Faculty Bibliography

BACKGROUND:Previous studies have demonstrated that gender role nonconformity (GRNC) is associated with negative psychological consequences, but that discrimination, bullying, and homophobic stigmatization are mechanisms through which GRNC impacts psychological health. In this secondary analysis, we test the hypothesis that people reporting higher levels of GRNC will experience increased sexual dysfunction, and that social support will act as an indirect mechanism. METHODS:We analyzed data from 781 participants from the Nathan Kline Institute Rockland Sample, performed quantile regression analyses to assess the relationships among social support, GRNC, and sexual dysfunction (while controlling for age, sex, sexual orientation, and socioeconomic status) and used a mediation analysis to explore social support as a mediator of the effect of GRNC on sexual dysfunction. RESULTS:GRNC significantly positively predicted sexual dysfunction and social support significantly predicted sexual dysfunction in the opposite direction. The indirect effect of GRNC via social support was also significant, suggesting that social support is a salient mechanism through which GRNC affects sexual dysfunction. CONCLUSIONS:We concluded that GRNC significantly predicts sexual dysfunction, and that social support significantly mediates this relationship. Although GRNC is associated with negative psychological and sexual consequences, the impacts appear to be mediated by the structure and quality of social relationships.

BACKGROUND AND HYPOTHESIS/OBJECTIVE:Individuals with schizophrenia (SZ) have well-documented behavioral and neural deficits to reinforcement learning (RL) from monetary feedback. Although they have a range of social functioning deficits, limited research has examined neural processes related to learning from social feedback. The present study examined how neural activation to social RL in SZ compares to activation to monetary RL. STUDY DESIGN/METHODS:Thirty participants with SZ and 31 healthy controls completed a Probabilistic RL paradigm that included both social and monetary RL tasks in the scanner, each with positively and negatively valenced trials. Analyses included a region of interest-based approach to examine activation in areas associated with reward, learning, and social processes and assessed neural activation when making task choices (Choice) and upon feedback receipt (Outcome) for social versus monetary RL. STUDY RESULTS/RESULTS:Results indicated that across tasks, SZ had reduced signal in regions such as caudate and orbitofrontal cortex during Choice but not Outcome. In addition, patterns of neural activation were similar during social and monetary RL, for both valences, and brain activation during RL was largely unrelated to behavioral RL performance in either group. CONCLUSIONS:Overall, the findings indicate that although SZ appear to have intact brain activation when receiving feedback about their choices, they may struggle to recruit the necessary circuitry in regions associated with generating expected values to successfully modulate their choices based on the received feedback. This aligns with literature on monetary RL in SZ and suggests that activation patterns may be similar during social RL.

IMPORTANCE/UNASSIGNED:Individuals with mood and psychotic disorders are at an increased risk for dementia. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, a class of antidiabetic medications with mitochondrial and metabolic properties, may offer protective benefits. OBJECTIVE/UNASSIGNED:To evaluate whether treatment with SGLT2 inhibitors is associated with reduced risk of incident dementia and other neuropsychiatric outcomes in patients with psychiatric disorders. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This cohort study used a target trial emulation design and data from the US Department of Veterans Affairs databases from January 1, 2016, to June 1, 2024. Participants were 65 years or older with a diagnosis of major depressive disorder, bipolar disorder, or schizophrenia spectrum disorder but without prior dementia diagnosis at baseline or history of SGLT2 inhibitor use. Analyses used marginal structural models weighted by inverse probability of treatment and censoring. INTERVENTIONS/UNASSIGNED:Initiation and noninitiation of SGLT2 inhibitor were calculated using intention-to-treat (ITT) analysis, and sustained and nonsustained use of SGLT2 inhibitor for ≥3 months were estimated using per-protocol (PP) analysis. MAIN OUTCOMES AND MEASURES/UNASSIGNED:The primary outcome was incident all-cause dementia, as defined by International Classification of Diseases-coded diagnoses. Secondary outcomes were time to psychiatric emergency department (PED) visit and time to psychiatric hospitalizations. Covariates included demographic characteristics, comorbidities, psychiatric diagnoses, and medication use. RESULTS/UNASSIGNED:In total, there were 112 725 individuals in the sample, of whom 7631 (6.8%) were exposed to an SGLT2 inhibitor. The sample had a median (IQR) age of 74.1 (69.7-77.6) years and predominantly consisted of males (104 818 [92.8%]); 49.3% of the patients had obesity. In the ITT analysis, SGLT2 inhibitor use was associated with reduced odds of all-cause dementia (odds ratio [OR], 0.61; 95% CI, 0.52-0.73) and PED visits (OR, 0.80; 95% CI, 0.66-0.97) but not psychiatric hospitalizations (OR, 0.68; 95% CI, 0.44-1.04). In the PP analysis, SGLT2 inhibitor use was associated with lower odds of all-cause dementia (OR, 0.54; 95% CI, 0.40-0.73) and psychiatric hospitalizations (OR, 0.56; 95% CI, 0.31-1.00) but not PED visits (OR, 0.74; 95% CI, 0.53-1.05). CONCLUSIONS AND RELEVANCE/UNASSIGNED:In this cohort study of older adults with mood and psychotic disorders, SGLT2 inhibitor use was associated with lower risk of dementia and PED visits. The results support a neuroprotective role of SGLT2 inhibitors in a high-risk psychiatric population.

OBJECTIVE/UNASSIGNED:, defined as impulsive action in the context of high positive or negative emotion states. The current study leverages a machine learning approach to examine the association of SSD symptoms, urgency, and suicide risk. METHOD/UNASSIGNED:=10.95, 13.3% female) Model 1 included demographics, childhood trauma, SSD symptoms, global cognitive ability, and urgency. In addition, Model 2 added neuroimaging data. The use of LASSO logistic regression allows for the identification of the strongest predictors among a large number of predictors. RESULTS/UNASSIGNED:Model 1 suggested that greater hostility, guilt, and negative urgency predicted higher likelihood of belonging to the high-risk group, whereas greater difficulty with abstract thinking predicted lower likelihood of belonging to the high-risk group. Model 2 suggested that greater hostility predicted higher likelihood of high-risk, whereas greater anterior cingulate thickness and increased activity in six brain regions-right superior frontal gyrus, left superior medial frontal gyrus, left superior frontal gyrus, right middle frontal gyrus, and right middle cingulate gyrus-predicted a lower likelihood of high SIB. DISCUSSION/UNASSIGNED:Negative urgency and SSD symptoms can classify high-and low-risk groups accurately, and inclusion of brain data slightly increased predictive accuracy.

BACKGROUND:A subset of first-episode schizophrenia (FES) patients responds poorly to initial antipsychotic therapy. The hippocampus is an early-affected region in schizophrenia, yet neurobiological markers predicting treatment response remain unclear. Arterial spin labeling (ASL) magnetic resonance imaging (MRI) allows non-invasive measurement of cerebral blood flow (CBF), but studies on hippocampal perfusion in acute FES, particularly in those receiving electroconvulsive therapy (ECT) with antipsychotics, are limited. METHODS:Fifty FES patients and 28 age- and sex-matched healthy controls underwent high-resolution ASL MRI to assess hippocampal CBF. Patients received either antipsychotics alone (n = 20) or in combination with ECT (n = 30). MRI Scans were acquired before and after six weeks of treatment. Analysis of covariance and linear mixed-effects models were used to assess group differences and longitudinal effects, adjusting for relevant covariates. RESULTS:At baseline, FES patients exhibited significantly lower hippocampal CBF compared to healthy controls, with no significant difference in hippocampal volume. Longitudinal analysis revealed a significant group × time interaction for hippocampal CBF. Post hoc analysis indicated a significant increase in CBF after treatment in the FES group, while hippocampal volume remained unchanged. CBF changes were not significantly correlated with symptom reduction. We further examined the group differences in longitudinal changes between the ECT + Drug group and the Drug group, however no significant results were found. CONCLUSION/CONCLUSIONS:Our findings suggest that functional, but not structural, hippocampal alterations are present in early schizophrenia and may be responsive to treatment. These preliminary results should be interpreted cautiously and validated in larger samples with extended follow-up and neurochemical assessments.

Myelin abnormalities in white matter have been implicated in the pathophysiology of psychotic spectrum disorders (PSD), which are characterized by brain dysconnectivity as a core feature. Among evidence from in vivo MRI studies, diffusion imaging findings have largely supported disrupted white matter integrity in PSD; however, they are not specific to myelin changes. Using a multimodal imaging approach, the current study aimed to further delineate myelin and microstructural changes in the white matter of a young PSD cohort. We utilized quantitative magnetization transfer (qMT) imaging combined with advanced diffusion imaging to estimate specific myelin-related biophysical properties in 51 young adult PSD patients compared with 38 age-matched healthy controls. The macromolecular proton fraction (MPF) obtained from qMT was used as a specific marker of myelin content. Additionally, MPF was employed along with diffusion metrics of axonal density (v_ic) and extra-cellular volume fraction to derive the g-ratio, a measure of relative myelin sheath thickness defined as the ratio of inner to outer axonal diameter. Compared to controls, we observed a widespread MPF reduction and localized g-ratio increase in patients, primarily those with a diagnosis of schizophrenia or depressive schizoaffective disorder. No between-group differences were noted in v_ic, suggesting similar axonal densities across groups. Correlation analysis revealed that lower MPF was significantly related to poorer working memory performance in PSD, while the HC group showed a positive association for working memory with both g-ratio and v_ic. The pattern of changes observed in our multimodal imaging markers suggests that PSD, depending on symptomatology, is characterized by specific alterations in white matter integrity and myelin-axonal geometry of major white matter tracts, which may impact working memory function. These findings provide a more detailed view of myelin-related white matter changes in early stages of PSD.

Deficits in cognitive control contribute to behavioral impairments across neuropsychiatric disorders. Cognitive control is captured as a construct in the Research Domain Construct (RDoC) matrix and incorporate subdomains of goal selection, response selection, and performance monitoring. Relevant tasks for these subdomains include the "AX" version of the continuous performance task (goal selection) and the Go/NoGo and Stop-Signal reaction time tasks (response selection). Underlying mechanisms for these domains have been investigated intensively using fMRI and event-related potential (ERP) approaches, which provide candidate biomarkers for translational research. In RDoC, impulsive behaviors are provisionally assigned to the cognitive control/response selection construct, but other factors may also contribute. Impulsivity has gained increased importance over recent years due to its link to aggression and suicidality, which is mediated especially through the constructs of urgency and frustrative nonreward. These constructs, in turn, may be captured through scales such as the Urgency, (Lack of) Premeditation, (Lack of) Perseverance, and Sensation Seeking (UPPS-P) impulsivity scale and the Point Subtraction Aggression Paradigm (PSAP), respectively. At present, no validated biomarkers exist for either urgency or aggressivity. Potential directions for the development of predictive biomarkers for both targets are discussed.

The aim of this study was to characterize dysfunctional cerebral activation in patients with schizophrenia while they performed a response inhibition task. To achieve this, performance on the task and functional magnetic resonance imaging (fMRI) were compared between healthy control subjects (HC) and patients with schizophrenia (SZ). We focused on the default mode network (DMN), as there is strong evidence in the literature that lack of DMN suppression in schizophrenia is associated with cognitive impairment including poor response inhibition. fMRI was used to measure blood-oxygen-level-dependent activation in 84 subjects (44 SZ and 40 HC) while they performed a Go NoGo task. The subjects were also evaluated for psychiatric symptoms and immediate visual memory. SZ performed more poorly than HC on the task; they had a higher number of commission errors. On the fMRI, the patients consistently evidenced higher activation than the controls in several areas of the default mode network (DMN) including the precuneus, rostral anterior cingulate, parahippocampus and insula. The higher brain activation in the patients with schizophrenia indicates a failure to deactivate the DMN while they perform the response inhibition task. These findings point to the importance of DMN dysfunction as an underlying cause of impairment in response inhibition in schizophrenia. DMN disruptions play an essential role in the cognitive impairment present in schizophrenia.