Genetics of preparation and response control in ADHD: the role of DRD4 and DAT1.

BACKGROUND: Difficulties with performance and brain activity related to attentional orienting (Cue-P3), cognitive or response preparation (Cue-CNV) and inhibitory response control (Nogo-P3) during tasks tapping executive functions are familial in ADHD and may represent endophenotypes. The aim of this study was to clarify the impact of dopamine receptor D4 (DRD4) and dopamine transporter (DAT1) gene polymorphisms on these processes in ADHD and control children. METHODS: Behavioural and electrophysiological parameters from cued continuous performance tests with low and high attentional load were assessed in boys with ADHD combined type (N = 94) and controls without family history of ADHD (N = 31). Both groups were split for the presence of at least one DRD4 7-repeat allele and the DAT1 10-6 haplotype. RESULTS: Children with ADHD showed diminished performance and lower Cue-P3, CNV and Nogo-P3 amplitudes. Children with DRD4 7R showed similar performance problems and lower Cue-P3 and CNV, but Nogo-P3 was not reduced. Children with the DAT1 10-6 haplotype had no difficulties with performance or Cue-P3 and CNV, but contrary to expectations increased Nogo-P3. There were no Genotype by ADHD interactions. CONCLUSIONS: This study detected specific effects of DRD4 7R on performance and brain activity related to attentional orienting and response preparation, while DAT1 10-6 was associated with elevated brain activity related to inhibitory response control, which potentially compensates increased impulsivity. As these genotype effects were additive to the impact of ADHD, the current results indicate that DRD4 and DAT1 polymorphisms are functionally relevant risk factors for ADHD and presumably other disorders sharing these endophenotypes.

Performance variability, impulsivity errors and the impact of incentives as gender-independent endophenotypes for ADHD.

BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) is one of the most common and highly heritable child psychiatric disorders. There is strong evidence that children with ADHD show slower and more variable responses in tasks such as Go/Nogo tapping aspects of executive functions like sustained attention and response control which may be modulated by motivational factors and/or state-regulation processes. The aim of this study was (1) to determine if these executive functions may constitute an endophenotype for ADHD; (2) to investigate for the first time whether known modulators of these executive functions may also be familial; and (3) to explore whether gender has an impact on these measures. METHODS: Two hundred and five children with ADHD combined type, 173 nonaffected biological siblings and 53 controls with no known family history of ADHD were examined using a Go/Nogo task in the framework of a multi-centre study. Performance-measures and modulating effects of event-rate and incentives were examined. Shared familial effects on these measures were assessed, and the influence of gender was tested. RESULTS: Children with ADHD responded more slowly and variably than nonaffected siblings or controls. Nonaffected siblings showed intermediate scores for reaction-time variability, false alarms and omission errors under fast and slow event-rates. A slower event-rate did not lead to reduced performance specific to ADHD. In the incentive condition, mean reaction-times speeded up and became less variable only in children with ADHD and their nonaffected siblings, while accuracy was improved in all groups. Males responded faster, but also committed more false alarms. There were no interactions of group by gender. CONCLUSIONS: Reaction-time variability and accuracy parameters could be useful neuropsychological endophenotypes for ADHD. Performance-modulating effects of incentives suggested a familially driven motivational dysfunction which may play an important role on etiologic pathways and treatment approaches for ADHD. The effects of gender were independent of familial effects or ADHD-status, which in turn suggests that the proposed endophenotypes are independent of gender.

DSM-IV combined type ADHD shows familial association with sibling trait scores: a sampling strategy for QTL linkage.

Attention deficit hyperactivity disorder (ADHD) is a discrete clinical syndrome characterized by the triad of inattention, hyperactivity, and impulsivity in the context of marked impairments. Molecular genetic studies have been successful in identifying genetic variants associated with ADHD, particularly with DSM-IV inattentive and combined subtypes. Quantitative trait locus (QTL) approaches to linkage and association mapping have yet to be widely used in ADHD research, although twin studies investigating individual differences suggest that genetic liability for ADHD is continuously distributed throughout the population, underscoring the applicability of quantitative dimensional approaches. To investigate the appropriateness of QTL approaches, we tested the familial association between 894 probands with a research diagnosis of DSM-IV ADHD combined type and continuous trait measures among 1,135 of their siblings unselected for phenotype. The sibling recurrence rate for ADHD combined subtype was 12.7%, yielding a sibling recurrence risk ratio (lambda(sib)) of 9.0. Estimated sibling correlations around 0.2-0.3 are similar to those estimated from the analysis of fraternal twins in population twin samples. We further show that there are no threshold effects on the sibling risk for ADHD among the ADHD probands; and that both affected and unaffected siblings contributed to the association with ADHD trait scores. In conclusion, these data confirm the main requirement for QTL mapping of ADHD by demonstrating that narrowly defined DSM-IV combined type probands show familial association with dimensional ADHD symptom scores amongst their siblings.

Inverse correlation of intracortical inhibition and brain-stem inhibition in humans.

OBJECTIVE: To determine whether intracortical inhibition and the conditioned blink reflex R2 inhibition correlate in healthy subjects. BACKGROUND: In Parkinson's disease and in focal dystonia the intracortical inhibition and the conditioned blink reflex R2 inhibition are abnormally weak. METHODS: In 10 healthy humans (average age 25.7 years) we investigated the intracortical excitability of the optimal representation of the abductor digiti minimi of the dominant hand using transcranial magnetic stimulation with a conditioning pulse (90% active motor threshold) followed by a pulse of 120% resting motor threshold after an interstimulus interval ranging from 1 to 30 ms. We investigated the blink reflex with two suprathreshold stimuli over the supraorbital nerve and EMG recording from the orbicularis oculi ipsilateral to electrical stimulation, the interstimulus intervals were 100, 250 and 500 ms. RESULTS: The intracortical inhibition, but not the intracortical facilitation, was inversely and significantly correlated with the R2 inhibition on the side of transcranial stimulation, but not with the contralateral R2 inhibition. CONCLUSIONS: The correlation of intracortical inhibitory interneurons and ipsilateral blink reflex interneurons may indicate a common influence, possibly from the basal ganglia, on either circuit, or a direct influence of cortical circuits on brain-stem circuits via corticopontine pathways.

Action monitoring in children with or without a family history of ADHD--effects of gender on an endophenotype parameter.

Attention-deficit/hyperactivity disorder (ADHD) is a frequent and highly heritable disorder overrepresented in boys. In a recent study investigating boys only, we found that action monitoring deficits as reflected by certain behavioral and electrophysiological parameters were familially driven. As gender may also have an important impact, this was examined in the current study with nonaffected children aged 8-15 years having relatives suffering from ADHD (N=37, 21 female symbol) and with age-matched controls without family history of ADHD (N=33, 11 female symbol). Extending our previous findings that action monitoring is a potential endophenotype for boys with ADHD, familially driven deficits were confirmed independently of gender. Thus, despite sharing the phenotype with controls, nonaffected siblings showed ADHD-like impairments albeit of smaller magnitude. However, girls performed generally more accurately, which in turn may have produced the differences between nonaffected siblings and controls in affective error processing that were not present in our boys-only assessment.

What can actigraphy add to the concept of labschool design in clinical trials?

Pharmacological intervention with methylphenidate (MPH) is very common and helpful in the treatment of attention-deficit/ hyperactivity disorder (ADHD). It ameliorates inattention, impulsivity and hyperactivity and improves psychosocial functioning. The core symptoms of ADHD are problematic mainly in demanding structured situations such as in the classroom. It was argued that MPH does not only lead to a decrease of hyperactivity in these situations but may also result in a general dampening of motor activity during non-structured leisure time. Unfortunately, only few clinical trials have investigated this practically important issue and thus it is still a matter of debate. It follows that many parents hesitate to accept psychotropic drugs for their children. To elucidate this problem in the current study, not only overall behavioral ratings (half-day blocks) but also day-long actigraphy was applied during an analogue classroom setting, where structured and non-structured situations alternated over time. Fourty-nine children with ADHD were assessed for treatment effects of once-daily extended-release and twice daily immediate-release methylphenidate (MPH) as well as placebo. Both MPH regimes yielded improved behavioral ratings during morning and afternoon, while actigraphy showed reduced motor activity in structured situations, but not during leisure time. Furthermore, the movement information obtained with actigraphy during structured situations could be differentiated from the one gained with overall behavioral ratings. Thus, while behavioral ratings provide a valid estimate of the overall symptomatology, additional information gathered with actigraphy may help to differentiate the impact of medication on hyperactive movement in different situations during the day. This may reflect a more valid picture of a child's real life and improve the quality of clinical trials. Thus, both methods may be regarded as complementary for the assessment of drug effects in children with ADHD and should be a standard of further laboratory school protocols in clinical trials.

Immunoglobulin therapy in idiopathic hypothalamic dysfunction.

Idiopathic hypothalamic dysfunction is a rare disorder presenting at age 3-7 years. Severe hypothalamic and brainstem dysfunction leads to death in 25% of patients. The disease is presumed to be autoimmune, or in some cases paraneoplastic. No successful treatment has been reported. Patient V. developed hyperphagia, hypersomnia, and extreme aggression at age 7 years, accompanied by episodes of hyperthermia, hypothermia, sinus bradycardia, hypernatremia, hyponatremia, persistent hyperprolactinemia, hypothyroidism, and growth-hormone deficiency. At age 9 years, a diagnosis of idiopathic hypothalamic dysfunction was rendered, and immunoglobulin therapy was commenced. Nine courses of immunoglobulins, at a dose of 2 g/kg every 4 weeks, were administered. Reproducible improvements in behavior and no further episodes of hyponatremia or hypernatremia and sinus bradycardia were evident. The endocrinologic abnormalities and poor thermoregulation remained. Administration of immunoglobulins during late stages of idiopathic hypothalamic dysfunction led to improvement in some but not all signs. Assuming an autoimmune basis for this disorder, treatment during early stages of disease should be more effective. To facilitate such early treatment, increased awareness of this disorder is necessary, to allow for early diagnosis.

Reaction time performance in ADHD: improvement under fast-incentive condition and familial effects.

BACKGROUND: Reaction time (RT) variability is one of the strongest findings to emerge in cognitive-experimental research of attention deficit hyperactivity disorder (ADHD). We set out to confirm the association between ADHD and slow and variable RTs and investigate the degree to which RT performance improves under fast event rate and incentives. Using a group familial correlation approach, we tested the hypothesis that there are shared familial effects on RT performance and ADHD. METHOD: A total of 144 ADHD combined-type probands, 125 siblings of the ADHD probands and 60 control participants, ages 6-18, performed a four-choice RT task with baseline and fast-incentive conditions. RESULTS: ADHD was associated with slow and variable RTs, and with greater improvement in speed and RT variability from baseline to fast-incentive condition. RT performance showed shared familial influences with ADHD. Under the assumption that the familial effects represent genetic influences, the proportion of the phenotypic correlation due to shared familial influences was estimated as 60-70%. CONCLUSIONS: The data are inconsistent with models that consider RT variability as reflecting a stable cognitive deficit in ADHD, but instead emphasize the extent to which energetic or motivational factors can have a greater effect on RT performance in ADHD. The findings support the role of RT variability as an endophenotype mediating the link between genes and ADHD.