Showing papers by "Barbara A. Cornblatt published in 2018"

Cerebello-thalamo-cortical hyperconnectivity as a state-independent functional neural signature for psychosis prediction and characterization.

Abstract: Understanding the fundamental alterations in brain functioning that lead to psychotic disorders remains a major challenge in clinical neuroscience. In particular, it is unknown whether any state-independent biomarkers can potentially predict the onset of psychosis and distinguish patients from healthy controls, regardless of paradigm. Here, using multi-paradigm fMRI data from the North American Prodrome Longitudinal Study consortium, we show that individuals at clinical high risk for psychosis display an intrinsic "trait-like" abnormality in brain architecture characterized as increased connectivity in the cerebello-thalamo-cortical circuitry, a pattern that is significantly more pronounced among converters compared with non-converters. This alteration is significantly correlated with disorganization symptoms and predictive of time to conversion to psychosis. Moreover, using an independent clinical sample, we demonstrate that this hyperconnectivity pattern is reliably detected and specifically present in patients with schizophrenia. These findings implicate cerebello-thalamo-cortical hyperconnectivity as a robust state-independent neural signature for psychosis prediction and characterization.

Use of Machine Learning to Determine Deviance in Neuroanatomical Maturity Associated With Future Psychosis in Youths at Clinically High Risk.

Abstract: Importance Altered neurodevelopmental trajectories are thought to reflect heterogeneity in the pathophysiologic characteristics of schizophrenia, but whether neural indicators of these trajectories are associated with future psychosis is unclear. Objective To investigate distinct neuroanatomical markers that can differentiate aberrant neurodevelopmental trajectories among clinically high-risk (CHR) individuals. Design, Setting, and Participants In this prospective longitudinal multicenter study, a neuroanatomical-based age prediction model was developed using a supervised machine learning technique with T1-weighted magnetic resonance imaging scans of 953 healthy controls 3 to 21 years of age from the Pediatric Imaging, Neurocognition, and Genetics (PING) study and then applied to scans of 275 CHR individuals (including 39 who developed psychosis) and 109 healthy controls 12 to 21 years of age from the North American Prodrome Longitudinal Study 2 (NAPLS 2) for external validation and clinical application. Scans from NAPLS 2 were collected from January 15, 2010, to April 30, 2012. Main Outcomes and Measures Discrepancy between neuroanatomical-based predicted age (hereafter referred to as brain age) and chronological age. Results The PING-derived model (460 females and 493 males; age range, 3-21 years) accurately estimated the chronological ages of the 109 healthy controls in the NAPLS 2 (43 females and 66 males; age range, 12-21 years), providing evidence of independent external validation. The 275 CHR individuals in the NAPLS 2 (111 females and 164 males; age range, 12-21 years) showed a significantly greater mean (SD) gap between model-predicted age and chronological age (0.64 [2.16] years) compared with healthy controls (P = .008). This outcome was significantly moderated by chronological age, with brain age systematically overestimating the ages of CHR individuals who developed psychosis at ages 12 to 17 years but not the brain ages of those aged 18 to 21 years. Greater brain age deviation was associated with a higher risk for developing psychosis (F = 3.70;P = .01) and a pattern of stably poor functioning over time, but only among younger CHR adolescents. Previously reported evidence of accelerated reduction in cortical thickness among CHR individuals who developed psychosis was found to apply only to those who were 18 years of age or older. Conclusions and Relevance These results are consistent with the view that neuroanatomical markers of schizophrenia may help to explain some of the heterogeneity of this disorder, particularly with respect to early vs later age of onset of psychosis, with younger and older individuals having differing intercepts and trajectories in structural brain parameters as a function of age. The results also suggest that baseline neuroanatomical measures are likely to be useful in estimating onset of psychosis, especially (or only) among CHR individuals with an earlier age of onset of prodromal symptoms.

Lack of Diagnostic Pluripotentiality in Patients at Clinical High Risk for Psychosis: Specificity of Comorbidity Persistence and Search for Pluripotential Subgroups

Abstract: More than 20 years after the clinical high risk syndrome for psychosis (CHR) was first articulated, it remains controversial whether the CHR syndrome predicts onset of psychosis with diagnostic specificity or predicts pluripotential diagnostic outcomes. Recently, analyses of observational studies, however, have suggested that the CHR syndrome is not pluripotential for emergent diagnostic outcomes. The present report conducted additional analyses in previously reported samples to determine (1) whether comorbid disorders were more likely to persist in CHR patients compared to a comparison group of patients who responded to CHR recruitment efforts but did not meet criteria, termed help-seeking comparison subjects (HSC); and (2) whether clinically defined pluripotential CHR subgroups could be identified. All data were derived from 2 multisite studies in which DSM-IV structured diagnostic interviews were conducted at baseline and at 6-month intervals. Across samples we observed persistence of any nonpsychotic disorder in 80/147 CHR cases (54.4%) and in 48/84 HSC cases (57.1%, n.s.). Findings with persistence of anxiety, depressive, and bipolar disorders considered separately were similar. Efforts to discover pluripotential CHR subgroups were unsuccessful. These findings add additional support to the view that the CHR syndrome is not pluripotential for predicting various diagnostic outcomes but rather is specific for predicting emergent psychosis.

Potentially important periods of change in the development of social and role functioning in youth at clinical high risk for psychosis

Abstract: The developmental course of daily functioning prior to first psychosis-onset remains poorly understood. This study explored age-related periods of change in social and role functioning. The longitudinal study included youth (aged 12-23, mean follow-up years = 1.19) at clinical high risk (CHR) for psychosis (converters [CHR-C], n = 83; nonconverters [CHR-NC], n = 275) and a healthy control group (n = 164). Mixed-model analyses were performed to determine age-related differences in social and role functioning. We limited our analyses to functioning before psychosis conversion; thus, data of CHR-C participants gathered after psychosis onset were excluded. In controls, social and role functioning improved over time. From at least age 12, functioning in CHR was poorer than in controls, and this lag persisted over time. Between ages 15 and 18, social functioning in CHR-C stagnated and diverged from that of CHR-NC, who continued to improve (p = .001). Subsequently, CHR-C lagged behind in improvement between ages 21 and 23, further distinguishing them from CHR-NC (p < .001). A similar period of stagnation was apparent for role functioning, but to a lesser extent (p = .007). The results remained consistent when we accounted for the time to conversion. Our findings suggest that CHR-C start lagging behind CHR-NC in social and role functioning in adolescence, followed by a period of further stagnation in adulthood.

Treatment Precedes Positive Symptoms in North American Adolescent and Young Adult Clinical High Risk Cohort.

Abstract: Early intervention for psychotic disorders, a growing international priority, typically targets help-seeking populations with emerging psychotic (“positive”) symptoms. We assessed the nature of and degree to which treatment of individuals at high risk for psychosis preceded or followed the onset of positive symptoms. The North American Prodrome Longitudinal Study–2 collected psychosocial treatment histories for 745 (98%) of 764 high-risk participants (M age = 18.9, 57% male, 57.5% Caucasian, 19.1% Hispanic) recruited from 8 North American communities. Similar to prior findings, 82% of participants reported psychosocial treatment prior to baseline assessment, albeit with significant variability across sites (71%–96%). Participants first received treatment a median of 1.7 years prior to the onset of a recognizable psychosis-risk syndrome. Only one fourth sought initial treatment in the year following syndrome onset. Although mean sample age differed significantly by site, age at initial treatment (M = 14.1,...

Networks of blood proteins in the neuroimmunology of schizophrenia.

Abstract: Levels of certain circulating cytokines and related immune system molecules are consistently altered in schizophrenia and related disorders. In addition to absolute analyte levels, we sought analytes in correlation networks that could be prognostic. We analyzed baseline blood plasma samples with a Luminex platform from 72 subjects meeting criteria for a psychosis clinical high-risk syndrome; 32 subjects converted to a diagnosis of psychotic disorder within two years while 40 other subjects did not. Another comparison group included 35 unaffected subjects. Assays of 141 analytes passed early quality control. We then used an unweighted co-expression network analysis to identify highly correlated modules in each group. Overall, there was a striking loss of network complexity going from unaffected subjects to nonconverters and thence to converters (applying standard, graph-theoretic metrics). Graph differences were largely driven by proteins regulating tissue remodeling (e.g. blood-brain barrier). In more detail, certain sets of antithetical proteins were highly correlated in unaffected subjects (e.g. SERPINE1 vs MMP9), as expected in homeostasis. However, for particular protein pairs this trend was reversed in converters (e.g. SERPINE1 vs TIMP1, being synthetical inhibitors of remodeling of extracellular matrix and vasculature). Thus, some correlation signals strongly predict impending conversion to a psychotic disorder and directly suggest pharmaceutical targets.

O3.2. brain hyperactivation during memory retrieval precedes and predicts conversion to psychosis in individuals at clinical high risk

Abstract: Memory deficits are a hallmark of psychotic disorders such as schizophrenia. However, whether the neural dysfunction underlying these deficits is present before the onset of illness and potentially predicts conversion to psychosis is unclear. In this study, we investigated brain functional alterations during memory processing in a sample of 155 individuals at clinical high risk (including 18 subjects who later converted to full psychosis) and 108 healthy controls drawn from the second phase of the North American Prodrome Longitudinal Study (NAPLS-2). All participants underwent functional magnetic resonance imaging with a paired-associate memory paradigm at the point of recruitment and were clinically followed up for approximately 2 years. We found that at baseline, subjects at high risk showed significantly higher activation during memory retrieval in the prefrontal, parietal, and bilateral temporal cortices (PFWE < .035). This effect was more pronounced in converters than nonconverters and was particularly manifested in unmedicated subjects (P < .001). The hyperactivation was significantly correlated with retrieval reaction time during scan in converters (P = .009) but not in nonconverters and controls, suggesting an exaggerated retrieval effort. These findings suggest that hyperactivation during memory retrieval may mark processes associated with conversion to psychosis, and such measures have potential as biomarkers for psychosis prediction.

24.2 neurocognitive profiles in the prodrome to psychosis in napls-1.

Abstract: Abstract Background The vast majority of studies of neuropsychological (NP) functioning in Clinical High Risk (CHR) cohorts have examined group averages, possibly concealing a range of subgroups ranging from very impaired to high functioning. Our objective was to assess NP profiles and to explore associations with conversion to psychosis, functional and diagnostic outcome. Methods Data were acquired from 324 participants (mean age 18.4) in the first phase of the North American Prodrome Longitudinal Study (NAPLS-1), a multi-site consortium following individuals for up to 2½ years. We applied Ward’s method for hierarchical clustering data to 8 baseline neurocognitive measures, in 166 CHR individuals, 49 non-CHR youth with a family history of psychosis, and 109 healthy controls. We tested whether cluster membership was associated with conversion to psychosis, social and role functioning, and follow-up diagnosis. Analyses were repeated after data were clustered based on independently developed clinical decision rules. Results Four neurocognitive clusters were identified: Significantly Impaired (n=33); Mildly Impaired (n=82); Normal (n=145) and High (n=64). The Significantly Impaired subgroup demonstrated the largest deviations on processing speed and memory tasks and had a conversion rate of 58%, a 40% chance of developing a schizophrenia spectrum diagnosis (compared to 24.4% in the Mildly Impaired, and 10.3% in the other two groups combined), and significantly worse functioning at baseline and 12-months. Data clustered using clinical decision rules yielded similar results, pointing to high convergent validity. Discussion Despite extensive neuropsychological investigations within CHR cohorts, this is one of the first studies to investigate NP clustering profiles as a contributor to heterogeneity in outcome. Our results indicate that the four NP profiles vary substantially in their outcome, underscoring the relevance of cognitive functioning in the prediction of illness progression. Our findings tentatively suggest that individualized cognitive profiling should be explored in clinical settings.

The relation of atypical antipsychotic use and stress with weight in individuals at clinical high risk for psychosis

Abstract: Atypical antipsychotics (AT) and stress are related to weight gain in individuals with severe mental illness. This cross-sectional study examines AT use, stressful life events, and baseline weight in a sample of youth at clinical high risk for psychosis. Results showed that dependent and desirable life events moderated the relationship between AT use and weight after controlling for demographic factors and selective serotonin reuptake inhibitor antidepressant (AD) use. The relation of AD and weight was explored as a secondary analysis and showed no relation between AD use and weight. Further, stress did not moderate the relationship between AD medication and weight after controlling for antipsychotic use. Results suggest that stress exposure may exacerbate the relationship between ATs and increased weight in clinical high-risk populations. Findings have implications for the development of interventions to address psychosocial factors that worsen or buffer the adverse effects of antipsychotic medication on weight.

F32. differences between youth at clinical high-risk for psychosis who do not transition to psychosis: the north american prodrome longitudinal study (napls-2).

Abstract: BackgroundIn the clinical high risk (CHR) for psychosis literature, typically, the focus is on determining the risk of conversion to psychosis. However, between 70% and 85% of youth who meet CHR criteria do not develop psychosis during the follow-up period of the study in which they participate. The aim of this study is to focus on CHR youth who did not transition to psychosis and to determine whether there are differences amongst them.MethodsThe North American Prodrome Longitudinal Study (NAPLS-2) is an 8-site prospective, longitudinal study including 764 help-seeking youth, age 12–35, meeting criteria for a psychosis risk syndrome based on the Structured Interview for Psychosis-risk Syndromes (SIPS), and 279 healthy controls (HC). For this analysis, only youth who did not make a transition to psychosis and completed 2 years of follow-up (n=278, 154 males, 124 females; mean age 18.8) were included. At the 24-month final assessment, the sample was divided into 3 groups: 1) those in remission, determined by scores ≤2 on all 5 attenuated psychotic symptoms on The Scale of Psychosis-risk Symptoms (SOPS); 2) symptomatic, determined by still having a rating of 3–5 on any one of the 5 attenuated psychotic symptoms on the SOPS; 3) prodromal progression, determined by continuing to meet the Criteria of Psychosis-risk Syndromes (COPS). The groups were compared at baseline and at 24-month follow-up on: age, gender, the presence of a current and lifetime psychiatric diagnosis, and social and role functioning. The use of antipsychotic medication was examined across all assessments (baseline, 6-, 12-, 18- & 24 months) using Generalized Linear Models to examine differences among the 3 groups.ResultsAmong the participants, 110 (39.57%) were in-remission, 93 (33.45%) symptomatic, and 75 (26.98%) prodromal progression. At baseline there were no significant differences in age, gender, social and role functioning, or SCID diagnoses except on current PTSD (p=.001) with most cases in the prodromal progression group, and on current anxiety disorder (p=≤.0001) with most cases in the symptomatic group. The prodromal progression had significantly higher ratings on unusual thought content compared to the in-remission group and significantly higher ratings on suspiciousness than the symptomatic group. At 24-month follow-up there were significant differences in negative symptoms (p=≤.0001) between prodromal progression (M=9.19), symptomatic (M=8.84), and in remission (M=5.99) groups; and social functioning (p=≤.005; M=6.56, M=6.68, M=7.20 respectively). Although the in-remission group had the highest ratings on social functioning these were significantly lower in social (M=7.20) and role (M=6.68) functioning than HC (M=8.73, M=8.62 respectively). The groups did not differ on their use of antipsychotics over the course of their 2 years in the study.DiscussionThere were very few differences on baseline measures amongst the different two-year outcome groups. At 2 years, even though those in remission had improved social and role functioning relative to the other 2 groups, they still had lower social and role functioning than HC.

F118. architecture of psychosis symptoms and neural predictors of conversion among clinical high risk individuals with autism spectrum disorder.

Abstract: BackgroundIndividuals with autism spectrum disorders (ASD) have symptoms, including social and sensory deficits, and neurobiological alterations that overlap with schizophrenia. Though there is evidence of high rates of psychosis symptoms in ASD, little is known about psychosis prodrome in ASD, or about predictors of psychosis conversion in this population. In this study, we leverage data from clinical high risk (CHR) patients from the NAPLS2 consortium to examine: a) baseline differences in psychosis symptoms and social functioning, b) relative risk of conversion, and c) whether neural response to sensory stimuli yields differential predictors of conversion in CHR individuals with and without ASD (CHR/ASD+; CHR/ASD-).MethodsClinical, electrophysiological, and 24-month follow-up data were available for 305 individuals (14 CHR/ASD+; 291 CHR/ASD-). We examined baseline differences on the SOPS, GFS, and TASIT. Conversion risk was computed with the Cannon conversion calculator, and conversion was defined as SOPS>6 at 2-year outcome. P300 event-related potentials (ERP) were extracted from ongoing EEG collected at baseline in response to Target and Novel auditory and visual stimuli, each presented on 10% of trials within streams of 80% standard stimuli in the same modality.ResultsIn line with our expectations, CHR/ASD+ had worse functioning than CHR/ASD- on the GF-Social scale (t=-4.2, p<.01) and TASIT total score (t=-2.9, p=<.01), but groups did not differ in their psychotic symptoms on the SOPS (Positive: p=.72; Negative: p=.13; Disorganization: p=.13; General: p=.86). Groups did not differ in the rate at which they converted to psychosis (CHR/ASD+: 15.4%; CHR/ASD-: 11.1%; p=.50), and the Cannon risk score was equally predictive of 2-year conversion across groups (p=.39). EEG data revealed dissociable profiles regarding neural response to sensory stimuli in those who did versus did not convert to psychosis, depending on ASD status. P300 response over central electrodes to Novel visual stimuli was weaker in CHR- converters (n=71) than CHR- non-converters (n=220), but stronger in CHR/ASD+ converters (n=4) than CHR/ASD+ non-converters (n=10) (Novel Stimuli: Modality by ASD interaction, F=5.66, p=.02; Modality by ASD by Converter Interaction, F=3.57, p=.06). For both auditory and visual Target stimuli, P300 response over parietal electrodes did not differ between CHR/ASD- converters and non-converters; however, whereas CHR/ASD+ individuals who did not convert had amplitudes similar to all CHR/ASD- individuals, CHR/ASD+ converters had substantially greater auditory and visual P300 amplitudes (Target Stimuli: ASD by Converter interaction, F=12.12, p=.001).DiscussionIndividuals with ASD and CHR have greater social deficits than the general CHR population, but show similar psychotic symptoms and have similar risk for conversion to psychosis. Neural response to sensory stimuli is important for understanding risk for conversion, and differs among CHR individuals dependent on whether they have ASD. In particular, whereas all CHR individuals who do not convert share a common pattern of attenuated ERP amplitudes reflecting attention allocation to target and novel auditory and visual stimuli, CHR/ASD+ who convert have a unique pattern of globally heightened P300 responses to infrequent novel and target stimuli. These findings have two important implications: 1) individuals with ASD do convert to psychosis and have similar CHR symptom and risk profiles to non-ASD CHR patients clinically; 2) in CHR individuals with ASD in particular, examining neural markers of attention allocation to sensory stimuli may reveal important predictive clues about risk for conversion.

S184. machine learning reveals deviance in neuroanatomical maturity predictive of future psychosis in youth at clinical high risk

Abstract: BackgroundBoth early (pre- and perinatal) and late (adolescent) neurodevelopmental disturbances are hypothesized to contribute to the pathophysiology of schizophrenia. Disturbances originating earlier in life (e.g., resulting from the interplay of genetic factors and obstetric complications) would be expected to affect brain integrity from birth onwards and could therefore help to explain cases with subtle deficits in premorbid functioning during childhood and earlier ages at onset of full psychosis (i.e., early to mid-teens). In contrast, disturbances that emerge during late adolescence and early adulthood (e.g., via abnormal neuromaturational events and/or environmental factors) could help to explain cases with normal premorbid psychological health and a more acute onset of psychotic symptoms and functional impairment in the late teens and early twenties. However, it is yet unclear whether neuroanatomical data among individuals at clinical high risk (CHR) for psychosis can be modeled to detect early versus late neurodevelopmental influences that is predictive of future psychosis onset. Therefore, in this study, we investigated whether the timing of the appearance or course of the deviation from normal brain maturation, as determined using a machine learning algorithm trained on structural MRI data to estimate age, is potentially relevant to the early versus late neurodevelopmental framework among CHR individuals.MethodsA neuroanatomical-based age prediction model was trained using a supervised machine learning technique with T1 MRI scans from 953 typically developing healthy controls (HC) from the Pediatric Imaging, Neurocognition, and Genetics study (PING) study. The trained model was then applied to 109 HCs and 275 CHR, including 39 converters (CHR-C), from the North American Prodrome Longitudinal Study (NAPLS2) and 14 cases of first episode psychosis patients (FE) for external validation and clinical application. Discrepancy between neuroanatomical-based estimated age and chronological age was computed for each individual (i.e., brain age gap) and compared across clinical groups.ResultsThe PING-derived model for estimating age accurately predicted NAPLS HC subjects’ chronological ages, explaining 51% of the variance (P < 0.001) in chronological age, with a mean absolute error of 1.41 years, providing evidence of independent external validation. CHR subjects and FE adolescents showed a significantly greater overestimated gap between model-predicted age and chronological age compared with HC (Ps < 0.01). This effect was significantly moderated by chronological age, with neuroanatomical-based estimated age systematically overestimating CHR cases aged 12–17 years, but not among those aged 18–21 years. In the ROC analysis, brain age gap was a significant predictor of conversion to psychosis with an area under the curve of 0.63 (P < 0.05) among younger adolescents. In addition, increased deviation of brain age gap predicted pattern of stably low functioning over time (P < 0.05) among CHR individuals. In contrast, previously reported evidence of an accelerated reduction in cortical thickness among CHR-C was found to apply only to those cases who were 18 years or older.DiscussionThese results are consistent with the view that both early and later neurodevelopmental disturbances contribute to the onset and course of schizophrenia, with the two sets of influences having differing implications for the intercepts and trajectories in structural brain parameters as a function of age. The results also suggest that baseline neuroanatomical measures are likely to be useful in prediction of psychosis especially (or only) among CHR cases who are below 18 years of age at the time of ascertainment.