Robust Brain Correlates of Cognitive Performance in Psychosis and its Prodrome.

BACKGROUND: Neurocognitive impairment is a well-known phenomenon in schizophrenia that begins prior to psychosis onset. Connectome-wide association studies have inconsistently linked cognitive performance to resting-state fMRI. We hypothesized a carefully selected cognitive instrument and refined population would allow identification of reliable brain-behavior associations with connectome-wide association studies. To test this hypothesis, we first identified brain-cognition correlations via a connectome-wide association study in early psychosis. We then asked, in an independent dataset, if these brain-cognition relationships would generalize to individuals who develop psychosis in the future. METHODS: The Seidman Auditory Continuous Performance Task (ACPT) effectively differentiates healthy participants from those with psychosis. Our connectome-wide association study used the Human Connectome Project for Early Psychosis (n=183) to identify links between connectivity and ACPT performance. We then analyzed the North American Prodrome Longitudinal Study 2 (n=345), a multi-site prospective study of individuals at risk for psychosis. We tested the connectome-wide association study-identified cognition-connectivity relationship in both individuals at risk for psychosis and controls. RESULTS: Our connectome-wide association study in early-course psychosis identified robust associations between better ACPT performance and higher prefrontal-somatomotor connectivity (p<.005). Prefrontal-somatomotor connectivity was also related to ACPT performance in at-risk individuals who would develop psychosis (n=17). This finding was not observed in nonconverters (n=196) or controls (n=132). CONCLUSIONS: This connectome-wide association study identified reproducible links between connectivity and cognition in separate samples of psychosis and at-risk individuals who would later develop psychosis. A carefully selected task and population improves the ability of connectome-wide association studies to identify reliable brain-phenotype relationships.

Data-driven, connectome-wide analysis identifies psychosis-specific brain correlates of fear and anxiety.

Decades of psychosis research highlight the prevalence and the clinical significance of negative emotions, such as fear and anxiety. Translational evidence demonstrates the pivotal role of the amygdala in fear and anxiety. However, most of these approaches have used hypothesis-driven analyses with predefined regions of interest. A data-driven analysis may provide a complimentary, unbiased approach to identifying brain correlates of fear and anxiety. The aim of the current study was to identify the brain basis of fear and anxiety in early psychosis and controls using a data-driven approach. We analyzed data from the Human Connectome Project for Early Psychosis, a multi-site study of 125 people with psychosis and 58 controls with resting-state fMRI and clinical characterization. Multivariate pattern analysis of whole-connectome data was used to identify shared and psychosis-specific brain correlates of fear and anxiety using the NIH Toolbox Fear-Affect and Fear-Somatic Arousal scales. We then examined clinical correlations of Fear-Affect scores and connectivity patterns. Individuals with psychosis had higher levels of Fear-Affect scores than controls (p < 0.05). The data-driven analysis identified a cluster encompassing the amygdala and hippocampus where connectivity was correlated with Fear-Affect score (p < 0.005) in the entire sample. The strongest correlate of Fear-Affect was between this cluster and the anterior insula and stronger connectivity was associated with higher Fear-Affect scores (r = 0.31, p = 0.0003). The multivariate pattern analysis also identified a psychosis-specific correlate of Fear-Affect score between the amygdala/hippocampus cluster and a cluster in the ventromedial prefrontal cortex (VMPFC). Higher Fear-Affect scores were correlated with stronger amygdala/hippocampal-VMPFC connectivity in the early psychosis group (r = 0.33, p = 0.002), but not in controls (r = -0.15, p = 0.28). The current study provides evidence for the transdiagnostic role of the amygdala, hippocampus, and anterior insula in the neural basis of fear and anxiety and suggests a psychosis-specific relationship between fear and anxiety symptoms and amygdala/hippocampal-VMPFC connectivity. Our novel data-driven approach identifies novel, psychosis-specific treatment targets for fear and anxiety symptoms and provides complimentary evidence to decades of hypothesis-driven approaches examining the brain basis of threat processing.

Isolation of Distinct Networks Driving Action and Cognition in Psychomotor Processes.

BACKGROUND: Psychomotor disturbances are observed across psychiatric disorders and often manifest as psychomotor slowing, agitation, disorganized behavior, or catatonia. Psychomotor function includes both cognitive and motor components, but the neural circuits driving these subprocesses and how they relate to symptoms have remained elusive for centuries. METHODS: We analyzed data from the HCP-EP (Human Connectome Project for Early Psychosis), a multisite study of 125 participants with early psychosis and 58 healthy participants with resting-state functional magnetic resonance imaging and clinical characterization. Psychomotor function was assessed using the 9-hole pegboard task, a timed motor task that engages mechanical and psychomotor components of action, and tasks assessing processing speed and task switching. We used multivariate pattern analysis of whole-connectome data to identify brain correlates of psychomotor function. RESULTS: We identified discrete brain circuits driving the cognitive and motor components of psychomotor function. In our combined sample of participants with psychosis (n = 89) and healthy control participants (n = 52), the strongest correlates of psychomotor function (pegboard performance) (p < .005) were between a midline cerebellar region and left frontal region and presupplementary motor area. Psychomotor function was correlated with both cerebellar-frontal connectivity (r = 0.33) and cerebellar-presupplementary motor area connectivity (r = 0.27). However, the cognitive component of psychomotor performance (task switching) was correlated only with cerebellar-frontal connectivity (r = 0.19), whereas the motor component (processing speed) was correlated only with cerebellar-presupplementary motor area connectivity (r = 0.15), suggesting distinct circuits driving unique subprocesses of psychomotor function. CONCLUSIONS: We identified cerebellar-cortical circuits that drive distinct subprocesses of psychomotor function. Future studies should probe relationships between cerebellar connectivity and psychomotor performance using neuromodulation.

Noninvasive Brain Stimulation for Nicotine Dependence in Schizophrenia: A Mini Review.

Individuals with schizophrenia are 10 times more likely to have a tobacco use disorder than the general population. Up to 80% of those with schizophrenia smoke tobacco regularly, a prevalence three-times that of the general population. Despite the striking prevalence of tobacco use in schizophrenia, current treatments are not tailored to the pathophysiology of this population. There is growing support for use of noninvasive brain stimulation (NIBS) to treat substance use disorders (SUDs), particularly for tobacco use in neurotypical smokers. NIBS interventions targeting the dorsolateral prefrontal cortex have been effective for nicotine dependence in control populations-so much so that transcranial magnetic stimulation is now FDA-approved for smoking cessation. However, this has not borne out in the studies using this approach in schizophrenia. We performed a literature search to identify articles using NIBS for the treatment of nicotine dependence in people with schizophrenia, which identified six studies. These studies yielded mixed results. Is it possible that nicotine has a unique effect in schizophrenia that is different than its effect in neurotypical smokers? Individuals with schizophrenia may receive additional benefit from nicotine's pro-cognitive effects than control populations and may use nicotine to improve brain network abnormalities from their illness. Therefore, clinical trials of NIBS interventions should test a schizophrenia-specific target for smoking cessation. We propose a generalized approach whereby schizophrenia-specific brain circuitry related to SUDs is be identified and then targeted with NIBS interventions.

Evidence for Schizophrenia-Specific Pathophysiology of Nicotine Dependence.

Tobacco use is the top preventable cause of early mortality in schizophrenia. Over 60% of people with schizophrenia smoke, three times the general prevalence. The biological basis of this increased risk is not understood, and existing interventions do not target schizophrenia-specific pathology. We therefore used a connectome-wide analysis to identify schizophrenia-specific circuits of nicotine addiction. We reanalyzed data from two studies: In Cohort 1, 35 smokers (18 schizophrenia, 17 control) underwent resting-state fMRI and clinical characterization. A multivariate pattern analysis of whole-connectome data was used to identify the strongest links between cigarette use and functional connectivity. In Cohort 2, 12 schizophrenia participants and 12 controls were enrolled in a randomized, controlled crossover study of nicotine patch with resting-state fMRI. We correlated change in network functional connectivity with nicotine dose. In Cohort 1, the strongest (p < 0.001) correlate between connectivity and cigarette use was driven by individual variation in default mode network (DMN) topography. In individuals with greater daily cigarette consumption, we observed a pathological expansion of the DMN territory into the identified parieto-occipital region, while in individuals with lower daily cigarette consumption, this region was external to the DMN. This effect was entirely driven by schizophrenia participants. Given the relationship between DMN topography and nicotine use we observed in Cohort 1, we sought to directly test the impact of nicotine on this network using an independent second cohort. In Cohort 2, nicotine reduced DMN connectivity in a dose-dependent manner (R = -0.50; 95% CI -0.75 to -0.12, p < 0.05). In the placebo condition, schizophrenia subjects had hyperconnectivity compared to controls (p < 0.05). Nicotine administration normalized DMN hyperconnectivity in schizophrenia. We here provide direct evidence that the biological basis of nicotine dependence is different in schizophrenia and in non-schizophrenia populations. Our results suggest the high prevalence of nicotine use in schizophrenia may be an attempt to correct a network deficit known to interfere with cognition.

Disparities in Gender and Race Among Physician-Scientists: A Call to Action and Strategic Recommendations.

The size of the physician-scientist workforce has declined for the past 3 decades, which raises significant concerns for the future of biomedical research. There is also a considerable gender disparity among physician-scientists. This disparity is exacerbated by race, resulting in a compounding effect for women of color. Proposed reasons for this disparity include the time and expense physicians must devote to obtaining specialized research training after residency while at the same time burdened with mounting medical school debt and domestic and caretaking responsibilities, which are disproportionately shouldered by women. These circumstances may contribute to the overall gender disparity in research funded by the National Institutes of Health (NIH). Women apply for NIH grants less often than men and are therefore less likely to receive an NIH grant. However, when women do apply for NIH grants, their funding success is comparable with that of men. Increasing representation of women and groups underrepresented in medicine (UIM) requires not only improving the pipeline (e.g., through training) but also assisting early- and midcareer women-and especially women who are UIM-to advance. In this article, the authors propose the following solutions to address the challenges women and other UIM individuals face at each of these career stages: developing specific NIH research training programs targeted to women and UIM individuals in medical school and residency; creating institutional and individual grant initiatives; increasing student loan forgiveness; setting up robust institutional mentorship programs for individuals seeking to obtain independent funding; providing childcare stipends as part of NIH grants; and instituting an NIH requirement that funded investigators participate in efforts to increase diversity in the physician-scientist workforce. Enabling more women and UIM individuals to enter and thrive in the physician-scientist workforce will increase the size and diversity of this critical component of biomedical research.

Using objective clinical metrics to understand the relationship between the electronic health record and physician well-being: observational pilot study.

BACKGROUND: Electronic health records (EHRs) are a significant contributor to physicians' low satisfaction, reduced engagement and increased burnout. Yet the majority of evidence around EHR and physician harms is based on self-reported screen time, which may both over- and underreport actual exposure. AIMS: The purpose of this study was to examine how objective EHR use correlates with physician well-being and to develop preliminary recommendations for well-being-based EHR interventions. METHOD: Prior to the onset of COVID-19, psychiatry residents and attending physicians working in an out-patient clinic at an academic medical centre provided consent for access to EHR-usage logs and completed a well-being assessment made up of three scales: the Maslach Burnout Inventory, the Urecht Work Engagement Scale and the Professional Quality of Life Measure. Survey responses and objective EHR data were analysed with descriptive statistics. RESULTS: Responses were obtained from 20 psychiatry residents (total eligible residents n = 27; 74% participation) and 16 clinical faculty members (total eligible faculty n = 24; 67% participation) with an overall response rate of 71% (total eligible residents and faculty n = 51 and total residents and faculty who completed survey n = 36). Moderate correlations for multiple well-being domains emerged in analysis for all participants, especially around the time spent per note and patient visits closed the same day. CONCLUSIONS: EHR-usage logs represent an objective tool in the evaluation and enhancement of physician well-being. Results from our pilot study suggest that metrics for note writing efficiency and closing patient visits the same day are associated with physician well-being. These metrics will be important to study in ongoing efforts involving well-being-based EHR interventions.

Borderline personality traits do not influence response to TMS.

Comorbid personality disorders are common in patients with major depressive disorder (MDD). Individuals with comorbid borderline personality disorder (BPD) may be less responsive to electroconvulsive therapy (ECT), but it remains unclear whether BPD affects responsiveness to transcranial magnetic stimulation (TMS). We sought to investigate the association between BPD and response to TMS. We conducted a retrospective analysis of individuals receiving TMS (n=356) at McLean Hospital. We also included individuals receiving ECT (n=1434) as a control. All individuals completed the McLean Screening Instrument for BPD (MSI-BPD) at baseline. Response to treatment was measured by the Quick Inventory of Depression Symptomatology Self-Report (QIDS-SR). We performed general linear models (GLMs) to assess the effect of BPD on treatment response to TMS and ECT. At baseline, the ECT group had a higher average QIDS-SR score (21.4 vs. 20.3, p<0.05). For both treatment groups, the number of treatments had a significant effect on depression severity. For the TMS group, there was no significant Group x Time interaction on QIDS-SR score (p=0.18). However, for individuals receiving ECT, there was a significant Group x Time interaction on QIDS-SR score (p=0.02), suggesting that BPD significantly impaired response. These results suggest that borderline personality traits did not affect treatment response to TMS for MDD. BPD traits modestly predicted response to ECT, which is consistent with the literature. These results require replication in a clinical trial.

Transcranial magnetic stimulation and neuroimaging for cocaine use disorder: Review and future directions.

Background: Cocaine use disorder (CUD) is a public health problem with limited treatment options and a significant relapse rate. Neuroimaging studies have identified abnormal functional connectivity in individuals with substance use disorders. Neuromodulation has been proposed to target this altered neurocircuitry. Combining TMS with neuroimaging has the potential to inform identification of biomarkers, diagnosis, and treatment.Objectives: We review the literature of transcranial magnetic stimulation (TMS) with neuroimaging for CUD and outline a research path forward whereby TMS can be used to identify brain network features as diagnostic or prognostic biomarkers for treatment.Methods: We reviewed the literature for primary research studies of TMS with neuroimaging for CUD. We searched PubMed using search terms of "cocaine," "transcranial magnetic stimulation," and "neuroimaging." Identified studies were screened by title and abstract. Full-text studies were reviewed for inclusion.Results: In our initial search, we identified 73 studies. Six studies met our inclusion criteria. These studies used rTMS (n = 3) and single or paired pulse TMS (n = 3) and included a total of 289 participants. All studies used fMRI as the neuroimaging modality. The most common outcome measure was craving and cue-reactivity (n = 3).Conclusion: The literature combining TMS with neuroimaging is small and heterogeneous. We propose that combining TMS with neuroimaging will accelerate our understanding of substance use disorder neurobiology and treatment. Once network biomarkers of substance use have been identified, TMS can be used to manipulate the dysfunctional circuits in order to identify a causal relationship between connectivity and psychopathology.

Resident Leadership in the Era of COVID-19: Harnessing Emotional Intelligence.

The COVID-19 pandemic is a public health emergency that demands leadership throughout the health care system. Leadership is the ability to guide a team or organization toward a stated goal or objective. In addition to hospital-wide leadership, there is need for leadership at the level of medical teams. Resident leadership is essential to ensure team function and patient care, yet residents are often overlooked as valuable leaders. This Perspective argues that residents can demonstrate leadership during a public health crisis by creating a culture of emotional intelligence in their medical teams. Emotional intelligence has been identified as a critical aspect of leadership and consists of self-awareness, self-management, social awareness, and relationship management. In psychiatry, patient interactions depend upon psychiatrists demonstrating a high level of attention to their own thoughts, feelings, and behaviors as well as those of the patient to communicate in a way that demonstrates both understanding and empathy. In this Perspective, a psychiatry resident uses expertise in emotional intelligence to recommend residents (1) be mindful, (2) ask and listen, (3) establish safety, and (4) unite around a common goal. These practical recommendations can be immediately implemented to increase emotional intelligence on medical teams to improve team function and patient care. Emotional intelligence is valuable at all levels of leadership, so hospital leadership and program directors should also heed these suggestions. While these recommendations are not unique to COVID-19, they are of paramount importance during the pandemic.

Perimenstrual psychiatric hospitalization: case report and literature review.

Despite the fact that menstrual psychosis has been described since the eighteenth century, there are only about 80 cases reported in the literature. The knowledge and awareness about the disorder remain poor, leading to inaccurate diagnoses and suboptimal treatment. This is the case of a 25-year-old woman with recurrent hospitalizations for mental status changes including psychotic phenomena and catatonia that appeared to follow a cyclical pattern that correlated with her menstrual periods, with complete symptom resolution and return to her usual level of functioning between episodes despite continued treatment with antipsychotic medications. This pattern remitted only after hormonal therapy was initiated. Through this case report, the authors review the literature on the menstrual psychoses, exemplified by this case, and discuss treatment options and prognosis. Menstrual psychosis is an underrecognized condition where psychotic symptoms recur cyclically with menses. Given the poor response that this entity shows to antipsychotic treatment, hormonal therapies have a prominent role.

Lurasidone Malabsorption Following Bariatric Surgery: A Case Report.

A significant segment of the United States adult population is obese. Bariatric surgery is one approach to weight loss when nonsurgical efforts have failed. In individuals with a body mass index ≥50, gastric reduction with duodenal switch is more effective than gastric bypass. More than half of bariatric surgery candidates report a history of mental illness and more than one third were taking at least one psychotropic medication at the time of surgery. Thus, the impact of surgery on absorption of psychiatric medications should be considered. Lurasidone, a second-generation antipsychotic used to treat schizophrenia and bipolar disorder, is recommended to be taken with food of at least 350 calories. We describe the case of a patient with incomplete response to lurasidone therapy in the year following a duodenal switch procedure. This case raises concern about the effect that the duodenal switch procedure may have on lurasidone absorption.

Rapid transition from methadone to buprenorphine using naltrexone-induced withdrawal: A case report.

Background: Patients taking methadone for opioid use disorder may desire transition to buprenorphine for a number of reasons. However, the current recommended approach for this transition generally takes weeks to months as an outpatient, causing considerable discomfort to the patient and a heightened risk of relapse during the transition period. Case: We describe the case of a patient on methadone maintenance who was rapidly transitioned to buprenorphine because of her desire to not return to her methadone clinic. In order to rapidly transition the patient from methadone to buprenorphine, naltrexone was administered to precipitate acute opioid withdrawal, which was followed soon after by buprenorphine induction. Discussion: Rapid transition from methadone maintenance to buprenorphine can be accomplished in inpatients by precipitating acute withdrawal with naltrexone, providing an effective alternative for patients who cannot tolerate the typical protracted methadone taper required prior to buprenorphine induction as an outpatient.