Our study of the relationship of DAT1 genotype and adult ADHD to task-positive and task-negative working memory networks yielded four principal findings: 1) we replicated the association of the 9R allele to adult ADHD, 2) we found that 9R-carriers showed marginally greater task-related suppression in mePFC compared to 10R-homozygotes; 3) we found a marginal genotype × diagnosis interaction in the dACC/pre-SMA, and 4) suppression in peak regions of the task-negative network predicted a greater number of ADHD inattentive symptoms.
Our first novel finding was a marginal relationship between DAT1
genotype and task-related suppression in mePFC (p-corrected = 0.055). These data introduce a novel target for DAT1
and suggest that gene effects on behavior and diagnosis may be at least partially mediated by DMN. The effect of DAT1
variation on DMN has not, to our knowledge, been studied before in any population. Our findings are, however, consistent with a recent PET-fMRI study by Tomasi et al (2009)
. They found that lower striatal DAT binding levels predicted greater DMN suppression in healthy adults, and we found that a genotype shown to result in lower striatal DAT expression (Heinz et al., 2000
; Mill et al., 2002
; Brookes et al., 2007
) also predicted greater suppression of DMN. Together, the two findings suggest that genotypic variance in DAT1
may affect DMN via striatal DA expression.
Our second novel finding was a relationship of task-related suppression of DMN to inattentive ADHD symptoms in adult patients. Based on previous literature supporting a negative relationship between mind-wandering/task-inappropriate thoughts and DMN suppression, we hypothesized that less suppression would predict more inattentive symptoms, but in fact we found that it predicted fewer. Importantly, this finding need be interpreted in the context of a lack of relationship between inattentive symptomology and performance on the n-back task (all r’s < 0.2, all p’s > 0.16), meaning that patients with a greater number of inattentive symptoms performed equally as well on the task as those ADHD participants with fewer inattentive symptoms. The correlation therefore suggests that the more inattentive ADHD subjects needed a greater magnitude of DMN suppression in order to perform the task as well as those participants with fewer symptoms. These findings extend the relationship of task-related suppression to a clinical inattentive phenotype measured outside the scanner, but suggest that these relationships must be interpreted in the context of task performance.
Additionally, we found that the 9R allele was associated with adult ADHD as well as marginally associated with increased DMN suppression; therefore it is not surprising that DMN suppression would predict ADHD severity in adults. These data converge with data from the child literature, which finds an association of both the 10R allele and decreased DMN suppression with ADHD. Thus, it is possible that DMN suppression is directionally linked to the two common DAT1
alleles, and that while the 10R childhood ADHD risk allele (Yang et al., 2007
; Gizer et al., 2009
) may predispose towards a lack of DMN suppression (as seen in neuroimaging studies of ADHD children; (Fassbender et al., 2009
; Peterson et al., 2009
)), the 9R adult
ADHD risk allele (Franke et al., 2010
) may predispose towards increased task related DMN suppression (as suggested by the current study). This relationship therefore poses task-related suppression of DMN on the path from the DAT1
risk allele to expression of symptoms in both child and adult ADHD.
In this adult sample, we did not find a diagnosis effect anywhere in our task-negative ROI, contrary to previous reports showing decreased task-related suppression in children with ADHD (Fassbender et al., 2009
; Peterson et al., 2009
). The lack of findings may be related to the high performance rates of both our groups on the fMRI task. Both ADHD and control groups performed the task well, and to equal levels. It may therefore be that task-related suppression is only altered in ADHD when task demands surpass an attentional or difficulty threshold. For instance, Fassbender et al (2009)
found that mePFC was significantly less suppressed in those ADHD children who showed greater RT variability. Since we did not find differences in RT variability between the diagnosis groups, it may be that the task parameters associated with DMN alterations in ADHD were not captured by our task, which may be a function of age (e.g., task more difficult for children). Future studies should test the effect of varying task demands on DMN response in ADHD.
Contrary to findings by Bertolino et al. (2006
), who found a main effect of DAT1
in DLPFC during N-back tasks, we did not find a main effect of DAT1
anywhere in our task-positive ROI. This discrepancy may be due to a lack of power in our group of control participants carrying the 9R allele, which only contained 12 subjects, or because of our use of ADHD patients and control subjects as opposed to control subjects only. The marginal genotype × diagnosis interaction effect did however suggest that genotype effects were in different directions in the ADHD and control samples. In ADHD the dACC/pre-SMA was found to be hypoactive in the 10R/10R group, consistent with a previous study in an overlapping sample (Brown et al., 2010
) during a different (interference) task. These findings suggest that in task-positive medial wall regions, DAT1
genotype effects may differ in the context of other ADHD-related risk factors.
Our finding of ADHD “hypofrontality” is consistent with many previous neuroimaging studies in both adults and children with ADHD including our own (Valera et al., 2005
; Valera et al., 2010
), and with dominant theories about the neuroanatomical underpinnings of the disorder (see Paloyelis et al., 2007
for review). The current sample overlaps with an initial report of brain activity during the n-back task by Valera et al (2005)
which includes only 27 (30%) of participants in the current report), and with a subsequent report (Valera et al., 2010
) which added additional subjects (includes 64 (70%) of participants in current report). In these studies, R DLPFC was found respectively to be marginally and significantly less active in the adults with ADHD, and thus our DLPFC findings are not new. However, the three overlapping reports strongly support DLPFC alterations in adults with ADHD, particularly in its role supporting working memory.
We replicated the meta-analytic study of Franke et al (2010)
, finding an association between the 9R allele and ADHD in adults. These findings are contrary to the association of the 10R allele to ADHD in children, which have also been confirmed with meta-analysis (Faraone et al., 2005
; Yang et al., 2007
; Gizer et al., 2009
). As mentioned above, it should be noted however that this discrepancy is consistent with our principal brain findings: in ADHD children DMN suppression (which we found to be linked to DAT1
) has been found to be lower in ADHD (Fassbender et al., 2009
; Peterson et al., 2009
), whereas in our adult sample DMN suppression was found to be increased with ADHD severity.
Limitations of our study include an unbalanced design, so that although we had a large sample size (N = 91), power was reduced by our smallest cell (N=12). Further, even though genotypes did not statistically differ in terms of ADHD medication history, the mixed history in our sample may be a confound given the effect of psychostimulants on DAT, and the unknown effect of previous psychopharmacological treatment on brain function. We also included ADHD subjects with varied DSM-IV subtypes and participants who had recently remitted from ADHD. Future studies might replicate results with a medication naïve sample, and test the effect of persistence and/or DSM-IV subtypes on brain data and the link to genes. Because data was collected and analyzed over an extended period (2001–2008), future studies should replicate the findings with newer methods. For instance, our paradigm employed a classic block design which has limitations including the inability to model individual responses, and we chose a univariate analytical approach which does not explore connectivity within or across components as can be done with an Independent Components Analysis. Finally, readers should take caution in interpreting the genotype and interaction effects as both of these findings were only marginally significant after correction for multiple comparisons across the entire respective ROI.
Despite these considerations, we found that the 9R allele was associated with both the diagnosis of ADHD and marginally with increased suppression in DMN in adults, the latter of which was associated with a greater number of inattentive symptoms. These findings therefore suggest that task-related suppression of DMN might act as an intermediate phenotype between DAT1 and ADHD. Further, the differences in direction between our DMN findings in this adult sample and those found previously in children mirror the DAT1 gene effects in adults vs. children with ADHD. While the childhood ADHD profile is associated with 10R-homozygosity and decreased task-related suppression in ADHD, our study in adults suggests associations to both the 9R allele and increased DMN suppression. These findings therefore introduce not only a novel neural target for DAT1, but provide a basis for future longitudinal studies to investigate differences in gene and brain effects between individuals with and without persistent forms of ADHD.