Gene × environment interactions for ADHD: synergistic effect of 5HTTLPR genotype and youth appraisals of inter-parental conflict

<p>Abstract</p> <p>Background</p> <p>Serotonin genes have been hypothesized to play a role in the etiology of attention-deficit hyperactivity disorder (ADHD); prior work suggests that serotonin may interact with psychosocial stressors in ADHD, perhaps via mechanisms involved in emotional dysregulation. Because the development of behavioral and emotional regulation depends heavily both on the child's experience within the family context and the child's construals of that experience, children's appraisals of inter-parental conflict are a compelling candidate potentiator of the effects of variation within the serotonin transporter gene promoter polymorphism (5HTTLPR) on liability for ADHD.</p> <p>Method</p> <p>304 youth from the local community underwent a multi-informant diagnostic assessment procedure to identify ADHD cases and non-ADHD controls. Youth also completed the Children's Perception of Inter-Parental Conflict (CPIC) scale to assess appraisals of self-blame in relation to their parents' marital disputes. The trialleic configuration of 5HTTLPR (long/short polymorphism with A> G substitution) was genotyped and participants were assigned as having high (La/La N = 78), intermediate (La/Lg, La/short, N = 137), or low (Lg/Lg, Lg/short, short/short, N = 89) serotonin transporter activity genotypes. Teacher reported behavior problems were examined as the target outcome to avoid informant overlap for moderator and outcome measures.</p> <p>Results</p> <p>Hierarchical linear regression analyses indicated significant 5HTTLPR × self-blame interactions for ADHD symptoms. Examination of the interactions indicated positive relations between reports of self-blame and ADHD symptoms for those with the high and low serotonin activity genotypes. There was no relation between self-blame and ADHD for those with intermediate activity 5HTTLPR genotypes.</p> <p>Conclusion</p> <p>Both high and low serotonergic activity may exert risk for ADHD when coupled with psychosocial distress such as children's self-blame in relation to inter-parental conflict. Results are discussed in relation to the role of serotonin in the etiology of the ADHD and related externalizing behaviors.</p

A Network Analysis of Developmental Change in ADHD Symptom Structure from Preschool to Adulthood

Although there is substantial support for the validity of the diagnosis of attention-deficit/hyperactivity disorder (ADHD), there is considerable disagreement about how to best capture developmental changes in the expression of ADHD symptomatology. This article examines the associations among the 18 individual ADHD symptoms using a novel network analysis approach, from preschool to adulthood. The 1,420 participants were grouped into four age brackets: preschool (ages 3–6, n = 109), childhood (ages 6–12, n = 548), adolescence (ages 13–17, n = 357), and young adulthood (ages 18–36, n = 406). All participants completed a multistage, multi-informant diagnostic process, and self and informant symptom ratings were obtained. Network analysis indicated ADHD symptom structure became more differentiated over development. Two symptoms, often easily distracted and difficulty sustaining attention, appeared as central, or core, symptoms across all age groups. Thus, a small number of core symptoms may warrant extra weighting in future diagnostic systems

Childhood Sleep Problems, Response Inhibition, and Alcohol and Drug Outcomes in Adolescence and Young Adulthood

To our knowledge, no prospective studies examine the relationships among childhood sleep problems, adolescent executive functioning, and substance outcomes (i.e., substance use and substance-related problems). In this study, we examined whether childhood sleep problems predicted adolescent sleep problems and response inhibition. We also tested whether adolescent sleep problems and poor response inhibition mediated the relationship between childhood sleep problems and substance (alcohol and drug) outcomes in young adulthood.Study participants were 292 boys and 94 girls (M = 4.85, SD = 1.47) from a community sample of high-risk families and controls.When compared to their counterparts, those with trouble sleeping in childhood were twice as likely to have the same problem in adolescence. Childhood overtiredness predicted poor response inhibition in adolescence. Persistent trouble sleeping from childhood to adolescence and response inhibition in adolescence mediated the relationship between childhood sleep problems and drug outcomes in young adulthood, whereas overtiredness in childhood directly predicted alcohol use outcomes and alcohol-related problems in young adulthood.This is the first study showing a long-term relationship between childhood sleep measures and subsequent alcohol and drug outcomes. The developmental and clinical implications of these findings were discussed. Prevention and intervention programs may want to consider the role of sleep problems and response inhibition on substance use and abuse.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/79313/1/j.1530-0277.2010.01178.x.pd

Affective Circuitry and Risk for Alcoholism in Late Adolescence: Differences in Frontostriatal Responses Between Vulnerable and Resilient Children of Alcoholic Parents

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65950/1/j.1530-0277.2007.00605.x.pd

Maturing Thalamocortical Functional Connectivity Across Development

Recent years have witnessed a surge of investigations examining functional brain organization using resting-state functional connectivity MRI (rs-fcMRI). To date, this method has been used to examine systems organization in typical and atypical developing populations. While the majority of these investigations have focused on cortical–cortical interactions, cortical–subcortical interactions also mature into adulthood. Innovative work by Zhang et al. (2008) in adults have identified methods that utilize rs-fcMRI and known thalamo-cortical topographic segregation to identify functional boundaries in the thalamus that are remarkably similar to known thalamic nuclear grouping. However, despite thalamic nuclei being well formed early in development, the developmental trajectory of functional thalamo-cortical relations remains unexplored. Thalamic maps generated by rs-fcMRI are based on functional relationships, and should modify with the dynamic thalamo-cortical changes that occur throughout maturation. To examine this possibility, we employed a strategy as previously described by Zhang et al. to a sample of healthy children, adolescents, and adults. We found strengthening functional connectivity of the cortex with dorsal/anterior subdivisions of the thalamus, with greater connectivity observed in adults versus children. Temporal lobe connectivity with ventral/midline/posterior subdivisions of the thalamus weakened with age. Changes in sensory and motor thalamo-cortical interactions were also identified but were limited. These findings are consistent with known anatomical and physiological cortical–subcortical changes over development. The methods and developmental context provided here will be important for understanding how cortical–subcortical interactions relate to models of typically developing behavior and developmental neuropsychiatric disorders

Resiliency in Adolescents at High Risk for Substance Abuse: Flexible Adaptation via Subthalamic Nucleus and Linkage to Drinking and Drug Use in Early Adulthood

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/92431/1/acer1741.pd

Real-time motion analytics during brain MRI improve data quality and reduce costs

Head motion systematically distorts clinical and research MRI data. Motion artifacts have biased findings from many structural and functional brain MRI studies. An effective way to remove motion artifacts is to exclude MRI data frames affected by head motion. However, such post-hoc frame censoring can lead to data loss rates of 50% or more in our pediatric patient cohorts. Hence, many scanner operators collect additional 'buffer data', an expensive practice that, by itself, does not guarantee sufficient high-quality MRI data for a given participant. Therefore, we developed an easy-to-setup, easy-to-use Framewise Integrated Real-time MRI Monitoring (FIRMM) software suite that provides scanner operators with head motion analytics in real-time, allowing them to scan each subject until the desired amount of low-movement data has been collected. Our analyses show that using FIRMM to identify the ideal scan time for each person can reduce total brain MRI scan times and associated costs by 50% or more

Are language production problems apparent in adults who no longer meet diagnostic criteria for attention-deficit/hyperactivity disorder?

In this study, we examined sentence production in a sample of adults (N = 21) who had had attention-deficit/hyperactivity disorder (ADHD) as children, but as adults no longer met DSM-IV diagnostic criteria (APA, 2000). This “remitted” group was assessed on a sentence production task. On each trial, participants saw two objects and a verb. Their task was to construct a sentence using the objects as arguments of the verb. Results showed more ungrammatical and disfluent utterances with one particular type of verb (i.e., participle). In a second set of analyses, we compared the remitted group to both control participants and a “persistent” group, who had ADHD as children and as adults. Results showed that remitters were more likely to produce ungrammatical utterances and to make repair disfluencies compared to controls, and they patterned more similarly to ADHD participants. Conclusions focus on language output in remitted ADHD, and the role of executive functions in language production

Altered Cortico-Striatal–Thalamic Connectivity in Relation to Spatial Working Memory Capacity in Children with ADHD

Introduction: Attention deficit hyperactivity disorder (ADHD) captures a heterogeneous group of children, who are characterized by a range of cognitive and behavioral symptoms. Previous resting-state functional connectivity MRI (rs-fcMRI) studies have sought to understand the neural correlates of ADHD by comparing connectivity measurements between those with and without the disorder, focusing primarily on cortical–striatal circuits mediated by the thalamus. To integrate the multiple phenotypic features associated with ADHD and help resolve its heterogeneity, it is helpful to determine how specific circuits relate to unique cognitive domains of the ADHD syndrome. Spatial working memory has been proposed as a key mechanism in the pathophysiology of ADHD. Methods: We correlated the rs-fcMRI of five thalamic regions of interest (ROIs) with spatial span working memory scores in a sample of 67 children aged 7–11 years [ADHD and typically developing children (TDC)]. In an independent dataset, we then examined group differences in thalamo-striatal functional connectivity between 70 ADHD and 89 TDC (7–11 years) from the ADHD-200 dataset. Thalamic ROIs were created based on previous methods that utilize known thalamo-cortical loops and rs-fcMRI to identify functional boundaries in the thalamus. Results/Conclusion: Using these thalamic regions, we found atypical rs-fcMRI between specific thalamic groupings with the basal ganglia. To identify the thalamic connections that relate to spatial working memory in ADHD, only connections identified in both the correlational and comparative analyses were considered. Multiple connections between the thalamus and basal ganglia, particularly between medial and anterior dorsal thalamus and the putamen, were related to spatial working memory and also altered in ADHD. These thalamo-striatal disruptions may be one of multiple atypical neural and cognitive mechanisms that relate to the ADHD clinical phenotype

Sequencing of sporadic Attention‐Deficit Hyperactivity Disorder (ADHD) identifies novel and potentially pathogenic de novo variants and excludes overlap with genes associated with autism spectrum disorder

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137575/1/ajmgb32527.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137575/2/ajmgb32527_am.pd