Tph2 gene variants modulate response control processes in adult ADHD patients and healthy individuals

Abstract

Although therapeutic interventions in attention-deficit/hyperactivity disorder (ADHD) still focus on the dopaminergic system, recent studies indicate a serotonergic dysfunction in this disease as well. In that respect, several variants of the tryptophan hydroxylase gene (TPH2), which codes for the rate-limiting enzyme in the biosynthesis of serotonin (5-HT), have been associated with ADHD. The rs4570625 G-allele polymorphisms of the TPH2 gene have already been related to altered reactivity of the brain during perception tasks with emotional stimuli in healthy adults. Here we investigated the influence of the ADHD related risk alleles for rs4570625 and for rs11178997 on prefrontal brain function during cognitive response control in large samples of adult ADHD patients (n = 124) and healthy controls (n = 84). Response control was elicited with a Go-NoGo task (continuous performance test; CPT) performed during recording of an ongoing EEG. From the resulting event-related potentials in the Go-and NoGo conditions of the CPT, the NoGo-anteriorization (NGA) has been calculated as a valid neurophysiological parameter for prefrontal brain function. In the current study, ADHD risk alleles of both polymorphisms were found to be associated with a reduction in the NGA in both healthy controls and ADHD patients. These findings are in line with the notion that genetic variations associated with altered serotonergic neurotransmission are also associated with the function of the prefrontal cortex during response inhibition. This mechanism might also be relevant in the pathophysiology of ADHD.

Dopamine Transporter (SLC6A3) Genotype Impacts Neurophysiological Correlates of Cognitive Response Control in an Adult Sample of Patients with ADHD

“…It also replicates previous reports of altered ERP measures of prefrontal response control in children suffering from ADHD (Fallgatter et al, 2004) and a diminished NGA in adults with a suspected ADHD during childhood (Fallgatter et al, 2005). In the latter study, the diminished NGA was mainly caused by a more anterior centroid in the Go condition (Fallgatter et al, 2005); this is also in line with our results, as patients showed a significantly more anterior location of the Go centroid as compared with that in the control group (see also Baehne et al, 2009).…”

“…In schizophrenic patients the NGA was found to be related to variants of the catechol-O-methyltransferase (COMT) gene (Ehlis et al, 2007). Furthermore, in one of our previous publications, the tryptophan hydroxylase (TPH2) gene was found to have a significant effect on the NGA in adult ADHD patients (Baehne et al, 2009). In this study, we hypothesized that the SLC6A3 genotype would significantly affect the NGA, particularly in ADHD patients.…”

“…Exclusion criteria were age below 18 and above 60 years, IQ below 90, current psychotropic medication, as well as serious somatic or neurological disorders. A total of 171 participants (94 ADHD patients, 77 controls) were also included in one of our previous publications (Baehne et al, 2009). All subjects were of Caucasian origin.…”

Mapping Attention-Deficit/Hyperactivity Disorder from Childhood to Adolescence—No Neurophysiologic Evidence for a Developmental Lag of Attention but Some for Inhibition

“…This agrees with our behavioral findings showing similar persistence of elevated scores on multiple CBCL scales, and of higher interview-derived inattention and hyperactivity/ impulsivity scores for the ADHD compared to the control group of this sample (4), even though earlier work had suggested a more prominent remission of behavioral impulsivity than of inattention scores (52). The findings also confirm that the cued CPT contains a well validated Go-NoGo task (53,54,55,56), and that a lower probability of the NoGo condition is not critical for typical anterior NoGo P300 topographies (57,58). Still, the inhibitory load on NoGo trials of this cued CPT is somewhat lower than in typical GoNoGo tasks, where Go probabilities of about 70% also require suppressing habitual, high probability responses.…”

The Role and Sources of Individual Differences in Critical-Analytic Thinking: a Capsule Overview

“…Indicators of response inhibition have also thought to be associated with the variation in noradrenaline and dopamine signaling systems, but specifics of these associations are somewhat different, pointing, in particular, to the variation in the DRD4 and DAT1/SLC6A3 (Congdon et al 2008) and COMT (Congdon et al 2009) genes. Although serotonin neuromodulation does not appear to be pivotal to response inhibition, there are studies connecting variation in this facet of EF and variation in the genes involved in the turnover of serotonin in the corresponding brain circuits, e.g., the variation in the TPH2 gene (Baehne et al 2009). …”