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Background: Neurocognitive functioning is an integral phenotype of 22q11.2 deletion syndrome relating to severity of psychopathology and outcomes. A neurocognitive battery that could be administered remotely to assess multiple cognitive domains would be especially beneficial to research on rare genetic variants, where in‐person assessment can be unavailable or burdensome. The current study compares in‐person and remote assessments of the Penn computerised neurocognitive battery (CNB). Methods: Participants (mean age = 17.82, SD = 6.94 years; 48% female) completed the CNB either in‐person at a laboratory (n = 222) or remotely (n = 162). Results: Results show that accuracy of CNB performance was equivalent across the two testing locations, while slight differences in speed were detected in 3 of the 11 tasks. Conclusions: These findings suggest that the CNB can be used in remote settings to assess multiple neurocognitive domains. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is an immune-mediated neurological disorder that affects one million people in the United States. Up to 50% of people with MS experience depression, yet the mechanisms of depression in MS remain under-investigated. Studies of medically healthy participants with depression have described associations between white matter variability and depressive symptoms, but frequently exclude participants with medical comorbidities and thus cannot be extrapolated to people with intracranial diseases. White matter lesions are a key pathologic feature of MS and could disrupt pathways involved in depression symptoms. The purpose of this study is to investigate the impact of brain network disruption on depression using MS as a model. We will obtain structured clinical and cognitive assessments from two hundred fifty participants with MS and prospectively evaluate white matter lesion burden as a predictor of depressive symptoms. Ethics approval was obtained from The University of Pennsylvania Institutional Review Board (Protocol #853883). The results of this study will be presented at scientific meetings and conferences and published in peer-reviewed journals., Competing Interests: COMPETING INTEREST STATEMENTS The authors declare no competing interests.

Rare recurrent copy number variants (CNVs) at chromosomal loci 22q11.2 and 16p11.2 are genetic disorders with lifespan risk for neuropsychiatric disorders. Microdeletions and duplications are associated with neurocognitive deficits, yet few studies compared these groups using the same measures to address confounding measurement differences. We report a prospective international collaboration applying the same computerized neurocognitive assessment, the Penn Computerized Neurocognitive Battery (CNB), administered in a multi-site study on rare genomic disorders: 22q11.2 deletions (n = 492); 22q11.2 duplications (n = 106); 16p11.2 deletion (n = 117); and 16p11.2 duplications (n = 46). Domains examined include executive functions, episodic memory, complex cognition, social cognition, and psychomotor speed. Accuracy and speed for each domain were included as dependent measures in a mixed-model repeated measures analysis. Locus (22q11.2, 16p11.2) and Copy number (deletion/duplication) were grouping factors and Measure (accuracy, speed) and neurocognitive domain were repeated measures factors, with Sex and Site as covariates. We also examined correlation with IQ. We found a significant Locus × Copy number × Domain × Measure interaction (p = 0.0004). 22q11.2 deletions were associated with greater performance accuracy deficits than 22q11.2 duplications, while 16p11.2 duplications were associated with greater specific deficits than 16p11.2 deletions. Duplications at both loci were associated with reduced speed compared to deletions. Performance profiles differed among the groups with particularly poor memory performance of the 22q11.2 deletion group while the 16p11.2 duplication group had greatest deficits in complex cognition. Average accuracy on the CNB was moderately correlated with Full Scale IQ. Deletions and duplications of 22q11.2 and 16p11.2 have differential effects on accuracy and speed of neurocognition indicating locus specificity of performance profiles. These profile differences can help inform mechanistic substrates to heterogeneity in presentation and outcome, and can only be established in large-scale international consortia using the same neurocognitive assessment. Future studies could aim to link performance profiles to clinical features and brain function., (© 2024. The Author(s).)

Background: Minor physical anomalies (MPAs) are congenital morphological abnormalities linked to disruptions of fetal development. MPAs are common in 22q11.2 deletion syndrome (22q11DS) and psychosis spectrum disorders (PS) and likely represent a disruption of early embryologic development that may help identify overlapping mechanisms linked to psychosis in these disorders., Methods: Here, 2D digital photographs were collected from 22q11DS (n = 150), PS (n = 55), and typically developing (TD; n = 93) individuals. Photographs were analyzed using two computer-vision techniques: (1) DeepGestalt algorithm (Face2Gene (F2G)) technology to identify the presence of genetically mediated facial disorders, and (2) Emotrics-a semi-automated machine learning technique that localizes and measures facial features., Results: F2G reliably identified patients with 22q11DS; faces of PS patients were matched to several genetic conditions including FragileX and 22q11DS. PCA-derived factor loadings of all F2G scores indicated unique and overlapping facial patterns that were related to both 22q11DS and PS. Regional facial measurements of the eyes and nose were smaller in 22q11DS as compared to TD, while PS showed intermediate measurements., Conclusions: The extent to which craniofacial dysmorphology 22q11DS and PS overlapping and evident before the impairment or distress of sub-psychotic symptoms may allow us to identify at-risk youths more reliably and at an earlier stage of development., (© 2024. The Author(s).)

Large-scale studies and burdened clinical settings require precise, efficient measures that assess multiple domains of psychopathology. Computerized adaptive tests (CATs) can reduce administration time without compromising data quality. We examined feasibility and validity of an adaptive psychopathology measure, GOASSESS, in a clinical community-based sample (N = 315; ages 18-35) comprising three groups: healthy controls, psychosis, mood/anxiety disorders. Assessment duration was compared between the Full and CAT GOASSESS. External validity was tested by comparing how the CAT and Full versions related to demographic variables, study group, and socioeconomic status. The relationships between scale scores and criteria were statistically compared within a mixed-model framework to account for dependency between relationships. Convergent validity was assessed by comparing scores of the CAT and the Full GOASSESS using Pearson correlations. The CAT GOASSESS reduced interview duration by more than 90 % across study groups and preserved relationships to external criteria and demographic variables as the Full GOASSESS. All CAT GOASSESS scales could replace those of the Full instrument. Overall, the CAT GOASSESS showed acceptable psychometric properties and demonstrated feasibility by markedly reducing assessment time compared to the Full GOASSESS. The adaptive version could be used in large-scale studies or clinical settings for intake screening., Competing Interests: Declaration of competing interest The authors report no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

This article describes the rationale, aims, and methodology of the Accelerating Medicines Partnership® Schizophrenia (AMP® SCZ). This is the largest international collaboration to date that will develop algorithms to predict trajectories and outcomes of individuals at clinical high risk (CHR) for psychosis and to advance the development and use of novel pharmacological interventions for CHR individuals. We present a description of the participating research networks and the data processing analysis and coordination center, their processes for data harmonization across 43 sites from 13 participating countries (recruitment across North America, Australia, Europe, Asia, and South America), data flow and quality assessment processes, data analyses, and the transfer of data to the National Institute of Mental Health (NIMH) Data Archive (NDA) for use by the research community. In an expected sample of approximately 2000 CHR individuals and 640 matched healthy controls, AMP SCZ will collect clinical, environmental, and cognitive data along with multimodal biomarkers, including neuroimaging, electrophysiology, fluid biospecimens, speech and facial expression samples, novel measures derived from digital health technologies including smartphone-based daily surveys, and passive sensing as well as actigraphy. The study will investigate a range of clinical outcomes over a 2-year period, including transition to psychosis, remission or persistence of CHR status, attenuated positive symptoms, persistent negative symptoms, mood and anxiety symptoms, and psychosocial functioning. The global reach of AMP SCZ and its harmonized innovative methods promise to catalyze the development of new treatments to address critical unmet clinical and public health needs in CHR individuals., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Background: The Penn Computerized Neurocognitive Battery is an efficient tool for assessing brain-behavior domains, and its efficiency was augmented via computerized adaptive testing (CAT). This battery requires validation in a separate sample to establish psychometric properties., Methods: In a mixed community/clinical sample of N = 307 18-to-35-year-olds, we tested the relationships of the CAT tests with the full-form tests. We compared discriminability among recruitment groups (psychosis, mood, control) and examined how their scores relate to demographics. CAT-Full relationships were evaluated based on a minimum inter-test correlation of 0.70 or an inter-test correlation within at least 0.10 of the full-form correlation with a previous administration of the full battery. Differences in criterion relationships were tested via mixed models., Results: Most tests (15/17) met the minimum criteria for replacing the full-form with the updated CAT version (mean r = 0.67; range = 0.53-0.80) when compared to relationships of the full-forms with previous administrations of the full-forms (mean r = 0.68; range = 0.50-0.85). Most (16/17) CAT-based relationships with diagnostics and other validity criteria were indistinguishable (interaction p > 0.05) from their full-form counterparts., Conclusions: The updated CNB shows psychometric properties acceptable for research. The full-forms of some tests should be retained due to insufficient time savings to justify the loss in precision., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. This work was supported by NIMH grants MH089983, MH117014, and MH096891., (Copyright © 2023 Elsevier Inc. All rights reserved.)

22q11.2 deletion syndrome (22q11DS) is the most frequently occurring microdeletion in humans. It is associated with a significant impact on brain structure, including prominent reductions in gray matter volume (GMV), and neuropsychiatric manifestations, including cognitive impairment and psychosis. It is unclear whether GMV alterations in 22q11DS occur according to distinct structural patterns. Then, 783 participants (470 with 22q11DS: 51% females, mean age [SD] 18.2 [9.2]; and 313 typically developing [TD] controls: 46% females, mean age 18.0 [8.6]) from 13 datasets were included in the present study. We segmented structural T1-weighted brain MRI scans and extracted GMV images, which were then utilized in a novel source-based morphometry (SBM) pipeline (SS-Detect) to generate structural brain patterns (SBPs) that capture co-varying GMV. We investigated the impact of the 22q11.2 deletion, deletion size, intelligence quotient, and psychosis on the SBPs. Seventeen GMV-SBPs were derived, which provided spatial patterns of GMV covariance associated with a quantitative metric (i.e., loading score) for analysis. Patterns of topographically widespread differences in GMV covariance, including the cerebellum, discriminated individuals with 22q11DS from healthy controls. The spatial extents of the SBPs that revealed disparities between individuals with 22q11DS and controls were consistent with the findings of the univariate voxel-based morphometry analysis. Larger deletion size was associated with significantly lower GMV in frontal and occipital SBPs; however, history of psychosis did not show a strong relationship with these covariance patterns. 22q11DS is associated with distinct structural abnormalities captured by topographical GMV covariance patterns that include the cerebellum. Findings indicate that structural anomalies in 22q11DS manifest in a nonrandom manner and in distinct covarying anatomical patterns, rather than a diffuse global process. These SBP abnormalities converge with previously reported cortical surface area abnormalities, suggesting disturbances of early neurodevelopment as the most likely underlying mechanism., (© 2024 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Objectives: Data from neurocognitive assessments may not be accurate in the context of factors impacting validity, such as disengagement, unmotivated responding, or intentional underperformance. Performance validity tests (PVTs) were developed to address these phenomena and assess underperformance on neurocognitive tests. However, PVTs can be burdensome, rely on cutoff scores that reduce information, do not examine potential variations in task engagement across a battery, and are typically not well-suited to acquisition of large cognitive datasets. Here we describe the development of novel performance validity measures that could address some of these limitations by leveraging psychometric concepts using data embedded within the Penn Computerized Neurocognitive Battery (PennCNB)., Methods: We first developed these validity measures using simulations of invalid response patterns with parameters drawn from real data. Next, we examined their application in two large, independent samples: 1) children and adolescents from the Philadelphia Neurodevelopmental Cohort ( n = 9498); and 2) adult servicemembers from the Marine Resiliency Study-II ( n = 1444)., Results: Our performance validity metrics detected patterns of invalid responding in simulated data, even at subtle levels. Furthermore, a combination of these metrics significantly predicted previously established validity rules for these tests in both developmental and adult datasets. Moreover, most clinical diagnostic groups did not show reduced validity estimates., Conclusions: These results provide proof-of-concept evidence for multivariate, data-driven performance validity metrics. These metrics offer a novel method for determining the performance validity for individual neurocognitive tests that is scalable, applicable across different tests, less burdensome, and dimensional. However, more research is needed into their application.

Background: Iron is essential to brain function, and iron deficiency during youth may adversely impact neurodevelopment. Understanding the developmental time course of iron status and its association with neurocognitive functioning is important for identifying windows for intervention., Objectives: This study aimed to characterize developmental change in iron status and understand its association with cognitive performance and brain structure during adolescence using data from a large pediatric health network., Methods: This study included a cross-sectional sample of 4899 participants (2178 males; aged 8-22 y at the time of participation, M [SD] = 14.24 [3.7]) who were recruited from the Children's Hospital of Philadelphia network. Prospectively collected research data were enriched with electronic medical record data that included hematological measures related to iron status, including serum hemoglobin, ferritin, and transferrin (33,015 total samples). At the time of participation, cognitive performance was assessed using the Penn Computerized Neurocognitive Battery, and brain white matter integrity was assessed using diffusion-weighted MRI in a subset of individuals., Results: Developmental trajectories were characterized for all metrics and revealed that sex differences emerged after menarche such that females had reduced iron status relative to males [all R 2 partial > 0.008; all false discovery rates (FDRs) < 0.05]. Higher socioeconomic status was associated with higher hemoglobin concentrations throughout development (R 2 partial = 0.005; FDR < 0.001), and the association was greatest during adolescence. Higher hemoglobin concentrations were associated with better cognitive performance during adolescence (R 2 partial = 0.02; FDR < 0.001) and mediated the association between sex and cognition (mediation effect = -0.107; 95% CI: -0.191, -0.02). Higher hemoglobin concentration was also associated with greater brain white matter integrity in the neuroimaging subsample (R 2 partial = 0.06, FDR = 0.028)., Conclusions: Iron status evolves during youth and is lowest in females and individuals of low socioeconomic status during adolescence. Diminished iron status during adolescence has consequences for neurocognition, suggesting that this critical period of neurodevelopment may be an important window for intervention that has the potential to reduce health disparities in at-risk populations., (Copyright © 2023 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Background: Self-directed performance monitoring is a critical contributor to cognitive performance and general functioning and is impacted by psychiatric symptoms and personality traits, but has been understudied in psychosis-risk states. We have shown that ventral striatum (VS) responds to correctness during cognitive tasks where no explicit feedback is required, and this intrinsic reinforcement response is reduced in schizophrenia., Methods: Here, we examined this phenomenon in youths (n = 796, age range 11-22 years) from the Philadelphia Neurodevelopmental Cohort (PNC) performing a working memory functional magnetic resonance imaging task. We hypothesized that VS would respond to internal correctness monitoring, while classic salience network regions, such as dorsal anterior cingulate cortex and anterior insular cortex, would reflect internal error monitoring and that these responses would increase with age. We expected that neurobehavioral measures of performance monitoring would be reduced in youths with subclinical psychosis spectrum features and would correlate with amotivation severity., Results: Supporting these hypotheses, we found correct>incorrect activation in VS and incorrect>correct activation in anterior cingulate cortex and anterior insular cortex. Furthermore, VS activation was positively correlated with age, reduced in youths with psychosis spectrum features, and inversely correlated with amotivation. However, these patterns were not significant in anterior cingulate cortex and anterior insular cortex., Conclusions: These findings advance our understanding of the neural underpinnings of performance monitoring and its impairment in adolescents with psychosis spectrum features. Such understanding can facilitate investigation of the developmental trajectory of normative and aberrant performance monitoring; contribute to early identification of youths at elevated risk for poor academic, occupational, or psychiatric outcomes; and provide potential targets for therapeutic development., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Neuropsychiatric disorders are common in 22q11.2 Deletion Syndrome (22q11DS) with about 25% of affected individuals developing schizophrenia spectrum disorders by young adulthood. Longitudinal evaluation of psychosis spectrum features and neurocognition can establish developmental trajectories and impact on functional outcome., Methods: 157 youth with 22q11DS were assessed longitudinally for psychopathology focusing on psychosis spectrum symptoms, neurocognitive performance and global functioning. We contrasted the pattern of positive and negative psychosis spectrum symptoms and neurocognitive performance differentiating those with more prominent Psychosis Spectrum symptoms (PS+) to those without prominent psychosis symptoms (PS-)., Results: We identified differences in the trajectories of psychosis symptoms and neurocognitive performance between the groups. The PS+ group showed age associated increase in symptom severity, especially negative symptoms and general nonspecific symptoms. Correspondingly, their level of functioning was worse and deteriorated more steeply than the PS- group. Neurocognitive performance was generally comparable in PS+ and PS- groups and demonstrated a similar age-related trajectory. However, worsening executive functioning distinguished the PS+ group from PS- counterparts. Notably, of the three executive function measures examined, only working memory showed a significant difference between the groups in rate of change. Finally, structural equation modeling showed that neurocognitive decline drove the clinical change., Conclusions: Youth with 22q11DS and more prominent psychosis features show worsening of symptoms and functional decline driven by neurocognitive decline, most related to executive functions and specifically working memory. The results underscore the importance of working memory in the developmental progression of psychosis.

Understanding how traumatic stress affects typical brain development during adolescence is critical to elucidate underlying mechanisms related to both maladaptive functioning and resilience after traumatic exposures. The current study aimed to map deviations from normative ranges of brain gray matter for youths with traumatic exposures. For each cortical and subcortical gray matter region, normative percentiles of variations were established using structural MRI from typically developing youths without any traumatic exposure (n = 245; age range = 8-23) from the Philadelphia Neurodevelopmental Cohort (PNC). The remaining PNC participants with neuroimaging data (n = 1129) were classified as either within the normative range (5-95%), delayed (>95%) or accelerated (<5%) maturational ranges for each region using the normative model. An averaged quantile regression index was calculated across all regions. Mediation models revealed that high traumatic stress load was positively associated with poorer cognitive functioning and greater psychopathology, and these associations were mediated by accelerated gray matter maturation. Furthermore, higher stressor reactivity scores, which represent a less resilient response under traumatic stress, were positively correlated with greater acceleration of gray matter maturation (r = 0.224, 95% CI = [0.17, 0.28], p < 0.001), suggesting that more accelerated maturation was linked to greater stressor response regardless of traumatic stress load. We conclude that traumatic stress is a source of deviation from normative brain development associated with poorer cognitive functioning and more psychopathology in the long run., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)