Dissecting Heterogeneity in Functional Network Connectivity Aberrations in Antipsychotic Medication-Naïve First Episode Psychosis Patients - A Normative Modeling Study.

Importance: While there is a general consensus that functional connectome pathology is a key mechanism underlying psychosis spectrum disorders, the literature is plagued with inconsistencies and translation into clinical practice is non-existent. This is perhaps because group-level findings may not be accurate reflections of pathology at the individual patient level. Objective: To characterize inter-individual heterogeneity in functional networks and investigate if normative values can be leveraged to identify biologically less heterogeneous subgroups of patients. Design Setting and Participants: We used data collected in a case-control study conducted at the University of Alabama at Birmingham (UAB). We recruited antipsychotic medication-naïve first-episode psychosis patients from UAB outpatient, inpatient, and emergency room settings. Main Outcomes and Measures: Individual-level patterns of deviations from a normative reference range in resting-state functional networks using the Yeo-17 atlas for parcellations. Results: Statistical analyses included 108 medication-naïve first-episode psychosis patients. We found that there is a high level of inter-individual heterogeneity in resting-state network connectivity deviations from the normative reference range. Interestingly 48% of patients did not have any functional connectivity deviations, and no more than 11.1% of patients shared functional deviations between the same regions of interest. In a post hoc analysis, we grouped patients based on deviations into four theoretically possible groups. We discovered that all four groups do exist in our experimental data and showed that subgroups based on deviation profiles were significantly less heterogeneous compared to the overall group (positive deviation group: z= -2.88, p = 0.002; negative deviation group: z= -3.36, p<0.001). Conclusions and Relevance: Our findings experimentally demonstrate that there is a high level of inter-individual heterogeneity in resting-state network pathology in first-episode psychosis patients which support the idea that group-level findings are not accurate reflections of pathology at the individual level. We also demonstrated that normative functional connectivity deviations may have utility for identifying biologically less heterogeneous subgroups of patients, even though they are not distinguishable clinically. Our findings constitute a significant step towards making precision psychiatry a reality, where patients are selected for treatments based on their individual biological characteristics. KEY POINTS: Question: How heterogeneous is individual-level resting-state functional network pathology in patients suffering from a first psychotic episode? Can normative reference values in functional network connectivity be leveraged to identify biologically more homogenous subgroups of patients?Findings: We report that functional network pathology is highly heterogeneous, with no more than 11% of patients sharing functional deviations between the same regions of interest.Meaning: Normative modeling is a tool that can map individual neurobiological differences and enables the classification of a clinically heterogenous patient group into subgroups that are neurobiologically less heterogenous.

Aberrant Effective Connectivity During Eye Gaze Processing Is Linked to Social Functioning and Symptoms in Schizophrenia.

BACKGROUND: Patients with schizophrenia show abnormal gaze processing, which is associated with social dysfunction. These abnormalities are related to aberrant connectivity among brain regions that are associated with visual processing, social cognition, and cognitive control. In this study, we investigated 1) how effective connectivity during gaze processing is disrupted in schizophrenia and 2) how this may contribute to social dysfunction and clinical symptoms. METHODS: Thirty-nine patients with schizophrenia/schizoaffective disorder (SZ) and 33 healthy control participants completed an eye gaze processing task during functional magnetic resonance imaging. Participants viewed faces with different gaze angles and performed explicit and implicit gaze processing. Four brain regions-the secondary visual cortex, posterior superior temporal sulcus, inferior parietal lobule, and posterior medial frontal cortex-were identified as nodes for dynamic causal modeling analysis. RESULTS: Both the SZ and healthy control groups showed similar model structures for general gaze processing. Explicit gaze discrimination led to changes in effective connectivity, including stronger excitatory, bottom-up connections from the secondary visual cortex to the posterior superior temporal sulcus and inferior parietal lobule and inhibitory, top-down connections from the posterior medial frontal cortex to the secondary visual cortex. Group differences in top-down modulation from the posterior medial frontal cortex to the posterior superior temporal sulcus and inferior parietal lobule were noted, such that these inhibitory connections were attenuated in the healthy control group but further strengthened in the SZ group. Connectivity was associated with social dysfunction and symptom severity. CONCLUSIONS: The SZ group showed notably stronger top-down inhibition during explicit gaze discrimination, which was associated with more social dysfunction but less severe symptoms among patients. These findings help pinpoint neural mechanisms of aberrant gaze processing and may serve as future targets for interventions that combine neuromodulation with social cognitive training.

Neurobehavioral indices of gaze perception are associated with social cognition across schizophrenia patients and healthy controls.

BACKGROUND: Gaze perception is a basic building block of social cognition, which is impaired in schizophrenia (SZ) and contributes to functional outcomes. Few studies, however, have investigated neural underpinnings of gaze perception and their relation to social cognition. We address this gap. METHOD: We recruited 77 SZ patients and 71 healthy controls, who completed various social-cognition tasks. During functional magnetic resonance imaging, participants (62 SZ, 54 controls) completed a gaze-perception task, where they judged whether faces with varying gaze angles were self-directed or averted; as a control condition, participants identified stimulus gender. Activation estimates were extracted based on (a) task versus baseline, (b) gaze-perception versus gender-identification, (c) parametric modulation by perception of stimuli as self-directed versus averted, and (d) parametric modulation by stimulus gaze angle. We used latent variable analysis to test associations among diagnostic group, brain activation, gaze perception, and social cognition. RESULTS: Preferential activation to gaze perception was observed throughout dorsomedial prefrontal cortex, superior temporal sulcus, and insula. Activation was modulated by stimulus gaze angle and perception of stimuli as self-directed versus averted. More precise gaze perception and higher task-related activation were associated with better social cognition. Patients with SZ showed hyperactivation within left pre-/postcentral gyrus, which was associated with more precise gaze perception and fewer symptoms and thus may be a compensatory mechanism. CONCLUSIONS: Neural and behavioral indices of gaze perception were related to social cognition, across patients and controls. This suggests gaze perception is an important perceptual building block for more complex social cognition. Results are discussed in the context of dimensional psychopathology and clinical heterogeneity. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Contrasting Case-Control and Normative Reference Approaches to Capture Clinically Relevant Structural Brain Abnormalities in Patients With First-Episode Psychosis Who Are Antipsychotic Naive.

Importance: To make progress toward precision psychiatry, it is crucial to move beyond case-control studies and instead capture individual variations and interpret them in the context of a normal range of biological systems. Objective: To evaluate whether baseline deviations from a normative reference range in subcortical volumes are better predictors of antipsychotic treatment response than raw volumes in patients with first-episode psychosis (FEP) who were naive to antipsychotic medication. Design, Setting, and Participants: In this prospective longitudinal study, patients with first-episode psychosis who were referred from different clinical settings (emergency department, inpatient units, and outpatient clinics) at the University of Alabama at Birmingham were included. A total of 286 patients were screened, 114 consented, 104 enrolled in the treatment trial, and 85 completed the trial. Patients were observed for 16 weeks. Controls were matched by age and sex. Data were collected between June 2016 and July 2021, and data were analyzed from August 2021 to June 2022. Interventions: Risperidone on a flexible dosing scheme for 16 weeks. There was an option to switch to aripiprazole for excessive adverse effects. Main Outcomes and Measures: The main outcome of this study was to evaluate, in patients with FEP who were naive to antipsychotic medication, the association of baseline raw volumes and volume deviations in subcortical brain regions with response to antipsychotic medication. Raw brain volumes or volume deviation changes after treatment were not examined. Results: Of 190 included participants, 111 (58.4%) were male, and the mean (SD) age was 23.7 (5.5) years. Volumes and deviations were quantified in 98 patients with FEP, and data from 92 controls were used as comparison for case-control contrasts and reference curve calibration. In case-control contrasts, patients with FEP had lower raw thalamus (P = .002; F = 9.63; df = 1), hippocampus (P = .009; F = 17.23; df = 1), amygdala (P = .01; F = 6.55; df = 1), ventral diencephalon (P = .03; F = 4.84; df = 1), and brainstem volumes (P = .004; F = 8.39; df = 1). Of 98 patients, 36 patients with FEP (36%) displayed extreme deviations. Associations with treatment response significantly differed between raw volume and deviation measures in the caudate (z = -2.17; P = .03) and putamen (z = -2.15; P = .03). Conclusions and Relevance: These data suggest that normative modeling allows capture of interindividual heterogeneity of regional brain volumes in patients with FEP and characterize structural pathology in a clinically relevant fashion. This holds promise for progress in precision medicine in psychiatry, where group-level studies have failed to derive reliable maps of structural pathology.