Joey W. Trampush

Neuropsychological outcome in adolescents/young adults with childhood ADHD: profiles of persisters, remitters and controls.

BACKGROUND This study examined neuropsychological functioning in a longitudinal sample of adolescents/young adults with attention deficit/hyperactivity disorder (ADHD) and controls as a function of the persistence of ADHD. We hypothesized that measures of executive processes would parallel adolescent clinical status, with ADHD-persisters, but not remitters, differing significantly from controls. In contrast, persisters and remitters were hypothesized to perform similarly, and different from controls, on tasks requiring less effortful processing. METHODS Ninety-eight participants diagnosed with ADHD in childhood were reevaluated approximately 10 years later. Eighty-five never-ADHD controls similar in age, IQ, and sex distribution served as a comparison group. Participants were administered a psychiatric interview and neuropsychological test battery. RESULTS Those with childhood ADHD demonstrated broad neuropsychological deficits relative to controls. When the group with childhood ADHD was subdivided based on adolescent ADHD status, compared to controls, both persisters and remitters showed deficient perceptual sensitivity and response variability, and increased ankle movements recorded by a solid-state actigraph. Only persisters differed from controls on several measures of more effortful executive processes. CONCLUSIONS Findings provide preliminary support to the hypothesis that ADHD is associated with early-appearing and enduring subcortical dysfunction, while recovery over the course of development is associated with improvements in executive control functions.

Catecholamine response to exercise in children with attention deficit hyperactivity disorder.

The objective of this study was to examine differences in catecholamine (CA) response to exercise between children who had received a diagnosis of attention-deficit/hyperactivity disorder (ADHD) and age- and gender-matched controls. On the basis of the notion of a CA dysfunction in ADHD, we reasoned that the normal robust increase in circulating CA seen in response to exercise would be blunted in children with ADHD. To test this, we recruited 10 treatment-naïve children with newly diagnosed ADHD and 8 age-matched controls (all male) and measured CA response to an exercise test in which the work was scaled to each subjects physical capability. After exercise, epinephrine and norepinephrine increased in both control and ADHD subjects (p = 0.006 and p = 0.002, respectively), but the responses were substantially blunted in the ADHD group (p = 0.018) even though the work performed did not differ from controls. Circulating dopamine increased significantly in the control subjects (p < 0.016), but no increase was noted in the subjects with ADHD. Finally, a significant attenuation in the lactate response to exercise was found in ADHD (between groups, p < 0.005). Our data suggest that CA excretion after exercise challenges in children with ADHD is deficient. This deficiency can be detected using a minimally invasive, nonpharmacologic challenge.

Effects of the BDNF Val66Met Polymorphism on White Matter Microstructure in Healthy Adults

The BDNF Val66Met polymorphism, a possible risk variant for mental disorders, is a potent modulator of neural plasticity in humans and has been linked to deficits in gray matter structure, function, and cognition. The impact of the variant on brain white matter structure, however, is controversial and remains poorly understood. Here, we used diffusion tensor imaging to examine the effects of BDNF Val66Met genotype on white matter microstructure in a sample of 85 healthy Caucasian adults. We demonstrate decreases of fractional anisotropy and widespread increases in radial diffusivity in Val/Val homozygotes compared with Met-allele carriers, particularly in prefrontal and occipital pathways. These data provide an independent confirmation of prior imaging genetics work, are consistent with complex effects of the BDNF Val66Met polymorphism on human brain structure, and may serve to generate hypotheses about variation in white matter microstructure in mental disorders associated with this variant.

GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium

The complex nature of human cognition has resulted in cognitive genomics lagging behind many other fields in terms of gene discovery using genome-wide association study (GWAS) methods. In an attempt to overcome these barriers, the current study utilized GWAS meta-analysis to examine the association of common genetic variation (~8M single-nucleotide polymorphisms (SNP) with minor allele frequency ⩾1%) to general cognitive function in a sample of 35 298 healthy individuals of European ancestry across 24 cohorts in the Cognitive Genomics Consortium (COGENT). In addition, we utilized individual SNP lookups and polygenic score analyses to identify genetic overlap with other relevant neurobehavioral phenotypes. Our primary GWAS meta-analysis identified two novel SNP loci (top SNPs: rs76114856 in the CENPO gene on chromosome 2 and rs6669072 near LOC105378853 on chromosome 1) associated with cognitive performance at the genome-wide significance level (P<5 × 10−8). Gene-based analysis identified an additional three Bonferroni-corrected significant loci at chromosomes 17q21.31, 17p13.1 and 1p13.3. Altogether, common variation across the genome resulted in a conservatively estimated SNP heritability of 21.5% (s.e.=0.01%) for general cognitive function. Integration with prior GWAS of cognitive performance and educational attainment yielded several additional significant loci. Finally, we found robust polygenic correlations between cognitive performance and educational attainment, several psychiatric disorders, birth length/weight and smoking behavior, as well as a novel genetic association to the personality trait of openness. These data provide new insight into the genetics of neurocognitive function with relevance to understanding the pathophysiology of neuropsychiatric illness.

Childhood Maltreatment and Conduct Disorder: Independent Predictors of Adolescent Substance Use Disorders in Youth with Attention Deficit/Hyperactivity Disorder

Children with attention deficit/hyperactivity disorder (ADHD) are at heightened risk for maltreatment and later substance use disorders (SUDs). We investigated the relationship of childhood maltreatment and other risk factors to SUDs among adolescents diagnosed with ADHD in childhood. Eighty adolescents diagnosed with ADHD when they were 7 to 11 years old were screened for histories of childhood maltreatment, and SUD diagnoses were formulated in accordance with the 4th edition of the Diagnostic and Statistical Manual of Mental Disorders. Lifetime history of problematic substance use was obtained for each parent at baseline. Childhood maltreatment predicted SUD outcome over and above that accounted for by childhood conduct disorder and problematic parental substance use, two potent predictors of adolescent SUDs.

The Impact of Childhood ADHD on Dropping Out of High School in Urban Adolescents/Young Adults

Objective: To examine cognitive and psychosocial factors associated with high school dropout in urban adolescents with and without childhood ADHD. Method: In a longitudinal study, 49 adolescents/young adults with childhood ADHD and 44 controls who either dropped out or graduated from high school are included. Risk factors examined as potential correlates of dropout were intelligence, reading skills, socioeconomic status, marijuana use, and paternal contact. Results: Lower IQ, reading ability, socioeconomic status, frequent marijuana use, and limited paternal contact significantly differentiated dropouts from graduates, irrespective of childhood ADHD. Follow-up analyses determined that IQ, marijuana use, and paternal contact independently contribute to the likelihood of dropout. Conclusion: Selected cognitive and psychosocial factors appear independently associated with the likelihood of high school dropout irrespective of ADHD. Notably, childhood ADHD did not increase this risk, suggesting that previous reports of increased dropout because of ADHD may become negated in urban areas when matched with similar community controls. (J. of Att. Dis. 2009; 13(2) 127-136)

Association Between Variation in Neuropsychological Development and Trajectory of ADHD Severity in Early Childhood

OBJECTIVE This longitudinal study examined if changes in neuropsychological functioning were associated with the trajectory of symptoms related to attention deficit hyperactivity disorder (ADHD) and impairment between preschool and school age. METHOD The sample consisted of 3- and 4-year-old children (N=138) who were identified as being at risk for ADHD based on parent and teacher reports. Neuropsychological functioning was measured annually using the NEPSY at four time points (mean ages, 4.19, 5.36, 6.35, and 7.35 years). ADHD symptoms and impairment were assessed with semiannual parent and teacher reports using the ADHD Rating Scale-IV and the Childrens Problems Checklist at 10 time points (mean ages at baseline and final assessment, 4.19 and 8.81 years, respectively). Hierarchical linear modeling was used to assess the trajectories of change in neuropsychological functioning and ADHD severity as well as the association of change in neuropsychological functioning with change in ADHD severity over time. RESULTS Baseline neuropsychological functioning was not significantly associated with the slope of change in ADHD severity. However, the magnitude of change in neuropsychological functioning was linearly associated with the trajectory of ADHD symptom severity and impairment, such that individuals with greater neuropsychological growth over time had a greater diminution of ADHD severity and impairment. Family socioeconomic status at baseline was significantly associated with initial ADHD severity and impairment, but not with change over time. CONCLUSIONS Interventions that enhance neuropsychological functioning at an early age may be beneficial in attenuating long-term ADHD severity and impairment.

Perceptual and motor inhibition in adolescents/young adults with childhood-diagnosed ADHD.

OBJECTIVE This study examined perceptual and motor inhibition in a longitudinal sample of adolescents/young adults who were diagnosed with ADHD in childhood, and as a function of the relative persistence of ADHD. METHOD Ninety-eight participants diagnosed with ADHD in childhood were reevaluated approximately 10 years later. Eighty-five never-ADHD controls similar in age, IQ, sociodemographic background, and gender distribution served as a comparison group. Participants were administered a psychiatric interview and the Stimulus and Response Conflict Tasks (Nassauer & Halperin, 2003). RESULTS Participants with childhood ADHD demonstrated slower and less accurate responses to both control and conflict conditions relative to the comparison group, as well as more variable responses in both conditions of the motor inhibition task; there was no specific effect of childhood ADHD on perceptual or motor inhibition. ADHD persisters and partial remitters did not differ in overall accuracy, speed or variability in responding, but relative to partial remitters, persisters demonstrated greater slowing in response to perceptual conflict. CONCLUSIONS These findings are consistent with theories positing state regulation, but not inhibitory control deficits in the etiology of ADHD, and suggest that improved perceptual inhibition may be associated with better outcome for ADHD.

Differential Effects of Common Variants in SCN2A on General Cognitive Ability, Brain Physiology, and messenger RNA Expression in Schizophrenia Cases and Control Individuals

IMPORTANCE One approach to understanding the genetic complexity of schizophrenia is to study associated behavioral and biological phenotypes that may be more directly linked to genetic variation. OBJECTIVE To identify single-nucleotide polymorphisms associated with general cognitive ability (g) in people with schizophrenia and control individuals. DESIGN, SETTING, AND PARTICIPANTS Genomewide association study, followed by analyses in unaffected siblings and independent schizophrenia samples, functional magnetic resonance imaging studies of brain physiology in vivo, and RNA sequencing in postmortem brain samples. The discovery cohort and unaffected siblings were participants in the National Institute of Mental Health Clinical Brain Disorders Branch schizophrenia genetics studies. Additional schizophrenia cohorts were from psychiatric treatment settings in the United States, Japan, and Germany. The discovery cohort comprised 339 with schizophrenia and 363 community control participants. Follow-up analyses studied 147 unaffected siblings of the schizophrenia cases and independent schizophrenia samples including a total of an additional 668 participants. Imaging analyses included 87 schizophrenia cases and 397 control individuals. Brain tissue samples were available for 64 cases and 61 control individuals. MAIN OUTCOMES AND MEASURES We studied genomewide association with g, by group, in the discovery cohort. We used selected genotypes to test specific associations in unaffected siblings and independent schizophrenia samples. Imaging analyses focused on activation in the prefrontal cortex during working memory. Brain tissue studies yielded messenger RNA expression levels for RefSeq transcripts. RESULTS The schizophrenia discovery cohort showed genomewide-significant association of g with polymorphisms in sodium channel gene SCN2A, accounting for 10.4% of g variance (rs10174400, P = 9.27 × 10(-10)). Control individuals showed a trend for g/genotype association with reversed allelic directionality. The genotype-by-group interaction was also genomewide significant (P = 1.75 × 10(-9)). Siblings showed a genotype association with g parallel to the schizophrenia group and the same interaction pattern. Parallel, but weaker, associations with cognition were found in independent schizophrenia samples. Imaging analyses showed a similar pattern of genotype associations by group and genotype-by-group interaction. Sequencing of RNA in brain revealed reduced expression in 2 of 3 SCN2A alternative transcripts in the patient group, with genotype-by-group interaction, that again paralleled the cognition effects. CONCLUSIONS AND RELEVANCE The findings implicate SCN2A and sodium channel biology in cognitive impairment in schizophrenia cases and unaffected relatives and may facilitate development of cognition-enhancing treatments.

Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals.

Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1 million individuals and identify 1,271 independent genome-wide-significant SNPs. For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10 independent genome-wide-significant SNPs and estimate a SNP heritability of around 0.3% in both men and women, consistent with partial dosage compensation. A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11–13% of the variance in educational attainment and 7–10% of the variance in cognitive performance. This prediction accuracy substantially increases the utility of polygenic scores as tools in research.Gene discovery and polygenic predictions from a genome-wide association study of educational attainment in 1.1 million individuals.