Domain-specific associations between psychopathology and neurocognitive functioning.

BACKGROUND: Neurocognitive dysfunction is a transdiagnostic finding in psychopathology, but relationships among cognitive domains and general and specific psychopathology dimensions remain unclear. This study aimed to examine associations between cognition and psychopathology dimensions in a large youth cohort. METHOD: The sample (N = 9350; age 8-21 years) was drawn from the Philadelphia Neurodevelopmental Cohort. Data from structured clinical interviews were modeled using bifactor confirmatory factor analysis (CFA), resulting in an overall psychopathology ('p') factor score and six orthogonal psychopathology dimensions: dysphoria/distress, obsessive-compulsive, behavioral/externalizing, attention-deficit/hyperactivity, phobias, and psychosis. Neurocognitive data were aggregated using correlated-traits CFA into five factors: executive functioning, memory, complex cognition, social cognition, and sensorimotor speed. We examined relationships among specific and general psychopathology dimensions and neurocognitive factors. RESULTS: The final model showed both overall and specific associations between cognitive functioning and psychopathology, with acceptable fit (CFI = 0.91; TLI = 0.90; RMSEA = 0.024; SRMR = 0.054). Overall psychopathology and most psychopathology dimensions were negatively associated with neurocognitive functioning (phobias [p < 0.0005], behavioral/externalizing [p < 0.0005], attention-deficit/hyperactivity [p < 0.0005], psychosis [p < 0.0005 to p < 0.05]), except for dysphoria/distress and obsessive-compulsive symptoms, which were positively associated with complex cognition (p < 0.05 and p < 0.01, respectively). CONCLUSION: By modeling a broad range of cognitive and psychopathology domains in a large, diverse sample of youth, we found aspects of neurocognitive functioning shared across clinical phenotypes, as well as domain-specific patterns. Findings support transdiagnostic examination of cognitive performance to parse variability in the link between neurocognitive functioning and clinical phenotypes.

Traumatic stress load and stressor reactivity score associated with accelerated gray matter maturation in youths indexed by normative models.

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.

Validation of the cognitive section of the Penn computerized adaptive test for neurocognitive and clinical psychopathology assessment (CAT-CCNB).

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.

Associations between neighborhood socioeconomic status, parental education, and executive system activation in youth.

Socioeconomic status (SES) can impact cognitive performance, including working memory (WM). As executive systems that support WM undergo functional neurodevelopment during adolescence, environmental stressors at both individual and community levels may influence cognitive outcomes. Here, we sought to examine how SES at the neighborhood and family level impacts task-related activation of the executive system during adolescence and determine whether this effect mediates the relationship between SES and WM performance. To address these questions, we studied 1,150 youths (age 8-23) that completed a fractal n-back WM task during functional magnetic resonance imaging at 3T as part of the Philadelphia Neurodevelopmental Cohort. We found that both higher neighborhood SES and parental education were associated with greater activation of the executive system to WM load, including the bilateral dorsolateral prefrontal cortex, posterior parietal cortex, and precuneus. The association of neighborhood SES remained significant when controlling for task performance, or related factors like exposure to traumatic events. Furthermore, high-dimensional multivariate mediation analysis identified distinct patterns of brain activity within the executive system that significantly mediated the relationship between measures of SES and task performance. These findings underscore the importance of multilevel environmental factors in shaping executive system function and WM in youth.

The Ethics of Risk Prediction for Psychosis and Suicide Attempt in Youth Mental Health.

OBJECTIVE: To identify potential clinical utility of polygenic risk scores (PRS) and exposomic risk scores (ERS) for psychosis and suicide attempt in youth and assess the ethical implications of these tools. STUDY DESIGN: We conducted a narrative literature review of emerging findings on PRS and ERS for suicide and psychosis as well as a literature review on the ethics of PRS. We discuss the ethical implications of the emerging findings for the clinical potential of PRS and ERS. RESULTS: Emerging evidence suggests that PRS and ERS may offer clinical utility in the relatively near future but that this utility will be limited to specific, narrow clinical questions, in contrast to the suggestion that population-level screening will have sweeping impact. Combining PRS and ERS might optimize prediction. This clinical utility would change the risk-benefit balance of PRS, and further empirical assessment of proposed risks would be necessary. Some concerns for PRS, such as those about counseling, privacy, and inequities, apply to ERS. ERS raise distinct ethical challenges as well, including some that involve informed consent and direct-to-consumer advertising. Both raise questions about the ethics of machine-learning/artificial intelligence approaches. CONCLUSIONS: Predictive analytics using PRS and ERS may soon play a role in youth mental health settings. Our findings help educate clinicians about potential capabilities, limitations, and ethical implications of these tools. We suggest that a broader discussion with the public is needed to avoid overenthusiasm and determine regulations and guidelines for use of predictive scores.

Executive function as a generalized determinant of psychopathology and functional outcome in school-aged autism spectrum disorder: a case-control study.

BACKGROUND: Individuals with autism spectrum disorder (ASD) are challenged not only by the defining features of social-communication deficits and restricted repetitive behaviors, but also by a myriad of psychopathology varying in severity. Different cognitive deficits underpin these psychopathologies, which could be subjected to intervention to alter the course of the disorder. Understanding domain-specific mediating effects of cognition is essential for developing targeted intervention strategies. However, the high degree of inter-correlation among different cognitive functions hinders elucidation of individual effects. METHODS: In the Philadelphia Neurodevelopmental Cohort, 218 individuals with ASD were matched with 872 non-ASD controls on sex, age, race, and socioeconomic status. Participants of this cohort were deeply and broadly phenotyped on neurocognitive abilities and dimensional psychopathology. Using structural equation modeling, inter-correlation among cognitive domains were adjusted before mediation analysis on outcomes of multi-domain psychopathology and functional level. RESULTS: While social cognition, complex cognition, and memory each had a unique pattern of mediating effect on psychopathology domains in ASD, none had significant effects on the functional level. In contrast, executive function was the only cognitive domain that exerted a generalized negative impact on every psychopathology domain (p factor, anxious-misery, psychosis, fear, and externalizing), as well as functional level. CONCLUSIONS: Executive function has a unique association with the severity of comorbid psychopathology in ASD, and could be a target of interventions. As executive dysfunction occurs variably in ASD, our result also supports the clinical utility of assessing executive function for prognostic purposes.

Psychosis spectrum features, neurocognition and functioning in a longitudinal study of youth with 22q11.2 deletion syndrome.

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.

Evaluation of a new intrinsic and extrinsic motivation scale in youth with psychosis spectrum symptoms.

BACKGROUND: Impairment in intrinsic motivation (IM), the drive to satisfy internal desires like mastery, may play a key role in disability in psychosis. However, we have limited knowledge regarding relative impairments in IM compared to extrinsic motivation (EM) or general motivation (GM), in part due to limitations in existing measures. METHODS: Here we address this gap using a novel Trait Intrinsic and Extrinsic Motivation self-report scale in a sample of n = 243 participants including those with schizophrenia, psychosis-risk, and healthy controls. Each of the 7 IM and 6 EM items used a 7-point Likert scale assessing endorsement of dispositional statements. Bifactor analyses of these items yielded distinct IM, EM, and GM factor scores. Convergent and discriminant validity were examined in relation to General Causality Orientation Scale (GCOS-CP) and Quality of Life 3-item IM measure (QLS-IM). Utility was assessed in relation to psychosis-spectrum (PS) status and CAINS clinical amotivation. RESULTS: IM and EM showed acceptable inter-item consistency (IM: α = 0.88; EM: α = 0.66); the bifactor model exhibited fit that varied from good to borderline to inadequate depending on the specific fit metric (SRMR = 0.038, CFI = 0.94, RMSEA = 0.106 ± 0.014). IM scores correlated with established IM measures: GCOS-CP Autonomy (rho = 0.38, p < 0.01) and QLS-IM (rho = 0.29, p < 0.01). Supporting discriminant validity, IM did not correlate with GCOS-CP Control (rho = -0.14, p > 0.05). Two-year stability in an available longitudinal subset (n = 35) was strong (IM: rho = 0.64, p < 0.01; EM: rho = 0.55, p < 0.01). Trait IM was lower in PS youth (t = 4.24, p < 0.01), and correlated with clinical amotivation (rho = -0.36, p < 0.01); EM did not show significant clinical associations. CONCLUSIONS: These results demonstrate the clinical relevance of IM in psychosis risk. They also provide preliminary support for the reliability, validity and utility of this new Trait IM-EM scale, which addresses a measurement gap and can facilitate identification of neurobehavioral and clinical correlates of IM deficits.

Hoarding behavior and its association with mental health and functioning in a large youth sample.

Hoarding behavior is prevalent in children and adolescents, yet clinicians do not routinely inquire about it and youth may not spontaneously report it due to stigma. It is unknown whether hoarding behavior, over and above obsessive-compulsive symptoms (OCS), is associated with major clinical factors in a general youth population. This observational study included N = 7054 youth who were not seeking help for mental health problems (ages 11-21, 54% female) and completed a structured interview that included evaluation of hoarding behavior and OCS, as a part of the Philadelphia Neurodevelopmental Cohort between November 2009 and December 2011. We employed regression models with hoarding behavior and OCS (any/none) as independent variables, and continuous (linear regression) or binary (logistic regression) mental health measures as dependent variables. All models covaried for age, sex, race, and socioeconomic status. A total of 374 participants endorsed HB (5.3%), most of which reported additional OCS (n = 317). When accounting for OCS presence, hoarding behavior was associated with greater dimensional psychopathology burden (i.e., higher P-factor) (ß = 0.19, p < .001), and with poorer functioning (i.e., lower score on the child global assessment scale) (ß = - 0.07, p < .001). The results were consistent when modeling psychopathology using binary variables. The results remained significant in sensitivity analyses accounting for count of endorsed OCS and excluding participants who met criteria for obsessive-compulsive disorder (n = 210). These results suggest that hoarding behavior among youth is associated with poorer mental health and functioning, independent of OCS. Brief hoarding-behavior assessments in clinical settings may prove useful given hoarding behavior's stigma and detrimental health associations.

Implementation of an Adapted Fidelity Scale for Pennsylvania Coordinated Specialty Care Programs for First Episode Psychosis.

Coordinated Specialty Care (CSC) is an evidence-based model for early intervention of first episode psychosis (FEP). Monitoring fidelity to CSC models is essential for proper evaluation of program outcomes and quality improvement. To address variability across CSC programs and fidelity assessment-associated burden, an adapted fidelity scale was developed and implemented statewide in Pennsylvania. This report describes the design and preliminary performance of the adapted scale. The Pennsylvania FEP Fidelity Scale (PA-FEP-FS) assesses adherence to the CSC model by focusing on essential model components of other established fidelity scales, in tandem with program evaluation data. Initial data from fourteen PA-FEP sites from 2018 to 2021 were examined as preliminary validation. Assessment-associated burdens and costs were also estimated. PA-FEP-FS captured essential components of CSC models and proved feasible for implementation across varying program structures, while minimizing burden and cost. Programs utilized annual feedback as CSC benchmarks, evidenced by increased scores over time. PA-FEP-FS provides a model for adapting CSC fidelity scales to meet state- or local-level requirements while reducing assessment burdens and costs that may be associated with existing scales.

Risk and Resilience Measures Related to Psychopathology in Youth.

Childhood adversity places youth at risk for multiple negative outcomes. The current study aimed to understand how a constellation of risk and resilience factors influenced mental health outcomes as a function of adversities: socioeconomic status (SES) and traumatic stressful events (TSEs). Specifically, we examined outcomes related to psychosis and mood disorders, as well as global clinical functioning. The current study is a longitudinal follow up of 140 participants from the Philadelphia Neurodevelopmental Cohort (PNC) assessed for adversities at Time 1 (Mean age: 14.11 years) and risk, resilience, and clinical outcomes at Time 2 (mean age: 21.54 years). In the context of TSE, a limited set of predictors emerged as important; a more diverse set of moderators emerged in the context of SES. Across adversities, social support was a unique predictor of psychosis spectrum diagnoses and global functioning; emotion dysregulation was an important predictor for mood diagnoses. The current findings underscore the importance of understanding effects of childhood adversity on maladaptive outcomes within a resilience framework.

Transdiagnostic symptom networks in relation to mental health service use in community youth.

OBJECTIVE: The objective of this study is to scrutinize whether psychopathology symptom networks differ between those with and without lifetime: treatment seeking, treatment and treatment of longer duration. METHODS: We created non-exclusive groups of subjects with versus without lifetime treatment seeking, treatment and treatment of mid-long-term duration. We estimated Ising models and carried out network comparison tests (NCTs) to compare (a) overall connectivity and (b) network structure. Furthermore, we examined node strength. We used propensity score matching (PSM) to minimize potential confounding by indication for service use. RESULTS: Based on data from 9,172 participants, there were no statistically significant differences in overall connectivity and network structure in those with versus without lifetime: treatment seeking (p = .75 and p = .82, respectively), treatment (p = .63 and p = .49, respectively) and treatment of mid-longterm duration (p = .15 and p = .62, respectively). Notably, comparing networks with versus without service use consistently revealed higher node strength in 'obsessions' and 'aggression' and lower node strength in 'elevated mood' in all networks with service use. CONCLUSIONS: Findings suggest that after adjusting for potential confounding by indication for service use, there was no indication of an association in overall connectivity or network structure for lifetime treatment seeking, treatment and treatment of longer duration. However, selected structurally important symptoms differed consistently in all three comparisons. Our findings highlight the potential of network analysis methods to examine treatment mechanisms and outcomes. Specifically, more granular network characteristics on the node level may complement and enrich traditional outcomes in clinical research.

Tele-mental Health Transitions for Pennsylvania Coordinated Specialty Care Programs for Early Psychosis During the COVID-19 Pandemic.

This study examined provider and client perspectives of tele-mental health (TMH) in early psychosis care during the COVID-19 pandemic. To achieve this goal, thirty-three mental health providers and 31 clients from Pennsylvania Coordinated Specialty Care (CSC) programs completed web-based surveys assessing TMH usage, experiences, and perceptions between May and September 2020. Three additional TMH-related questions were asked two years later of PA CSC Program Directors between Feb and March 2022. Descriptive statistics characterized responses. Open-ended items were coded and grouped into themes for qualitative synthesis. As early as mid-2020, participants reported extensive use of TMH technologies, including telephone and video visits. Although most providers and clients preferred in-person care to TMH, most clients still found TMH to be comparable to or better than in-person care; 94% of clients indicated interest in future TMH services. Providers also noted more successes than challenges with TMH. Nine themes emerged regarding provider-perceived client characteristics that could benefit from TMH and were grouped into two categories: client-level (access to technology, comfort with technology, transportation, young age, symptom severity, functioning level, motivation for treatment adherence) and interpersonal-level (external support systems and engagement with program prior to the pandemic) characteristics. Two years later, program directors reported continued perceived advantages of TMH in CSCs, although some barriers persisted. Despite the unexpected shift to TMH in early psychosis programs during the COVID-19 pandemic, findings indicated a relatively positive transition to TMH and perceived promise of TMH as a sustained part of routine care.

Development of a probability calculator for psychosis risk in children, adolescents, and young adults.

BACKGROUND: Assessment of risks of illnesses has been an important part of medicine for decades. We now have hundreds of 'risk calculators' for illnesses, including brain disorders, and these calculators are continually improving as more diverse measures are collected on larger samples. METHODS: We first replicated an existing psychosis risk calculator and then used our own sample to develop a similar calculator for use in recruiting 'psychosis risk' enriched community samples. We assessed 632 participants age 8-21 (52% female; 48% Black) from a community sample with longitudinal data on neurocognitive, clinical, medical, and environmental variables. We used this information to predict psychosis spectrum (PS) status in the future. We selected variables based on lasso, random forest, and statistical inference relief; and predicted future PS using ridge regression, random forest, and support vector machines. RESULTS: Cross-validated prediction diagnostics were obtained by building and testing models in randomly selected sub-samples of the data, resulting in a distribution of the diagnostics; we report the mean. The strongest predictors of later PS status were the Children's Global Assessment Scale; delusions of predicting the future or having one's thoughts/actions controlled; and the percent married in one's neighborhood. Random forest followed by ridge regression was most accurate, with a cross-validated area under the curve (AUC) of 0.67. Adjustment of the model including only six variables reached an AUC of 0.70. CONCLUSIONS: Results support the potential application of risk calculators for screening and identification of at-risk community youth in prospective investigations of developmental trajectories of the PS.

Diminished reward responsiveness is associated with lower reward network GluCEST: an ultra-high field glutamate imaging study.

Low reward responsiveness (RR) is associated with poor psychological well-being, psychiatric disorder risk, and psychotropic treatment resistance. Functional MRI studies have reported decreased activity within the brain's reward network in individuals with RR deficits, however the neurochemistry underlying network hypofunction in those with low RR remains unclear. This study employed ultra-high field glutamate chemical exchange saturation transfer (GluCEST) imaging to investigate the hypothesis that glutamatergic deficits within the reward network contribute to low RR. GluCEST images were acquired at 7.0 T from 45 participants (ages 15-29, 30 females) including 15 healthy individuals, 11 with depression, and 19 with psychosis spectrum symptoms. The GluCEST contrast, a measure sensitive to local glutamate concentration, was quantified in a meta-analytically defined reward network comprised of cortical, subcortical, and brainstem regions. Associations between brain GluCEST contrast and Behavioral Activation System Scale RR scores were assessed using multiple linear regressions. Analyses revealed that reward network GluCEST contrast was positively and selectively associated with RR, but not other clinical features. Follow-up investigations identified that this association was driven by the subcortical reward network and network areas that encode the salience of valenced stimuli. We observed no association between RR and the GluCEST contrast within non-reward cortex. This study thus provides new evidence that reward network glutamate levels contribute to individual differences in RR. Decreased reward network excitatory neurotransmission or metabolism may be mechanisms driving reward network hypofunction and RR deficits. These findings provide a framework for understanding the efficacy of glutamate-modulating psychotropics such as ketamine for treating anhedonia.

Characterizing Youth-Caregiver Concordance and Discrepancies in Psychopathology Symptoms in a US Community Sample.

Evidence shows that reports of psychopathology symptoms by youth and their caregiver informants differ. To quantify youth-caregiver discrepancies in psychopathology symptoms and factors associated with such discrepancies, we investigated differences in how youth and their caregivers rated psychopathology symptoms. The sample (N = 5094) was extracted from the Philadelphia Neurodevelopmental Cohort, a community-based sample of youth and included participants ages 11-17 years old with both youth and caregiver reported symptom scores. Across psychopathology symptoms, youth-caregiver concordance was poor to fair (Cohens kappa for symptom items ranged between 0.03-0.41). Psychosis symptoms had the lowest concordance-Cohen's kappa ranged from 0.03 to 0.17 across psychosis symptoms. Discrepancies between youth and caregiver symptom reports were greater than average for Black youth and for youth of low socioeconomic status; discrepancies were also higher than average in youth with any psychiatric disorder when compared to typically developing youth. Network analysis of difference scores obtained by subtracting youth symptom scores from caregiver reported symptom scores showed that network connectivity (i.e., correlated difference scores) was sparsest for psychosis spectrum compared to other psychiatric disorders. Using a large sample, we show that youth and their caregiver informants tend to report psychopathology symptoms differently. Youth-caregiver discrepancies were the most pronounced for Black youth and youth of low socio-economic status. Race and socioeconomic status contribute to significant differences in how youth and their caregivers report such symptoms and are important factors that should be accounted for to facilitate accurate mental health symptom assessment and evaluation.

Longitudinal Development of Brain Iron Is Linked to Cognition in Youth.

Brain iron is vital to multiple aspects of brain function, including oxidative metabolism, myelination, and neurotransmitter synthesis. Atypical iron concentration in the basal ganglia is associated with neurodegenerative disorders in aging and cognitive deficits. However, the normative development of brain iron concentration in adolescence and its relationship to cognition are less well understood. Here, we address this gap in a longitudinal sample of 922 humans aged 8-26 years at the first visit (M = 15.1, SD = 3.72; 336 males, 486 females) with up to four multiecho T2* scans each. Using this sample of 1236 imaging sessions, we assessed the longitudinal developmental trajectories of tissue iron in the basal ganglia. We quantified tissue iron concentration using R2* relaxometry within four basal ganglia regions, including the caudate, putamen, nucleus accumbens, and globus pallidus. The longitudinal development of R2* was modeled using generalized additive mixed models (GAMMs) with splines to capture linear and nonlinear developmental processes. We observed significant increases in R2* across all regions, with the greatest and most prolonged increases occurring in the globus pallidus and putamen. Further, we found that the developmental trajectory of R2* in the putamen is significantly related to individual differences in cognitive ability, such that greater cognitive ability is increasingly associated with greater iron concentration through late adolescence and young-adulthood. Together, our results suggest a prolonged period of basal ganglia iron enrichment that extends into the mid-twenties, with diminished iron concentration associated with poorer cognitive ability during late adolescence.SIGNIFICANCE STATEMENT Brain tissue iron is essential to healthy brain function. Atypical basal ganglia tissue iron levels have been linked to impaired cognition in iron deficient children and adults with neurodegenerative disorders. However, the normative developmental trajectory of basal ganglia iron concentration during adolescence and its association with cognition are less well understood. In the largest study of tissue iron development yet reported, we characterize the developmental trajectory of tissue iron concentration across the basal ganglia during adolescence and provide evidence that diminished iron content is associated with poorer cognitive performance even in healthy youth. These results highlight the transition from adolescence to adulthood as a period of dynamic maturation of tissue iron concentration in the basal ganglia.

Alterations in white matter microstructure in individuals at persistent risk for psychosis.

Abnormalities in brain white matter (WM) are reported in youth at-risk for psychosis. Yet, the neurodevelopmental time course of these abnormalities remains unclear. Thus, longitudinal diffusion-weighted imaging (DWI) was used to investigate WM abnormalities in youth at-risk for psychosis. A subset of individuals from the Philadelphia Neurodevelopmental Cohort (PNC) completed two DWI scans approximately 20 months apart. Youths were identified through structured interview as having subthreshold persistent psychosis risk symptoms (n = 46), and were compared to healthy typically developing participants (TD; n = 98). Analyses were conducted at voxelwise and regional levels. Nonlinear developmental patterns were examined using penalized splines within a generalized additive model. Compared to TD, youth with persistent psychosis risk symptoms had lower whole-brain WM fractional anisotropy (FA) and higher radial diffusivity (RD). Voxelwise analyses revealed clusters of significant WM abnormalities within the temporal and parietal lobes. Lower FA within the cingulum bundle of hippocampus and cerebrospinal tracts were the most robust deficits in individuals with persistent psychosis symptoms. These findings were consistent over two visits. Thus, it appears that WM abnormalities are present early in youth with persistent psychosis risk symptoms, however, there is little evidence to suggest that these features emerge in late adolescence or early adulthood. Future studies should seek to characterize WM abnormalities in younger individuals and follow individuals as subthreshold psychotic symptoms emerge.

Association between family history of suicide attempt and neurocognitive functioning in community youth.

BACKGROUND: Suicidal behavior is highly familial. Neurocognitive deficits have been proposed as an endophenotype for suicide risk that may contribute to the familial transmission of suicide. Yet, there is a lack of research on the neurocognitive functioning of first-degree biological relatives of suicide attempters. The aim of the present study is to conduct the largest investigation to date of neurocognitive functioning in community youth with a family history of a fatal or nonfatal suicide attempt (FH). METHODS: Participants aged 8-21 years from the Philadelphia Neurodevelopmental Cohort completed detailed clinical and neurocognitive evaluations. A subsample of 501 participants with a FH was matched to a comparison group of 3,006 participants without a family history of suicide attempt (no-FH) on age, sex, race, and lifetime depression. RESULTS: After adjusting for multiple comparisons and including relevant clinical and demographic covariates, youth with a FH had significantly lower executive function factor scores (F[1,3432] = 6.63, p = .010) and performed worse on individual tests of attention (F[1,3382] = 7.08, p = .008) and language reasoning (F[1,3387] = 5.12, p = .024) than no-FH youth. CONCLUSIONS: Youth with a FH show small differences in executive function, attention, and language reasoning compared to youth without a FH. Further research is warranted to investigate neurocognitive functioning as an endophenotype for suicide risk. Implications for the prevention and treatment of suicidal behaviors are discussed.

Association of anxiety phenotypes with risk of depression and suicidal ideation in community youth.

BACKGROUND: Anxiety symptoms are common in adolescence and are often considered developmentally benign. Yet for some, anxiety presents with serious comorbid nonanxiety psychopathology. Early identification of such "malignant" anxiety presentations is a major challenge. We aimed to characterize anxiety symptoms suggestive of risk for depression and suicidal ideation (SI) in community youths. METHODS: Cross-sectional associations were evaluated in community youths (n = 7,054, mean age: 15.8) who were assessed for anxiety, depression, and SI. We employed factor and latent class analyses to identify anxiety clusters and subtypes. Longitudinal risk of anxiety was evaluated in a subset of 330 youths with longitudinal data on depression and SI (with baseline mean age of 12.3 years and follow-up mean age of 16.98 years). OUTCOMES: Almost all (92%) adolescents reported anxiety symptoms. Data-driven approaches revealed anxiety factors and subtypes that were differentially associated with depression and SI. Cross-sectional analyses revealed that panic and generalized anxiety symptoms show the most robust associations with depression and SI. Longitudinal, multivariate analyses revealed that panic symptoms during early adolescence, not generalized anxiety symptoms, predict depression and SI for later adolescent years, particularly in males. INTERPRETATION: Anxiety is common in youths, with certain symptom clusters/subtypes predicting risk for depression and SI. Panic symptoms in early adolescence, even below disorder threshold, predict high risk for late adolescent depression and SI.