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Background:There are no objective, biological markers that can robustly predict methylphenidate response in attention deficit hyperactivity disorder. This study aimed to examine whether applying machine learning approaches to pretreatment demographic, clinical questionnaire, environmental, neuropsychological, neuroimaging, and genetic information can predict therapeutic response following methylphenidate administration.Methods:The present study included 83 attention deficit hyperactivity disorder youth. At baseline, parents completed the ADHD Rating Scale-IV and Disruptive Behavior Disorder rating scale, and participants undertook the continuous performance test, Stroop color word test, and resting-state functional MRI scans. The dopamine transporter gene, dopamine D4 receptor gene, alpha-2A adrenergic receptor gene (ADRA2A) and norepinephrine transporter gene polymorphisms, and blood lead and urine cotinine levels were also measured. The participants were enrolled in an 8-week, open-label trial of methylphenidate. Four different machine learning algorithms were used for data analysis.Results:Support vector machine classification accuracy was 84.6% (area under receiver operating characteristic curve 0.84) for predicting methylphenidate response. The age, weight, ADRA2A MspI and DraI polymorphisms, lead level, Stroop color word test performance, and oppositional symptoms of Disruptive Behavior Disorder rating scale were identified as the most differentiating subset of features.Conclusions:Our results provide preliminary support to the translational development of support vector machine as an informative method that can assist in predicting treatment response in attention deficit hyperactivity disorder, though further work is required to provide enhanced levels of classification performance.

Alterations in reward-related brain activity have been linked to response to psychological treatment in adolescents with anxiety disorders. However, it remains unknown whether these effects are driven by reward anticipation or feedback, which reflect different functional roles in motivated behavior, or whether brain activity changes as a function of treatment response. The current study investigated these questions in the context of a randomized controlled trial of cognitive-behavioral therapy (CBT) for anxiety disorders in adolescents. This study used an fMRI paradigm to investigate reward-related brain activity in youth aged 9–14 with anxiety disorders (ANX; N = 133; 57 female) before and after 16 weeks of CBT or an active comparison (child-centered therapy, CCT). Age- and sex-matched healthy comparison (HC) youth (N = 38; 17 female) completed scans on a similar timeline. A subset of ANX youth completed a 2-year follow-up assessment of depressive symptoms. At pretreatment, ANX compared to HC youth demonstrated reduced brain activity in reward-related regions (e.g. dorsal striatum, thalamus) during reward anticipation, and elevated activity in angular gyrus, PCC and inferior frontal gyrus during reward feedback. Reduced pretreatment activation in the precuneus/cuneus and pre-to-post reductions in left angular gyrus corresponded with treatment response. Finally, pre-to-post increases in posterior cingulate cortex (PCC) corresponded with increased depressive symptoms at 2 years. Our results suggest that reward-related brain activity outside of striatal reward regions, including PCC, precuneus and angular gyrus, plays a role in treatment response in youth with anxiety disorders. Trial registration: ClinicalTrials.gov NCT00774150.

Objectives: To identify mood symptoms that distinguishes bipolar disorder (BP) depression versus unipolar depression in youth during an acute depressive episode. Methods: Youth with BP (N = 30) were compared with youth with unipolar depression (N = 59) during an acute depressive episode using the depression and mania items derived from the Schedule for Affective Disorders and Schizophrenia for Children (K-SADS)-Present Version. The results were adjusted for multiple comparisons, and any significant between-group differences in demographic, nonmood comorbid disorders, and psychiatric family history. Results: In comparison with unipolar depressed youth, BP depressed youth had significantly higher scores in several depressive symptoms and all subsyndromal manic symptoms, with the exception of increased goal-directed activity. Among the depressive symptoms, higher ratings of nonsuicidal physical self-injurious acts and mood reactivity, and lower ratings of aches/pains, were the symptoms that best discriminated BP from unipolar depressed youth. Subsyndromal manic symptoms, particularly motor hyperactivity, distractibility, and pressured speech, were higher in BP depressed youth and discriminated BP depressed from unipolar depressed youth. Conclusions: The results of this study suggest that it is possible to differentiate BP depression from unipolar depression based on depressive symptoms, and in particular subsyndromal manic symptoms. If replicated, these results have important clinical and research implications.

Close proximity to an attachment figure, such as a caregiver, has been shown to attenuate threat-related activity in limbic regions such as the hypothalamus in healthy individuals. We hypothesized that such features might be similarly attenuated by proximity during a potentially stressful situation in a clinically anxious population of youths. Confirmation of this hypothesis could support the role of attachment figures in the management of anxiety among children and adolescents. Three groups were analyzed: anxious children and adolescents who requested that their caregiver accompany them in the scanner room, anxious children and adolescents without their caregiver in the scanner room and healthy controls (each of N = 10). The groups were matched for age and, among the two anxious groups, for diagnosis (mean age 9.5). The children and adolescents were exposed to physical threat words during an fMRI assessment. Results indicate that activity in the hypothalamus, ventromedial, and ventrolateral prefrontal cortex were significantly reduced in anxious children and adolescents who requested that their caregiver accompany them in the scanner room compared to those without their caregiver in the scanner room. Mean activity in these regions in anxious children and adolescents with their caregiver in the scanner room was comparable to that of healthy controls. These data suggest links between social contact and neural mechanisms of emotional reactivity; specifically, presence of caregivers moderates the increase in anxiety seen with stressful stimuli. Capitalizing on the ability of anxious youths to manifest low levels of anxiety-like information processing in the presence of a caregiver could help in modeling adaptive function in behavioral treatments.

Anxiety is the most prevalent psychological disorder among youth, and even following treatment, it confers risk for anxiety relapse and the development of depression. Anxiety disorders are associated with heightened response to negative affective stimuli in the brain networks that underlie emotion processing. One factor that can attenuate the symptoms of anxiety and depression in high-risk youth is parental warmth. The current study investigates whether parental warmth helps to protect against future anxiety and depressive symptoms in adolescents with histories of anxiety and whether neural functioning in the brain regions that are implicated in emotion processing and regulation can account for this link. Following treatment for anxiety disorder (Time 1), 30 adolescents ( M age = 11.58, SD = 1.26) reported on maternal warmth, and 2 years later (Time 2) they participated in a functional neuroimaging task where they listened to prerecorded criticism and neutral statements from a parent. Higher maternal warmth predicted lower neural activation during criticism, compared with the response during neutral statements, in the left amygdala, bilateral insula, subgenual anterior cingulate (sgACC), right ventrolateral prefrontal cortex, and anterior cingulate cortex. Maternal warmth was associated with adolescents’ anxiety and depressive symptoms due to the indirect effects of sgACC activation, suggesting that parenting may attenuate risk for internalizing through its effects on brain function.

Adult mood disturbances are highly correlated with obesity, although little is known about the developmental relationship between mood disorders and weight. This study investigated the relationship between childhood psychopathology and weight over the course of 3 years. Body Mass Index (BMI) percentiles and demographic data of children (ages 8–18) with depression ( n  = 143) or anxiety ( n  = 43) were compared to healthy controls ( n  = 99). Both childhood depression ( χ 2  = 4.6, p  = 0.03) and anxiety ( χ 2  = 6.0, p  = 0.01) were associated with increased BMI percentiles. Compared to controls, BMI percentiles of depressed females over the course of the study differed profoundly ( χ 2  = 7.0, p  = 0.01) and BMI percentiles of anxious females approached significance ( χ 2  = 3.7, p  = 0.06). Males with anxiety showed a greater trend towards overweight ( χ 2  = 3.3, p  = 0.07) in comparison to controls. The major finding that depression and anxiety are associated with increased BMI percentiles in a non-obese sample suggests that childhood psychopathology is an important factor that should be carefully monitored.

Abstract Study Objectives Structural brain maturation and sleep are complex processes that exhibit significant changes over adolescence and are linked to many physical and mental health outcomes. We investigated whether sleep–gray matter relationships are developmentally invariant (i.e. stable across age) or developmentally specific (i.e. only present during discrete time windows) from late childhood through young adulthood. Methods We constructed the Neuroimaging and Pediatric Sleep Databank from eight research studies conducted at the University of Pittsburgh (2009–2020). Participants completed a T1-weighted structural MRI scan (sMRI) and 5–7 days of wrist actigraphy to assess naturalistic sleep. The final analytic sample consisted of 225 participants without current psychiatric diagnoses (9–25 years). We extracted cortical thickness and subcortical volumes from sMRI. Sleep patterns (duration, timing, continuity, regularity) were estimated from wrist actigraphy. Using regularized regression, we examined cross-sectional associations between sMRI measures and sleep patterns, as well as the effects of age, sex, and their interaction with sMRI measures on sleep. Results Shorter sleep duration, later sleep timing, and poorer sleep continuity were associated with thinner cortex and altered subcortical volumes in diverse brain regions across adolescence. In a discrete subset of regions (e.g. posterior cingulate), thinner cortex was associated with these sleep patterns from late childhood through early-to-mid adolescence but not in late adolescence and young adulthood. Conclusions In childhood and adolescence, developmentally invariant and developmentally specific associations exist between sleep patterns and gray matter structure, across brain regions linked to sensory, cognitive, and emotional processes. Sleep intervention during specific developmental periods could potentially promote healthier neurodevelopmental outcomes.

Abstract Study Objectives Healthy sleep is important for adolescent neurodevelopment, and relationships between brain structure and sleep can vary in strength over this maturational window. Although cortical gyrification is increasingly considered a useful index for understanding cognitive and emotional outcomes in adolescence, and sleep is also a strong predictor of such outcomes, we know relatively little about associations between cortical gyrification and sleep. We aimed to identify developmentally invariant (stable across age) or developmentally specific (observed only during discrete age intervals) gyrification-sleep relationships in young people. Methods A total of 252 Neuroimaging and Pediatric Sleep Databank participants (9–26 years; 58.3% female) completed wrist actigraphy and a structural MRI scan. Local gyrification index (lGI) was estimated for 34 bilateral brain regions. Naturalistic sleep characteristics (duration, timing, continuity, and regularity) were estimated from wrist actigraphy. Regularized regression for feature selection was used to examine gyrification-sleep relationships. Results For most brain regions, greater lGI was associated with longer sleep duration, earlier sleep timing, lower variability in sleep regularity, and shorter time awake after sleep onset. lGI in frontoparietal network regions showed associations with sleep patterns that were stable across age. However, in default mode network regions, lGI was only associated with sleep patterns from late childhood through early-to-mid adolescence, a period of vulnerability for mental health disorders. Conclusions We detected both developmentally invariant and developmentally specific ties between local gyrification and naturalistic sleep patterns. Default mode network regions may be particularly susceptible to interventions promoting more optimal sleep during childhood and adolescence. Graphical Abstract Graphical Abstract

Background Anxious youth have shown altered behavioral performance on the dot‐probe task, but neural activation patterns provoked by the task remain poorly understood. In particular, neural mechanisms of threat disengagement, a clinically relevant construct, have been inadequately explored. Method During fMRI acquisition, 121 youth (ages 9–13; 90 with Generalized Anxiety Disorder, Separation Anxiety Disorder, and/or Social Phobia; 31 nonanxious controls) completed a dot‐probe task, which required participants to identify the location of a dot replacing either a neutral or fearful face in a pair containing both faces. We assessed neural substrates of threat disengagement by comparing congruent trials (in which the dot replaces the fearful face) to incongruent trials (in which the dot replaces the neutral face). Results Across subjects, decreased rostrodorsal anterior cingulate cortex (rdACC) activity was observed specifically during incongruent trials. Nonanxious youth showed a convergent pattern in bilateral parahippocampal and hippocampal regions, whereas anxious youth showed an opposing pattern in these limbic areas, suggesting less integration of response across cortical and limbic areas relevant to threat appraisal. Reduced functional connectivity between rdACC and left parahippocampus/hippocampus was associated with greater anxiety. Conclusions In the largest dot‐probe fMRI sample to date, both anxious and nonanxious youth showed a neural pattern consistent with successful disengagement of threat reactivity in the rdACC. However, anxious youth showed evidence of abnormal disengagement in bilateral parahippocampal/hippocampal clusters when attention was directed away from threat. Early interventions targeting neural mechanisms of threat disengagement may be beneficial, for example, by increasing integration across rdACC and limbic regions.