Gene copy number variation and pediatric mental health/neurodevelopment in a general population.

We assessed the relationship of gene copy number variation (CNV) in mental health/neurodevelopmental traits and diagnoses, physical health and cognition in a community sample of 7100 unrelated children and youth of European or East Asian ancestry (Spit for Science). Clinically significant or susceptibility CNVs were present in 3.9% of participants and were associated with elevated scores on a continuous measure of attention-deficit/hyperactivity disorder (ADHD) traits (P = 5.0 × 10-3), longer response inhibition (a cognitive deficit found in several mental health and neurodevelopmental disorders; P = 1.0 × 10-2) and increased prevalence of mental health diagnoses (P = 1.9 × 10-6, odds ratio: 3.09), specifically ADHD, autism spectrum disorder anxiety and learning problems/learning disorder (P's < 0.01). There was an increased burden of rare deletions in gene-sets related to brain function or expression in brain associated with more ADHD traits. With the current mental health crisis, our data established a baseline for delineating genetic contributors in pediatric-onset conditions.

Novel Oppositional Defiant Disorder or Conduct Disorder 24 Months After Traumatic Brain Injury in Children and Adolescents.

OBJECTIVE: The authors sought to identify predictive factors of new-onset or novel oppositional defiant disorder or conduct disorder assessed 24 months after traumatic brain injury (TBI). METHODS: Children ages 5 to 14 years who had experienced TBI were recruited from consecutive hospital admissions. Soon after injury, participants were assessed for preinjury characteristics, including psychiatric disorders, socioeconomic status (SES), psychosocial adversity, and family function, and the presence and location of lesions were documented by MRI. Psychiatric outcomes, including novel oppositional defiant disorder or conduct disorder, were assessed 24 months after injury. RESULTS: Of the children without preinjury oppositional defiant disorder, conduct disorder, or disruptive behavior disorder not otherwise specified who were recruited in this study, 165 were included in this sample; 95 of these children returned for the 24-month assessment. Multiple imputation was used to address attrition. The prevalence of novel oppositional defiant disorder or conduct disorder was 23.7 out of 165 (14%). In univariable analyses, novel oppositional defiant disorder or conduct disorder was significantly associated with psychosocial adversity (p=0.049) and frontal white matter lesions (p=0.016) and was marginally but not significantly associated with SES. In the final multipredictor model, frontal white matter lesions were significantly associated with novel oppositional defiant disorder or conduct disorder (p=0.021), and psychosocial adversity score was marginally but not significantly associated with the outcome. The odds ratio of novel oppositional defiant disorder or conduct disorder among the children with versus those without novel depressive disorder was significantly higher for girls than boys (p=0.025), and the odds ratio of novel oppositional defiant disorder or conduct disorder among the children with versus those without novel attention-deficit hyperactivity disorder (ADHD) was significantly higher for boys than girls (p=0.006). CONCLUSION: Approximately 14% of children with TBI developed oppositional defiant disorder or conduct disorder. The risk for novel oppositional defiant disorder or conduct disorder can be understood from a biopsychosocial perspective. Sex differences were evident for comorbid novel depressive disorder and comorbid novel ADHD.

The genetic architecture of youth anxiety: a study protocol.

BACKGROUND: Anxiety disorders are the most common psychiatric problems among Canadian youth and typically have an onset in childhood or adolescence. They are characterized by high rates of relapse and chronicity, often resulting in substantial impairment across the lifespan. Genetic factors play an important role in the vulnerability toward anxiety disorders. However, genetic contribution to anxiety in youth is not well understood and can change across developmental stages. Large-scale genetic studies of youth are needed with detailed assessments of symptoms of anxiety disorders and their major comorbidities to inform early intervention or preventative strategies and suggest novel targets for therapeutics and personalization of care. METHODS: The Genetic Architecture of Youth Anxiety (GAYA) study is a Pan-Canadian effort of clinical and genetic experts with specific recruitment sites in Calgary, Halifax, Hamilton, Toronto, and Vancouver. Youth aged 10-19 (n = 13,000) will be recruited from both clinical and community settings and will provide saliva samples, complete online questionnaires on demographics, symptoms of mental health concerns, and behavioural inhibition, and complete neurocognitive tasks. A subset of youth will be offered access to a self-managed Internet-based cognitive behavioral therapy resource. Analyses will focus on the identification of novel genetic risk loci for anxiety disorders in youth and assess how much of the genetic risk for anxiety disorders is unique or shared across the life span. DISCUSSION: Results will substantially inform early intervention or preventative strategies and suggest novel targets for therapeutics and personalization of care. Given that the GAYA study will be the biggest genomic study of anxiety disorders in youth in Canada, this project will further foster collaborations nationally and across the world.

Is irritability multidimensional: Psychometrics of The Irritability and Dysregulation of Emotion Scale (TIDES-13).

Irritability is a common, impairing, and potentially multifaceted manifestation of psychopathology. We designed The Irritability and Dysregulation of Emotion Scale (TIDES-13) to determine whether various expressions of irritability in children and youth form multiple subdimensions with distinct correlates. We administered parent-report (n = 3875, mean age = 8.9) and youth self-report (n = 579, mean age = 15.1) versions of TIDES-13 in a population and community-based sample. We conducted exploratory/confirmatory factor analyses and regression analyses to examine the dimensionality of TIDES-13 and the associations of the scale with age, gender, anxiety, depression, ODD, ADHD traits, and the Affective Reactivity Index (ARI). A higher-order model with a global irritability dimension and four subdimensions, including proneness to anger (PA), internalized negative emotional reactivity (iNER), externalized negative emotional reactivity (eNER), and reactive aggression (RA), showed good to excellent fit in both parent-report and self-report. The global irritability dimension showed excellent internal reliability (⍵Total; parent-report = 0.97, ⍵Total; self-report = 0.95), explained a majority of the item variance (⍵Hierarchical; parent-report = 0.94, ⍵Hierarchical; self-report = 0.90), and was moderately correlated with the ARI (rparent = 0.68, rself = 0.77). Subdimensions PA, eNER, and RA were negatively associated with age in males, whereas iNER was positively associated with age in females. Traits of ODD and ADHD were associated primarily with the global irritability dimension, whereas iNER was strongly associated with anxiety and depression traits over and above the global irritability dimension. Our results support a unidimensional interpretation of irritability in a population sample. However, limited evidence of specific behavioral, age, and sex correlates with particular irritability subdimensions may warrant further investigation.

Novel Psychiatric Disorder 6 Months After Traumatic Brain Injury in Children and Adolescents.

OBJECTIVE: To investigate the factors predictive of novel psychiatric disorders in the interval 0-6 months following traumatic brain injury (TBI). METHODS: Children ages 5-14 years consecutively hospitalized for mild to severe TBI at five hospitals were recruited. Participants were evaluated at baseline (soon after injury) for pre-injury characteristics including psychiatric disorders, socioeconomic status (SES), psychosocial adversity, family function, family psychiatric history, and adaptive function. In addition to the psychosocial variables, injury severity and lesion location detected with acquisition of a research MRI were measured to develop a biopsychosocial predictive model for development of novel psychiatric disorders. Psychiatric outcome, including occurrence of a novel psychiatric disorder, was assessed 6 months after the injury. RESULTS: The recruited sample numbered 177 children, and 141 children (80%) returned for the six-month assessment. Of the 141 children, 58 (41%) developed a novel psychiatric disorder. In univariable analyses, novel psychiatric disorder was significantly associated with lower SES, higher psychosocial adversity, and lesions in frontal lobe locations, such as frontal white matter, superior frontal gyrus, inferior frontal gyrus, and orbital gyrus. Multivariable analyses found that novel psychiatric disorder was independently and significantly associated with frontal-lobe white matter, superior frontal gyrus, and orbital gyrus lesions. CONCLUSION: The results demonstrate that occurrence of novel psychiatric disorders following pediatric TBI requiring hospitalization is common and has identifiable psychosocial and specific biological predictors. However, only the lesion predictors were independently related to this adverse psychiatric outcome.

Obsessive-compulsive disorder in children and youth: neurocognitive function in clinic and community samples.

BACKGROUND: Neurocognitive impairments are common in OCD, although not well studied in children and youth with the disorder. METHOD: Using the stop-signal task (SST), we measured response inhibition (stop-signal reaction time-SSRT), sustained attention (reaction time variability-RTV), reaction time (RT), and performance monitoring (post-error slowing-PES) in OCD cases and controls from two samples of children and youth. A Clinic OCD group (n = 171, aged 7-17 years) was recruited from a specialty clinic after rigorous assessment. A typically developing (Clinic TD, n = 157) group was enlisted through advertisement. A community OCD sample (Community OCD, n = 147) and controls (Community TD n = 13,832, aged 6-17 years) were recruited at a science museum. We also identified a community group with high OCD traits without an OCD diagnosis (Community High Trait; n = 125). RESULTS: Clinic OCD participants had longer SSRT and greater RTV than Clinic TD. These effects were greater in younger OCD participants and, for SSRT, in those on medication for OCD. The Community OCD group did not differ from Controls but was similar to the Clinic OCD group in ADHD and ASD comorbidity and medication usage. The Community High Trait group had longer SSRT and atypical PES suggesting that symptom severity predicts neurocognitive function. No group differences were found in RT. CONCLUSIONS: In the largest study of neurocognitive performance in children with OCD to date, we found impaired response inhibition and sustained attention in OCD participants in comparison to typically developing peers. Performance was worse in younger OCD participants. In the community sample, participants with high OCD trait scores but no OCD diagnosis had impaired response inhibition and error processing, suggesting that OCD might be under-recognized.

Novel Oppositional Defiant Disorder 12 Months After Traumatic Brain Injury in Children and Adolescents.

OBJECTIVE: The investigators examined the factors predictive of novel oppositional defiant disorder in the 6-12 months following traumatic brain injury (TBI). METHODS: Children ages 5-14 years old who experienced a TBI were recruited from consecutive admissions to five hospitals. Participants were evaluated soon after injury (baseline) for preinjury characteristics, including psychiatric disorders, adaptive function, family function, psychosocial adversity, family psychiatric history, socioeconomic status, and injury severity, to develop a biopsychosocial predictive model for development of novel oppositional defiant disorder. MRI analyses were conducted to examine potential brain lesions. Psychiatric outcome, including that of novel oppositional defiant disorder, was assessed 12 months after injury. RESULTS: Although 177 children were recruited for the study, 120 children without preinjury oppositional defiant disorder, conduct disorder, or disruptive behavior disorder not otherwise specified (DBD NOS) returned for the 12-month assessment. Of these 120 children, seven (5.8%) exhibited novel oppositional defiant disorder, and none developed conduct disorder or DBD NOS in the 6-12 months postinjury. Novel oppositional defiant disorder was significantly associated with lower socioeconomic status, higher psychosocial adversity, and lower preinjury adaptive functioning. CONCLUSIONS: These results demonstrate that novel oppositional defiant disorder following TBI selectively and negatively affects an identifiable group of children. Both proximal (preinjury adaptive function) and distal (socioeconomic status and psychosocial adversity) psychosocial variables significantly increase risk for this outcome.

Novel Oppositional Defiant Disorder 6 Months After Traumatic Brain Injury in Children and Adolescents.

OBJECTIVE: The investigators aimed to assess predictive factors of novel oppositional defiant disorder (ODD) among children and adolescents in the first 6 months following traumatic brain injury (TBI). METHODS: Children ages 5-14 years who experienced a TBI were recruited from consecutive admissions to five hospitals. Testing of a biopsychosocial model that may elucidate the development of novel ODD included assessment soon after injury (baseline) of preinjury characteristics, including psychiatric disorders, adaptive function, family function, psychosocial adversity, family psychiatric history, socioeconomic status, injury severity, and postinjury processing speed (which may be a proxy for brain injury). MRI analyses were also conducted to examine potential brain lesions. Psychiatric outcome, including that of novel ODD, was assessed 6 months after the injury. RESULTS: A total of 177 children and adolescents were recruited for the study, and 134 who were without preinjury ODD, conduct disorder, or disruptive behavior disorder not otherwise specified (DBD NOS) returned for the 6-month assessment. Of those who returned 6 months postinjury, 11 (8.2%) developed novel ODD, and none developed novel conduct disorder or DBD NOS. Novel ODD was significantly associated with socioeconomic status, preinjury family functioning, psychosocial adversity, and processing speed. CONCLUSIONS: These findings show that an important minority of children with TBI developed ODD. Psychosocial and injury-related variables, including socioeconomic status, lower family function, psychosocial adversity, and processing speed, significantly increase risk for this outcome.

Mostly worse, occasionally better: impact of COVID-19 pandemic on the mental health of Canadian children and adolescents.

This large cross-sectional study examined the impact of COVID-19 emergency measures on child/adolescent mental health for children/adolescents with and without pre-existing psychiatric diagnoses. Using adapted measures from the CRISIS questionnaire, parents of children aged 6-18 (N = 1013; 56% male; 62% pre-existing psychiatric diagnosis) and self-reporting children/adolescents aged 10-18 (N = 385) indicated changes in mental health across six domains: depression, anxiety, irritability, attention, hyperactivity, and obsessions/compulsions. Changes in anxiety, irritability, and hyperactivity were calculated for children aged 2-5 years using the Strengths and Difficulties Questionnaire. COVID-19 exposure, compliance with emergency measures, COVID-19 economic concerns, and stress from social isolation were measured with the CRISIS questionnaire. Prevalence of change in mental health status was estimated for each domain; multinomial logistic regression was used to determine variables associated with mental health status change in each domain. Depending on the age group, 67-70% of children/adolescents experienced deterioration in at least one mental health domain; however, 19-31% of children/adolescents experienced improvement in at least one domain. Children/adolescents without and with psychiatric diagnoses tended to experience deterioration during the first wave of COVID-19. Rates of deterioration were higher in those with a pre-exiting diagnosis. The rate of deterioration was variable across different age groups and pre-existing psychiatric diagnostic groups: depression 37-56%, anxiety 31-50%, irritability 40-66%, attention 40-56%, hyperactivity 23-56%, obsessions/compulsions 13-30%. Greater stress from social isolation was associated with deterioration in all mental health domains (all ORs 11.12-55.24). The impact of pre-existing psychiatric diagnosis was heterogenous, associated with deterioration in depression, irritability, hyperactivity, obsession/compulsions for some children (ORs 1.96-2.23) but also with improvement in depression, anxiety, and irritability for other children (ORs 2.13-3.12). Economic concerns were associated with improvement in anxiety, attention, and obsessions/compulsions (ORs 3.97-5.57). Children/adolescents with and without pre-existing psychiatric diagnoses reported deterioration. Deterioration was associated with increased stress from social isolation. Enhancing social interactions for children/adolescents will be an important mitigation strategy for current and future COVID-19 waves.

Mental health profiles of autistic children and youth during the COVID-19 pandemic.

Objectives: Canadian province-wide lockdowns have challenged children's mental health (MH) during the COVID-19 pandemic, with autistic children being at particular risk. The purpose of our study was to identify sub-groups of autistic children with distinct mental health change profiles, to understand the child-, parent-, and system-specific factors associated with such profiles in order to ultimately inform future interventions. Methods: Data were drawn from a large Canadian cohort (N=1,570) across Ontario, resulting in 265 autistic children (mean age=10.9 years, 76% male). K-means clustering analyses were employed to partition distinct MH profiles in six MH measures (mood, anxiety, OCD symptoms, irritability, inattention, hyperactivity) and group differences were examined with reference to the above factors. Additionally, we investigated the characteristics of children who accessed acute MH services. Results: The optimal number of clusters was two; one included those experiencing MH deterioration across all six MH measures (61.3%, 95% confidence interval [CI]=54.9 to 67.4), and a second included youth that did not experience MH changes (38.7%, 95%CI=32.6 to 45.1). Child-specific factors associated with MH deterioration included higher pre-existing internalizing symptoms, high levels of COVID stress. Parental MH challenges and system-specific factors, such as the loss of learning supports, access to physicians and material deprivation, were also associated with MH deterioration. Access to acute MH services were primarily associated with financial insecurity and loss of services. Conclusions: More than half of autistic children experienced MH deterioration, and person-specific (pre-existing MH, COVID related stress), parent-specific (Parent MH) and system-level (loss of services and material deprivation) characteristics were associated with such decline, providing clinical and policy opportunities for intervention at multiple levels.

Cognitive and behavioral risk factors for low quality of life in survivors of childhood acute lymphoblastic leukemia.

BACKGROUND: With high survival rates for pediatric acute lymphoblastic leukemia (ALL), long-term quality of life is a prominent consideration in treatment. We concurrently evaluated cognition, behavior, and quality of life in child and adolescent ALL survivors and determined associations between them. METHODS: The sample included 83 controls (mean age: 12.5 years) and 71 ALL survivors (mean age: 11.9 years, mean age at diagnosis: 3.8 years). Participants completed measures of general intellectual abilities, math achievement, and fine motor skills. Parents and teachers completed a survey assessing child participants' cognitive, behavioral, and emotional function. Parents additionally completed a survey about their child's quality of life. RESULTS: Survivors had lower scores on measures of working memory, processing speed, timed math, and fine motor skills (effect size 0.5-1, p < 0.001). Parents identified more problems with executive function and learning in survivors than controls (effect size > 0.7, p < 0.001), and indicated a lower quality of life in all categories evaluated (effect size > 0.7, p < 10-4). Reduced quality of life was associated with lower math achievement scores and with inattention and executive function problems. CONCLUSIONS: ALL survivors experience diffuse cognitive, behavioral, and motor impairments, which are associated with reduced quality of life. These findings underscore the need to address these challenges in ALL survivors. IMPACT: Compared with cancer-free peers, parents of childhood acute lymphoblastic leukemia survivors treated with chemotherapy only reported reduced quality of life. Math difficulties and behavioral problems increased the risk for reduced quality of life. Reduced quality of life is associated with mild cognitive and behavioral difficulties, suggesting that even relatively mild impairments have broad implications for ALL survivors. Screening and early intervention targeting cognitive and behavioral function may enhance quality of life for ALL survivors.

Serotonin system genes and hoarding with and without other obsessive-compulsive traits in a population-based, pediatric sample: A genetic association study.

BACKGROUND: Hoarding, originally only considered a symptom of obsessive-compulsive disorder (OCD), is now categorized as a separate disorder in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). We studied candidate serotonergic genes and the distinctness of hoarding in children and adolescents and hypothesized that unique gene variants would be associated with hoarding alone. METHODS: We examined obsessive-compulsive (OC) traits, including hoarding, in a total of 5,213 pediatric participants in the community. We genotyped candidate serotonin genes (5-HTTLPR polymorphism in SLC6A4 for 2,018 individuals and single nucleotide polymorphisms [SNPs] across genes SLC6A4, HTR2A, and HTR1B for 4,711 individuals). In a previous study conducted by our group in the same sample, we identified a significant association between 5-HTTLPR and hoarding in males. In this study, we examined hoarding more closely by testing the association between serotonin gene variants and hoarding traits with and without other accompanying OC traits. RESULTS: The [LG +S] variant in 5-HTTLPR was significantly associated with hoarding alone in males (p-value of 0.009). There were no significant findings for 5-HTTLPR in females. There were no significant findings after correction for multiple comparisons using SNP array data, but top SNP findings suggested that variation downstream of HTR1B may be implicated in hoarding alone in females. CONCLUSIONS: Our results suggest specific serotonin gene variants are associated with hoarding traits alone, differing between sexes. Top findings are in line with our former study, suggesting that individuals with hoarding alone were driving previous results. Our paper supports hoarding disorder's new designation.

Serotonin system genes and obsessive-compulsive trait dimensions in a population-based, pediatric sample: a genetic association study.

BACKGROUND: Serotonin system genes are commonly studied in obsessive-compulsive disorder (OCD), but genetic studies to date have produced inconsistent results, possibly because phenotypic heterogeneity has not been adequately accounted for. In this paper, we studied candidate serotonergic genes and homogenous phenotypic subgroups as presented through obsessive-compulsive (OC) trait dimensions in a general population of children and adolescents. We hypothesized that different serotonergic gene variants are associated with different OC trait dimensions and, furthermore, that they vary by sex. METHODS: Obsessive-compulsive trait dimensions (Cleaning/Contamination, Counting/Checking, Symmetry/Ordering, Superstition, Rumination, and Hoarding) were examined in a total of 5,213 pediatric participants in the community using the Toronto Obsessive-Compulsive Scale (TOCS). We genotyped candidate serotonin genes (directly genotyping the 5-HTTLPR polymorphism in SLC6A4 for 2018 individuals and using single nucleotide polymorphism (SNP) array data for genes SLC6A4, HTR2A, and HTR1B for 4711 individuals). We assessed the association between variants across these genes and each of the OC trait dimensions, within males and females separately. We analyzed OC traits as both (a) dichotomized based on a threshold value and (b) quantitative scores. RESULTS: The [LG + S] variant in 5-HTTLPR was significantly associated with hoarding in males (p-value of 0.003 and 0.004 for categorical and continuous analyses, respectively). There were no significant findings for 5-HTTLPR in females. Using SNP array data, there were significant findings for rumination in males for HTR2A SNPs (p-value of 1.04e-6 to 5.20e-6). CONCLUSIONS: This represents the first genetic association study of OC trait dimensions in a community-based pediatric sample. Our strongest results indicate that hoarding and rumination may be distinct in their association with serotonin gene variants and that serotonin gene variation may be specific to sex. Future genetic association studies in OCD should properly account for heterogeneity, using homogenous subgroups stratified by symptom dimension, sex, and age group.

SWAN scale for ADHD trait-based genetic research: a validity and polygenic risk study.

BACKGROUND: Population-based samples with valid, quantitative and genetically informative trait measures of psychopathology could be a powerful complement to case/control genetic designs. We report the convergent and predictive validity of the parent- and self-report versions of the Strengths and Weaknesses of ADHD Symptoms and Normal Behavior Rating Scale (SWAN). We tested if SWAN scores were associated with ADHD diagnosis, ADHD polygenic risk, as well as traits and polygenic risk for disorders that co-occur with ADHD: anxiety and obsessive-compulsive disorder (OCD). METHODS: We collected parent- and self-report SWAN scores in a sample of 15,560 children and adolescents (6-17 years) recruited at a science museum (Spit for Science sample). We established age and sex norms for the SWAN. Sensitivity-specificity analyses determined SWAN cut-points that discriminated those with and without a reported ADHD diagnosis. These cut-points were validated in a clinic sample (266 ADHD cases; 36 controls). Convergent validity was established using the Conners' parent- and self-report scales. Using Spit for Science participants with genome-wide data (n = 5,154), we tested if low, medium and high SWAN scores were associated with polygenic risk for ADHD, OCD and anxiety disorders. RESULTS: Parent- and self-report SWAN scores showed high convergent validity with Conners' scales and distinguished ADHD participants with high sensitivity and specificity in the Spit for Science sample. In a clinic sample, the Spit for Science cut-points discriminated ADHD cases from controls with a sensitivity of 84% and specificity of 92%. High SWAN scores and scores above the Spit for Science cut-points were significantly associated with polygenic risk for ADHD. SWAN scores were not associated with polygenic risk for OCD or anxiety disorders. CONCLUSIONS: Our study supports the validity of the parent- and self-report SWAN scales and their potential in ADHD population-based genetic research.

Disruption of the ASTN2/TRIM32 locus at 9q33.1 is a risk factor in males for autism spectrum disorders, ADHD and other neurodevelopmental phenotypes.

Rare copy number variants (CNVs) disrupting ASTN2 or both ASTN2 and TRIM32 have been reported at 9q33.1 by genome-wide studies in a few individuals with neurodevelopmental disorders (NDDs). The vertebrate-specific astrotactins, ASTN2 and its paralog ASTN1, have key roles in glial-guided neuronal migration during brain development. To determine the prevalence of astrotactin mutations and delineate their associated phenotypic spectrum, we screened ASTN2/TRIM32 and ASTN1 (1q25.2) for exonic CNVs in clinical microarray data from 89 985 individuals across 10 sites, including 64 114 NDD subjects. In this clinical dataset, we identified 46 deletions and 12 duplications affecting ASTN2. Deletions of ASTN1 were much rarer. Deletions near the 3' terminus of ASTN2, which would disrupt all transcript isoforms (a subset of these deletions also included TRIM32), were significantly enriched in the NDD subjects (P = 0.002) compared with 44 085 population-based controls. Frequent phenotypes observed in individuals with such deletions include autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), speech delay, anxiety and obsessive compulsive disorder (OCD). The 3'-terminal ASTN2 deletions were significantly enriched compared with controls in males with NDDs, but not in females. Upon quantifying ASTN2 human brain RNA, we observed shorter isoforms expressed from an alternative transcription start site of recent evolutionary origin near the 3' end. Spatiotemporal expression profiling in the human brain revealed consistently high ASTN1 expression while ASTN2 expression peaked in the early embryonic neocortex and postnatal cerebellar cortex. Our findings shed new light on the role of the astrotactins in psychopathology and their interplay in human neurodevelopment.

Personality Change Due to Traumatic Brain Injury in Children and Adolescents: Neurocognitive Correlates.

Personality change due to traumatic brain injury (PC) in children is an important psychiatric complication of injury and is a form of severe affective dysregulation. This study aimed to examine neurocognitive correlates of PC. The sample included 177 children 5-14 years old with traumatic brain injury who were enrolled from consecutive admissions to five trauma centers. Patients were followed up prospectively at baseline and at 6 months, and they were assessed with semistructured psychiatric interviews. Injury severity, socioeconomic status, and neurocognitive function (measures of attention, processing speed, verbal memory, IQ, verbal working memory, executive function, naming/reading, expressive language, motor speed, and motor inhibition) were assessed with standardized instruments. Unremitted PC was present in 26 (18%) of 141 participants assessed at 6 months postinjury. Attention, processing speed, verbal memory, IQ, and executive function were significantly associated with PC even after socioeconomic status, injury severity, and preinjury attention deficit hyperactivity disorder were controlled. These findings are a first step in characterizing concomitant cognitive impairments associated with PC. The results have implications beyond brain injury to potentially elucidate the neurocognitive symptom complex associated with mood instability regardless of etiology.

Psychiatric disorders in children and adolescents 24 months after mild traumatic brain injury.

This study aimed to better understand the occurrence of novel psychiatric disorders (NPDs) in children with mild traumatic brain injury (mTBI) in relation to preinjury variables, injury-related variables, and concurrent neurocognitive outcome. Eighty-seven children aged 5-14 years who had experienced mTBI were studied from consecutive hospital admissions with semistructured psychiatric interviews soon after injury (baseline). Fifty-four children were reassessed 24 months postinjury. Standardized instruments were used to evaluate injury severity, lesion characteristics, preinjury variables (lifetime psychiatric disorder, family psychiatric history, family function, socioeconomic status, psychosocial adversity, adaptive function, and academic function), and finally, postinjury neurocognitive and adaptive function. At 24 months postinjury, NPDs had occurred in 17 of 54 (31%) participants. NPD at 24 months was related to frontal white matter lesions and was associated with estimated preinjury reading, preinjury adaptive function, and concurrent deficits in reading, processing speed, and adaptive function. These findings extend earlier reports that the psychiatric morbidity after mTBI in children is more common than previously thought, and moreover, it is linked to preinjury individual variables and injury characteristics and is associated with postinjury adaptive and neurocognitive functioning.

Neuropsychological performance of youth with secondary attention-deficit/hyperactivity disorder 6- and 12-months after traumatic brain injury.

The present study compared executive dysfunction among children with attention-deficit/hyperactivity disorder (ADHD) after traumatic brain injury (TBI), also called secondary ADHD (S-ADHD), pre-injury ADHD and children with TBI only (i.e., no ADHD). Youth aged 6-16 years admitted for TBI to five trauma centers were enrolled (n=177) and evaluated with a semi-structured psychiatric interview scheduled on three occasions (within 2 weeks of TBI, i.e., baseline assessment for pre-injury status; 6-months and 12-months post-TBI). This permitted the determination of 6- and 12-month post-injury classifications of membership in three mutually exclusive groups (S-ADHD; pre-injury ADHD; TBI-only). Several executive control measures were administered. Unremitted S-ADHD was present in 17/141 (12%) children at the 6-month assessment, and in 14/125 (11%) children at 12-months post-injury. The study found that children with S-ADHD exhibited deficient working memory, attention, and psychomotor speed as compared to children with pre-injury ADHD. Furthermore, the children with S-ADHD and the children with TBI-only were impaired compared to the children with pre-injury ADHD with regard to planning. No group differences related to response inhibition emerged. Age, but not injury severity, gender, or adaptive functioning was related to executive function outcome. Neuropsychological sequelae distinguish among children who develop S-ADHD following TBI and those with TBI only. Moreover, there appears to be a different pattern of executive control performance in those who develop S-ADHD than in children with pre-injury ADHD suggesting that differences exist in the underlying neural mechanisms that define each disorder, underscoring the need to identify targeted treatment interventions.

Dorsal Striatal Functional Connectivity and Repetitive Behavior Dimensions in Children and Youths With Neurodevelopmental Disorders.

BACKGROUND: Impairing repetitive behaviors are one of the core diagnostic symptoms in autism spectrum disorder and obsessive-compulsive disorder, but they also manifest in attention-deficit/hyperactivity disorder. Although the dorsal striatal circuit has been implicated in repetitive behaviors, extensive heterogeneity in and cross-diagnostic manifestations of these behaviors have suggested phenotypic and likely neurobiological heterogeneity across neurodevelopmental disorders (NDDs). METHODS: Intrinsic dorsal striatal functional connectivity was examined in 3 NDDs (autism spectrum disorder, obsessive-compulsive disorder, and attention-deficit/hyperactivity disorder) and typically developing control participants in a large single-cohort sample (N = 412). To learn how diagnostic labels and overlapping behaviors manifest in dorsal striatal functional connectivity measured with functional magnetic resonance imaging, the main and interaction effects of diagnosis and behavior were examined in 8 models (2 seed functional connectivity [caudate and putamen] × 4 sub-behavioral domains [sameness/ritualistic, self-injury, stereotypy, and compulsions]). RESULTS: The obsessive-compulsive disorder group demonstrated distinctive patterns in visual and visuomotor coordination regions compared with the other diagnostic groups. Lower-order repetitive behaviors (self-injury and stereotypy) manifesting across all participants were implicated in regions involved in motor and cognitive control, although the findings did not survive effects of multiple comparisons, suggesting heterogeneity in these behavioral domains. An interaction between self-injurious behavior and an attention-deficit/hyperactivity disorder diagnosis were observed on caudate-cerebellum functional connectivity. CONCLUSIONS: These findings confirmed high heterogeneity and overlapping behavioral manifestations in NDDs and their complex underlying neural mechanisms. A call for diagnosis-free symptom measures that can capture not only observable symptoms and severity across NDDs but also the underlying functions and motivations of such behaviors across diagnoses is needed.