Endophenotypic measures of altered inhibitory brain processes in ADHD

Objectives: Deficits in response inhibition are, amongst others, considered as candidate endophenotypes of altered prefrontal brain function in ADHD. Based on their superior time resolution, electrophysiological methods like Event-Related Potentials (ERPs) are adequate for the measurement of such endophenotypes, i.e. abnormalities in brain functions underlying psychiatric diseases like ADHD. Moreover, ERPs seem to be particular suited to measure effects of functionally relevant genetic variants directly affecting neuro-transmission systems and brain function. This principle of imaging genetics with ERPs has been demonstrated as early as 1999 for the serotonin transporter promoter polymorphism affecting prefrontal brain function (Fallgatter et al., International Journal of Neuropsychopharmacology, 1999).

Design and Methods: We employed a multi-channel EEG during performance of a Go-NoGo task to assess the electrophysiological basis of the endophenotype response inhibition in healthy subjects as well as in patients with ADHD. The ERP-measure derived from this protocol was termed NoGo-Anteriorisation (NGA) and is characterized by a high interindividual stability, high short- and long-term test-retest reliability and, moreover, is independent from age- and gender. Results: In patients with ADHD the NGA was diminished as compared to age- and sexmatched healthy controls. Furthermore, a three-dimensional source location analysis with Low Resolution Electromagnetic Tomography (LORETA) indicated an electrical dysfunction of the medial prefrontal cortex comprising the anterior cingulate cortex (ACC) in ADHD patients in childhood as well as in adulthood. Recent studies showed a significant influence of variants of dopaminergic as well as serotonergic genes on this measure of prefrontal brain function.

Conclusions: These results exemplify the measurement of disease related disturbances in brain function with ERPs. Future studies will show whether such electrophysiological endophenotypes may contribute to the diagnosis of subgroups of ADHD and whether they may serve as endophenotypes to further clarify genetic contributions to the disease.