Frontostriatal salience network expansion in individuals in depression.

Decades of neuroimaging studies have shown modest differences in brain structure and connectivity in depression, hindering mechanistic insights or the identification of risk factors for disease onset1. Furthermore, whereas depression is episodic, few longitudinal neuroimaging studies exist, limiting understanding of mechanisms that drive mood-state transitions. The emerging field of precision functional mapping has used densely sampled longitudinal neuroimaging data to show behaviourally meaningful differences in brain network topography and connectivity between and in healthy individuals2-4, but this approach has not been applied in depression. Here, using precision functional mapping and several samples of deeply sampled individuals, we found that the frontostriatal salience network is expanded nearly twofold in the cortex of most individuals with depression. This effect was replicable in several samples and caused primarily by network border shifts, with three distinct modes of encroachment occurring in different individuals. Salience network expansion was stable over time, unaffected by mood state and detectable in children before the onset of depression later in adolescence. Longitudinal analyses of individuals scanned up to 62 times over 1.5 years identified connectivity changes in frontostriatal circuits that tracked fluctuations in specific symptoms and predicted future anhedonia symptoms. Together, these findings identify a trait-like brain network topology that may confer risk for depression and mood-state-dependent connectivity changes in frontostriatal circuits that predict the emergence and remission of depressive symptoms over time.

Influence of Large-Scale Brain State Dynamics on the Evoked Response to Brain Stimulation.

Understanding how spontaneous brain activity influences the response to neurostimulation is crucial for the development of neurotherapeutics and brain-computer interfaces. Localized brain activity is suggested to influence the response to neurostimulation, but whether fast-fluctuating (i.e., tens of milliseconds) large-scale brain dynamics also have any such influence is unknown. By stimulating the prefrontal cortex using combined transcranial magnetic stimulation (TMS) and electroencephalography (EEG), we examined how dynamic global brain state patterns, as defined by microstates, influence the magnitude of the evoked brain response. TMS applied during what resembled the canonical microstate C was found to induce a greater evoked response for up to 80 milliseconds compared to other microstates. This effect was found in a repeated experimental session, was absent during sham stimulation, and was replicated in an independent dataset. Ultimately, ongoing and fast-fluctuating global brain states, as probed by microstates, may be associated with intrinsic fluctuations in connectivity and excitation-inhibition balance and influence the neurostimulation outcome. We suggest that the fast-fluctuating global brain states be considered when developing any related paradigms.Significance Statement Previous findings suggested local spontaneous neural oscillations can influence neurophysiological response to stimuli. However, beyond the local oscillatory activity, the brain state is rapidly fluctuating on a millisecond time resolution on a global spatial scale. We investigated whether these rapid global fluctuations influenced the evoked response to brain stimulation. We used combined transcranial magnetic stimulation and electroencephalography (TMS-EEG) to stimulate the prefrontal cortex while recording global brain states via EEG microstates. The evoked neurophysiological response was significantly larger when stimulation was applied after the occurrence of a specific global brain state (i.e., microstate C) linked to mind-wandering. The finding was selective to active stimulation, replicated for the same individuals in a repeated session, and replicated in an entirely independent dataset.

N100 as a response prediction biomarker for accelerated 1 Hz right DLPFC-rTMS in major depression.

BACKGROUND AND OBJECTIVE: Repetitive transcranial magnetic stimulation (rTMS) is a safe and effective treatment for major depressive disorder (MDD); however, this treatment currently lacks reliable biomarkers of treatment response. TMS-evoked potentials (TEPs), measured using TMS-electroencephalography (TMS-EEG), have been suggested as potential biomarker candidates, with the N100 peak being one of the most promising. This study investigated the association between baseline N100 amplitude and 1 Hz right dorsolateral prefrontal cortex (R-DLPFC) accelerated rTMS (arTMS) treatment in MDD. METHODS: Baseline TMS-EEG sessions were performed for 23 MDD patients. All patients then underwent 40 sessions of 1 Hz R-DLPFC (F4) arTMS over 5 days and a follow-up TMS-EEG session one week after the end of theses arTMS sessions. RESULTS: Baseline N100 amplitude at F4 showed a strong positive association (p < .001) with treatment outcome. The association between the change in N100 amplitude (baseline to follow-up) and treatment outcome did not remain significant after Bonferroni correction (p = .06, corrected; p = .03, uncorrected). Furthermore, treatment responders had a significantly larger mean baseline F4 TEP amplitude during the N100 time frame compared to non-responders (p < .001). Topographically, after Bonferroni correction, F4 is the only electrode at which its baseline N100 amplitude showed a significant positive association (p < .001) with treatment outcome. LIMITATIONS: Lack of control group and auditory masking. CONCLUSION: Baseline N100 amplitude showed a strong association with treatment outcome and thus demonstrated great potential to be utilized as a cost-effective and widely adoptable biomarker of rTMS treatment in MDD.

Cognitive Profiles in Treatment-Resistant Late-Life Depression and their Impact on Treatment Outcomes.

BACKGROUND: Late-life depression (LLD) is associated with cognitive impairment, yet substantial heterogeneity exists among patients. Data on the extent of cognitive impairments is inconclusive, particularly in patients with treatment-resistant depression (TRD). We investigated the cognitive profiles of patients with treatment-resistant vs. nonresistant LLD and aimed to identify distinct cognitive subgroups. Additionally, we examined whether cognitive subgroups differentially responded to treatment with bilateral repetitive transcranial magnetic stimulation (rTMS). METHODS: 165 patients with LLD were divided into treatment-resistant and nonresistant groups and compared to healthy controls (HC) on measures of executive function, information processing speed, verbal learning, and memory. Cluster analysis identified subgroups based on cognitive scores. Demographic and clinical variables, as well as outcomes with bilateral rTMS, were compared between cognitive subgroups. RESULTS: Patients with LLD, particularly TRD, exhibited significantly worse cognitive performance than HC. A three-cluster solution was found, including "Cognitively Intact" (n = 89), "Cognitively Diminished" (n = 29), and "Impaired Memory" (n = 47) subgroups. Both the "Cognitively Diminished" and "Impaired Memory" subgroups had more anxiety symptoms and a higher proportion of patients with TRD than the "Cognitively Intact" group, though the latter did not survive multiple comparison correction. No significant differences were observed in outcomes to rTMS treatment. CONCLUSIONS: Patients with LLD exhibited impairments across cognitive domains, which were more pronounced in TRD. Three identified cognitive subgroups responded similarly to rTMS treatment, indicating its effectiveness across cognitive profiles, especially when medications are not tolerated. Future research should examine the relationship among cognitive subgroups, cognitive decline, and neurodegeneration.

Densely sampled stimulus-response map of human cortex with single pulse TMS-EEG and its relation to whole brain neuroimaging measures.

Large-scale networks underpin brain functions. How such networks respond to focal stimulation can help decipher complex brain processes and optimize brain stimulation treatments. To map such stimulation-response patterns across the brain non-invasively, we recorded concurrent EEG responses from single-pulse transcranial magnetic stimulation (i.e., TMS-EEG) from over 100 cortical regions with two orthogonal coil orientations from one densely-sampled individual. We also acquired Human Connectome Project (HCP)-styled diffusion imaging scans (six), resting-state functional Magnetic Resonance Imaging (fMRI) scans (120 mins), resting-state EEG scans (108 mins), and structural MR scans (T1- and T2-weighted). Using the TMS-EEG data, we applied network science-based community detection to reveal insights about the brain's causal-functional organization from both a stimulation and recording perspective. We also computed structural and functional maps and the electric field of each TMS stimulation condition. Altogether, we hope the release of this densely sampled (n=1) dataset will be a uniquely valuable resource for both basic and clinical neuroscience research.

No Consistent Antidepressant Effects of Deep Brain Stimulation of the Bed Nucleus of the Stria Terminalis.

BACKGROUND: Applying deep brain stimulation (DBS) to several brain regions has been investigated in attempts to treat highly treatment-resistant depression, with variable results. Our initial pilot data suggested that the bed nucleus of the stria terminalis (BNST) could be a promising therapeutic target. OBJECTIVE: The aim of this study was to gather blinded data exploring the efficacy of applying DBS to the BNST in patients with highly refractory depression. METHOD: Eight patients with chronic severe treatment-resistant depression underwent DBS to the BNST. A randomised, double-blind crossover study design with fixed stimulation parameters was followed and followed by a period of open-label stimulation. RESULTS: During the double-blind crossover phase, no consistent antidepressant effects were seen with any of the four stimulation parameters applied, and no patients achieved response or remission criteria during the blinded crossover phase or during a subsequent period of three months of blinded stimulation. Stimulation-related side effects, especially agitation, were reported by a number of patients and were reversible with adjustment of the stimulation parameters. CONCLUSIONS: The results of this study do not support the application of DBS to the BNST in patients with highly resistant depression or ongoing research utilising stimulation at this brain site. The blocked randomised study design utilising fixed stimulation parameters was poorly tolerated by the participants and does not appear suitable for assessing the efficacy of DBS at this location.

Effects of repetitive transcranial magnetic stimulation on individual variability of resting-state functional connectivity in major depressive disorder.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for major depressive disorder (MDD), but substantial heterogeneity in outcomes remains. We examined a potential mechanism of action of rTMS to normalize individual variability in resting-state functional connectivity (rs-fc) before and after a course of treatment. METHODS: Variability in rs-fc was examined in healthy controls (baseline) and individuals with MDD (baseline and after 4-6 weeks of rTMS). Seed-based connectivity was calculated to 4 regions associated with MDD: left dorsolateral prefrontal cortex (DLPFC), right subgenual anterior cingulate cortex (sgACC), bilateral insula, and bilateral precuneus. Individual variability was quantified for each region by calculating the mean correlational distance of connectivity maps relative to the healthy controls; a higher variability score indicated a more atypical/idiosyncratic connectivity pattern. RESULTS: We included data from 66 healthy controls and 252 individuals with MDD in our analyses. Patients with MDD did not show significant differences in baseline variability of rs-fc compared with controls. Treatment with rTMS increased rs-fc variability from the right sgACC and precuneus, but the increased variability was not associated with clinical outcomes. Interestingly, higher baseline variability of the right sgACC was significantly associated with less clinical improvement (p = 0.037, uncorrected; did not survive false discovery rate correction).Limitations: The linear model was constructed separately for each region of interest. CONCLUSION: This was, to our knowledge, the first study to examine individual variability of rs-fc related to rTMS in individuals with MDD. In contrast to our hypotheses, we found that rTMS increased the individual variability of rs-fc. Our results suggest that individual variability of the right sgACC and bilateral precuneus connectivity may be a potential mechanism of rTMS.

Cognitive function based on theta-gamma coupling vs. clinical diagnosis in older adults with mild cognitive impairment with or without major depressive disorder.

Whether individuals with mild cognitive impairment (MCI) and a history of major depressive disorder (MDD) are at a higher risk for cognitive decline than those with MCI alone is still not clear. Previous work suggests that a reduction in prefrontal cortical theta phase-gamma amplitude coupling (TGC) is an early marker of cognitive impairment. This study aimed to determine whether using a TGC cutoff is better at separating individuals with MCI or MCI with remitted MDD (MCI+rMDD) on cognitive performance than their clinical diagnosis. Our hypothesis was that global cognition would differ more between TGC-based groups than diagnostic groups. We analyzed data from 128 MCI (mean age: 71.8, SD: 7.3) and 85 MCI+rMDD (mean age: 70.9, SD: 4.7) participants. Participants completed a comprehensive neuropsychological battery; TGC was measured during the N-back task. An optimal TGC cutoff was determined during the performance of the 2-back. This TGC cutoff was used to classify participants into low vs. high-TGC groups. We then compared Cohen's d of the difference in global cognition between the high and low TGC groups to Cohen's d between the MCI and MCI+rMDD groups. We used bootstrapping to determine 95% confidence intervals for Cohen's d values using the whole sample. As hypothesized, Cohen's d for the difference in global cognition between the TGC groups was larger (0.64 [0.32, 0.88]) than between the diagnostic groups (0.10 [0.004, 0.37]) with a difference between these two Cohen's d's of 0.54 [0.10, 0.80]. Our findings suggest that TGC is a useful marker to identify individuals at high risk for cognitive decline, beyond clinical diagnosis. This could be due to TGC being a sensitive marker of prefrontal cortical dysfunction that would lead to an accelerated cognitive decline.

Predictors of remission after repetitive transcranial magnetic stimulation for the treatment of late-life depression.

Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment in patients with depression, yet treatment response remains variable. While previous work has identified predictors of remission in younger adults, relatively little data exists in late-life depression (LLD). To address this gap, data from 164 participants with LLD from a randomized non-inferiority treatment trial comparing standard bilateral rTMS to bilateral theta burst stimulation (TBS) (ClinicalTrials.gov identifier: NCT02998580) were analyzed using binary logistic regression and conditional inference tree (CIT) modeling. Lower baseline depression symptom severity, fewer prior antidepressant treatment failures, and higher global cognition predicted remission following rTMS treatment. The CIT predicted a higher likelihood of achieving remission for patients with a total score of 19 or lower on the Montgomery-Åsberg Depression Rating Scale, 1 or fewer prior antidepressant treatment failures, and a total score of 23 or higher on the Montreal Cognitive Assessment. Our results indicate that older adults with lower severity of depression, fewer antidepressant treatment failures, and higher global cognition benefit more from current forms of rTMS. The results suggest that there is potentially higher value in using rTMS earlier in the treatment pathway for depression in older adults.

The importance of individual beliefs in assessing treatment efficacy.

In recent years, there has been debate about the effectiveness of treatments from different fields, such as neurostimulation, neurofeedback, brain training, and pharmacotherapy. This debate has been fuelled by contradictory and nuanced experimental findings. Notably, the effectiveness of a given treatment is commonly evaluated by comparing the effect of the active treatment versus the placebo on human health and/or behaviour. However, this approach neglects the individual's subjective experience of the type of treatment she or he received in establishing treatment efficacy. Here, we show that individual differences in subjective treatment - the thought of receiving the active or placebo condition during an experiment - can explain variability in outcomes better than the actual treatment. We analysed four independent datasets (N = 387 participants), including clinical patients and healthy adults from different age groups who were exposed to different neurostimulation treatments (transcranial magnetic stimulation: Studies 1 and 2; transcranial direct current stimulation: Studies 3 and 4). Our findings show that the inclusion of subjective treatment can provide a better model fit either alone or in interaction with objective treatment (defined as the condition to which participants are assigned in the experiment). These results demonstrate the significant contribution of subjective experience in explaining the variability of clinical, cognitive, and behavioural outcomes. We advocate for existing and future studies in clinical and non-clinical research to start accounting for participants' subjective beliefs and their interplay with objective treatment when assessing the efficacy of treatments. This approach will be crucial in providing a more accurate estimation of the treatment effect and its source, allowing the development of effective and reproducible interventions.

Neuromodulation is a type of intervention that relies on various non-invasive techniques to temporarily stimulate the brain and nervous system. It can be used for the treatment of depression or other medical conditions, as well as the improvement of cognitive abilities such as attention. However, there is conflicting evidence regarding whether this approach has beneficial effects. Most studies aiming to assess the efficiency of a treatment rely on examining the outcomes of people who received the intervention in comparison to participants who undergo a similar procedure with no therapeutic effect (or placebo). However, the influence of other, 'subjective' factors on these results ­ such as the type of intervention participants think they have received ­ remains poorly investigated. To bridge this gap, Fassi and Hochman et al. used statistical modeling to assess how patients' beliefs about their treatment affected the results of four neuromodulation studies on mind wandering, depression and attention deficit hyperactivity disorder symptoms. In two studies, participants' perceptions of their treatment status were more strongly linked to changes in depression scores and mind-wandering than the actual treatment. Results were more nuanced in the other two studies. In one of them, participants who received the real neuromodulation but believed they received the placebo showed the most improvement in depressive symptoms; in the other study, subjective beliefs and objective treatment both explained changes in inattention symptoms. Taken together, the results by Fassi and Hochman et al. suggest that factoring in patients' subjective beliefs about their treatment may be necessary in studies of neuromodulation and other interventions like virtual reality or neurofeedback, where participants are immersed in cutting-edge research settings and might therefore be more susceptible to develop beliefs about treatment efficacy.

Dimensional and Categorical Solutions to Parsing Depression Heterogeneity in a Large Single-Site Sample.

BACKGROUND: Recent studies have reported significant advances in modeling the biological basis of heterogeneity in major depressive disorder, but investigators have also identified important technical challenges, including scanner-related artifacts, a propensity for multivariate models to overfit, and a need for larger samples with more extensive clinical phenotyping. The goals of the current study were to evaluate dimensional and categorical solutions to parsing heterogeneity in depression that are stable and generalizable in a large, single-site sample. METHODS: We used regularized canonical correlation analysis to identify data-driven brain-behavior dimensions that explain individual differences in depression symptom domains in a large, single-site dataset comprising clinical assessments and resting-state functional magnetic resonance imaging data for 328 patients with major depressive disorder and 461 healthy control participants. We examined the stability of clinical loadings and model performance in held-out data. Finally, hierarchical clustering on these dimensions was used to identify categorical depression subtypes. RESULTS: The optimal regularized canonical correlation analysis model yielded 3 robust and generalizable brain-behavior dimensions that explained individual differences in depressed mood and anxiety, anhedonia, and insomnia. Hierarchical clustering identified 4 depression subtypes, each with distinct clinical symptom profiles, abnormal resting-state functional connectivity patterns, and antidepressant responsiveness to repetitive transcranial magnetic stimulation. CONCLUSIONS: Our results define dimensional and categorical solutions to parsing neurobiological heterogeneity in major depressive disorder that are stable, generalizable, and capable of predicting treatment outcomes, each with distinct advantages in different contexts. They also provide additional evidence that regularized canonical correlation analysis and hierarchical clustering are effective tools for investigating associations between functional connectivity and clinical symptoms.

Pre-clinical indications of brain stimulation treatments for non-affective psychiatric disorders, a status update.

Over the past two decades noninvasive brain stimulation (NIBS) techniques have emerged as powerful therapeutic options for a range of psychiatric and neurological disorders. NIBS are hypothesized to rebalance pathological brain networks thus reducing symptoms and improving functioning. This development has been fueled by controlled studies with increasing size and rigor aiming to characterize how treatments induce clinically effective change. Clinical trials of NIBS for specific indications have resulted in federal approval for unipolar depression, bipolar depression, smoking cessation, and obsessive-compulsive disorder in the United States, and several other indications worldwide. As a rapidly emerging field, there are numerous pre-clinical indications currently in development using a variety of electrical and magnetic, non-convulsive, and convulsive approaches. This review discusses the state-of-the-science surrounding promising avenues of NIBS currently in pre-approval stages for non-affective psychiatric disorders. We consider emerging therapies for psychosis, anxiety disorders, obsessive-compulsive disorder, and borderline personality disorder, utilizing transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), and magnetic seizure therapy (MST), with an additional brief section for early-stage techniques including transcranial focused ultrasound stimulation (tFUS) and transcranial alternating current stimulation (tACS). As revealed in this review, there is considerable promise across all four psychiatric indications with different NIBS approaches. Positive findings are notable for the treatment of psychosis using tDCS, MST, and rTMS. While rTMS is already FDA approved for the treatment of obsessive-compulsive disorder, methodologies such as tDCS also demonstrate potential in this condition. Emerging techniques show promise for treating non-affective disorders likely leading to future regulatory approvals.

Baseline markers of cortical excitation and inhibition predict response to theta burst stimulation treatment for youth depression.

Theta burst stimulation (TBS), a specific form of repetitive transcranial magnetic stimulation (TMS), is a promising treatment for youth with Major Depressive Disorder (MDD) who do not respond to conventional therapies. However, given the variable response to TBS, a greater understanding of how baseline features relate to clinical response is needed to identify which patients are most likely to benefit from this treatment. In the current study, we sought to determine if baseline neurophysiology, specifically cortical excitation and/or inhibition, is associated with antidepressant response to TBS. In two independent open-label clinical trials, youth (aged 16-24 years old) with MDD underwent bilateral dorsolateral prefrontal cortex (DLPFC) TBS treatment. Clinical trial one and two consisted of 10 and 20 daily sessions of bilateral DLPFC TBS, respectively. At baseline, single-pulse TMS combined with electroencephalography was used to assess the neurophysiology of 4 cortical sites: bilateral DLPFC and inferior parietal lobule. Measures of cortical excitation and inhibition were indexed by TMS-evoked potentials (i.e., P30, N45, P60, N100, and P200). Depression severity was measured before, during and after treatment completion using the Hamilton Rating Scale for Depression-17. In both clinical trials, the baseline left DLPFC N45 and P60, which are believed to reflect inhibitory and excitatory mechanisms respectively, were predictors of clinical response. Specifically, greater (i.e., more negative) N45 and smaller P60 baseline values were associated with greater treatment response to TBS. Accordingly, cortical excitation and inhibition circuitry of the left DLPFC may have value as a TBS treatment response biomarker for youth with MDD.Clinical trial 1 registration number: NCT02472470 (June 15, 2015).Clinical trial 2 registration number: NCT03708172 (October 17, 2018).

Magnetic seizure therapy and electroconvulsive therapy increase aperiodic activity.

Major depressive disorder (MDD) is a leading cause of disability worldwide. One of the most efficacious treatments for treatment-resistant MDD is electroconvulsive therapy (ECT). Recently, magnetic seizure therapy (MST) was developed as an alternative to ECT due to its more favorable side effect profile. While these approaches have been very successful clinically, the neural mechanisms underlying their therapeutic effects are unknown. For example, clinical "slowing" of the electroencephalogram beginning in the postictal state and extending days to weeks post-treatment has been observed in both treatment modalities. However, a recent longitudinal study of a small cohort of ECT patients revealed that, rather than delta oscillations, clinical slowing was better explained by increases in aperiodic activity, an emerging EEG signal linked to neural inhibition. Here we investigate the role of aperiodic activity in a cohort of patients who received ECT and a cohort of patients who received MST treatment. We find that aperiodic neural activity increases significantly in patients receiving either ECT or MST. Although not directly related to clinical efficacy in this dataset, increased aperiodic activity is linked to greater amounts of neural inhibition, which is suggestive of a potential shared neural mechanism of action across ECT and MST.

Efficacy of insula deep repetitive transcranial magnetic stimulation combined with varenicline for smoking cessation: A randomized, double-blind, sham controlled trial.

BACKGROUND: Current smoking cessation treatments are limited in terms of efficacy, particularly with regards to long term abstinence. There is a large amount of evidence implicating the insula in nicotine addiction. OBJECTIVE: To examine the efficacy of bilateral repetitive transcranial magnetic stimulation (rTMS) directed to the insular cortex with the H11 coil, relative to sham stimulation, on smoking abstinence and smoking outcomes in smokers who are receiving standard varenicline treatment. METHODS: This randomized, double-blind, sham controlled trial recruited 42 participants who were randomized to receive either active (n = 24) or sham (n = 18) high frequency rTMS directed to the insula (4 weeks), while receiving varenicline treatment (12 weeks). The primary outcome was 7-day point prevalence abstinence at the end of 12 weeks. RESULTS: Smokers in the active group had significantly higher abstinence rates than those in the sham group (82.4% vs. 30.7%, p = 0.013) at the end of treatment (Week 12). Secondary outcome measures of abstinence rate at the end of rTMS treatment (Week 4), abstinence rate at 6 months, and smoking outcomes (e.g., craving, withdrawal) showed no significant differences between groups. No differences were found in adverse events reported between the groups. CONCLUSION: This study provides evidence of the potential benefit of having a combined treatment for smoking cessation using insula rTMS with the H11 coil and varenicline. Maintenance rTMS sessions and continuation of varenicline for those in abstinence may induce longer-term effects and should be considered in future studies.

A naturalistic study comparing the efficacy of unilateral and bilateral sequential theta burst stimulation in treating major depression - the U-B-D study protocol.

BACKGROUND: Major depressive disorder (MDD) is a prevalent mental health condition affecting millions worldwide, leading to disability and reduced quality of life. MDD poses a global health priority due to its early onset and association with other disabling conditions. Available treatments for MDD exhibit varying effectiveness, and a substantial portion of individuals remain resistant to treatment. Repetitive transcranial magnetic stimulation (rTMS), applied to the left and/or right dorsolateral prefrontal cortex (DLPFC), is an alternative treatment strategy for those experiencing treatment-resistant MDD. The objective of this study is to investigate whether this newer form of rTMS, namely theta burst stimulation (TBS), when performed unilaterally or bilaterally, is efficacious in treatment-resistant MDD. METHODS: In this naturalistic, randomized double-blinded non-inferiority trial, participants with a major depressive episode will be randomized to receive either unilateral (i.e., continuous TBS [cTBS] to the right and sham TBS to the left DLPFC) or bilateral sequential TBS (i.e., cTBS to the right and intermittent TBS [iTBS] to the left DLPFC) delivered 5 days a week for 4-6 weeks. Responders will move onto a 6-month flexible maintenance phase where TBS treatment will be delivered at a decreasing frequency depending on degree of symptom mitigation. Several clinical assessments and neuroimaging and neurophysiological biomarkers will be collected to investigate treatment response and potential associated biomarkers. A non-inferiority analysis will investigate whether bilateral sequential TBS is non-inferior to unilateral TBS and regression analyses will investigate biomarkers of treatment response. We expect to recruit a maximal of 256 participants. This trial is approved by the Research Ethics Board of The Royal's Institute of Mental Health Research (REB# 2,019,071) and will follow the Declaration of Helsinki. Findings will be published in peer-reviewed journals. DISCUSSION: Comprehensive assessment of symptoms and neurophysiological biomarkers will contribute to understanding the differential efficacy of the tested treatment protocols, identifying biomarkers for treatment response, and shedding light into underlying mechanisms of TBS. Our findings will inform future clinical trials and aid in personalizing treatment selection and scheduling for individuals with MDD. TRIAL REGISTRATION: The trial is registered on https://clinicaltrials.gov/ct2/home (#NCT04142996).

The use of theta burst stimulation in patients with schizophrenia - A systematic review.

Transcranial magnetic stimulation (TMS) can offer therapeutic benefits and provide value in neurophysiological research. One of the newer TMS paradigms is theta burst stimulation (TBS) which can be delivered in two patterns: continuous (cTBS - inducing LTD-like effects) and intermittent (iTBS - inducing LTP-like effects). This review paper aims to explore studies that have utilized TBS protocols over different areas of the cortex to study the neurophysiological functions and treatment of patients with schizophrenia. PubMed was searched using the following keywords "schizophrenia", "schizoaffective", or "psychosis", and "theta burst stimulation". Out of the 90 articles which were found, thirty met review inclusion criteria. The inclusion criteria included studying the reported effect (clinical, physiological, or both) of at least one session of TBS on human subjects, and abstracts (at minimum) must have been in English. The main target areas included prefrontal cortex (12 studies - 10 dorsolateral prefrontal cortex (DLPFC), 2 dorsomedial prefrontal cortex (DMPFC)) vermal cerebellum (5), and temporo-parietal cortex (8). Other target areas included inferior parietal lobe (2), and motor cortex (3). TBS neurophysiological effect was explored in 5 studies using functional magnetic resonance image (fMRI), magnetic resonance spectroscopy (MRS), electroencephalography (EEG), electromyography (EMG) and positron emission topography (PET) scan. Overall, TBS can offer great therapeutic potential as it is well-tolerated, feasible, and has few, if any, adverse effects. TBS may be targeted to treat specific symptomatology, as an augmenting intervention to pharmacotherapy, or even improving patient's insight into their diagnosis.

Expansion of a frontostriatal salience network in individuals with depression.

Hundreds of neuroimaging studies spanning two decades have revealed differences in brain structure and functional connectivity in depression, but with modest effect sizes, complicating efforts to derive mechanistic pathophysiologic insights or develop biomarkers. 1 Furthermore, although depression is a fundamentally episodic condition, few neuroimaging studies have taken a longitudinal approach, which is critical for understanding cause and effect and delineating mechanisms that drive mood state transitions over time. The emerging field of precision functional mapping using densely-sampled longitudinal neuroimaging data has revealed unexpected, functionally meaningful individual differences in brain network topology in healthy individuals, 2-5 but these approaches have never been applied to individuals with depression. Here, using precision functional mapping techniques and 11 datasets comprising n=187 repeatedly sampled individuals and >21,000 minutes of fMRI data, we show that the frontostriatal salience network is expanded two-fold in most individuals with depression. This effect was replicable in multiple samples, including large-scale, group-average data (N=1,231 subjects), and caused primarily by network border shifts affecting specific functional systems, with three distinct modes of encroachment occurring in different individuals. Salience network expansion was unexpectedly stable over time, unaffected by changes in mood state, and detectable in children before the subsequent onset of depressive symptoms in adolescence. Longitudinal analyses of individuals scanned up to 62 times over 1.5 years identified connectivity changes in specific frontostriatal circuits that tracked fluctuations in specific symptom domains and predicted future anhedonia symptoms before they emerged. Together, these findings identify a stable trait-like brain network topology that may confer risk for depression and mood-state dependent connectivity changes in frontostriatal circuits that predict the emergence and remission of depressive symptoms over time.

Treatment outcomes in major depressive disorder in patients with comorbid alcohol use disorder: A STAR*D analysis.

INTRODUCTION: Guidance on Major Depressive Disorder (MDD) treatment in those with comorbid Alcohol Use Disorder (AUD) is limited. We performed a secondary analysis on the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, examining the association between comorbid AUD and depression outcomes. METHODS: STAR*D was a real-world effectiveness trial starting with citalopram in level 1. Non-responding participants progressed through 3 other sequential treatment levels with different switch or augmentation options. Antidepressant outcomes were compared between MDD (n = 2826) and comorbid MDD and AUD (n = 864). Logistic regressions were performed to evaluate remission and response predictors in the total STAR*D sample and the AUD-comorbidity interaction. RESULTS: Chi-squared tests showed no significant difference in response or remission rates from depression between groups across treatment levels. Higher Hamilton Rating Scale for Depression (HRSD) score was associated with overall lower odds of remission in treatment level 1 (OR = 0.93, p < 0.001) and 2 (OR = 0.95, p < 0.001), with no significant interaction with comorbid AUD. Higher baseline suicidality had overall lower odds of remission in level 1 (OR = 0.82, p < 0.001) and 2 (OR = 0.1, p < 0.001), but with comorbid AUD compared to no AUD, suicidality increased odds of level 1 remission (OR = 1.30, p = 0.012). In comorbid AUD in level 2, venlafaxine was associated with lower odds of remission (OR = 0.13, p = 0.013) and response (OR = 0.12, p = 0.006); bupropion with lower odds of response (OR = 0.22, p = 0.024). LIMITATIONS: Open label study design and lack of alcohol use data. CONCLUSIONS: Comorbid AUD may interact with predictors of antidepressant response in MDD and using venlafaxine or bupropion may be less effective. Addressing this comorbidity requires unique assessment and treatment approaches.