Diffusion imaging markers of bipolar versus general psychopathology risk in youth at-risk.

Bipolar disorder (BD) is highly heritable. Thus, studies in first-degree relatives of individuals with BD could lead to the discovery of objective risk markers of BD. Abnormalities in white matter structure reported in at-risk individuals could play an important role in the pathophysiology of BD. Due to the lack of studies with other at-risk offspring, however, it remains unclear whether such abnormalities reflect BD-specific or generic risk markers for future psychopathology. Using a tract-profile approach, we examined 18 major white matter tracts in 38 offspring of BD parents, 36 offspring of comparison parents with non-BD psychopathology (depression, attention-deficit/hyperactivity disorder), and 41 offspring of healthy parents. Both at-risk groups showed significantly lower fractional anisotropy (FA) in left-sided tracts (cingulum, inferior longitudinal fasciculus, forceps minor), and significantly greater FA in right-sided tracts (uncinate fasciculus and inferior longitudinal fasciculus), relative to offspring of healthy parents (P < 0.05). These abnormalities were present in both healthy and affected youth in at-risk groups. Only offspring (particularly healthy offspring) of BD parents showed lower FA in the right superior longitudinal fasciculus relative to healthy offspring of healthy parents (P < 0.05). We show, for the first time, important similarities, and some differences, in white matter structure between offspring of BD and offspring of non-BD parents. Findings suggest that lower left-sided and higher right-sided FA in tracts important for emotional regulation may represent markers of risk for general, rather than BD-specific, psychopathology. Lower FA in the right superior longitudinal fasciculus may protect against development of BD in offspring of BD parents.

Reward-related neural activity and structure predict future substance use in dysregulated youth.

BACKGROUND: Identifying youth who may engage in future substance use could facilitate early identification of substance use disorder vulnerability. We aimed to identify biomarkers that predicted future substance use in psychiatrically un-well youth. METHOD: LASSO regression for variable selection was used to predict substance use 24.3 months after neuroimaging assessment in 73 behaviorally and emotionally dysregulated youth aged 13.9 (s.d. = 2.0) years, 30 female, from three clinical sites in the Longitudinal Assessment of Manic Symptoms (LAMS) study. Predictor variables included neural activity during a reward task, cortical thickness, and clinical and demographic variables. RESULTS: Future substance use was associated with higher left middle prefrontal cortex activity, lower left ventral anterior insula activity, thicker caudal anterior cingulate cortex, higher depression and lower mania scores, not using antipsychotic medication, more parental stress, older age. This combination of variables explained 60.4% of the variance in future substance use, and accurately classified 83.6%. CONCLUSIONS: These variables explained a large proportion of the variance, were useful classifiers of future substance use, and showed the value of combining multiple domains to provide a comprehensive understanding of substance use development. This may be a step toward identifying neural measures that can identify future substance use disorder risk, and act as targets for therapeutic interventions.

Neurocognitive functioning in individuals with bipolar disorder and their healthy siblings: A preliminary study.

BACKGROUND: Cognitive deficits have been consistently reported in individuals with bipolar disorder (BD). The cognitive profile of siblings of individuals with BD is, however, less clearly established possibly due to the heterogeneity of neuropsychological measures used in previous studies. The aim of this exploratory study was to assess the cognitive function of siblings of individuals with BD and compare it with that of their first-degree relatives suffering with BD, and healthy controls (HC) using the Cambridge Neuropsychological Test Automated Battery (CANTAB) - a comprehensive and validated computerized cognitive battery. METHODS: We recruited 23 HC (33.52±10.29 years, 8 males), 27 individuals with BD (34.26±10.19 years, 9 males, 25 BDI, 1BDII and 1 BD-NOS), and 15 of their biologically related siblings (37.47±13.15 years, 4 males). Siblings had no current or lifetime history of mental disorders. Participants performed the CANTAB and completed questionnaires assessing mood and global functioning. Multivariate analyses compared CANTAB measures across the three participant groups. RESULTS: Individuals with BD and their siblings were less accurate in a task of sustained attention (Rapid Visual Processing) when compared to HC. Further, individuals with BD displayed pronounced deficits in affective processing (Affective Go/No-Go) compared to HC. There were no cognitive differences between siblings and individuals with BD. After correcting for current depressive symptoms, these results did not reach statistical significance. CONCLUSIONS: Subthreshold depressive symptoms may be associated with reduced sustained attention in healthy siblings of BD patients. This preliminary result needs to be corroborated by large-scale, longitudinal studies assessing the relationship between cognition and mood in vulnerable individuals.

Predicting clinical outcome from reward circuitry function and white matter structure in behaviorally and emotionally dysregulated youth.

Behavioral and emotional dysregulation in childhood may be understood as prodromal to adult psychopathology. Additionally, there is a critical need to identify biomarkers reflecting underlying neuropathological processes that predict clinical/behavioral outcomes in youth. We aimed to identify such biomarkers in youth with behavioral and emotional dysregulation in the Longitudinal Assessment of Manic Symptoms (LAMS) study. We examined neuroimaging measures of function and white matter in the whole brain using 80 youth aged 14.0 (s.d.=2.0) from three clinical sites. Linear regression using the LASSO (Least Absolute Shrinkage and Selection Operator) method for variable selection was used to predict severity of future behavioral and emotional dysregulation measured by the Parent General Behavior Inventory-10 Item Mania Scale (PGBI-10M)) at a mean of 14.2 months follow-up after neuroimaging assessment. Neuroimaging measures, together with near-scan PGBI-10M, a score of manic behaviors, depressive behaviors and sex, explained 28% of the variance in follow-up PGBI-10M. Neuroimaging measures alone, after accounting for other identified predictors, explained ~1/3 of the explained variance, in follow-up PGBI-10M. Specifically, greater bilateral cingulum length predicted lower PGBI-10M at follow-up. Greater functional connectivity in parietal-subcortical reward circuitry predicted greater PGBI-10M at follow-up. For the first time, data suggest that multimodal neuroimaging measures of underlying neuropathologic processes account for over a third of the explained variance in clinical outcome in a large sample of behaviorally and emotionally dysregulated youth. This may be an important first step toward identifying neurobiological measures with the potential to act as novel targets for early detection and future therapeutic interventions.

Neural transcriptome of constitutional Pten dysfunction in mice and its relevance to human idiopathic autism spectrum disorder.

Autism spectrum disorder (ASD) is a neurodevelopmental condition with a clear, but heterogeneous, genetic component. Germline mutations in the tumor suppressor Pten are a well-established risk factor for ASD with macrocephaly, and conditional Pten mouse models have impaired social behavior and brain development. Some mutations observed in patients disrupt the normally balanced nuclear-cytoplasmic localization of the Pten protein, and we developed the Pten(m3m4) model to study the effects of a cytoplasm-predominant Pten. In this model, germline mislocalization of Pten causes inappropriate social behavior with intact learning and memory, a profile reminiscent of high-functioning ASD. These animals also exhibit histological evidence of neuroinflammation and expansion of glial populations by 6 weeks of age. We hypothesized that the neural transcriptome of this model would be altered in a manner that could inform human idiopathic ASD, a constitutional condition. Using total RNA sequencing, we found progressive disruption of neural gene expression in Pten(m3m4) mice from 2-6 weeks of age, involving both immune and synaptic pathways. These alterations include downregulation of many highly coexpressed human ASD-susceptibility genes. Comparison with a human cortical development coexpression network revealed that genes disrupted in Pten(m3m4) mice were enriched in the same areas as those of human ASD. Although Pten-related ASD is relatively uncommon, our observations suggest that the Pten(m3m4) model recapitulates multiple molecular features of human ASD, and that Pten operates far upstream of common pathways within ASD pathogenesis.

Molecular and phenotypic abnormalities in individuals with germline heterozygous PTEN mutations and autism.

PTEN is a tumor suppressor associated with an inherited cancer syndrome and an important regulator of ongoing neural connectivity and plasticity. The present study examined molecular and phenotypic characteristics of individuals with germline heterozygous PTEN mutations and autism spectrum disorder (ASD) (PTEN-ASD), with the aim of identifying pathophysiologic markers that specifically associate with PTEN-ASD and that may serve as targets for future treatment trials. PTEN-ASD patients (n=17) were compared with idiopathic (non-PTEN) ASD patients with (macro-ASD, n=16) and without macrocephaly (normo-ASD, n=38) and healthy controls (n=14). Group differences were evaluated for PTEN pathway protein expression levels, global and regional structural brain volumes and cortical thickness measures, neurocognition and adaptive behavior. RNA expression patterns and brain characteristics of a murine model of Pten mislocalization were used to further evaluate abnormalities observed in human PTEN-ASD patients. PTEN-ASD had a high proportion of missense mutations and showed reduced PTEN protein levels. Compared with the other groups, prominent white-matter and cognitive abnormalities were specifically associated with PTEN-ASD patients, with strong reductions in processing speed and working memory. White-matter abnormalities mediated the relationship between PTEN protein reductions and reduced cognitive ability. The Pten(m3m4) murine model had differential expression of genes related to myelination and increased corpus callosum. Processing speed and working memory deficits and white-matter abnormalities may serve as useful features that signal clinicians that PTEN is etiologic and prompting referral to genetic professionals for gene testing, genetic counseling and cancer risk management; and could reveal treatment targets in trials of treatments for PTEN-ASD.

Comparability of the Rey and Mack forms of the Complex Figure Test.

Equivalent versions of the Complex Figure Test (CFT) are useful for assessing change over time in constructional skills, planning, spatial organization, and visual-spatial memory while minimizing practice effects. To address the need for an equivalent version of the CFT to the Rey, the present study compared copy and 45 min-delayed recall accuracy scores of the Rey and Mack CFTs obtained from 245 adults involved in a study of the neuropsychological correlates of sleep apnea and its treatment. Accuracy scores did not significantly differ between individuals with and without sleep apnea. Also, there was no significant difference between copy or recall accuracy scores obtained on the Rey and Mack CFTs. Similar correlations were found between relevant demographic factors, estimated IQ, and accuracy scores for both CFTs. These data suggest that the Mack figure may be a useful alternative to the Rey CFT.

Control of human vigilance by concurrent schedules.

Twenty four subjects were studied for ten 1-hr sessions to determine whether the human observer's visual monitoring of individual meters in a complex display can be differentially controlled by concurrent scheduling of signals. Subjects were divided into two main groups of 12 each. One group was given fixed-interval, variable-interval, and differential-reinforcement-of-low-rates schedules. The second group was given fixed-interval, fixed-ratio, and differential-reinforcement-of-low-rates schedules. Test subjects were instructed only to detect as many signals as possible. Results indicated that observing responses to the individual meters corresponded to the temporal patterns known to be associated with the schedules for the group given fixed-ratio instead of variable-interval as a component schedule. The group given the variable-interval schedule in the three-schedule combination tended to exhibit the same pattern of viewing across each of the three meters during any given session. However, subsequent testing was performed on two more subjects over 64 sessions, by adding initial feedback of signal detection results, and instructions concerning schedule construction. These results indicated that with knowledge of schedule construction and initial feedback of detection data, differentiated responding can be maintained efficiently over long periods of time by the combination including fixed-interval, variable-interval, and differential-reinforcement-of-low-rates schedules.