Proactive versus reactive inhibition in ADHD: Genetics, Neurobiology and pharmacology

An estimated 3-5% of all children that attend school suffers of from
Attention-Deficit Hyperactivity Disorder (ADHD). In the majority of the cases
treatment consist of medication, with the psychostimant methylphenidate (MPH).
Seventy to 80% of these children benifit from this treatment, however 20-30%
does not. At the moment there are no objective methods to predict whether or
not a patient will benefit from treatment. The possibility to be able to
predict this response would be of great clinical value.
The current proposal stems from a new framework from ADHD, in which proactive
and reactive regulation 'inhibition' are central concepts, and sets the stage
for a decisive differentiation of these two components in terms of genetics,
neurobiological mechanisms, and pharmacology, with considerable implications
for future treatment possibilities.
Different brain changes associated with ADHD form viable endophenotypes for
ADHD-research (Durston et al., 2006; Durston et al., 2004; Mulder et al.,
2008). Our recent work shows that these endophenotypes can be used to separate
different brain systems involved in ADHD (e.g. (Durston et al., 2007)).
Neurobiological systems involved in cognitive control, the ability to inhibit
ongoing behaviour in favour of other behaviours, are one of three brain systems
important for ADHD. Both proactive and reactive inhibition are key aspects of
this ability. Results from neuroimaging studies suggest that the dopamine
transporter gene (DAT1) is a key player in mediating the effects of genes on
brain structure and function (Durston et al., 2005; Durston et al., 2008)
Another line in our research on inhibitory control has focussed on inhibitory
control and its disturbances in adult ADHD as measured using the stop task. The
stop task is a continuous performance task that includes occasional signals to
interrupt an ongoing response. Studies using EEG to measure event-related
potentials (ERPs) have shown two electrocortical mechanisms associated with
stopping: The stop N1 and the stop P3 (Bekker et al., 2005a; De Jong et al.,
1990). Stop N1 is associated with an inhibitory connection between the sensory
cortex receiving the stop signal, and the motor system. The efficacy of this
connection is most likely controlled by the right inferior frontal gyrus (Aron
et al., 2003), in a proactive way (that is, IFG exerts this control in
anticipation of a possible stop signal). This control function depends on
interactions between IFG and basal ganglia (Aron et al., 2007; Aron and
Poldrack, 2006) and is dependent on adequate dopamine transporter (DAT)
functioning; consistently, the stop N1 is absent in adult ADHD (Bekker et al.,
2005), but restored by methylphenidate that increases synaptic dopamine levels
by blocking the dopamine transporter (Overtoom et al., 2009). The stop P3 is
reduced although not absent, in both adult and child ADHD (Overtoom et al.,
2002). The stop P3 is not remedied by MPH. It is most likely associated with a
more last-minute reactive mechanism activated by the stop signal, and based in
the superior frontal gyrus (SFG; Bekker et al., 2005a; (Chambers et al., 2009;
Floden and Stuss, 2006). These results point to frontal dopamine mechanisms
that do not depend on DAT function to the same degree, but rather on other
dopamine-modulating mechanisms such as Catechol-O-methyl transferase (COMT).
The main hypothesis we aim to address is that there are two mechanisms involved
in behavioural control in ADHD, one proactive mechanism, regulated by DAT
function in fronto-striatal networks, and one reactive mechanism regulated by
COMT function in prefrontal cortex (SFG).

The aim of this research is, following the aforementioned theoretical
framework, to investigate whether the two candidate genes in combination with
EEG and fMRI markers differentiate between children that do and do not show a
clinical response to Methylphenidate.

Eighty ADHD children will perform the stop task both in the fMRI scanner and
during EEG recording, before receiving (their first dose of) MPH. After a
single dose of MPH they will again perform the stop task to assess improvements
in performance on the cognitive task. Within a month, it will be clear whether
they can be considered clinical responders or not. We predict that (1) both
cognitive and clinical positive response will be associated with at-risk
DAT1-genotype/ reduced IFG activity on fMRI/ reduced N1 ERP at baseline, but
(2) not with variation in COMT-genotype/ SFG-activity on fMRI/ stop P3 ERP; and
(3) that poor responders will have higher IFG activity on fMRI/ stop N1 ERP at
baseline.

There are no known risks associated with EEG or MRI acquisition. Both
techniques are non-invasive, and do not require administration of any contrast
agent or ionizing radiation. For the EEG, an electrode net will be fitted on
the child*s head. Although this may take up to 10 minutes, it is not unpleasant
for the subject. The MRI procedure is painless and not uncomfortable, although
it does require the subject to lie still with the head and part of the body in
a tunnel-like device. Children do not find the experience particularly
problematic. Many of our child participants have asked to be considered for
follow-up studies, and send unsolicited letters to express their enjoyment of
the experience.
There is no added risk associated with MPH administration, as subjects will
only be included if they are (1) already on MPH or (2) about to be started on
MPH for clinical reasons. Any risks associated with taking MPH on the test day
therefore, are no greater than the clinical risks associated with MPH use.