Understanding Cognitive Behavioral Therapy for Psychosis Through the Predictive Coding Framework.

Psychological treatments for persecutory delusions, particularly cognitive behavioral therapy for psychosis, are efficacious; however, mechanistic theories explaining why they work rarely bridge to the level of cognitive neuroscience. Predictive coding, a general brain processing theory rooted in cognitive and computational neuroscience, has increasing experimental support for explaining symptoms of psychosis, including the formation and maintenance of delusions. Here, we describe recent advances in cognitive behavioral therapy for psychosis-based psychotherapy for persecutory delusions, which targets specific psychological processes at the computational level of information processing. We outline how Bayesian learning models employed in predictive coding are superior to simple associative learning models for understanding the impact of cognitive behavioral interventions at the algorithmic level. We review hierarchical predictive coding as an account of belief updating rooted in prediction error signaling. We examine how this process is abnormal in psychotic disorders, garnering noisy sensory data that is made sense of through the development of overly strong delusional priors. We argue that effective cognitive behavioral therapy for psychosis systematically targets the way sensory data are selected, experienced, and interpreted, thus allowing for the strengthening of alternative beliefs. Finally, future directions based on these arguments are discussed.

Delusions are distressing and disabling psychiatric symptoms. Cognitive behavioral therapy for psychosis (CBTp) is the leading psychotherapeutic approach for treating delusions. Predictive coding is a contemporary cognitive neuroscience framework that is increasingly being used to explain mechanisms of delusions. In this article, we attempt to integrate CBTp within the predictive coding framework, outlining how effective CBTp techniques impact aspects of the predictive coding model to contribute to cutting-edge treatment and cognitive neuroscience research on delusions and inform recommendations for treatment advancement.

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 functional magnetic resonance imaging. We hypothesized that 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 HCP-EP (Human Connectome Project for Early Psychosis) (n = 183) to identify links between connectivity and ACPT performance. We then analyzed data from the NAPLS2 (North American Prodrome Longitudinal Study 2) (n = 345), a multisite 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 control participants. 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 control participants (n = 132). CONCLUSIONS: This connectome-wide association study identified reproducible links between connectivity and cognition in separate samples of individuals with 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.

Altered brain and physiological stress responses in early psychosis.

Stress is proposed to be a crucial factor in the onset and presentation of psychosis. The early stage of psychosis provides a window into how stress interacts with the emergence of psychosis. Yet, how people with early psychosis respond to stress remains unclear. The current study examined how stress responses (brain, physiological, self-report) differ in early psychosis. Forty participants (20 early psychosis [EP], 20 healthy controls [HC]) completed a stress task in the scanner that involved viewing stressful and neutral-relaxing images. Physiological responses (cortisol, heart rate) and self-report of stress were also assessed. Region of Interest analyses were conducted with brain regions previously shown to be activated during the stress task (amygdala, hippocampus, striatum, hypothalamus, prefrontal cortex [dorsolateral, ventrolateral, medial orbital]). Linear mixed models were used to test for effects of group (EP, HC) and emotion (stress, neutral-relaxing). HC had higher hippocampus activation to stress versus neutral-relaxing conditions while EP did not show a difference (group x emotion interaction, p = 0.04). There were also significant main effects of group with EP having higher amygdala activation (p = 0.01), ventrolateral prefrontal cortex activation (vlPFC, p = 0.03), self-report of stress (p = 0.01), and heart rate (p < 0.001). Our study found preliminary evidence that people with early psychosis showed heightened response to stressful and non-threatening situations, across multiple levels of stress responses. Our findings suggest a novel perspective on stress alterations in early psychosis and highlight the importance of considering both stressful and non-stressful situations.

Genome-Wide Association Study of Treatment-Resistant Depression: Shared Biology With Metabolic Traits.

OBJECTIVE: Treatment-resistant depression (TRD) occurs in roughly one-third of all individuals with major depressive disorder (MDD). Although research has suggested a significant common variant genetic component of liability to TRD, with heritability estimated at 8% when compared with non-treatment-resistant MDD, no replicated genetic loci have been identified, and the genetic architecture of TRD remains unclear. A key barrier to this work has been the paucity of adequately powered cohorts for investigation, largely because of the challenge in prospectively investigating this phenotype. The objective of this study was to perform a well-powered genetic study of TRD. METHODS: Using receipt of electroconvulsive therapy (ECT) as a surrogate for TRD, the authors applied standard machine learning methods to electronic health record data to derive predicted probabilities of receiving ECT. These probabilities were then applied as a quantitative trait in a genome-wide association study of 154,433 genotyped patients across four large biobanks. RESULTS: Heritability estimates ranged from 2% to 4.2%, and significant genetic overlap was observed with cognition, attention deficit hyperactivity disorder, schizophrenia, alcohol and smoking traits, and body mass index. Two genome-wide significant loci were identified, both previously implicated in metabolic traits, suggesting shared biology and potential pharmacological implications. CONCLUSIONS: This work provides support for the utility of estimation of disease probability for genomic investigation and provides insights into the genetic architecture and biology of TRD.

Network Structure of Childhood Trauma, Bodily Disturbances, and Schizotypy in Schizophrenia and Nonclinical Controls.

Background and Hypothesis: Exposure to childhood trauma has been linked to the development of psychosis and bodily self-disturbances, 2 hallmarks of schizophrenia (SZ). Prior work demonstrated that bodily disturbances serve as a bridge between childhood trauma and SZ symptomatology, but the diagnostic specificity of these connections remains unknown. This study uses network analysis to bridge this gap by comparing the interplays between childhood trauma, bodily self-disturbances, and schizotypy in clinical and general populations. Study Design: Networks were constructed to examine the relationships between schizotypy (Schizotypal Personality Questionnaire; SPQ), bodily self-disturbances (Perceptual Aberration Scale; PAS), and childhood trauma (Childhood Trauma Questionnaire, CTQ) in 152 people with SZ and 162 healthy comparison participants (HC). The Fused Graphical Lasso was used to jointly estimate the networks in the 2 groups and the structure and strength of the networks were compared. Node centrality and shortest paths between CTQ, PAS, and schizotypy were examined. Study Results: When comparing SZ and HC, the network of bodily self-disturbances, childhood trauma, and schizotypy were similarly structured, but the network was significantly stronger in SZ than HC. In both groups, bodily self-disturbances were on one of the shortest paths between childhood trauma to schizotypal experiences. Conclusions: Our findings revealed reliable associations between childhood trauma, bodily self-disturbance, and schizotypy, with bodily disturbances acting as a bridge from childhood trauma to schizotypy. The elevated strength of the SZ network indicates a more highly interconnected, and therefore reactive network in which exposure to childhood trauma can more easily activate bodily disturbances and schizotypy.

Lifespan development of thalamic nuclei and characterizing thalamic nuclei abnormalities in schizophrenia using normative modeling.

Thalamic abnormalities have been repeatedly implicated in the pathophysiology of schizophrenia and other neurodevelopmental disorders. Uncovering the etiology of thalamic abnormalities and how they may contribute to illness phenotypes faces at least two obstacles. First, the typical developmental trajectories of thalamic nuclei and their association with cognition across the lifespan are largely unknown. Second, modest effect sizes indicate marked individual differences and pose a significant challenge to personalized medicine. To address these knowledge gaps, we characterized the development of thalamic nuclei volumes using normative models generated from the Human Connectome Project Lifespan datasets (5-100+ years), then applied them to an independent clinical cohort to determine the frequency of thalamic volume deviations in people with schizophrenia (17-61 years). Normative models revealed diverse non-linear age effects across the lifespan. Association nuclei exhibited negative age effects during youth but stabilized in adulthood until turning negative again with older age. Sensorimotor nuclei volumes remained relatively stable through youth and adulthood until also turning negative with older age. Up to 18% of individuals with schizophrenia exhibited abnormally small (i.e., below the 5th centile) mediodorsal and pulvinar volumes, and the degree of deviation, but not raw volumes, correlated with the severity of cognitive impairment. While case-control differences are robust, only a minority of patients demonstrate unusually small thalamic nuclei volumes. Normative modeling enables the identification of these individuals, which is a necessary step toward precision medicine.

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.

The insula: Leveraging cellular and systems-level research to better understand its roles in health and schizophrenia.

Schizophrenia is a highly heterogeneous disorder characterized by a multitude of complex and seemingly non-overlapping symptoms. The insular cortex has gained increasing attention in neuroscience and psychiatry due to its involvement in a diverse range of fundamental human experiences and behaviors. This review article provides an overview of the insula's cellular and anatomical organization, functional and structural connectivity, and functional significance. Focusing on specific insula subregions and using knowledge gained from humans and preclinical studies of insular tracings in non-human primates, we review the literature and discuss the functional roles of each subregion, including in somatosensation, interoception, salience processing, emotional processing, and social cognition. Building from this foundation, we then extend these findings to discuss reported abnormalities of these functions in individuals with schizophrenia, implicating insular involvement in schizophrenia pathology. This review underscores the insula's vast role in the human experience and how abnormal insula structure and function could result in the wide-ranging symptoms observed in schizophrenia.

Interplay between childhood trauma, bodily self-disturbances, and clinical phenomena in schizophrenia spectrum disorders: A network analysis.

BACKGROUND: Bodily self-disturbances have long been considered central to schizophrenia. Exposure to childhood trauma has been linked to the development of both psychosis and bodily self-disturbances, yet little work has examined the role of bodily self-disturbances in the relationship between childhood trauma and schizophrenia symptomatology. This study uses network analysis to bridge this gap. METHODS: Networks were constructed to examine relationships between schizophrenia symptoms (Positive and Negative Symptom Scale; PANSS), bodily self-disturbances (Perceptual Aberration Scale; PAS), and self-reported exposure to childhood trauma (Childhood Trauma Questionnaire, Short-Form; CTQ-SF) in 152 people with a schizophrenia-spectrum disorder. Shortest path and bridge analyses were conducted to assess the role of bodily self-disturbances in linking childhood trauma to schizophrenia symptomatology. Three networks were constructed: 1) PAS, childhood trauma, and PANSS sub-scale composites (positive, negative, general); 2) PAS, childhood trauma, and positive symptoms, 3) PAS, childhood trauma, and distress symptoms. RESULTS: Shortest path analysis revealed that bodily self-disturbances were on the shortest path between childhood trauma and positive and general symptoms (Network 1), between trauma and hallucinations (Network 2), and between trauma and depression (Network 3). Bodily self-disturbances were also found to serve as a bridge between childhood trauma and positive symptoms of schizophrenia, particularly delusions and hallucinations. CONCLUSIONS: Using a novel, data-driven approach, we showed that bodily self-disturbances play a key role in linking childhood trauma to positive and co-morbid affective symptoms of schizophrenia. Threat experiences (i.e., abuse) specifically relate to bodily self-disturbances and psychotic symptoms.

Threat Responses in Schizophrenia: A Negative Valence Systems Framework.

PURPOSE OF REVIEW: Emotions are prominent in theories and accounts of schizophrenia but are largely understudied compared to cognition. Utilizing the Research Domain Criteria (RDoC) Negative Valence Systems framework, we review the current knowledge of emotions in schizophrenia. Given the pivotal role of threat responses in theories of schizophrenia and the substantial evidence of altered threat responses, we focus on three components of Negative Valence Systems tied to threat responses: responses to acute threat, responses to potential threat, and sustained threat. RECENT FINDINGS: Individuals with schizophrenia show altered responses to neutral stimuli during acute threat, bed nucleus of the stria terminalis connectivity in response to potential threat, and threat responses associated with sustained threat. Our review concludes that Negative Valence Systems are altered in schizophrenia; however, the level and evidence of alterations vary across the types of threat responses. We suggest avenues for future research to further understand and intervene on threat responses in schizophrenia.

Smaller anterior hippocampal subfields in the early stage of psychosis.

Hippocampal volume is smaller in schizophrenia, but it is unclear when in the illness the changes appear and whether specific regions (anterior, posterior) and subfields (CA1, CA2/3, dentate gyrus, subiculum) are affected. Here, we used a high-resolution T2-weighted sequence specialized for imaging hippocampal subfields to test the hypothesis that anterior CA1 volume is lower in early psychosis. We measured subfield volumes across hippocampal regions in a group of 90 individuals in the early stage of a non-affective psychotic disorder and 70 demographically similar healthy individuals. We observed smaller volume in the anterior CA1 and dentate gyrus subfields in the early psychosis group. Our findings support models that implicate anterior CA1 and dentate gyrus subfield deficits in the mechanism of psychosis.

Mapping Psychomotor Behavior in the Brain.

This Viewpoint describes a new conception of brain regions that may be associated with abnormal psychomotor behaviors in psychotic and mood disorders.

In-hospital catatonia, delirium, and coma and mortality: Results from the delirium and catatonia prospective cohort investigation.

BACKGROUND: Catatonia, a form of acute brain dysfunction typically linked with severe affective and psychotic disorders, occurs in critical illness with delirium and coma. Delirium and coma are associated with mortality, though catatonia's relationship with mortality is unclear. We aim to describe whether catatonia, delirium, and coma are associated with mortality. METHODS: We enrolled a convenience cohort of critically ill adults (N = 378) at an academic medical center. We assessed catatonia, delirium, and coma using the Bush-Francis Catatonia Rating Scale, the Confusion Assessment Method for the Intensive Care Unit and the Richmond Agitation-Sedation Scale, respectively. We tested the associations between previous day brain dysfunction state occurrence with in-hospital and one-year mortality using multivariable time-dependent risk models. Additionally, we tested the association between brain dysfunction duration and one-year mortality. RESULTS: Catatonia was not associated with death on the day after diagnosis during hospitalization, and neither previous catatonia occurrence nor duration was associated with one-year mortality. Delirium was not associated with death on any day following diagnosis during hospitalization, and neither previous delirium occurrence nor duration was associated with one-year mortality. The occurrence of coma was associated with death on any day after diagnosis during hospitalization (HR 2.30,CI 1.19-4.44,p = 0.014), as well as through one year following hospital discharge (HR 1.68,CI 1.09-2.59,p = 0.02). CONCLUSIONS: Coma, but neither catatonia nor delirium, was associated with future day in-hospital and one-year mortality. More research is needed to understand catatonia's clinical impact. Delirium results differ from existing literature likely due to cohort demographics and size. Coma results highlight the prognostic significance of suppressed arousal while critically ill.

Exploring genetic risk for catatonia in a genome wide association study and polygenic risk score analysis.

BACKGROUND: Catatonia is an under-recognized disorder characterized by psychomotor (increased, decreased, or abnormal) changes, affective symptoms, and disturbance of volition, which may arise in the setting of decompensated psychiatric or non-psychiatric medical disorders. Genetic studies of catatonia are limited, and to the best of our knowledge no prior genome wide association studies of catatonia have been performed to date. METHODS: First we performed a genome wide association study of catatonia regardless of etiology (psychiatric or non-psychiatric). Secondarily we evaluated whether there was an elevated genetic risk profile for predisposing psychiatric disorders (schizophrenia spectrum disorder, bipolar affective disorder, etc.) in patients with catatonia. We used a matched case control design and applied polygenic risk scores to evaluate for a shared polygenetic contribution to catatonia from common psychiatric phenotypes that show a high prevalence of catatonia in their decompensated states. RESULTS: Anxiety, bipolar affective disorder, schizophrenia spectrum disorder and cross disorder polygenic risk scores were significantly associated with catatonia case status in both unadjusted and adjusted logistic regression models for the European Ancestry set even after correcting for multiple comparisons. Depression, Alzheimer's, Autism Spectrum Disorder and Obsessive Disorder polygenic risk scores were not significantly associated with catatonia status in participants of European Ancestry. In the African Ancestry set, no psychiatric polygenic risk scores were significantly associated with catatonia status in either the unadjusted or adjusted regression models. CONCLUSIONS: Even after controlling for relevant covariates, anxiety, bipolar affective disorder, schizophrenia spectrum disorder and cross disorders were significantly associated with catatonia status suggesting that there might be a shared genetic risk for those disorders amongst patients with catatonia.

Modulation of hippocampal activity in schizophrenia with levetiracetam: a randomized, double-blind, cross-over, placebo-controlled trial.

Hippocampal hyperactivity is a novel pharmacological target in the treatment of schizophrenia. We hypothesized that levetiracetam (LEV), a drug binding to the synaptic vesicle glycoprotein 2 A, normalizes hippocampal activity in persons with schizophrenia and can be measured using neuroimaging methods. Thirty healthy control participants and 30 patients with schizophrenia (28 treated with antipsychotic drugs), were randomly assigned to a double-blind, cross-over trial to receive a single administration of 500 mg oral LEV or placebo during two study visits. At each visit, we assessed hippocampal function using resting state fractional amplitude of low frequency fluctuations (fALFF), cerebral blood flow (CBF) with arterial spin labeling, and hippocampal blood-oxygen-level-dependent (BOLD) signal during a scene processing task. After placebo treatment, we found significant elevations in hippocampal fALFF in patients with schizophrenia, consistent with hippocampal hyperactivity. Additionally, hippocampal fALFF in patients with schizophrenia after LEV treatment did not significantly differ from healthy control participants receiving placebo, suggesting that LEV may normalize hippocampal hyperactivity. In contrast to our fALFF findings, we did not detect significant group differences or an effect of LEV treatment on hippocampal CBF. In the context of no significant group difference in BOLD signal, we found that hippocampal recruitment during scene processing is enhanced by LEV more significantly in schizophrenia. We conclude that pharmacological modulation of hippocampal hyperactivity in schizophrenia can be studied with some neuroimaging methods, but not others. Additional studies in different cohorts, employing alternate neuroimaging methods and study designs, are needed to establish levetiracetam as a treatment for schizophrenia.

The schizophrenia syndrome, circa 2024: What we know and how that informs its nature.

With new data about different aspects of schizophrenia being continually generated, it becomes necessary to periodically revisit exactly what we know. Along with a need to review what we currently know about schizophrenia, there is an equal imperative to evaluate the construct itself. With these objectives, we undertook an iterative, multi-phase process involving fifty international experts in the field, with each step building on learnings from the prior one. This review assembles currently established findings about schizophrenia (construct, etiology, pathophysiology, clinical expression, treatment) and posits what they reveal about its nature. Schizophrenia is a heritable, complex, multi-dimensional syndrome with varying degrees of psychotic, negative, cognitive, mood, and motor manifestations. The illness exhibits a remitting and relapsing course, with varying degrees of recovery among affected individuals with most experiencing significant social and functional impairment. Genetic risk factors likely include thousands of common genetic variants that each have a small impact on an individual's risk and a plethora of rare gene variants that have a larger individual impact on risk. Their biological effects are concentrated in the brain and many of the same variants also increase the risk of other psychiatric disorders such as bipolar disorder, autism, and other neurodevelopmental conditions. Environmental risk factors include but are not limited to urban residence in childhood, migration, older paternal age at birth, cannabis use, childhood trauma, antenatal maternal infection, and perinatal hypoxia. Structural, functional, and neurochemical brain alterations implicate multiple regions and functional circuits. Dopamine D-2 receptor antagonists and partial agonists improve psychotic symptoms and reduce risk of relapse. Certain psychological and psychosocial interventions are beneficial. Early intervention can reduce treatment delay and improve outcomes. Schizophrenia is increasingly considered to be a heterogeneous syndrome and not a singular disease entity. There is no necessary or sufficient etiology, pathology, set of clinical features, or treatment that fully circumscribes this syndrome. A single, common pathophysiological pathway appears unlikely. The boundaries of schizophrenia remain fuzzy, suggesting the absence of a categorical fit and need to reconceptualize it as a broader, multi-dimensional and/or spectrum construct.

Hippocampal Network Dysfunction in Early Psychosis: A 2-Year Longitudinal Study.

Background: Hippocampal abnormalities are among the most consistent findings in schizophrenia. Numerous studies have reported deficits in hippocampal volume, function, and connectivity in the chronic stage of illness. While hippocampal volume and function deficits are also present in the early stage of illness, there is mixed evidence of both higher and lower functional connectivity. Here, we use graph theory to test the hypothesis that hippocampal network connectivity is broadly lowered in early psychosis and progressively worsens over 2 years. Methods: We examined longitudinal resting-state functional connectivity in 140 participants (68 individuals in the early stage of psychosis, 72 demographically similar healthy control individuals). We used an anatomically driven approach to quantify hippocampal network connectivity at 2 levels: 1) a core hippocampal-medial temporal lobe cortex (MTLC) network; and 2) an extended hippocampal-cortical network. Group and time effects were tested in a linear mixed effects model. Results: Early psychosis patients showed elevated functional connectivity in the core hippocampal-MTLC network, but contrary to our hypothesis, did not show alterations within the broader hippocampal-cortical network. Hippocampal-MTLC network hyperconnectivity normalized longitudinally and predicted improvement in positive symptoms but was not associated with increasing illness duration. Conclusions: These results show abnormally elevated functional connectivity in a core hippocampal-MTLC network in early psychosis, suggesting that selectively increased hippocampal signaling within a localized cortical circuit may be a marker of the early stage of psychosis. Hippocampal-MTLC hyperconnectivity could have prognostic and therapeutic implications.