Cognitive endophenotypes of ADHD

Abstract

Attention Deficit Hyperactivity Disorder is an impairing childhood-onset neuropsychiatric disorder, highly influenced by (multi)genetic factors. The precise genetic constellation of ADHD is still unknown. Since it is increasingly recognized that the traditional nosological categories described in the DSM-IV and ICD-10 are suboptimal when it comes to describing who is affected and carrying susceptibility genes and who is not, emphasis should be on the description of endophenotypes. Endophenotypes are latent traits that carry genetic loading and which are related indirectly to the classic behavioral symptoms as defined in DSM-IV or ICD-10. The main aim of this thesis was to uncover candidate cognitive endophenotypes of ADHD. The chapters 2 and 3 focused respectively on response inhibition and fine motor functioning as candidate endophenotypes of ADHD. These aspects of executive functioning were examined in a family-genetic study design with 25 carefully phenotyped ADHD probands with a family history of ADHD, their non-affected siblings (n = 25), and 48 normal controls (age ranged from 6 to 17 years in all groups). The non-affected siblings were compared with the ADHD probands and with the controls on response inhibition (chapter 2), and fine motor functioning (chapter 3). It was hypothesized that the non-affected siblings of ADHD probands would exhibit deficits in response inhibition and fine motor functioning intermediate between that of the controls and the ADHD probands. The most striking finding from the study on response inhibition (chapter 2) was that the non-affected siblings had results similar to those of the ADHD probands, which demonstrated that deficient response inhibition might constitute a cognitive endophenotype of ADHD. The results of the study on motor functioning (chapter 3) revealed that the non-affected siblings experienced fine motor problems similar to those of their affected siblings, but only in movements that required high levels of executive functioning. The study described in chapter 4 investigated whether executive function deficits could identify a meaningful familial subtype of ADHD. To examine the hypothesis that familial ADHD may represent a distinct and meaningful subtype of ADHD characterised by executive dysfunctioning, the cognitive performance of 29 ADHD probands with a family history of ADHD was compared with the performance of 26 ADHD probands without a family history of the disorder, and with that of 28 controls. Different measures of response inhibition, higher-order controlled motor functioning and attentional control were used. Contrary to the hypothesis, none of the executive functions, except for one aspect of attentional control, could differentiate between the familial- and nonfamilial ADHD groups. The study in chapter 5 examined familial clustering of executive functioning to provide support for the notion that different aspects of executive dysfunctioning might constitute endophenotypes to ADHD. Tasks measuring response inhibition, fine motor functioning, and attentional control were administered to 52 ADHD affected sibling pairs ranging in age from 6 to 18 years. Significant sibling correlations were found for measures of these aspects of executive functioning. With respect to fine motor functioning, only motor skills that made high demands on executive functioning showed significant sibling correlation. In chapter 6, attentional control, and mental flexibility were examined in the family-genetic study design that is used in the first two studies. The results revealed that the performance of the non-affected siblings did not differ from that of the ADHD probands on attentional control, nor on most measures of mental flexibility. The linear changes of these measures across the groups reflected an intermediate position of the non-affected siblings between the ADHD probands and controls. Chapter 7 presented the results of a post hoc principal component analysis in which the cognitive measures that are used in the experimental studies (chapter 2 up to 6) were included to identify interpretable underlying constructs of executive functioning in a sample of ADHD siblings. The PCA revealed that a three-factor model was the best solution to summarize the data: attentional and motor control, mental flexibility, and response inhibition. Chapter 8 provided a discussion of the overall findings, and implications for future research and clinical practice.