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.

Bridging Neuroscience and Clinical Assessment in a Patient with Alcohol Use Disorder, Anxiety, and Trauma.

This article presents a unique framework that combines insights from neuroscience with clinical assessment to evaluate individuals who have co-occurring alcohol use disorder, anxiety, and trauma. Through the use of a case study, the authors demonstrate the practical application of this framework and contextualize the relevant neurocircuitry associated with alcohol withdrawal, maladaptive fear and anxiety, and chronic stress. By integrating these perspectives, they provide a comprehensive approach for assessing and treating patients with complex psychiatric histories, particularly those presenting with anxiety symptoms, offering valuable insights for practitioners.

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.

Altered bed nucleus of the stria terminalis and amygdala responses to threat in combat veterans with posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) significantly impacts many veterans. Although PTSD has been linked to alterations in the fear brain network, the disorder likely involves alterations in both the fear and anxiety networks. Fear involves responses to imminent, predictable threat and is driven by the amygdala, whereas anxiety involves responses to potential, unpredictable threat and engages the bed nucleus of the stria terminalis (BNST). The BNST has been implicated in PTSD, but the role of the BNST in combat veterans with PTSD has yet to be examined. Identifying alterations in BNST responses to unpredictable threat could provide important new targets for treatment. The current study examined whether veterans with PTSD have altered BNST or amygdala responses (function and connectivity) to unpredictable and predictable threat. The fMRI task involved viewing predictable threat cues followed by threat images, predictable neutral cues followed by neutral images, and unpredictable threat cues followed by either a threat or neutral image. Participants included 32 combat-exposed veterans with PTSD and 13 combat-exposed controls without PTSD. Across all conditions, veterans with PTSD had heightened BNST activation and displayed stronger BNST and amygdala connectivity with multiple fear and anxiety regions (hypothalamus, hippocampus, insula, ventromedial prefrontal cortex) relative to controls. In contrast, combat controls showed a pattern of stronger connectivity during neutral conditions (e.g., BNST-vmPFC), which may suggest a neural signature of resilience to developing PTSD, ηp 2 = .087-.527, ps < .001. These findings have implications for understanding fear and anxiety networks that may contribute to the development and maintenance of PTSD.

Alterations in BNST Intrinsic Functional Connectivity in Early Abstinence from Alcohol Use Disorder.

AIMS: Maintaining abstinence from alcohol use disorder (AUD) is extremely challenging, partially due to increased symptoms of anxiety and stress that trigger relapse. Rodent models of AUD have identified that the bed nucleus of the stria terminalis (BNST) contributes to symptoms of anxiety-like behavior and drug-seeking during abstinence. In humans, however, the BNST's role in abstinence remains poorly understood. The aims of this study were to assess BNST network intrinsic functional connectivity in individuals during abstinence from AUD compared to healthy controls and examine associations between BNST intrinsic functional connectivity, anxiety and alcohol use severity during abstinence. METHODS: The study included resting state fMRI scans from participants aged 21-40 years: 20 participants with AUD in abstinence and 20 healthy controls. Analyses were restricted to five pre-selected brain regions with known BNST structural connections. Linear mixed models were used to test for group differences, with sex as a fixed factor given previously shown sex differences. RESULTS: BNST-hypothalamus intrinsic connectivity was lower in the abstinent group relative to the control group. There were also pronounced sex differences in both the group and individual analyses; many of the findings were specific to men. Within the abstinent group, anxiety was positively associated with BNST-amygdala and BNST-hypothalamus connectivity, and men, not women, showed a negative relationship between alcohol use severity and BNST-hypothalamus connectivity. CONCLUSIONS: Understanding differences in connectivity during abstinence may help explain the clinically observed anxiety and depression symptoms during abstinence and may inform the development of individualized treatments.

Anterior hippocampal dysfunction in early psychosis: a 2-year follow-up study.

BACKGROUND: Cross-sectional studies indicate that hippocampal function is abnormal across stages of psychosis. Neural theories of psychosis pathophysiology suggest that dysfunction worsens with illness stage. Here, we test the hypothesis that hippocampal function is impaired in the early stage of psychosis and declines further over the next 2 years. METHODS: We measured hippocampal function over 2 years using a scene processing task in 147 participants (76 individuals in the early stage of a non-affective psychotic disorder and 71 demographically similar healthy control individuals). Two-year follow-up was completed in 97 individuals (50 early psychosis, 47 healthy control). Voxelwise longitudinal analysis of activation in response to scenes was carried out within a hippocampal region of interest to test for group differences at baseline and a group by time interaction. RESULTS: At baseline, we observed lower anterior hippocampal activation in the early psychosis group relative to the healthy control group. Contrary to our hypothesis, hippocampal activation remained consistent and did not show the predicted decline over 2 years in the early psychosis group. Healthy controls showed a modest reduction in hippocampal activation after 2 years. CONCLUSIONS: The results of this study suggest that hippocampal dysfunction in early psychosis does not worsen over 2 years and highlight the need for longer-term longitudinal studies.

Neural responding during uncertain threat anticipation in pediatric anxiety.

Excessive fear responses to uncertain threat are a key feature of anxiety disorders (ADs), though most mechanistic work considers adults. As ADs onset in childhood and confer risk for later psychopathology, we sought to identify conditions of uncertain threat that distinguish 8-17-year-old youth with AD (n = 19) from those without AD (n = 33), and assess test-retest reliability of such responses in a companion sample of healthy adults across three sites (n = 19). In an adapted uncertainty of threat paradigm, visual cues parametrically signaled threat of aversive stimuli (fear faces) in 25 % increments (0 %, 25 %, 50 %, 100 %), while participants underwent functional magnetic resonance imaging (fMRI). We compared neural response elicited by cues signaling different degrees of probability regarding the subsequent delivery of fear faces. Overall, youth displayed greater engagement of bilateral inferior parietal cortex, fusiform gyrus, and lingual gyrus during uncertain threat anticipation in general. Relative to healthy youth, AD youth exhibited greater activation in ventrolateral prefrontal cortex (vlPFC)/BA47 during uncertain threat anticipation in general. Further, AD differed from healthy youth in scaling of ventral striatum/sgACC activation with threat probability and attenuated flexibility of responding during parametric uncertain threat. Complementing these results, significant, albeit modest, cross-site test-retest reliability in these regions was observed in an independent sample of healthy adults. While preliminary due to a small sample size, these findings suggest that during uncertainty of threat, AD youth engage vlPFC regions known to be involved in fear regulation, response inhibition, and cognitive control. Findings highlight the potential of isolating neural correlates of threat anticipation to guide treatment development and translational work in youth.

Structural Brain Correlates of Childhood Inhibited Temperament: An ENIGMA-Anxiety Mega-analysis.

Temperament involves stable behavioral and emotional tendencies that differ between individuals, which can be first observed in infancy or early childhood and relate to behavior in many contexts and over many years.1 One of the most rigorously characterized temperament classifications relates to the tendency of individuals to avoid the unfamiliar and to withdraw from unfamiliar people, objects, and unexpected events. This temperament is referred to as behavioral inhibition or inhibited temperament (IT).2 IT is a moderately heritable trait1 that can be measured in multiple species.3 In humans, levels of IT can be quantified from the first year of life through direct behavioral observations or reports by caregivers or teachers. Similar approaches as well as self-report questionnaires on current and/or retrospective levels of IT1 can be used later in life.

Fear reacquisition and symptoms of combat-related PTSD: Specificity and preliminary examination of the influence of the 5-HT3A receptor gene.

Several studies have examined the acquisition and extinction of fear in PTSD in the context of Pavlovian conditioning. However, research examining reconditioning of fear following extinction, a form of post-extinction re-emergence of conditioned behavior is limited. Although the 5-HT3A receptor gene polymorphism has been linked to trauma responses, its influence on the re-emergence of conditioned fear among those exposed to trauma remain unclear. In the present study, combat-exposed veterans (N = 114) completed a differential fear conditioning task in which one colored rectangle (CS+) predicted a loud scream (US), whereas a different colored rectangle (CS-) predicted no US. Acquisition, extinction, and post-extinction reconditioning effects indexed by conditioned anxiety, US expectancy, and skin conductance response were examined. Associations with allelic variation in the serotonin 5-HT3 gene, HTR3A (rs1062613) were also examined. Participants rated the CS+ as significantly more anxiety inducing and associated with greater US expectancy than the CS- during acquisition. The CS+ also elicited a stronger skin conductance response than the CS- during acquisition. A significant decrease in anxiety and US expectancy in response to the CS+ was observed after extinction and a re-emergence of conditioned responses to the CS+ was observed during reacquisition. Although a diagnosis of PTSD was characterized by greater anxiety to the CS + but not the CS- during acquisition and extinction, those with and without a PTSD diagnosis did not differ in the reacquisition of fear following extinction. Subsequent preliminary analysis did show that increased posttraumatic symptoms and cognitions were associated with increased US expectancy at reacquisition for the CS+ and CS- among CC carriers but not among T carriers of HTR3A (rs1062613). These findings suggest that posttraumatic symptoms among trauma exposed veterans with the CC polymorphism of the HTR3A gene may be associated with stronger reconditioning of fear following extinction.

Incomplete Hippocampal Inversion: A Neurodevelopmental Mechanism for Hippocampal Shape Deformation in Schizophrenia.

BACKGROUND: Shape analyses of patients with schizophrenia have revealed bilateral deformations of the anterolateral hippocampus, primarily localized to the CA1 subfield. Incomplete hippocampal inversion (IHI), an anatomical variant of the human hippocampus resulting from an arrest during neurodevelopment, is more prevalent and severe in patients with schizophrenia. We hypothesized that IHI would affect the shape of the hippocampus and contribute to hippocampal shape differences in schizophrenia. METHODS: We studied 199 patients with schizophrenia and 161 healthy control participants with structural magnetic resonance imaging to measure the prevalence and severity of IHI. High-fidelity hippocampal surface reconstructions were generated with the SPHARM-PDM toolkit. We used general linear models in SurfStat to test for group shape differences, the impact of IHI on hippocampal shape variation, and whether IHI contributes to hippocampal shape abnormalities in schizophrenia. RESULTS: Not including IHI as a main effect in our between-group comparison replicated well-established hippocampal shape differences in patients with schizophrenia localized to the CA1 subfield in the anterolateral hippocampus. Shape differences were also observed near the uncus and hippocampal tail. IHI was associated with outward displacements of the dorsal and ventral surfaces of the hippocampus and inward displacements of the medial and lateral surfaces. Including IHI as a main effect in our between-group comparison eliminated the bilateral shape differences in the CA1 subfield. Shape differences in the uncus persisted after including IHI. CONCLUSIONS: IHI impacts hippocampal shape. Our results suggest IHI as a neurodevelopmental mechanism for the well-known shape differences, particularly in the CA1 subfield, in schizophrenia.

Increased amplitude of hippocampal low frequency fluctuations in early psychosis: A two-year follow-up study.

Neuroimaging studies have revealed hippocampal hyperactivity in schizophrenia. In the early stage of the illness, hyperactivity is present in the anterior hippocampus and is thought to spread to other regions as the illness progresses. However, there is limited evidence for changes in basal hippocampal function following the onset of psychosis. Resting state functional MRI signal amplitude may be a proxy measure for increased metabolism and disrupted oscillatory activity, both consequences of an excitation/inhibition imbalance underlying hippocampal hyperactivity. Here, we used fractional amplitude of low frequency fluctuations (fALFF) to test the hypothesis of progressive hippocampal hyperactivity in a two-year longitudinal case-control study. We found higher fALFF in the anterior and posterior hippocampus of individuals in the early stage of non-affective psychosis at study entry. Contrary to our hypothesis of progressive hippocampal dysfunction, we found evidence for normalization of fALFF over time in psychosis. Our findings support a model in which hippocampal fALFF is a marker of psychosis vulnerability or acute illness state rather than an enduring feature of the illness.

Longitudinal predictors of depression, anxiety, and alcohol use following COVID-19-related stress.

The COVID-19 pandemic imposed profound effects on health and daily life, with widespread stress exposure and increases in psychiatric symptoms. Despite these challenges, pandemic research provides unique insights into individual differences in emotion and cognition that predict responses to stress, with general implications for understanding stress vulnerability. We examined predictors of responses to COVID-19-related stress in an online sample of 450 emerging adults recruited in May 2020 to complete questionnaires assessing baseline stress and psychiatric symptoms, rumination, cognitive reappraisal use and intolerance of uncertainty. Stress and symptoms were re-assessed 3 months later (N = 200). Greater pandemic-related stressful events were associated with increases in symptoms of depression, anxiety and alcohol use severity. Additionally, individual differences in emotional and cognitive styles emerged as longitudinal predictors of stress responses. Specifically, greater rumination predicted increased depression. Reduced cognitive reappraisal use interacted with stress to predict increases in alcohol use. An unexpected pattern emerged for intolerance of uncertainty, such that stress was associated with increases in depression for those high in intolerance of uncertainty but increases in alcohol use at relatively low levels of intolerance of uncertainty. These results highlight unique vulnerabilities that predict specific outcomes following stress exposure and offer potential prevention targets.

Bed nucleus of the stria terminalis and amygdala responses to unpredictable threat in children.

Substantial evidence from studies in humans suggests the amygdala is pivotal for anxiety. Findings from animal models and translational studies suggests the bed nucleus of the stria terminalis (BNST) is also critical for anxiety and the anticipation of unpredictable threat in adults. However, it remains unknown whether the BNST is involved in unpredictable threat anticipation in children. Forty-two 8-10-year-olds completed resting-state functional magnetic resonance imaging (fMRI) scans and an unpredictable threat fMRI task in which they were trained to associate cues with images. Intrinsic connectivity analyses were performed to establish functional BNST and amygdala networks. BNST and amygdala activation to cues and images was tested. Significant findings were followed by task-based functional connectivity analyses. Children showed evidence for BNST and amygdala intrinsic connectivity that was similar to previous patterns observed in adults. In response to unpredictable cues relative to neutral face cues, children had a significant amygdala response but no response in the BNST. The amygdala, but not the BNST, also showed a significantly greater response to fear face images relative to neutral images. Thus, unpredictable threat activated the amygdala, but not BNST, in children. This finding is contrary to studies showing robust BNST activation to unpredictable threat in adults and may suggest that the BNST's role in threat processing emerges later in development.

Functional anatomy of the bed nucleus of the stria terminalis-hypothalamus neural circuitry: Implications for valence surveillance, addiction, feeding, and social behaviors.

The bed nucleus of the stria terminalis (BNST) is a medial basal forebrain structure that modulates the hypothalamo-pituitary-adrenal (HPA) axis. The heterogeneous subnuclei of the BNST integrate inputs from mood and reward-related areas and send direct inhibitory projections to the hypothalamus. The connections between the BNST and hypothalamus are conserved across species, promote activation of the HPA axis, and can increase avoidance of aversive environments, which is historically associated with anxiety behaviors. However, BNST-hypothalamus circuitry is also implicated in motivated behaviors, drug seeking, feeding, and sexual behavior. These complex and diverse roles, as well its sexual dimorphism, indicate that the BNST-hypothalamus circuitry is an essential component of the neural circuitry that may underlie various psychiatric diseases, ranging from anorexia to anxiety to addiction. The following review is a cross-species exploration of BNST-hypothalamus circuitry. First, we describe the BNST subnuclei, microcircuitry and complex reciprocal connections with the hypothalamus. We will then discuss the behavioral functions of BNST-hypothalamus circuitry, including valence surveillance, addiction, feeding, and social behavior. Finally, we will address sex differences in morphology and function of the BNST and hypothalamus.

Clinical Outcomes Following Acute Residential Psychiatric Treatment in Transgender and Gender Diverse Adolescents.

Importance: Transgender and gender diverse (TGD) individuals, who have a gender identity that differs from their sex assigned at birth, are at increased risk of mental health problems, including depression, anxiety, self-injurious behavior, and suicidality, relative to cisgender peers. Objective: To examine mental health outcomes among TGD vs cisgender adolescents in residential treatment. Design, Setting, and Participants: This cohort study's longitudinal design was used to compare groups at treatment entry and discharge, and 1-month postdischarge follow-up. The setting was an adolescent acute residential treatment program for psychiatric disorders. Participants were TGD or cisgender adolescents enrolled in the treatment program. Statistical analysis was performed October 2019 to March 2021. Exposure: Adolescents participated in a 2-week acute residential treatment program for psychiatric disorders. Main Outcomes and Measures: Primary outcomes were depressive (the Center for Epidemiologic Studies Depression Scale [CES-D]) and anxiety (the Multidimensional Anxiety Scale for Children [MASC]) symptoms, and emotional dysregulation (the Difficulties in Emotion Regulation Scale [DERS]), measured at treatment entry and discharge, and postdischarge follow-up. Age of depression onset, suicidality, self-injury, and childhood trauma also were assessed at treatment entry. Results: Of 200 adolescent participants who completed treatment entry and discharge assessments, the mean (SD) age was 16.2 (1.5) years; 109 reported being assigned female at birth (54.5%), 35 were TGD (17.5%), and 66 (49.3%) completed 1-month follow-up. TGD participants had an earlier mean (SD) age of depression onset (TGD: 10.8 [2.4] years vs cisgender: 11.9 [2.3] years; difference: 1.07 years; 95% CI, 0.14-2.01 years; P = .02), higher mean (SD) suicidality scores (TGD: 44.4 [23.1] vs cisgender: 28.5 [25.4]; difference: 16.0; 95% CI, 6.4-25.5; P = .001), more self-injurious behavior (mean [SD] RBQ-A score for TGD: 3.1 [2.5] vs cisgender: 1.7 [1.9]; difference: 1.42; 95% CI, 0.69-2.21; P = .001) and more childhood trauma (eg, mean [SD] CTQ-SF score for emotional abuse in TGD: 12.7 [5.4] vs cisgender: 9.8 [4.7]; difference: 2.85; 95% CI, 1.06-4.64; P = .002). The TGD group also had higher symptom scores (CES-D mean difference: 7.69; 95% CI, 3.30 to 12.08; P < .001; MASC mean difference: 7.56; 95% CI, 0.46 to 14.66; P = .04; and DERS mean difference: 18.43; 95% CI, 8.39 to 28.47; P < .001). Symptom scores were significantly higher at entry vs discharge (CES-D mean difference, -12.16; 95% CI, -14.50 to -9.80; P < .001; MASC mean difference: -3.79; 95% CI, -6.16 to -1.42; P = .02; and DERS mean difference: -6.37; 95% CI, -10.80 to -1.94; P = .05) and follow-up (CES-D mean difference: -9.69; 95% CI, -13.0 to -6.42; P < .001; MASC mean difference: -6.92; 95% CI, -10.25 to -3.59; P < .001; and DERS mean difference: -12.47; 95% CI, -18.68 to -6.26; P < .001). Conclusions and Relevance: This cohort study found mental health disparities in TGD youth relative to cisgender youth, with worse scores observed across assessment time points. For all participants, primary clinical outcome measures were significantly lower at treatment discharge than at entry, with no significant differences between discharge and 1-month follow-up. Given the substantial degree of mental health disparities reported in TGD individuals, these findings warrant focused clinical attention to optimize treatment outcomes in gender minority populations.

BNST and amygdala connectivity are altered during threat anticipation in schizophrenia.

In schizophrenia, impairments in affect are prominent and anxiety disorders are prevalent. Neuroimaging studies of fear and anxiety in schizophrenia have focused on the amygdala and show alterations in connectivity. Emerging evidence suggests that the bed nucleus of the stria terminalis (BNST) also plays a critical role in anxiety, especially during anticipation of an unpredictable threat; however, previous studies have not examined the BNST in schizophrenia. In the present study, we examined BNST function and connectivity in people with schizophrenia (n = 31; n = 15 with comorbid anxiety) and controls (n = 15) during anticipation of unpredictable and predictable threat. A secondary analysis tested for differences in activation and connectivity of the central nucleus of the amygdala (CeA), which has also been implicated in threat anticipation. Analyses tested for group differences in both activation and connectivity during anticipation of unpredictable threat and predictable threat (p < .05). Relative to controls, individuals with schizophrenia showed stronger BNST-middle temporal gyrus (MTG) connectivity during unpredictable threat anticipation and stronger BNST-MTG and BNST-dorsolateral prefrontal connectivity during predictable threat anticipation. Comparing subgroups of individuals with schizophrenia and a comorbid anxiety disorder (SZ+ANX) to those without an anxiety disorder (SZ-ANX) revealed broader patterns of altered connectivity. During unpredictable threat anticipation, the SZ+ANX group had stronger BNST connectivity with regions of the salience network (insula, dorsal anterior cingulate cortex). During predictable threat anticipation, the SZ+ANX group had stronger BNST connectivity with regions associated with fear processing (insula, extended amygdala, prefrontal cortex). A secondary CeA analysis revealed a different pattern; the SZ+ANX group had weaker CeA connectivity across multiple brain regions during threat anticipation compared to the SZ-ANX group. These findings provide novel evidence for altered functional connectivity during threat anticipation in schizophrenia, especially in individuals with comorbid anxiety.

Insula sub-regions across the psychosis spectrum: morphology and clinical correlates.

The insula is a heterogeneous cortical region, comprised of three cytoarchitecturally distinct sub-regions (agranular, dysgranular, and granular), which traverse the anterior-posterior axis and are differentially involved in affective, cognitive, and somatosensory processing. Smaller insula volume is consistently reported in psychosis-spectrum disorders and is hypothesized to result, in part, from abnormal neurodevelopment. To better understand the regional and diagnostic specificity of insula abnormalities in psychosis, their developmental etiology, and clinical correlates, we characterized insula volume and morphology in a large group of adults with a psychotic disorder (schizophrenia spectrum, psychotic bipolar disorder) and a community-ascertained cohort of psychosis-spectrum youth (age 8-21). Insula volume and morphology (cortical thickness, gyrification, sulcal depth) were quantified from T1-weighted structural brain images using the Computational Anatomy Toolbox (CAT12). Healthy adults (n = 196), people with a psychotic disorder (n = 303), and 1368 individuals from the Philadelphia Neurodevelopmental Cohort (PNC) (381 typically developing (TD), 381 psychosis-spectrum (PS) youth, 606 youth with other psychopathology (OP)), were investigated. Insula volume was significantly reduced in adults with psychotic disorders and psychosis-spectrum youth, following an anterior-posterior gradient across granular sub-regions. Morphological abnormalities were limited to lower gyrification in psychotic disorders, which was specific to schizophrenia and associated with cognitive ability. Insula volume and thickness were associated with cognition, and positive and negative symptoms of psychosis. We conclude that smaller insula volume follows an anterior-posterior gradient in psychosis and confers a broad risk for psychosis-spectrum disorders. Reduced gyrification is specific to schizophrenia and may reflect altered prenatal development that contributes to cognitive impairment.

Alterations in connectivity of the bed nucleus of the stria terminalis during early abstinence in individuals with alcohol use disorder.

BACKGROUND: For individuals with Alcohol Use Disorder (AUD), long-term recovery is difficult in part due to symptoms of anxiety that occur during early abstinence and can trigger relapse. Research in rodent models of AUD has identified the bed nucleus of the stria terminalis (BNST), a small, sexually dimorphic, subcortical region, as critical for regulating anxiety-like behaviors during abstinence, particularly in female mice. Furthermore, prolonged alcohol use and subsequent abstinence alter BNST afferent and efferent connections to other brain regions. To our knowledge, however, no studies of early abstinence have investigated BNST structural connectivity in humans during abstinence; this study addresses that gap. METHODS: Nineteen participants with AUD currently in early abstinence and 20 healthy controls completed a diffusion tensor imaging (DTI) scan. BNST structural connectivity was evaluated using probabilistic tractography. A linear mixed model was used to test between-groups differences in BNST network connectivity. Exploratory analyses were conducted to test for correlations between BNST connectivity and alcohol use severity and anxiety within the abstinence group. Sex was included as a factor for all analyses. RESULTS: The BNST showed stronger structural connectivity with the BNST network in early abstinence women than in control women, which was not seen in men. Women also showed region-specific differences, with stronger BNST-hypothalamus structural connectivity but weaker vmPFC-BNST structural connectivity than men. Exploratory analyses also demonstrated a relationship between alcohol use severity and vmPFC-BNST structural connectivity that was moderated by sex. CONCLUSIONS: This study is the first to demonstrate BNST structural connectivity differences in early abstinence and revealed key sex differences. The sex-specific differences in BNST structural connectivity during early abstinence could underlie known sex differences in abstinence symptoms and relapse risk and help to inform potential sex-specific treatments.

Incomplete hippocampal inversion in schizophrenia: prevalence, severity, and impact on hippocampal structure.

Incomplete hippocampal inversion (IHI) is an anatomical variant of the human brain resulting from an arrest in brain development, especially prevalent in the left hemisphere. We hypothesized that IHI is more common in schizophrenia and contributes to the well-known hippocampal structural differences. We studied 199 schizophrenia patients and 161 healthy control participants with 3 T MRI to establish IHI prevalence and the relationship of IHI with hippocampal volume and asymmetry. IHI was more prevalent (left hemisphere: 15% of healthy control participants, 27% of schizophrenia patients; right hemisphere: 4% of healthy control participants, 10% of schizophrenia patients) and more severe in schizophrenia patients compared to healthy control participants. Severe IHI cases were associated with a higher rate of automated segmentation failure. IHI contributed to smaller hippocampal volume and increased R > L volume asymmetry in schizophrenia. The increased prevalence and severity of IHI supports the neurodevelopmental model of schizophrenia. The impact of this developmental variant deserves further exploration in studies of the hippocampus in schizophrenia.

Fear-induced brain activations distinguish anxious and trauma-exposed brains.

Translational models of fear conditioning and extinction have elucidated a core neural network involved in the learning, consolidation, and expression of conditioned fear and its extinction. Anxious or trauma-exposed brains are characterized by dysregulated neural activations within regions of this fear network. In this study, we examined how the functional MRI activations of 10 brain regions commonly activated during fear conditioning and extinction might distinguish anxious or trauma-exposed brains from controls. To achieve this, activations during four phases of a fear conditioning and extinction paradigm in 304 participants with or without a psychiatric diagnosis were studied. By training convolutional neural networks (CNNs) using task-specific brain activations, we reliably distinguished the anxious and trauma-exposed brains from controls. The performance of models decreased significantly when we trained our CNN using activations from task-irrelevant brain regions or from a brain network that is irrelevant to fear. Our results suggest that neuroimaging data analytics of task-induced brain activations within the fear network might provide novel prospects for development of brain-based psychiatric diagnosis.