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.

Functional and structural effects of repetitive transcranial magnetic stimulation (rTMS) for the treatment of auditory verbal hallucinations in schizophrenia: A systematic review.

BACKGROUND: Auditory verbal hallucinations (AVH) are a disabling symptom for people with schizophrenia (SCZ), and do not always respond to antipsychotics. Repetitive transcranial magnetic stimulation (rTMS) has shown efficacy for medication-refractory AVH, though the underlying neural mechanisms by which rTMS produces these effects remain unclear. This systematic review evaluated the structural and functional impact of rTMS for AVH in SCZ, and its association with clinical outcomes. METHODS: A systematic search was conducted in Medline, PsychINFO, and PubMed using terms for four key concepts: AVH, SCZ, rTMS, neuroimaging. Using PRISMA guidelines, 18 studies were identified that collected neuroimaging data of an rTMS intervention for AVH in SCZ. Risk of bias assessments was conducted. RESULTS: Low frequency (<5 Hz) rTMS targeting left hemispheric language processing regions may normalize brain abnormalities in AVH patients at structural, functional, electrophysiological, and topological levels, with concurrent symptom improvement. Amelioration of aberrant neural activity in frontotemporal networks associated with speech and auditory processing was commonly observed, as well as in cerebellar and emotion regulation regions. Neuroimaging analyses identified neural substrates with direct correlations to post-rTMS AVH severity, propounding their use as therapeutic targets. DISCUSSION: Combined rTMS-neuroimaging highlights the multidimensional alterations of rTMS on brain activity and structure in treatment-resistant AVH, which may be used to develop more efficacious therapies. Larger randomized, sham-controlled studies are needed. Future studies should explore alternate stimulation targets, investigate the neural effects of high-frequency rTMS and evaluate long-term neuroimaging outcomes.

A systematic review and meta-analysis of neuromodulation therapies for substance use disorders.

While pharmacological, behavioral and psychosocial treatments are available for substance use disorders (SUDs), they are not always effective or well-tolerated. Neuromodulation (NM) methods, including repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS) and deep brain stimulation (DBS) may address SUDs by targeting addiction neurocircuitry. We evaluated the efficacy of NM to improve behavioral outcomes in SUDs. A systematic literature search was performed on MEDLINE, PsychINFO, and PubMed databases and a list of search terms for four key concepts (SUD, rTMS, tDCS, DBS) was applied. Ninety-four studies were identified that examined the effects of rTMS, tDCS, and DBS on substance use outcomes (e.g., craving, consumption, and relapse) amongst individuals with SUDs including alcohol, tobacco, cannabis, stimulants, and opioids. Meta-analyses were performed for alcohol and tobacco studies using rTMS and tDCS. We found that rTMS reduced substance use and craving, as indicated by medium to large effect sizes (Hedge's g > 0.5). Results were most encouraging when multiple stimulation sessions were applied, and the left dorsolateral prefrontal cortex (DLPFC) was targeted. tDCS also produced medium effect sizes for drug use and craving, though they were highly variable and less robust than rTMS; right anodal DLPFC stimulation appeared to be most efficacious. DBS studies were typically small, uncontrolled studies, but showed promise in reducing misuse of multiple substances. NM may be promising for the treatment of SUDs. Future studies should determine underlying neural mechanisms of NM, and further evaluate extended treatment durations, accelerated administration protocols and long-term outcomes with biochemical verification of substance use.

Cancer-related information behavior among Black and Hispanic populations in an NCI-designated comprehensive cancer center catchment.

OBJECTIVE: This study aims to better understand health behaviors, particularly health information seeking, and how this impacts cancer care within underserved minority populations in a specific catchment area in Florida. METHODS: We conducted an analysis of survey data from a 2019 community health survey conducted by the Moffit Cancer Center (MCC). We utilized the Comprehensive Model of Information Seeking (CMIS) as a framework and performed structural equation modeling (SEM) and related statistical analyses. RESULTS: Our findings confirm that characteristics and demographics present a positive relationship to Online Health Information Seeking (OHIS). We also found that Utility had a negative significant relationship to OHIS. CONCLUSIONS: We concluded that the CMIS is a useful framework for studying cancer-related information seeking, and that when properly executed in the confines of a study, can lend itself to in-depth statistical analyses as found in SEM. IMPLICATIONS: The SEM revealed the CMIS to be promising with results in our analysis worthy of further investigation of cancer care and healthcare information access considering undeserved and minority populations. PRACTICE IMPLICATIONS: Models such as the CMIS can be useful for understanding information seeking behaviors and to design information and communication interventions to improve access and health outcomes.

Mediating Role of Lifestyle Behaviors in the Association between Education and Cancer: Results from the European Prospective Investigation into Cancer and Nutrition.

BACKGROUND: Many studies have shown that socioeconomic position (SEP) is associated with the incidence of malignant tumors at different sites. This study aims to estimate the association between educational level (as proxy for SEP) and cancer incidence and to understand whether the observed associations might be partially explained by lifestyle behaviors. METHODS: The analyses were performed on data from the European Prospective Investigation into Cancer and Nutrition (EPIC) study, globally and by sex. We used Cox proportional hazards models together with mediation analysis to disentangle the total effect (TE) of educational level [measured through the Relative Index of Inequality (RII)] on cancer incidence into pure direct (PDE) and total indirect (TIE) effect, unexplained and explained by mediators, respectively. PDE and TIE were then combined to compute the proportions mediated (PM). RESULTS: After an average of 14 years of follow-up, 52,422 malignant tumors were ascertained. Low educated participants showed higher risk of developing stomach, lung, kidney (in women), and bladder (in men) cancers, and, conversely, lower risk of melanoma and breast cancer (in post-menopausal women), when compared with more educated participants. Mediation analyses showed that portions of the TE of RII on cancer could be explained by site-specific related lifestyle behaviors for stomach, lung, and breast (in women). CONCLUSIONS: Cancer incidence in Europe is determined at least in part by a socioeconomically stratified distribution of risk factors. IMPACT: These observational findings support policies to reduce cancer occurrence by altering mediators, such as lifestyle behaviors, particularly focusing on underprivileged strata of the population.

Impact of low health literacy on patients' health outcomes: a multicenter cohort study.

BACKGROUND: This study aims to assess the health literacy of medical patients admitted to hospitals and examine its correlation with patients' emergency department visits, hospital readmissions, and durations of hospital stay. METHODS: This prospective cohort study recruited patients admitted to the general internal medicine units at the two urban tertiary care hospitals. Health literacy was measured using the full-length Test of Functional Health Literacy in Adults. Logistic regression analyses were performed to examine the correlation between health literacy and the desired outcomes. The primary outcome of interest of this study was to determine the correlation between health literacy and emergency department revisit within 90 days of discharge. The secondary outcomes of interest were to assess the correlation between health literacy and length of stay and hospital readmission within 90 days of discharge. RESULTS: We found that 50% had adequate health literacy, 32% had inadequate, and 18% of patients had marginal health literacy. Patients with inadequate health literacy were more likely to revisit the emergency department as compared to patients with adequate health literacy (odds ratio: 3.0; 95% Confidence Interval: 1.3-6.9, p = 0.01). In patients with inadequate health literacy, the mean predicted probability of emergency department revisits was 0.22 ± 0.11 if their education level was some high school or less and 0.57 ± 0.18 if they had completed college. No significant correlation was noted between health literacy and duration of hospital stay or readmission. CONCLUSIONS: Only half of the patients admitted to the general internal medicine unit had adequate health literacy. Patients with low health literacy, but high education, had a higher probability of emergency department revisits.

Switching from originator infliximab to biosimilar versus continuing on originator in inflammatory bowel disease: results from the observational Project NORTH study.

OBJECTIVE: Project NORTH compared real-world clinical and economic outcomes in Swedish patients with inflammatory bowel disease (IBD) who switched from originator infliximab to its biosimilar. MATERIALS AND METHODS: Data from electronic medical records and Swedish national registries were linked. Switchers (patients switching from originator infliximab to its biosimilar between 1 April 2014, and 31 December 2017) and non-switchers (patients who received originator infliximab and did not switch to a biosimilar by 31 December 2017) were followed up until 31 October 2019. RESULTS: Baseline concomitant medication use, disease duration, and inflammatory markers were lower among switchers than non-switchers. At 6 months, the proportion of patients with stable disease was higher among switchers than non-switchers (71/109 [65%] vs 54/107 [50%]; p = .0385); differences were not significant in subsequent follow-ups. At 6 and 24 months, 98% and 93% of switchers, respectively, used concomitant medications versus 96% and 79% of non-switchers. Throughout the study, all-cause treatment discontinuation occurred in 74 (67%) switchers and 105 (95%) non-switchers. At 36-months, mean (SD) number of IBD-related in-patient care days was higher among non-switchers (2.95 [4.71]) than switchers (1.40 [4.20]), as were total medical costs (€16,740 vs €3,872). CONCLUSIONS: No substantial differences in clinical outcomes or healthcare resource utilization were observed between switchers and non-switchers. Several analyses indicate that non-switchers might have more poorly controlled/severe disease than switchers at baseline. Overall, numerous difficulties might arise when executing a high-quality, real-world study, including possible selection bias for patients with better disease control for NMS, limiting the generalizability of the results.

Body Size at Different Ages and Risk of 6 Cancers: A Mendelian Randomization and Prospective Cohort Study.

It is unclear if body weight in early life affects cancer risk independently of adult body weight. To investigate this question for 6 obesity-related cancers, we performed univariable and multivariable analyses using 1) Mendelian randomization (MR) analysis and 2) longitudinal analyses in prospective cohorts. Both the MR and longitudinal analyses indicated that larger early life body size was associated with higher risk of endometrial (odds ratioMR = 1.61, 95% confidence interval = 1.23 to 2.11) and kidney (odds ratioMR = 1.40, 95% confidence interval = 1.09 to 1.80) cancer. These associations were attenuated after accounting for adult body size in both the MR and cohort analyses. Early life body mass index (BMI) was not consistently associated with the other investigated cancers. The lack of clear independent risk associations suggests that early life BMI influences endometrial and kidney cancer risk mainly through pathways that are common with adult BMI.

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.

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.

Autism and autistic traits in those who died by suicide in England.

BACKGROUND: Autism and autistic traits are risk factors for suicidal behaviour. AIMS: To explore the prevalence of autism (diagnosed and undiagnosed) in those who died by suicide, and identify risk factors for suicide in this group. METHOD: Stage 1: 372 coroners' inquest records, covering the period 1 January 2014 to 31 December 2017 from two regions of England, were analysed for evidence that the person who died had diagnosed autism or undiagnosed possible autism (elevated autistic traits), and identified risk markers. Stage 2: 29 follow-up interviews with the next of kin of those who died gathered further evidence of autism and autistic traits using validated autism screening and diagnostic tools. RESULTS: Stage 1: evidence of autism (10.8%) was significantly higher in those who died by suicide than the 1.1% prevalence expected in the UK general alive population (odds ratio (OR) = 11.08, 95% CI 3.92-31.31). Stage 2: 5 (17.2%) of the follow-up sample had evidence of autism identified from the coroners' records in stage 1. We identified evidence of undiagnosed possible autism in an additional 7 (24.1%) individuals, giving a total of 12 (41.4%); significantly higher than expected in the general alive population (1.1%) (OR = 19.76, 95% CI 2.36-165.84). Characteristics of those who died were largely similar regardless of evidence of autism, with groups experiencing a comparably high number of multiple risk markers before they died. CONCLUSIONS: Elevated autistic traits are significantly over-represented in those who die by suicide.

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.

Evaluation of protein and amino acid intake estimates from the EPIC dietary questionnaires and 24-h dietary recalls using different food composition databases.

BACKGROUND AND AIMS: This study aimed to expand the European Prospective Investigation into Cancer and Nutrition (EPIC) nutrient database (ENDB) by adding amino acid (AA) values, using the U.S. nutrient database (USNDB). Additionally, we aimed to evaluate these new protein and AA intake estimates from the EPIC dietary questionnaires (DQ) and 24-h dietary recalls (24-HDR) using different matching procedures. METHODS AND RESULTS: Dietary energy, protein and AA intakes were assessed via DQ and 24-HDR by matching with the USNDB food composition table. Energy and protein intakes calculated using USNDB matching were compared with those calculated using ENDB, that uses country specific food composition tables. Pearson correlations, Cohen's weighted kappa statistic and Bland-Altman plots were used to compare data resulting from USNDB matching with our reference from ENDB matching. Very high correlations were found when comparing daily energy (r = 0.99) and dietary protein intakes (r = 0.97) assessed via USNDB with those obtained via ENDB (matching for DQ and 24-HDR). Significant positive correlations were also found with energy and protein intakes acquired via 24-HDRs in the EPIC calibration sample. CONCLUSION: Very high correlations between total energy and protein intake obtained via the USDA matching and those available in ENDB suggest accuracy in the food matching. Individual AA have been included in the extended EPIC Nutrient database that will allow important analyses on AA disease prospective associations in the EPIC study.