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.

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.

Cerebellar Effects on Abnormal Psychomotor Function Are Mediated by Processing Speed in Psychosis Spectrum.

Psychomotor disturbance has been identified as a key feature of psychotic disorders, with motor signs observed in upwards of 66% of unmedicated, first-episode patients. Aberrations in the cerebellum have been directly linked to sensorimotor processing deficits including processing speed, which may underly psychomotor disturbance in psychosis, though these brain-behavior-symptom relationships are unclear, in part due to within-diagnosis heterogeneity across these levels of analysis. In 339 psychosis patients (242 schizophrenia-spectrum, 97 bipolar with psychotic features) and 217 controls, we evaluated the relationship between cerebellar grey matter volume in the Yeo sensorimotor network and psychomotor disturbance (mannerisms and posturing, retardation, excitement of the Positive and Negative Syndrome Scale [PANSS]), as mediated by processing speed (assessed via the SCIP). Models included intracranial volume, age, sex, and chlorpromazine equivalents as covariates. We observed significant mediation by processing speed, with a small positive effect of the cerebellum on processing speed (ß = 0.172, p = 0.029, d = 0.24) and a medium negative effect of processing speed on psychomotor disturbance (ß = -0.254, p < 0.001, d = 0.60), with acceptable specificity and sensitivity suggesting this model is robust against unmeasured confounding. The current findings suggest a critical role of cerebellar circuitry in a well-established sensorimotor aberration in psychosis (processing speed) and the presentation of related psychomotor phenotypes within psychosis. Establishing such relationships is critical for intervention research, such as TMS. Future work will employ more dimensional measures of psychomotor disturbance and cognitive processes to capture normative and aberrant brain-behavior-symptom relationships and may also determine the magnitude of these relationships within subtypes of psychosis (e.g., disorganized behavior, catatonia).

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.

Characterizing effects of age, sex and psychosis symptoms on thalamocortical functional connectivity in youth.

The thalamus is composed of multiple nuclei densely connected with the cortex in an organized manner, forming parallel thalamocortical networks critical to sensory, motor, and cognitive functioning. Thalamocortical circuit dysfunction has been implicated in multiple neurodevelopmental disorders, including schizophrenia, which also often exhibit sex differences in prevalence, clinical characteristics, and neuropathology. However, very little is known about developmental and sex effects on thalamocortical networks in youth. The present study characterized the effects of age, sex and psychosis symptomatology in anatomically constrained thalamocortical networks in a large community sample of youth (n = 1100, aged 8-21) from the Philadelphia Neurodevelopmental Cohort (PNC). Cortical functional connectivity of seven anatomically defined thalamic nuclear groups were examined: anterior, mediodorsal, ventral lateral, ventral posterolateral, pulvinar, medial and lateral geniculate nuclear groups. Age and sex effects were characterized using complementary thalamic region-of-interest (ROI) to cortical ROI and voxel-wise analyses. Effects of clinical symptomatology were analyzed by separating youth into three groups based on their clinical symptoms; typically developing youth (n = 298), psychosis spectrum youth (n = 320), and youth with other psychopathologies (n = 482). As an exploratory analysis, association with PRIME scores were used as a dimensional measure of psychopathology. Age effects were broadly characterized by decreasing connectivity with sensory/motor cortical areas, and increasing connectivity with heteromodal prefrontal and parietal cortical areas. This pattern was most pronounced for thalamic motor and sensory nuclei. Females showed greater connectivity between multiple thalamic nuclear groups and the visual cortex compared to males, while males showed greater connectivity with the inferior frontal and orbitofrontal cortices. Youth with psychosis spectrum symptoms showed a subtle decrease in thalamic connectivity with the premotor and prefrontal cortices. Across all youth, greater PRIME scores were associated with lower connectivity between the prefrontal cortex and mediodorsal thalamus. By characterizing typical development in anatomically constrained thalamocortical networks, this study provides an anchor for conceptualizing disruptions to the integrity of these networks observed in neurodevelopmental disorders.

Preliminary Evidence That Cortical Amyloid Burden Predicts Poor Response to Antidepressant Medication Treatment in Cognitively Intact Individuals With Late-Life Depression.

OBJECTIVE: Amyloid accumulation, the pathological hallmark of Alzheimer's disease, may predispose some older adults to depression and cognitive decline. Deposition of amyloid also occurs prior to the development of cognitive decline. It is unclear whether amyloid influences antidepressant outcomes in cognitively intact depressed elders. DESIGN: A pharmacoimaging trial utilizing florbetapir (18F) PET scanning followed by 2 sequential 8-week antidepressant medication trials. PARTICIPANTS: Twenty-seven depressed elders who were cognitively intact on screening. MEASUREMENTS AND INTERVENTIONS: After screening, diagnostic testing, assessment of depression severity and neuropsychological assessment, participants completed florbetapir (18F) PET scanning. They were then randomized to receive escitalopram or placebo for 8 weeks in a double-blinded two-to-one allocation rate. Individuals who did not respond to initial treatment transitioned to a second open-label trial of bupropion for another 8 weeks. RESULTS: Compared with 22 amyloid-negative participants, 5 amyloid-positive participants exhibited significantly less change in depression severity and a lower likelihood of remission. In the initial blinded trial, 4 of 5 amyloid-positive participants were nonremitters (80%), while only 18% (4 of 22) of amyloid-negative participants did not remit (p = 0.017; Fisher's Exact test). In separate models adjusting for key covariates, both positive amyloid status (t = 3.07, 21 df, p = 0.003) and higher cortical amyloid binding by standard uptake value ratio (t = 2.62, 21 df, p = 0.010) were associated with less improvement in depression severity. Similar findings were observed when examining change in depression status across both antidepressant trials. CONCLUSIONS: In this preliminary study, amyloid status predicted poor antidepressant response to sequential antidepressant treatment. Alternative treatment approaches may be needed for amyloid-positive depressed elders.

BNST-insula structural connectivity in humans.

The bed nucleus of the stria terminalis (BNST) is emerging as a critical region in multiple psychiatric disorders including anxiety, PTSD, and alcohol and substance use disorders. In conjunction with growing knowledge of the BNST, an increasing number of studies examine connections of the BNST and how those connections impact BNST function. The importance of this BNST network is highlighted by rodent studies demonstrating that projections from other brain regions regulate BNST activity and influence BNST-related behavior. While many animal and human studies replicate the components of the BNST network, to date, structural connections between the BNST and insula have only been described in rodents and have yet to be shown in humans. In this study, we used probabilistic tractography to examine BNST-insula structural connectivity in humans. We used two methods of dividing the insula: 1) anterior and posterior insula, to be consistent with much of the existing insula literature; and 2) eight subregions that represent informative cytoarchitectural divisions. We found evidence of a BNST-insula structural connection in humans, with the strongest BNST connectivity localized to the anteroventral insula, a region of agranular cortex. BNST-insula connectivity differed by hemisphere and was moderated by sex. These results translate rodent findings to humans and lay an important foundation for future studies examining the role of BNST-insula pathways in psychiatric disorders.

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.

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.

Dopaminergic mechanisms of individual differences in human effort-based decision-making.

Preferences for different combinations of costs and benefits are a key source of variability in economic decision-making. However, the neurochemical basis of individual differences in these preferences is poorly understood. Studies in both animals and humans have demonstrated that direct manipulation of the neurotransmitter dopamine (DA) significantly impacts cost/benefit decision-making, but less is known about how naturally occurring variation in DA systems may relate to individual differences in economic behavior. In the present study, 25 healthy volunteers completed a dual-scan PET imaging protocol with [(18)F]fallypride and d-amphetamine to measure DA responsivity and separately completed the effort expenditure for rewards task, a behavioral measure of cost/benefit decision-making in humans. We found that individual differences in DA function in the left striatum and ventromedial prefrontal cortex were correlated with a willingness to expend greater effort for larger rewards, particularly when probability of reward receipt was low. Additionally, variability in DA responses in the bilateral insula was negatively correlated with willingness to expend effort for rewards, consistent with evidence implicating this region in the processing of response costs. These findings highlight the role of DA signaling in striatal, prefrontal, and insular regions as key neurochemical mechanisms underlying individual differences in cost/benefit decision-making.

Prefrontal cortex activity during response selection predicts processing speed impairment in schizophrenia.

Processing speed is the most impaired neuropsychological domain in schizophrenia and a robust predictor of functional outcome. Determining the specific cognitive operations underlying processing speed dysfunction and identifying their neural correlates may assist in developing pro-cognitive interventions. Response selection, the process of mapping stimuli onto motor responses, correlates with neuropsychological tests of processing speed and may contribute to processing speed impairment in schizophrenia. This study investigated the relationship between behavioral and neural measures of response selection, and a neuropsychological index of processing speed in schizophrenia. Twenty-six patients with schizophrenia and 21 healthy subjects underwent functional magnetic resonance imaging scanning during performance of two- and four-choice reaction time (RT) tasks and completed the Wechsler Adult Intelligence Scale-III (WAIS) Processing Speed Index (PSI). Response selection, defined as RT slowing between two- and four-choice RT, was impaired in schizophrenia and correlated with psychometric processing speed. Greater activation of the dorsolateral prefrontal cortex (PFC) was observed in schizophrenia and correlated with poorer WAIS PSI scores. Deficient response selection and abnormal recruitment of the dorsolateral PFC during response selection contribute to processing speed impairment in schizophrenia. Interventions that improve response selection and normalize dorsolateral PFC function may improve processing speed in schizophrenia.

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.

Evaluation of resampling-based inference for topological features of neuroimages.

Many recent studies have demonstrated the inflated type 1 error rate of the original Gaussian random field (GRF) methods for inference of neuroimages and identified resampling (permutation and bootstrapping) methods that have better performance. There has been no evaluation of resampling procedures when using robust (sandwich) statistical images with different topological features (TF) used for neuroimaging inference. Here, we consider estimation of distributions TFs of a statistical image and evaluate resampling procedures that can be used when exchangeability is violated. We compare the methods using realistic simulations and study sex differences in life-span age-related changes in gray matter volume in the Nathan Kline Institute Rockland sample. We find that our proposed wild bootstrap and the commonly used permutation procedure perform well in sample sizes above 50 under realistic simulations with heteroskedasticity. The Rademacher wild bootstrap has fewer assumptions than the permutation and performs similarly in samples of 100 or more, so is valid in a broader range of conditions. We also evaluate the GRF-based pTFCE method and show that it has inflated error rates in samples less than 200. Our R package, pbj , is available on Github and allows the user to reproducibly implement various resampling-based group level neuroimage analyses.

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.

Cerebellar Structure and Cognitive Ability in Psychosis.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Development of Thalamocortical Structural Connectivity in Typically Developing and Psychosis Spectrum Youths.

BACKGROUND: Thalamocortical white matter connectivity is disrupted in psychosis and is hypothesized to play a role in its etiology and associated cognitive impairment. Attenuated cognitive symptoms often begin in adolescence, during a critical phase of white matter and cognitive development. However, little is known about the development of thalamocortical white matter connectivity and its association with cognition. METHODS: This study characterized effects of age, sex, psychosis symptomatology, and cognition in thalamocortical networks in a large sample of youths (N = 1144, ages 8-22 years, 46% male) from the Philadelphia Neurodevelopmental Cohort, which included 316 typically developing youths, 330 youths on the psychosis spectrum, and 498 youths with other psychopathology. Probabilistic tractography was used to quantify percent total connectivity between the thalamus and six cortical regions and assess microstructural properties (i.e., fractional anisotropy) of thalamocortical white matter tracts. RESULTS: Overall, percent total connectivity of the thalamus was weakly associated with age and was not associated with psychopathology or cognition. In contrast, fractional anisotropy of all thalamocortical tracts increased significantly with age, was generally higher in males than females, and was lowest in youths on the psychosis spectrum. Fractional anisotropy of tracts linking the thalamus to prefrontal and posterior parietal cortices was related to better cognitive function across subjects. CONCLUSIONS: By characterizing the pattern of typical development and alterations in those at risk for psychotic disorders, this study provides a foundation for further conceptualization of thalamocortical white matter microstructure as a marker of neurodevelopment supporting cognition and an important risk marker for psychosis.

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.

Attention-deficit/hyperactivity disorder in youth with psychosis spectrum symptoms.

BACKGROUND: Childhood attention deficit-hyperactivity disorder (ADHD) is common in psychotic disorders. However, prevalence estimates vary widely and the impact of ADHD on the severity of psychotic symptoms and associated features is unclear. We used the Philadelphia Neurodevelopmental Cohort (PNC; n = 9498 youth age 8-21), which includes a comprehensive structured interview of clinical symptoms and the Penn Computerized Neurocognitive Battery (CNB), to clarify the prevalence of ADHD in psychosis spectrum (PS) youth and determine if comorbid ADHD is associated with severity of psychotic symptoms and cognitive impairment. METHODS: Prevalence of ADHD among PS youth was established by comparing PS youth to all other youth in the PNC cohort. Cognition was compared between four groups: typically developing (TD), ADHD, PS without ADHD (PS-ADHD), and PS with ADHD (PS+ADHD). To evaluate the impact of ADHD on psychosis symptomatology, severity of positive and negative psychotic symptoms was compared between PS-ADHD and PS+ADHD groups. RESULTS: ADHD was more prevalent in PS youth compared to non-PS youth (45% vs. 20%). Cognition was significantly impaired in PS youth compared to TD youth, but the presence of ADHD in PS youth was not associated with greater cognitive impairment. Co-morbid ADHD was, however, associated with more severe psychosis symptoms in PS youth. CONCLUSION: ADHD is more common among PS youth compared to youth without PS symptoms and is associated with more severe psychotic symptoms, but not severity of cognitive impairment. The association between ADHD and psychotic disorders may be mediated by psychosis symptoms in youth and may manifest a more stable cognitive impairment.

Stable habituation deficits in the early stage of psychosis: a 2-year follow-up study.

Neural habituation, the decrease in brain response to repeated stimuli, is a fundamental, highly conserved mechanism that acts as an essential filter for our complex sensory environment. Convergent evidence indicates neural habituation is disrupted in both early and chronic stages of schizophrenia, with deficits co-occurring in brain regions that show inhibitory dysfunction. As inhibitory deficits have been proposed to contribute to the onset and progression of illness, habituation may be an important treatment target. However, a crucial first step is clarifying whether habituation deficits progress with illness. In the present study, we measured neural habituation in 138 participants (70 early psychosis patients (<2 years of illness), 68 healthy controls), with 108 participants assessed longitudinally at both baseline and 2-year follow-up. At follow-up, all early psychosis patients met criteria for a schizophrenia spectrum disorder (i.e., schizophreniform disorder, schizophrenia, schizoaffective disorder). Habituation slopes (i.e., rate of fMRI signal change) to repeated images were computed for the anterior hippocampus, occipital cortex, and the fusiform face area. Habituation slopes were entered into a linear mixed model to test for effects of group and time by region. We found that early psychosis patients showed habituation deficits relative to healthy control participants across brain regions, and that these deficits were maintained, but did not worsen, over two years. These results suggest a stable period of habituation deficits in the early stage of schizophrenia.