Source-based morphometry reveals structural brain pattern abnormalities in 22q11.2 deletion syndrome.

22q11.2 deletion syndrome (22q11DS) is the most frequently occurring microdeletion in humans. It is associated with a significant impact on brain structure, including prominent reductions in gray matter volume (GMV), and neuropsychiatric manifestations, including cognitive impairment and psychosis. It is unclear whether GMV alterations in 22q11DS occur according to distinct structural patterns. Then, 783 participants (470 with 22q11DS: 51% females, mean age [SD] 18.2 [9.2]; and 313 typically developing [TD] controls: 46% females, mean age 18.0 [8.6]) from 13 datasets were included in the present study. We segmented structural T1-weighted brain MRI scans and extracted GMV images, which were then utilized in a novel source-based morphometry (SBM) pipeline (SS-Detect) to generate structural brain patterns (SBPs) that capture co-varying GMV. We investigated the impact of the 22q11.2 deletion, deletion size, intelligence quotient, and psychosis on the SBPs. Seventeen GMV-SBPs were derived, which provided spatial patterns of GMV covariance associated with a quantitative metric (i.e., loading score) for analysis. Patterns of topographically widespread differences in GMV covariance, including the cerebellum, discriminated individuals with 22q11DS from healthy controls. The spatial extents of the SBPs that revealed disparities between individuals with 22q11DS and controls were consistent with the findings of the univariate voxel-based morphometry analysis. Larger deletion size was associated with significantly lower GMV in frontal and occipital SBPs; however, history of psychosis did not show a strong relationship with these covariance patterns. 22q11DS is associated with distinct structural abnormalities captured by topographical GMV covariance patterns that include the cerebellum. Findings indicate that structural anomalies in 22q11DS manifest in a nonrandom manner and in distinct covarying anatomical patterns, rather than a diffuse global process. These SBP abnormalities converge with previously reported cortical surface area abnormalities, suggesting disturbances of early neurodevelopment as the most likely underlying mechanism.

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.

Multilayer depressive symptom networks in adults with bodily pain living in precarious housing or homelessness.

Housing insecurity is associated with co-occurring depression and pain interfering with daily activities. Network analysis of depressive symptoms along with associated risk or protective exposures may identify potential targets for intervention in patients with co-occurring bodily pain. In a community-based sample of adults (n = 408) living in precarious housing or homelessness in Vancouver, Canada, depressive symptoms were measured by the Beck Depression Inventory; bodily pain and impact were assessed with the 36-item Short Form Health Survey. Network and bootstrap permutation analyses were used to compare depressive symptoms endorsed by Low versus Moderate-to-Severe (Mod + Pain) groups. Multilayer networks estimated the effects of risk and protective factors. The overall sample was comprised of 78% men, mean age 40.7 years, with 53% opioid use disorder and 14% major depressive disorder. The Mod + Pain group was characterized by multiple types of pain, more persistent pain, more severe depressive symptoms and a higher rate of suicidal ideation. Global network connectivity did not differ between the two pain groups. Suicidal ideation was a network hub only in the Mod + Pain group, with high centrality and a direct association with exposure to lifetime trauma. Antidepressant medications had limited impact on suicidal ideation. Guilt and increased feelings of failure represented symptoms from two other communities of network nodes, and completed the shortest pathway from trauma exposure through suicidal ideation, to the non-prescribed opioid exposure node. Interventions targeting these risk factors and symptoms could affect the progression of depression among precariously housed patients.

A randomized sham-controlled trial of high-dosage accelerated intermittent theta burst rTMS in major depression: study protocol.

BACKGROUND: Intermittent theta burst stimulation (iTBS), a novel form of repetitive transcranial magnetic stimulation (rTMS), can be administered in 1/10th of the time of standard rTMS (~ 3 min vs. 37.5 min) yet achieves similar outcomes in depression. The brief nature of the iTBS protocol allows for the administration of multiple iTBS sessions per day, thus reducing the overall course length to days rather than weeks. This study aims to compare the efficacy and tolerability of active versus sham iTBS using an accelerated regimen in patients with treatment-resistant depression (TRD). As a secondary objective, we aim to assess the safety, tolerability, and treatment response to open-label low-frequency right-sided (1 Hz) stimulation using an accelerated regimen in those who do not respond to the initial week of treatment. METHODS: Over three years, approximately 230 outpatients at the Centre for Addiction and Mental Health and University of British Columbia Hospital, meeting diagnostic criteria for unipolar MDD, will be recruited and randomized to a triple blind sham-controlled trial. Patients will receive five consecutive days of active or sham iTBS, administered eight times daily at 1-hour intervals, with each session delivering 600 pulses of iTBS. Those who have not achieved response by the week four follow-up visit will be offered a second course of treatment, regardless of whether they initially received active or sham stimulation. DISCUSSION: Broader implementation of conventional iTBS is limited by the logistical demands of the current standard course consisting of 4-6 weeks of daily treatment. If our proposed accelerated iTBS protocol enables patients to achieve remission more rapidly, this would offer major benefits in terms of cost and capacity as well as the time required to achieve clinical response. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04255784.

Non-Motor Effects of Low-Frequency Deep Brain Stimulation of the Subthalamic Nucleus in Parkinson's Disease: A Systematic Review.

INTRODUCTION: Deep brain stimulation of the subthalamic nucleus is an effective therapy for the motor symptoms of Parkinson's disease (PD). Typically, stimulation is applied at a high frequency (≥100 Hz) to alleviate motor symptoms. However, the effects on non-motor symptoms can be variable. Low-frequency oscillations are increasingly recognized as playing an important role in the non-motor functions of the subthalamic nucleus. Therefore, it has been hypothesized that low-frequency stimulation of the subthalamic nucleus (<100 Hz) may have a direct effect on these non-motor functions, thereby preferentially impacting non-motor symptoms of PD. Despite important therapeutic implications, the literature on this topic has not been summarized. METHOD: To understand the current state of the field, we performed a comprehensive systematic review of the literature assessing the non-motor effects of low-frequency stimulation of the subthalamic nucleus in PD. We performed a supplementary meta-analysis to assess the effects of low- versus high-frequency stimulation on verbal fluency outcomes. RESULTS: Our search returned 7,009 results, of which we screened 4,199 results. A total of 145 studies were further assessed for eligibility, and a total of 21 studies met our inclusion criteria, representing 297 patients. These studies were a mix of case reports and control trials. The four clinical outcomes measured were sleep, sensory perception, cognition, and mood. A supplementary meta-analysis of six studies investigating the impact of low-frequency stimulation on verbal fluency did not find any significant results when pooling across subgroups. CONCLUSION: LFS of the STN may have benefits on a range of cognitive and affective symptoms in PD. However, current studies in this space are heterogeneous, and the effect sizes are small. Factors that impact outcomes can be divided into stimulation and patient factors. Future work should consider the interactions between stimulation location and stimulation frequency as well as how these interact depending on the specific non-motor phenotype.

Intermittent theta burst transcranial magnetic stimulation induces hippocampal mossy fibre plasticity in male but not female mice.

Transcranial magnetic stimulation (TMS) induces electric fields that depolarise or hyperpolarise neurons. Intermittent theta burst stimulation (iTBS), a patterned form of TMS that is delivered at the theta frequency (~5 Hz), induces neuroplasticity in the hippocampus, a brain region that is implicated in memory and learning. One form of plasticity that is unique to the hippocampus is adult neurogenesis; however, little is known about whether TMS or iTBS in particular affects newborn neurons. Here, we therefore applied repeated sessions of iTBS to male and female mice and measured the extent of adult neurogenesis and the morphological features of immature neurons. We found that repeated sessions of iTBS did not significantly increase the amount of neurogenesis or affect the gross dendritic morphology of new neurons, and there were no sex differences in neurogenesis rates or aspects of afferent morphology. In contrast, efferent properties of newborn neurons varied as a function of sex and stimulation. Chronic iTBS increased the size of mossy fibre terminals, which synapse onto Cornu Ammonis 3 (CA3) pyramidal neurons, but only in males. iTBS also increased the number of terminal-associated filopodia, putative synapses onto inhibitory interneurons but only in male mice. This efferent plasticity could result from a general trophic effect, or it could reflect accelerated maturation of immature neurons. Given the important role of mossy fibre synapses in hippocampal learning, our results identify a neurobiological effect of iTBS that might be associated with sex-specific changes in cognition.

Psychotic symptoms in frontotemporal dementia with TDP-43 tend to be associated with type B pathology.

AIMS: Psychotic symptoms are increasingly recognized as a distinguishing clinical feature in patients with dementia due to frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP). Within this group, carriers of the C9orf72 repeat expansion are particularly prone to develop delusions and hallucinations. METHODS: The present retrospective study sought to provide novel details about the relationship between FTLD-TDP pathology and the presence of psychotic symptoms during life. RESULTS: We found that FTLD-TDP subtype B was more frequent in patients with psychotic symptoms than in those without. This relationship was present even when corrected for the presence of C9orf72 mutation, suggesting that pathophysiological processes leading to the development of subtype B pathology may increase the risk of psychotic symptoms. Within the group of FTLD-TDP cases with subtype B pathology, psychotic symptoms tended to be associated with a greater burden of TDP-43 pathology in the white matter and a lower burden in lower motor neurons. When present, pathological involvement of motor neurons was more likely to be asymptomatic in patients with psychosis. CONCLUSIONS: This work suggests that psychotic symptoms in patients with FTLD-TDP tend to be associated with subtype B pathology. This relationship is not completely explained by the effects of the C9orf72 mutation and raises the possibility of a direct link between psychotic symptoms and this particular pattern of TDP-43 pathology.

Competencies for Repetitive Transcranial Magnetic Stimulation in Postgraduate Medical Education: Expert Consensus Using a Modified Delphi Process.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is recommended in Canadian guidelines as a first-line treatment for major depressive disorder. With the shift towards competency-based medical education, it remains unclear how to determine when a resident is considered competent in applying knowledge of rTMS to patient care. Given inconsistencies between postgraduate training programmes with regards to training requirements, defining competencies will improve the standard of care in rTMS delivery. OBJECTIVE: The goal of this study was to develop competencies for rTMS that can be implemented into a competency-based training curriculum in postgraduate training programmes. METHODS: A working group drafted competencies for postgraduate psychiatry trainees. Fourteen rTMS experts from across Canada were invited to participate in the modified Delphi process. RESULTS: Ten experts participated in all three rounds of the modified Delphi process. A total of 20 items reached a consensus. There was improvement in the Cronbach's alpha over the rounds of modified Delphi process (Cronbach's alpha increased from 0.554 to 0.824) suggesting improvement in internal consistency. The intraclass correlation coefficient (ICC) increased from 0.543 to 0.805 suggesting improved interrater agreement. CONCLUSIONS: This modified Delphi process resulted in expert consensus on competencies to be acquired during postgraduate medical education programmes where a learner is training to become competent as a consultant and/or practitioner in rTMS treatment. This is a field that still requires development, and it is expected that as more evidence emerges the competencies will be further refined. These results will help the development of other curricula in interventional psychiatry.

Dynamic networks of psychotic symptoms in adults living in precarious housing or homelessness.

BACKGROUND: People living in precarious housing or homelessness have higher than expected rates of psychotic disorders, persistent psychotic symptoms, and premature mortality. Psychotic symptoms can be modeled as a complex dynamic system, allowing assessment of roles for risk factors in symptom development, persistence, and contribution to premature mortality. METHOD: The severity of delusions, conceptual disorganization, hallucinations, suspiciousness, and unusual thought content was rated monthly over 5 years in a community sample of precariously housed/homeless adults (n = 375) in Vancouver, Canada. Multilevel vector auto-regression analysis was used to construct temporal, contemporaneous, and between-person symptom networks. Network measures were compared between participants with (n = 219) or without (n = 156) history of psychotic disorder using bootstrap and permutation analyses. Relationships between network connectivity and risk factors including homelessness, trauma, and substance dependence were estimated by multiple linear regression. The contribution of network measures to premature mortality was estimated by Cox proportional hazard models. RESULTS: Delusions and unusual thought content were central symptoms in the multilevel network. Each psychotic symptom was positively reinforcing over time, an effect most pronounced in participants with a history of psychotic disorder. Global connectivity was similar between those with and without such a history. Greater connectivity between symptoms was associated with methamphetamine dependence and past trauma exposure. Auto-regressive connectivity was associated with premature mortality in participants under age 55. CONCLUSIONS: Past and current experiences contribute to the severity and dynamic relationships between psychotic symptoms. Interrupting the self-perpetuating severity of psychotic symptoms in a vulnerable group of people could contribute to reducing premature mortality.

Effect of high frequency versus theta-burst repetitive transcranial magnetic stimulation on suicidality in patients with treatment-resistant depression.

OBJECTIVE: To investigate the effect of 10 Hz repetitive transcranial magnetic stimulation (rTMS) and intermittent theta-burst stimulation (iTBS) on suicidality in patients with treatment-resistant depression (TRD). METHODS: We used data from a three-site randomized clinical trial comparing 10 Hz rTMS and iTBS applied to the left dorsolateral prefrontal cortex (DLPFC) in patients with TRD. We compared the effect of 10Hz rTMS and iTBS on suicidality as measured by the suicide item of the Hamilton Depression Rating Scale 17-item (HDRS-17). RESULTS: Suicidality remitted in 71 (43.7%) participants randomized to 10Hz stimulation and 91 (49.1%) participants randomized to iTBS, without a significant difference between the proportions in the two groups (Χ2  = 0.674, df = 1, p = 0.4117). There was a significant correlation between change in suicidality and change in depression severity for both modalities (10 Hz, Pearson's r = 0.564; iTBS, Pearson's r = 0.502), with a significantly larger decrease in depression severity for those in whom suicidality remitted compared to those in whom it did not (t = 10.912, df = 276.8, p < 0.001). CONCLUSIONS: Both 10 Hz and iTBS rTMS were effective in reducing suicidality in TRD. Future trials of iTBS for depression should include discrete measures of suicidality.

Combined Yoga and Transcranial Direct Current Stimulation Increase Functional Connectivity and Synchronization in the Frontal Areas.

Transcranial direct current stimulation (tDCS) is a non-invasive neuro-stimulation technique that can modulate cortical excitability. Similarly, yoga is shown to affect the brain's neural activity and networks. Here, we aimed to investigate the effect of combined yoga and tDCS on brain oscillations and networks using resting-state electroencephalography recordings. In a randomized, cross-over, double-blind design, twenty-two healthy subjects participated in a yoga/active tDCS session (2 mA; 20 min; anode-F3, cathode F4) or yoga/sham tDCS on 2 separate days. Resting-state EEG data were collected before and after each intervention. Power spectral density (PSD) and functional connectivity, measured by a synchronization measure, phase-locking value, were computed for each condition. There were no significant differences in PSD values among the two interventions. The network-based statistic method was employed for detecting functional connectivity differences between yoga/active and yoga/sham tDCS interventions. Results show that the addition of active tDCS to yoga is associated with increased functional connectivity of the scalp and source EEG data in the frontal area. The changes were widespread, intra-hemispheric, and inter-hemispheric connections, which were mainly between the frontal area to other regions. At the source level, most of the connectivity changes were found in the fronto-parietal network. These findings suggest that combining yoga with tDCS might lead to brain network changes related to the executive and attentional functions.

Repetitive Transcranial Magnetic Stimulation Shows Longitudinal Improvements in Memory in Patients With Treatment-Resistant Depression.

BACKGROUND: Cognitive dysfunction (CD) is a commonly reported symptom of major depressive disorder (MDD). Patients with treatment-resistant depression (TRD) tend to experience greater rates of CD; however, treatment options are limited. Repetitive transcranial magnetic stimulation (rTMS) is effective in treating affective symptoms in patients with TRD, but its potential effect on CD in TRD has not been established. OBJECTIVES: This study sought to establish the potential cognitive benefits of rTMS in patients with TRD. MATERIALS AND METHODS: This study used data from a noninferiority clinical trial investigating two excitatory rTMS protocols to the left dorsolateral prefrontal cortex in unipolar outpatients with TRD. Cognitive testing was performed at baseline and three months posttreatment in 47 patients and a demographically matched cohort of 22 healthy volunteers. Changes in cognitive performance from baseline to posttreatment were assessed using repeated-measures analysis of variance, using both normative and individualized cognitive scoring methods. RESULTS: Patients with baseline neurocognitive dysfunction showed significant changes in verbal memory at three months posttreatment when using individualized cognitive scoring. Furthermore, improvement in verbal memory within this subset was associated with improvements in affective symptoms. LIMITATIONS: This analysis was performed on a relatively small sample of patients with TRD who were not prescreened for CD and did not include a clinical comparator group. CONCLUSIONS: rTMS may be associated with improvements in verbal memory in patients with TRD who present with global CD and who are clinical responders to the treatment. These findings warrant replication in a larger sample as well as further investigations into the neural mechanisms of cognitive improvement after rTMS.

Sex effects on cortical morphological networks in healthy young adults.

Understanding sex-related differences across the human cerebral cortex is an important step in elucidating the basis of psychological, behavioural and clinical differences between the sexes. Prior structural neuroimaging studies primarily focused on regional sex differences using univariate analyses. Here we focus on sex differences in cortical morphological networks (CMNs) derived using multivariate modelling of regional cortical measures of volume and surface from high-quality structural MRI scans from healthy participants in the Human Connectome Project (HCP) (n = 1,063) and the Southwest University Longitudinal Imaging Multimodal (SLIM) study (n = 549). The functional relevance of the CMNs was inferred using the NeuroSynth decoding function. Sex differences were widespread but not uniform. In general, females had higher volume, thickness and cortical folding in networks that involve prefrontal (both ventral and dorsal regions including the anterior cingulate) and parietal regions while males had higher volume, thickness and cortical folding in networks that primarily include temporal and posterior cortical regions. CMN loading coefficients were used as input features to linear discriminant analyses that were performed separately in the HCP and SLIM; sex was predicted with a high degree of accuracy (81%-85%) across datasets. The availability of behavioral data in the HCP enabled us to show that male-biased surface-based CMNs were associated with externalizing behaviors. These results extend previous literature on regional sex-differences by identifying CMNs that can reliably predict sex, are relevant to the expression of psychopathology and provide the foundation for the future investigation of their functional significance in clinical populations.

High-Dose Fluvoxamine Augmentation to Clozapine in Treatment-Resistant Psychosis.

BACKGROUND: Although clozapine is the gold standard for treatment-resistant schizophrenia, more than 30% of patients remain unresponsive to clozapine monotherapy and may benefit from augmentation strategies. Fluvoxamine augmentation of clozapine may be beneficial in treatment resistance because of pharmacokinetic interactions, allowing for lower clozapine dosages with higher clozapine serum levels and an increased clozapine-to-norclozapine ratio, which can modify adverse effects. An augmentation strategy using higher fluvoxamine doses may also improve persistent negative, anxiety, and obsessive-compulsive symptoms through fluvoxamine's serotonergic activity. METHODS: Through chart review, we identified 4 cases of patients with treatment-resistant psychosis who underwent high-dose fluvoxamine augmentation of clozapine to target residual negative symptoms, refractory psychosis, anxiety, and obsessive-compulsive symptoms. FINDINGS: This augmentation strategy continued in 2 patients after discharge who showed clinical improvement without significant adverse effects. Two patients experienced adverse effects that led to the fluvoxamine discontinuation. Despite the fact that fluvoxamine augmentation led to symptom improvement in only 2 patients, all patients achieved high serum clozapine levels. Hematologic parameters were monitored in all patients, and no abnormalities were observed. No severe adverse effects of clozapine were experienced. CONCLUSIONS: Although high variability of responses and adverse effects were observed during fluvoxamine augmentation to clozapine, this strategy was successful in increasing clozapine serum levels. Through fluvoxamine's serotonergic effects, this strategy may confer benefit to residual negative, obsessive, and anxiety symptoms. Limitations of this case series include the retrospective nature, absence of controls, diversity of diagnoses, multiple interventions in each patient, and lack of masked raters.

Large-scale mapping of cortical alterations in 22q11.2 deletion syndrome: Convergence with idiopathic psychosis and effects of deletion size.

The 22q11.2 deletion (22q11DS) is a common chromosomal microdeletion and a potent risk factor for psychotic illness. Prior studies reported widespread cortical changes in 22q11DS, but were generally underpowered to characterize neuroanatomic abnormalities associated with psychosis in 22q11DS, and/or neuroanatomic effects of variability in deletion size. To address these issues, we developed the ENIGMA (Enhancing Neuro Imaging Genetics Through Meta-Analysis) 22q11.2 Working Group, representing the largest analysis of brain structural alterations in 22q11DS to date. The imaging data were collected from 10 centers worldwide, including 474 subjects with 22q11DS (age = 18.2 ± 8.6; 46.9% female) and 315 typically developing, matched controls (age = 18.0 ± 9.2; 45.9% female). Compared to controls, 22q11DS individuals showed thicker cortical gray matter overall (left/right hemispheres: Cohen's d = 0.61/0.65), but focal thickness reduction in temporal and cingulate cortex. Cortical surface area (SA), however, showed pervasive reductions in 22q11DS (left/right hemispheres: d = -1.01/-1.02). 22q11DS cases vs. controls were classified with 93.8% accuracy based on these neuroanatomic patterns. Comparison of 22q11DS-psychosis to idiopathic schizophrenia (ENIGMA-Schizophrenia Working Group) revealed significant convergence of affected brain regions, particularly in fronto-temporal cortex. Finally, cortical SA was significantly greater in 22q11DS cases with smaller 1.5 Mb deletions, relative to those with typical 3 Mb deletions. We found a robust neuroanatomic signature of 22q11DS, and the first evidence that deletion size impacts brain structure. Psychotic illness in this highly penetrant deletion was associated with similar neuroanatomic abnormalities to idiopathic schizophrenia. These consistent cross-site findings highlight the homogeneity of this single genetic etiology, and support the suitability of 22q11DS as a biological model of schizophrenia.

Effect of repetitive transcranial magnetic stimulation on anxiety symptoms in patients with major depression: An analysis from the THREE-D trial.

BACKGROUND: Despite the advances in the use of repetitive transcranial magnetic stimulation (rTMS) for the treatment of major depressive disorder (MDD), there is relatively little information about its effect on comorbid anxiety symptoms. METHODS: Data from a large randomized noninferiority trial comparing intermittent theta-burst stimulation (iTBS) and high-frequency (10 Hz) rTMS delivered to the left dorsolateral prefrontal cortex (HFL) were analyzed. The primary aim was assessing changes in anxiety/somatization items from the 17-item Hamilton Depression Rating Scale (HAM-D) and the Brief Symptom Inventory (BSI-A), using baseline-adjusted change with an analysis of covariance (ANCOVA), with the final scores as the outcome and baseline scores as the adjustment covariates. RESULTS: The analytical cohort comprised 388 participants (189 in HFL and 199 in iTBS groups). From baseline to the end of the rTMS course, the combined score from the anxiety items from the HAM-D dropped from 7.43 (SD = 2.15) to 4.24 (SD = 2.33) in the HFL group, and 7.33 (SD = 2.13) to 3.76 (SD = 2.23) in the iTBS group. The ANCOVA resulted in an effect from time (p < .0001), but not from group allocation (p = .793) or time × group interaction (p = .976). We observed mean changes in the BSI-A of -3.5 (SD = 5.4) and -3.2 (SD = 4.8), with significant effect of time (p < .0001) in the ANCOVA, but not group allocation (p = .793) or group × time interaction (.664). CONCLUSIONS: Our findings suggest that both 10 Hz and iTBS may yield potential reductions in anxiety symptoms when used for the treatment of MDD. Our findings warrant future research into the effects of left-sided rTMS on depressed patients struggling with concurrent anxiety symptoms.

Treatment-resistant major depressive disorder: Canadian expert consensus on definition and assessment.

BACKGROUND: Treatment-resistant depression (TRD) is a debilitating chronic mental illness that confers increased morbidity and mortality, decreases the quality of life, impairs occupational, social, and offspring development, and translates into increased costs on the healthcare system. The goal of this study is to reach an agreement on the concept, definition, staging model, and assessment of TRD. METHODS: This study involved a review of the literature and a modified Delphi process for consensus agreement. The Appraisal of Guidelines for Research & Evaluation II guidelines were followed for the literature appraisal. Literature was assessed for quality and strength of evidence using the grading, assessment, development, and evaluations system. Canadian national experts in depression were invited for the modified Delphi process based on their prior clinical and research expertize. Survey items were considered to have reached a consensus if 80% or more of the experts supported the statement. RESULTS: Fourteen Canadian experts were recruited for three rounds of surveys to reach a consensus on a total of 27 items. Experts agreed that a dimensional definition for treatment resistance was a useful concept to describe the heterogeneity of this illness. The use of staging models and clinical scales was recommended in evaluating depression. Risk factors and comorbidities were identified as potential predictors for treatment resistance. CONCLUSIONS: TRD is a meaningful concept both for clinical practice and research. An operational definition for TRD will allow for opportunities to improve the validity of predictors and therapeutic options for these patients.

Psychiatric, Motor, and Autonomic Effects of Bifrontal ECT in Depressed Parkinson's Disease Patients.

OBJECTIVE: Depressive symptoms are a source of significant morbidity in Parkinson's disease (PD). Electroconvulsive therapy (ECT) is a promising treatment for depression in PD (dPD); however, data remain limited, including data on optimal electrode placement. In this retrospective study, the investigators aimed to characterize the effects of bifrontal ECT for dPD on psychiatric and motor symptoms, as well as autonomic response. METHODS: Clinical data were retrieved from a university-affiliated ECT service in Vancouver, British Columbia, for patients with dPD receiving bifrontal ECT between 2014 and 2018. Clinical Global Impression (depressive symptoms) and Unified Parkinson's Disease Rating Scale (motor symptoms) scores and cardiovascular measurements during ECT, as well as doses of dopaminergic medications, were recorded. RESULTS: Eight patients met criteria for inclusion. Six patients (75%) met response criteria for improvement of depressive symptoms, including 83% of patients who completed a full ECT course. Five patients went on to receive maintenance ECT, with only one patient relapsing by the 1-year follow-up (20%). For patients with motor scales reported, 60% showed a clinically significant improvement in motor symptoms. Among patients who completed ECT, a reduction in the median dopaminergic medication dose was also observed (-350 mg). Two patients discontinued ECT as a result of tolerability concerns. Participants demonstrated a relatively typical pattern of autonomic response to ECT, with low incidence of bradycardic events. CONCLUSIONS: The results provide preliminary evidence of the benefit of bifrontal ECT in dPD for both depressive and motor symptoms. The autonomic data suggest that most patients with dPD respond in a typical physiological manner to ECT stimulus; however, further investigation is needed.

Effect of combined yoga and transcranial direct current stimulation intervention on working memory and mindfulness.

Transcranial direct stimulation, a non-invasive neurostimulation technique for modulating cortical excitability, and yoga have both respectively been shown to positively affect cognition. While preliminary research has shown that combined transcranial direct stimulation and meditation may have synergistic effects on mood and cognition, this was the first study to explore the combination of transcranial direct stimulation and yoga. Twenty-two healthy volunteers with a regular yoga practice were randomized to receive either active transcranial direct stimulation (anodal left, cathodal right dorsolateral prefrontal cortex) followed by yoga intervention or sham transcranial direct stimulation followed by yoga intervention a double-blind, cross-over design over two separate intervention days. Outcome measures included working memory performance, measured with the n-back task and mindfulness state, measured with the Toronto Mindfulness Scale, and were conducted offline, with pre-post assessments. Twenty participants completed both days of the intervention. Active transcranial direct stimulation did not have a significant effect on working memory or levels of mindfulness. There was a significant placebo effect, with better performance on day 1 of the intervention, irrespective of whether participants received active or sham transcranial direct stimulation. There was no significant difference between active versus sham transcranial direct stimulation concerning working memory performance and mindfulness, which may be accounted by the small sample size, the transient nature of the intervention, the fact that yoga and transcranial direct stimulation concerning were not conducted simultaneously, and the specific site of stimulation.

Associations of substance use, psychosis, and mortality among people living in precarious housing or homelessness: A longitudinal, community-based study in Vancouver, Canada.

BACKGROUND: The "trimorbidity" of substance use disorder and mental and physical illness is associated with living in precarious housing or homelessness. The extent to which substance use increases risk of psychosis and both contribute to mortality needs investigation in longitudinal studies. METHODS AND FINDINGS: A community-based sample of 437 adults (330 men, mean [SD] age 40.6 [11.2] years) living in Vancouver, Canada, completed baseline assessments between November 2008 and October 2015. Follow-up was monthly for a median 6.3 years (interquartile range 3.1-8.6). Use of tobacco, alcohol, cannabis, cocaine, methamphetamine, and opioids was assessed by interview and urine drug screen; severity of psychosis was also assessed. Mortality (up to November 15, 2018) was assessed from coroner's reports and hospital records. Using data from monthly visits (mean 9.8, SD 3.6) over the first year after study entry, mixed-effects logistic regression analysis examined relationships between risk factors and psychotic features. A past history of psychotic disorder was common (60.9%). Nonprescribed substance use included tobacco (89.0%), alcohol (77.5%), cocaine (73.2%), cannabis (72.8%), opioids (51.0%), and methamphetamine (46.5%). During the same year, 79.3% of participants reported psychotic features at least once. Greater risk was associated with number of days using methamphetamine (adjusted odds ratio [aOR] 1.14, 95% confidence interval [CI] 1.05-1.24, p = 0.001), alcohol (aOR 1.09, 95% CI 1.01-1.18, p = 0.04), and cannabis (aOR 1.08, 95% CI 1.02-1.14, p = 0.008), adjusted for demographic factors and history of past psychotic disorder. Greater exposure to concurrent month trauma was associated with increased odds of psychosis (adjusted model aOR 1.54, 95% CI 1.19-2.00, p = 0.001). There was no evidence for interactions or reverse associations between psychotic features and time-varying risk factors. During 2,481 total person years of observation, 79 participants died (18.1%). Causes of death were physical illness (40.5%), accidental overdose (35.4%), trauma (5.1%), suicide (1.3%), and unknown (17.7%). A multivariable Cox proportional hazard model indicated baseline alcohol dependence (adjusted hazard ratio [aHR] 1.83, 95% CI 1.09-3.07, p = 0.02), and evidence of hepatic fibrosis (aHR 1.81, 95% CI 1.08-3.03, p = 0.02) were risk factors for mortality. Among those under age 55 years, a history of a psychotic disorder was a risk factor for mortality (aHR 2.38, 95% CI 1.03-5.51, p = 0.04, adjusted for alcohol dependence at baseline, human immunodeficiency virus [HIV], and hepatic fibrosis). The primary study limitation concerns generalizability: conclusions from a community-based, diagnostically heterogeneous sample may not apply to specific diagnostic groups in a clinical setting. Because one-third of participants grew up in foster care or were adopted, useful family history information was not obtainable. CONCLUSIONS: In this study, we found methamphetamine, alcohol, and cannabis use were associated with higher risk for psychotic features, as were a past history of psychotic disorder, and experiencing traumatic events. We found that alcohol dependence, hepatic fibrosis, and, only among participants <55 years of age, history of a psychotic disorder were associated with greater risk for mortality. Modifiable risk factors in people living in precarious housing or homelessness can be a focus for interventions.