Martijn Mulder

Activation in Ventral Prefrontal Cortex is Sensitive to Genetic Vulnerability for Attention-Deficit Hyperactivity Disorder

BACKGROUND Attention-deficit hyperactivity disorder (ADHD) is a heritable neuropsychiatric disorder, associated with atypical patterns of brain activation in functional imaging studies. Neuroimaging measures may serve as an intermediate phenotype in genetic studies of ADHD, as they are putatively more closely linked to gene expression than a clinical diagnosis. METHODS We used rapid, mixed-trial, event-related functional magnetic resonance imaging (fMRI) to investigate changes in brain activation during a go no-go task in boys with ADHD, their unaffected siblings, and matched control subjects. RESULTS On the hardest inhibitory trials in our task, children and adolescents with ADHD had lower accuracy than control subjects, whereas their unaffected siblings did not. Control subjects activated a network of regions, including ventral prefrontal and inferior parietal cortex. Both children and adolescents with ADHD and their unaffected siblings showed decreased activation in these areas, as well as fewer correlations between performance and activation. CONCLUSIONS These findings suggest that the magnitude of activation during successful inhibitions is sensitive to genetic vulnerability for ADHD in a number of regions, including ventral prefrontal cortex. If this can be replicated in future studies, this suggests that neuroimaging measures related to inhibitory control may be suitable as intermediate phenotypes in studies investigating gene effects in ADHD.

Dopamine Transporter Genotype Conveys Familial Risk of Attention-Deficit/Hyperactivity Disorder Through Striatal Activation

OBJECTIVE The dopamine transporter (DAT1) gene has been implicated in attention-deficit/hyperactivity disorder (ADHD), although the mechanism by which it exerts its effects remains unknown. The polymorphism associated with ADHD has been shown to affect expression of the transporter in vitro and in vivo. Dopamine transporters are predominantly expressed in the striatum, but also in the cerebellar vermis. Stimulant medication is often effective in ADHD and is believed to exert its effects by blocking dopamine transporters in the striatum. We set out to investigate the effect of the DAT1 genotype in ADHD in a small, preliminary study. We hypothesized that the DAT1 genotype would affect brain activation patterns in a manner similar to that of stimulant medication, with the lesser expressing allele mirroring its effects. METHOD We investigated DAT1 gene effects on brain activation patterns in an all-male sample of sibling pairs discordant for ADHD (n = 20) and controls (n = 9). All of the subjects participated in a functional magnetic resonance imaging session using a go/no-go paradigm and provided a DNA sample for analysis. RESULTS DAT1 genotype affected activation in the striatum and cerebellar vermis. The genotype interacted with familial risk of ADHD in the striatum but not the vermis. CONCLUSIONS These preliminary results suggest that the DAT1 gene effects in the striatum are involved in translating the genetic risk of ADHD into a neurobiological substrate. As such, this study represents a first step in elucidating the neurobiological mechanisms underlying genetic influences in ADHD. Furthermore, these results may contribute to long-term possibilities for the development of new treatments: If the DAT1 genotype has differential effects on striatal activation, then it may be useful as a surrogate endpoint in individualized treatments targeting genotype/functional magnetic resonance imaging activation profiles.

Familial Vulnerability to ADHD Affects Activity in the Cerebellum in Addition to the Prefrontal Systems.

OBJECTIVE Familial vulnerability to attention-deficit/hyperactivity disorder (ADHD) has been shown to be related to atypical prefrontal activity during cognitive control tasks. However, ADHD is associated with deficits in the cerebellum as well as deficits in frontostriatal circuitry and associated cognitive control. In this study, we investigated whether cerebellar systems are sensitive to familial risk for ADHD in addition to frontostriatal circuitry. METHOD We used an event-related, rapid mixed-trial functional magnetic resonance imaging design. The paradigm was a variation on a go/no-go task, with expected (go) and unexpected (no-go) events at expected and unexpected times. A total of 36 male children and adolescents completed the study, including 12 sibling pairs discordant for ADHD and 12 matched controls. RESULTS Children and adolescents with ADHD were less accurate on unexpected events than control subjects. Performance by unaffected siblings was intermediate, between that of children and adolescents with ADHD and controls. Functional neuroimaging results showed dissociation between activation in the cerebellum and anterior cingulate cortex: Activity in the anterior cingulate cortex was decreased for subjects with ADHD and their unaffected siblings compared with controls for manipulations of stimulus type (no-go trials), but not timing. In contrast, cerebellar activity was decreased for subjects with ADHD and their unaffected siblings for manipulations of timing, but not stimulus type. CONCLUSIONS These findings suggest that activity in both the prefrontal cortex and cerebellum is sensitive to familial vulnerability to ADHD. Unaffected siblings of individuals with ADHD show deficits similar to affected probands in prefrontal areas for unexpected events and in cerebellum for events atunexpected times.

Salivary cortisol and short and long-term memory for emotional faces in healthy young women

Elevated levels of the stress hormone cortisol are associated with increased episodic memory for emotional events. Elevated levels of cortisol are also seen in anxiety and depression disorders. Because it is well documented how both depression and anxiety are related to valence-specific biases in attention and memory, the present study sought to establish relations between basal cortisol levels and episodic memory for neutral, positive and negative stimuli. Thirty-nine healthy young women performed an immediate recall and long-term (20 min) version of a task measuring spatial memory for neutral, happy and fearful faces. The sample as a whole showed a valence-specific better performance for happy faces than for neutral faces in the immediate recall condition, and a better performance for all emotional faces in the long-term condition. Salivary cortisol measures were found to be related to better memory for emotional faces in the long-term condition. This relation to cortisol was not valence-specific and is similar to effects predicted by a model on long-term consolidation and the influence of cortisol in this process.

Adolescents let sufficient evidence accumulate before making a decision when large incentives are at stake

Adolescent decision-making has been described as impulsive and suboptimal in the presence of incentives. In this study we examined the neural substrates of adolescent decision-making using a perceptual discrimination task for which small and large rewards were associated with correctly detecting the direction of motion of a cloud of moving dots. Adults showed a reward bias of faster reaction times on trials for which the direction of motion was associated with a large reward. Adolescents, in contrast, were slower to make decisions on trials associated with large rewards. This behavioral pattern in adolescents was paralleled by greater recruitment of fronto-parietal regions important in representing the accumulation of evidence sufficient for selecting one choice over its alternative and the certainty of that choice. The findings suggest that when large incentives are dependent on performance, adolescents may require more evidence to accumulate prior to responding, to be certain to maximize their gains. Adults, in contrast, appear to be quicker in evaluating the evidence for a decision when primed by rewards. Overall these findings suggest that rather than reacting hastily, adolescents can be incentivized to take more time to make decisions when large rewards are at stake. A video abstract of this article can be viewed at http://youtu.be/1g4F5vzFDl0.

Functional connectivity between cognitive control regions is sensitive to familial risk for ADHD

Familial risk for attention‐deficit hyperactivity disorder (ADHD) has been associated with changes in brain activity related to cognitive control. However, it is not clear whether changes in activation are the primary deficit or whether they are related to impaired communication between regions involved in this ability. We investigated whether (1) functional connectivity between regions involved in cognitive control was affected by familial risk and (2) changes were specific to these regions. Correlational seed analyses were used to investigate temporal covariance between cognitive control and motor regions in two independent samples of typically developing controls, subjects with ADHD and their unaffected siblings. In both samples, correlation coefficients between cognitive control regions were greater for typically developing controls than for subjects with ADHD, with intermediate values for unaffected siblings. Within the motor network, unaffected siblings showed correlations similar to typically developing children. There were no differences in activity between the brain regions involved. These data show that functional connectivity between cognitive control regions is sensitive to familial risk for ADHD. Results suggest that changes in connectivity associated with cognitive control may be suitable as an intermediate phenotype for future studies. Hum Brain Mapp, 2010.