may be altered in children with ADHD, and the differences appear to be related to each other. These findings suggest potentially novel neuropharmacological and neuromodulatory targets for ADHD.

Active versus resting neuro-navigated robotic transcranial magnetic stimulation motor mapping.

Transcranial magnetic stimulation (TMS) motor mapping is a safe, non-invasive method that can be used to study corticomotor organization. Motor maps are typically acquired at rest, and comparisons to maps obtained during muscle activation have been both limited and contradictory. Understanding the relationship between functional activation of the corticomotor system as recorded by motor mapping is crucial for their use clinically and in research. The present study utilized robotic TMS paired with personalized neuro-navigation to examine the relationship between resting and active motor map measures and their relationship with motor performance. Twenty healthy right-handed participants underwent resting and active robotic TMS motor mapping of the first dorsal interosseous to 10% maximum voluntary contraction. Motor map parameters including map area, volume, and measures of map centrality were compared between techniques using paired sample tests of difference and Bland-Altman plots and analysis. Map area, volume, and hotspot magnitude were larger in the active motor maps, while map center of gravity and hotspot locations remained consistent between both maps. No associations were observed between motor maps and motor performance as measured by the Purdue Pegboard Test. Our findings support previous suggestions that maps scale with muscle contraction. Differences in mapping outcomes suggest rest and active motor maps may reflect functionally different corticomotor representations. Advanced analysis methods may better characterize the underlying neurophysiology of both types of motor mapping.

Transcranial magnetic stimulation in the treatment of adolescent depression: a systematic review and meta-analysis of aggregated and individual-patient data from uncontrolled studies.

Transcranial magnetic stimulation (TMS) is a non-invasive treatment for adolescent major depressive disorder (MDD). Existing evidence on the efficacy of TMS in adolescent MDD awaits quantitative synthesis. A systematic literature search was conducted, and data from eligible studies were synthesized using random-effects models. Treatment-covariate interactions were examined in exploratory analyses of individual-patient data (IPD). Systematic search of the literature yielded 1264 hits, of which 10 individual studies (2 randomized trials) were included for quantitative synthesis of mainly uncontrolled studies. Individual patient data (IPD) were available from five trials (all uncontrolled studies). Quantitative synthesis of aggregated data revealed a statistically significant negative overall standardized mean change (pooled SMCC = 2.04, 95% CI [1.46; 2.61], SE = 0.29, p < .001), as well as a significant overall treatment response rate (Transformed Proportion = 41.30%, 95% CI [31.03; 51.57], SE = 0.05; p < 0.001), considering data from baseline to post-treatment. Exploratory IPD analyses suggests TMS might be more effective in younger individuals and individuals with more severe depression, and efficacy might be enhanced with certain treatment modality settings, including higher number of TMS sessions, longer treatment durations, and unilateral and not bilateral stimulation. Existing studies exhibit methodological shortcomings, including small-study effects and lack of control group, blinding, and randomization-compromising the credibility of the present results. To date, two randomized controlled trials on TMS in adolescent depression have been published, and the only large-scale randomized trial suggests TMS is not more effective than sham stimulation. Future large-scale, randomized, and sham-controlled trials are warranted. Future trials should ensure appropriate selection of patients for TMS treatment and guide precision medicine approaches for stimulation protocols.