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Reporting effect size index estimates with their confidence intervals (CIs) can be an excellent way to simultaneously communicate the strength and precision of the observed evidence. We recently proposed a robust effect size index (RESI) that is advantageous over common indices because it’s widely applicable to different types of data. Here, we use statistical theory and simulations to develop and evaluate RESI estimators and confidence/credible intervals that rely on different covariance estimators. Our results show (1) counter to intuition, the randomness of covariates reduces coverage for Chi-squared and F CIs; (2) when the variance of the estimators is estimated, the non-central Chi-squared and F CIs using the parametric and robust RESI estimators fail to cover the true effect size at the nominal level. Using the robust estimator along with the proposed nonparametric bootstrap or Bayesian (credible) intervals provides valid inference for the RESI, even when model assumptions may be violated. This work forms a unified effect size reporting procedure, such that effect sizes with confidence/credible intervals can be easily reported in an analysis of variance (ANOVA) table format.

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.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.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.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.

Background The AARS2 gene encodes a mitochondrial alanyl-transfer RNA synthetase. Defects in this gene have been linked with autosomal recessive inheritance of a variety of different clinical phenotypes. Case A 13 year-old boy developed behavioral and psychiatric problems following a mild head injury. At age 21 he developed tremor, parkinsonism, and eye nystagmus. MRI revealed white matter changes consistent with a leukoencephalopathy. Genetic studies revealed two pathogenic mutations in the AARS2 gene (c.647dupG and c.595C > T). Literature review Only 47 cases of AARS2-associated disorders have been reported, with equal numbers of males and females, and age at onset ranging from infancy to 44 years. The most common clinical problems include movement disorders (71%), cognitive impairment (67%), corticospinal signs (64%), behavioral or psychiatric features (46%), and eye signs (34%). Imaging evidence suggestive of leukoencephalopathy is common, but not invariant. Premature ovarian failure is frequent in females, but not universal. Conclusions Defects in the AARS2 gene are a rare cause for a variety of movement disorders, often associated with brain imaging evidence suggestive of leukoencephalopathy.

Examining volumetric differences of the amygdala and anterior-posterior regions of the hippocampus is important for understanding cognition and clinical disorders. However, the gold standard manual segmentation of these structures is time and labor-intensive. Automated, accurate, and reproducible techniques to segment the hippocampus and amygdala are desirable. Here, we present a hierarchical approach to multi-atlas segmentation of the hippocampus head, body and tail and the amygdala based on atlases from 195 individuals. The Open Vanderbilt Archive of the temporal Lobe (OVAL) segmentation technique outperforms the commonly used FreeSurfer, FSL FIRST, and whole-brain multi-atlas segmentation approaches for the full hippocampus and amygdala and nears or exceeds inter-rater reproducibility for segmentation of the hippocampus head, body and tail. OVAL has been released in open-source and is freely available.

Emil Kraepelin, more than any other individual, has shaped the nature of our psychiatric diagnostic system. Kraepelin published his final contribution to psychiatric nosology as an essay in 1920, which both modified and explicated the conceptual foundation for this approach to diagnosis. This essay was a response to a new generation of psychiatrists, particularly Karl Jaspers, Karl Birnbaum, and Ernst Kretschmer, who each challenged Kraepelin’s view that psychiatric disorders represent natural kinds, (i.e., truly distinct entities). They had argued for a structural analysis of psychosis stressing the impact of unique, personal attributes on the causes and clinical presentations of mental diseases. The authors give this text a close reading and conclude that it offers a final nuanced description of Kraepelin’s advanced nosologic views and his emerging interest in life history and culture. Kraepelin held fast to his position that psychiatric disorders represented distinct natural kinds, but acknowledged that the distinctions between them were often obscured by personality, life experiences, and/or cultural effects. Kraepelin used several metaphors to illustrate his final views, that of an “organ register” being the most prominent. Psychiatric disorders, he postulated, belong to three registers, each with its own distinct clinical features and putative brain-based mechanisms. Published a century ago, this final synthesis of Kraepelin’s views, a capstone to his career, raises central issues about the nature of psychiatric illness and the appropriate goals for psychiatric nosology. They are fertile issues for psychiatric research and practice today.

Treatment resistant depression (TRD), often defined by absence of symptomatic remission following at least two adequate treatment trials, occurs in roughly a third of all individuals with major depressive disorder (MDD). Prior work has suggested a significant common variant genetic component of liability to TRD, with heritability estimates of 8% when comparing to non-treatment resistant MDD. Despite this evidence of heritability, 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. Using electroconvulsive therapy (ECT) as a surrogate for TRD, we applied standard machine learning methods to electronic health record (EHR) data to derive predicted probabilities of receiving ECT. We applied these probabilities as a quantitative trait in a genome-wide association study (GWAS) over 154,433 genotyped patients across four large biobanks. With this approach, we demonstrate heritability ranging from 2% to 4.2% and significant genetic overlap with cognition, attention deficit hyperactivity disorder, schizophrenia, alcohol and smoking traits and body mass index. We identify two genome-wide significant loci, both previously implicated in metabolic traits, suggesting shared biology and potential pharmacological implications. 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.

Background Schizophrenia can be understood as a disturbance of functional connections within brain networks. However, functional alterations that involve white matter (WM) specifically, or their cognitive correlates, have seldomly been investigated, especially during tasks. Methods Resting state and task fMRI images were acquired on 84 patients and 67 controls. Functional connectivities (FC) between 46 WM bundles and 82 cortical regions were compared between the groups under two conditions (i.e., resting state and during working memory retention period). The FC density of each WM bundle was then compared between groups. Associations of FC with cognitive scores were evaluated. Results FC measures were lower in schizophrenia relative to controls for external capsule, cingulum (cingulate and hippocampus), uncinate fasciculus, as well as corpus callosum (genu and body) under the rest or the task condition, and were higher in the posterior corona radiata and posterior thalamic radiation during the task condition. FC for specific WM bundles was correlated with cognitive performance assessed by working memory and processing speed metrics. Conclusions The findings suggest that the functional abnormalities in patients' WM are heterogeneous, possibly reflecting several underlying mechanisms such as structural damage, functional compensation and excessive effort on task, and that WM FC disruption may contribute to the impairments of working memory and processing speed. This is the first report on WM FC abnormalities in schizophrenia relative to controls and their cognitive associates during both rest and task and highlights the need to consider WM functions as components of brain functional networks in schizophrenia.

Catatonia is a clinical syndrome characterized by psychomotor, neurological and behavioral changes. The clinical picture of catatonia ranges from akinetic stupor to severe motoric excitement. Catatonia can occur in the setting of a primary psychiatric condition such as bipolar disorder or secondary to a general medical illness like autoimmune encephalitis. Importantly, it can co-occur with delirium or coma. Malignant catatonia describes catatonia that presents with clinically significant autonomic abnormalities including change in temperature, blood pressure, heart rate, and respiratory rate. It is a life-threatening form of acute brain dysfunction that has several motoric manifestations and occurs secondary to a primary psychiatric condition or a medical cause. Many of the established predisposing and precipitating factors for catatonia such as exposure to neuroleptic medications or withdrawal states are common in the setting of critical illness. Catatonia typically improves with benzodiazepines and treatment of its underlying psychiatric or medical conditions, with electroconvulsive therapy reserved for catatonia refractory to benzodiazepines or for malignant catatonia. However, some forms of catatonia, such as catatonia secondary to a general medical condition or catatonia comorbid with delirium, may be less responsive to traditional treatments. Prompt recognition and treatment of catatonia are crucial because malignant catatonia may be fatal without treatment. Given the high morbidity and mortality associated with malignant catatonia, intensivists should familiarize themselves with this important and under-recognized condition.

In 1880 Carl Wernicke gave this plenary lecture at an annual meeting of German physicians and natural scientists. He used principles from his 1874 aphasia monograph to build a neural model of mental illness. He proposed that the brain keeps a record of experiences in distinct areas of the sensory and motor cortices in the form of memory images, which allows for recognition of objects and the planning of motor acts. He conjectured that imperfections, partial defects and complete loss of such memory images lead, respectively, to mild, moderate and severe forms of psychopathology in sensory and motor realms. The lecture is an early presentation of Wernicke’s system of psychiatry. Several of his concepts have remained relevant in contemporary neuroscience.

Introduction Delirium and catatonia are two representations of acute brain dysfunction that can occur in medically ill patients. It has become increasingly evident that delirium and catatonia can co-occur in the setting of medical illnesses. Delirium and catatonia have been separately described as neuropsychiatric sequelae of Coronavirus Disease 2019 (COVID-19) infection; however, to the best of our knowledge the co-occurrence of delirium and catatonia in the setting of COVID-19 has not been previously reported. Case We describe a case of concurrent delirium and catatonia in a 70-year-old woman with multiple medical comorbidities but with no prior psychiatric history, who was hospitalized with COVID-19 pneumonia. Her symptoms of both delirium and catatonia improved with administration of low-dose lorazepam. Discussion We highlight the importance of recognizing catatonia in medically ill patients and the overlap between and co-occurrence of delirium and catatonia in this population. We explore how the conditions imposed by COVID-19 illness and its unique pathophysiology predispose patients to the development of both delirium and catatonia, as well as the challenges imposed by traditionally different approaches to treatment of these two conditions. Conclusion Delirium and catatonia can co-occur in the context of acute COVID-19 illness. Features specific to COVID-19, both pathophysiological and environmental, create a unique set of conditions, which predispose patients to co-occurring delirium and catatonia. Delirium and co-occurring catatonia may improve with administration of low-dose lorazepam in selected patients.

Background The conceptualization of risk for psychiatric illness is moving from risk factors for specific psychiatric disorders to factors that confer risk for multiple disorders. One potential transdiagnostic risk factor is inhibited temperament, a trait characterized by a fearful or avoidant response to novelty. Inhibited temperament is an established risk factor for anxiety disorders, and evidence suggests inhibited temperament is elevated in schizophrenia, bipolar disorder, and major depressive disorder. Methods In the current study, we tested the hypothesis that inhibited temperament is a transdiagnostic factor in 490 participants including individuals with schizophrenia (n=184), psychotic bipolar disorder (n=61), major depression disorder (n=53), or no disorders (n=192). Participants completed assessments of temperament, personality, clinical symptoms, cognition, and functioning. An ANOVA was used to test for group differences in inhibited temperament scores. Regressions were used to test whether inhibited temperament scores were associated with the current measures and whether the associations were similar across disorders. Results Inhibited temperament was similarly elevated in all patient groups compared to controls. Inhibited temperament was similarly associated with anxiety, depression, negative affect, and quality of life across patient groups. Inhibited temperament was not associated with cognition or functional impairment. Limitation Although the inhibited temperament measure is commonly used, it is a retrospective self-report which may be susceptible to biases. Conclusions The current study provides evidence that inhibited temperament is a transdiagnostic factor impacting affective systems across mood and psychotic disorders. Inhibited patients may especially benefit from treatments that specifically target anxiety and depression.

Reduced hippocampal volume is a consistent finding in neuroimaging studies of individuals with schizophrenia. While these studies have the advantage of large-sample sizes, they are unable to quantify the cellular basis of structural or functional changes. In contrast, postmortem studies are well suited to explore subfield and cellular alterations, but low sample sizes and subject heterogeneity impede establishment of statistically significant differences. Here we use a meta-analytic approach to synthesize the extant literature of hippocampal subfield volume and cellular composition in schizophrenia patients and healthy control subjects. Following pre-registration (PROSPERO CRD42019138280), PubMed, Web of Science, and PsycINFO were searched using the term: (schizophrenia OR schizoaffective) AND (post-mortem OR postmortem) AND hippocampus. Subjects were adult men and women with schizophrenia or schizoaffective disorder or non-psychiatric control subjects, and key outcomes, stratified by hippocampal hemisphere and subfield, were volume, neuron number, neuron density, and neuron size. A random effects meta-analysis was performed. Thirty-two studies were included (413 patients, 415 controls). In patients, volume and neuron number were significantly reduced in multiple hippocampal subfields in left, but not right hippocampus, whereas neuron density was not significantly different in any hippocampal subfield. Neuron size, averaged bilaterally, was also significantly reduced in all calculated subfields. Heterogeneity was minimal to moderate, with rare evidence of publication bias. Meta-regression of age and illness duration did not explain heterogeneity of total hippocampal volume effect sizes. These results extend neuroimaging findings of smaller hippocampal volume in schizophrenia patients and further our understanding of regional and cellular neuropathology in schizophrenia.

BackgroundRelational memory, the ability to bind information into complex memories, is moderately impaired in early psychosis and severely impaired in chronic schizophrenia, suggesting relational memory may worsen throughout the course of illness.MethodsWe examined relational memory in 66 early psychosis patients and 64 healthy control subjects, with 59 patients and 52 control subjects assessed longitudinally at baseline and 2-year follow-up. Relational memory was assessed with 2 complementary tasks, to test how individuals learn relationships between items (face-scene binding task) and make inferences about trained relationships (associative inference task).ResultsThe early psychosis group showed impaired relational memory in both tasks relative to the healthy control group. The ability to learn relationships between items remained impaired in early psychosis patients, while the ability to make inferences about trained relationships improved, although never reaching the level of healthy control performance. Early psychosis patients who did not progress to schizophrenia at follow-up had better relational memory than patients who did.ConclusionsRelational memory impairments, some of which improve and are less severe in patients who do not progress to schizophrenia, are a target for intervention in early psychosis.

Background Anatomical connectivity between the thalamus and cortex, including the prefrontal cortex (PFC), is abnormal in schizophrenia. Overlapping phenotypes, including deficits in executive cognitive abilities dependent on PFC-thalamic circuitry, suggest dysrupted thalamocortical anatomical connectivity may extend to psychotic bipolar disorder. We tested this hypothesis and examined the impact of illness stage to inform when in the illness course thalamocortical dysconnectivity emerges. Methods Diffusion-weighted imaging data were collected on 70 healthy individuals and 124 people with a psychotic disorder (schizophrenia spectrum = 75; psychotic bipolar disorder = 49), including 62 individuals in the early stage of psychosis. Anatomical connectivity between major divisions of the cortex and thalamus was quantified using probabilistic tractography and compared between groups. Associations between PFC-thalamic anatomical connectivity and executive cognitive abilities were examined using regression analysis. Results Psychosis was associated with lower PFC-thalamic and elevated somatosensory-thalamic anatomical connectivity. Follow-up analyses established that lower PFC-thalamic and elevated somatosensory-thalamic anatomical connectivity were present in both schizophrenia and psychotic bipolar disorder. Lower PFC-thalamic anatomical connectivity was also present in early-stage and chronic psychosis. Contrary to expectations, lower PFC-thalamic anatomical connectivity was not associated with impaired executive cognitive abilities. Conclusions Altered thalamocortical anatomical connectivity, especially reduced PFC-thalamic connectivity, is a transdiagnostic feature of psychosis detectable in the early stage of illness. Further work is required to elucidate the functional consequences of the full spectrum of thalamocortical connectivity abnormalities in psychosis.

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.

Dysconnectivity theories, combined with advances in fundamental cognitive neuroscience, have led to increased interest in characterizing cerebellar abnormalities in psychosis. Smaller cerebellar gray matter volume has been found in schizophrenia spectrum disorders. However, the course of these deficits across illness stage, specificity to schizophrenia (vs. psychosis more broadly), and relationship to clinical phenotypes, primarily cognitive impairment, remain unclear.The Spatially Unbiased Infratentorial toolbox, a gold standard for analyzing human neuroimaging data of the cerebellum, was used to quantify cerebellar volumes and conduct voxel-based morphometry on structural magnetic resonance images obtained from 574 individuals (249 schizophrenia spectrum, 108 bipolar with psychotic features, 217 nonpsychiatric control). Analyses examining diagnosis (schizophrenia spectrum, bipolar disorder), illness stage (early, chronic), and cognitive effects on cerebellum structure in psychosis were performed.Cerebellar structure in psychosis did not differ significantly from healthy participants, regardless of diagnosis and illness stage (effect size = 0.01-0.14). In contrast, low premorbid cognitive functioning was associated with smaller whole and regional cerebellum volumes, including cognitive (lobules VI and VII, Crus I, frontoparietal and attention networks) and motor (lobules I-IV, V, and X; somatomotor network) regions in psychosis (effect size = 0.36-0.60). These effects were not present in psychosis cohorts with average estimated premorbid cognition.Cerebellar structural abnormalities in psychosis are related to lower premorbid cognitive functioning implicating early antecedents, atypical neurodevelopment, or both in cerebellar dysfunction. Future research focused on identifying the impact of early-life risk factors for psychosis on the development of the cerebellum and cognition is warranted.

OBJECTIVE: In schizophrenia, the anterior hippocampus is hyperactive and shows reduced task-related recruitment, but the relationship between these two findings is unclear. Here we tested the hypothesis that hyperactivity impairs recruitment of the anterior hippocampus during scene processing. METHOD: We analyzed functional MRI data from 45 early psychosis patients and 35 demographically-matched healthy controls using a block design 1-back scene processing task. We measured hippocampal activation in response to scenes and faces compared to scrambled images. In a subset of 20 early psychosis patients and 31 healthy controls we measured baseline hippocampal activity using cerebral blood volume (CBV) mapping. We used correlation analyses to examine the association between baseline hippocampal activity and task-related hippocampal activation. RESULTS: Activation of the anterior hippocampus was significantly reduced and CBV in the anterior hippocampus was significantly increased in the early stage of psychosis. Increased CBV in early psychosis patients was inversely correlated with task-related activation during scene processing in the anterior hippocampus. CONCLUSIONS: Anterior hippocampal hyperactivity in early psychosis patients limits effective recruitment of this region during task performance. These findings provide novel support for the anterior hippocampus as a therapeutic target in the treatment of cognitive deficits in psychosis.

Learning and memory are impaired in schizophrenia. Some theories have proposed that one form of memory, habituation, is particularly impaired. Preliminary evidence suggests that memory impairment is associated with failed hippocampal habituation in patients with chronic schizophrenia. We studied how abnormal habituation of the hippocampus is related to relational memory deficits in the early stage of psychosis.We measured hippocampal activity in 62 patients with early psychosis and 70 healthy individuals using functional magnetic resonance imaging. Habituation was defined as the slope of functional magnetic resonance imaging signal change to repeated presentations of faces and objects. Relational memory ability was measured as the slope of preferential viewing during a face-scene pair eye movement task outside the scanner.Patients with early psychosis showed impaired relational memory (p.001) and less hippocampal habituation to objects (p = .01) than healthy control subjects. In the healthy control group, better relational memory was associated with faster anterior hippocampal habituation (faces, r = -.28, p = .03). In contrast, patients with early psychosis showed no brain-behavior relationship (r = .12, p = .40).We found evidence for disrupted hippocampal habituation in the early stage of psychosis along with an altered association between hippocampal habituation and relational memory ability. These results suggest that neural habituation may provide a novel target for early cognitive interventions in psychosis.

Background Humans constantly take in vast amounts of information, which must be filtered, flexibly manipulated, and integrated into cohesive relational memories in order to choose relevant behaviors. Relational memory is impaired in chronic schizophrenia, which has been linked to hippocampal dysfunction. It is unclear whether relational memory is impaired in the early stage of psychosis. Methods We studied eye movements during a face-scene pairs task as an indirect measure of relational memory in 89 patients in the early stage of psychosis and 84 healthy control participants. During testing, scenes were overlaid with three equally-familiar faces and participants were asked to recall the matching (i.e. previously-paired) face. During Match trials, one face had been previously paired with the scene. During Non-Match trials, no faces matched the scene. Forced-choice explicit recognition was recorded as a direct measure of relational memory. Results Healthy control subjects rapidly (within 250–500 ms) showed preferential viewing of the matching face during Match trials. In contrast, preferential viewing was delayed in patients in the early stage of psychosis. Explicit recognition of the matching face was also impaired in the patient group. Conclusions This study provides novel evidence for a relational memory deficit in the early stage of psychosis. Patients showed deficits in both explicit recognition as well as abnormal eye-movement patterns during memory recall. Eye movements provide a promising avenue for the study of relational memory in psychosis, as they allow for the assessment of rapid, nonverbal memory processes.

Across networks, connectivity within the frontoparietal network (FPN) and cingulo-opercular network (CON) exhibits reductions earliest during healthy aging, contributing to cognitive impairment. Individuals with psychotic disorders demonstrate evidence of accelerated aging across multiple biological systems. By leveraging a large sample of patients with psychosis from early to chronic illness stages, this study sought to determine whether the CON and FPN exhibit evidence of accelerated aging in psychotic disorders, confirm associations between network efficiency and cognition, and determine whether reduced network efficiency is observed in early-stage psychosis.Resting-state functional magnetic resonance imaging and cognitive data were obtained on 240 patients with psychotic disorder and 178 healthy control participants (HCs). Global efficiency, a measure of functional integration, was calculated for the CON, FPN, subcortical network, and visual network. Associations with age and cognition were assessed and compared between groups.Consistent with accelerated aging, significant group by age interactions reflected significantly stronger relationships between efficiency and age in patients with psychosis than in HCs for both the CON (psychosis: r = -.37; HC: r = -.16) and FPN (psychosis: r = -.31; HC: r = -.05). Accelerated aging was not observed in either the subcortical or visual network, suggesting specificity for cognitive networks that decline earliest in healthy aging. Replicating prior findings, efficiency of both the CON and FPN correlated with cognitive function across all participants (rs.11, ps.031). Furthermore, patients with chronic psychosis (p = .004), but not patients with early psychosis (p = .553), exhibited significantly lower FPN efficiency compared with HCs.Functional integration of higher-order cognitive networks is intact in early psychosis but exhibits evidence of accelerated aging, suggesting the potential for intervention targeting cognition within the early psychosis period.

Catatonia is a psychomotor syndrome associated with several psychiatric and medical conditions. Psychomotor signs range from stupor to agitation, and include pathognomonic features such as verbigeration and waxy flexibility. Disturbances of volition led to the classification of catatonia as a subtype of schizophrenia, but changes in nosology now recognise the high prevalence in mood disorders, overlap with delirium, and comorbidity with medical conditions. Initial psychometric studies have revealed three behavioural factors, but the structure of catatonia is still unknown. Evidence from brain imaging studies of patients with psychotic disorders indicates increased neural activity in premotor areas in patients with hypokinetic catatonia. However, whether this localised hyperactivity is due to corticocortical inhibition or excess activity of inhibitory corticobasal ganglia loops is unclear. Current treatment of catatonia relies on benzodiazepines and electroconvulsive therapy-both effective, yet unspecific in their modes of action. Longitudinal research and treatment studies, with neuroimaging and brain stimulation techniques, are needed to advance our understanding of catatonia.

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.

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.

Generalizability is an important problem in deep neural networks, especially in the context of the variability of data acquisition in clinical magnetic resonance imaging (MRI). Recently, the Spatially Localized Atlas Network Tiles (SLANT) approach has been shown to effectively segment whole brain non-contrast T1w MRI with 132 volumetric labels. Enhancing generalizability of SLANT would enable broader application of volumetric assessment in multi-site studies. Transfer learning (TL) is commonly to update neural network weights for local factors; yet, it is commonly recognized to risk degradation of performance on the original validation/test cohorts. Here, we explore TL by data augmentation to address these concerns in the context of adapting SLANT to anatomical variation (e.g., adults versus children) and scanning protocol (e.g., non-contrast research T1w MRI versus contrast-enhanced clinical T1w MRI). We consider two datasets: First, 30 T1w MRI of young children with manually corrected volumetric labels, and accuracy of automated segmentation defined relative to the manually provided truth. Second, 36 paired datasets of pre- and post-contrast clinically acquired T1w MRI, and accuracy of the post-contrast segmentations assessed relative to the pre-contrast automated assessment. For both studies, we augment the original TL step of SLANT with either only the new data or with both original and new data. Over baseline SLANT, both approaches yielded significantly improved performance (pediatric: 0.89 vs. 0.82 DSC, p

BackgroundCross-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.MethodsWe 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.ResultsAt 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.ConclusionsThe 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.