Esther Aarts

Anticipatory Activity in Anterior Cingulate Cortex Can Be Independent of Conflict and Error Likelihood

Previous studies have found no agreement on whether anticipatory activity in the anterior cingulate cortex (ACC) reflects upcoming conflict, error likelihood, or actual control adjustments. Using event-related functional magnetic resonance imaging, we investigated the nature of preparatory activity in the ACC. Informative cues told the participants whether an upcoming target would or would not involve conflict in a Stroop-like task. Uninformative cues provided no such information. Behavioral responses were faster after informative than after uninformative cues, indicating cue-based adjustments in control. ACC activity was larger after informative than uninformative cues, as would be expected if the ACC is involved in anticipatory control. Importantly, this activation in the ACC was observed for informative cues even when the information conveyed by the cue was that the upcoming target evokes no response conflict and has low error likelihood. This finding demonstrates that the ACC is involved in anticipatory control processes independent of upcoming response conflict or error likelihood. Moreover, the response of the ACC to the target stimuli was critically dependent on whether the cue was informative or not. ACC activity differed among target conditions after uninformative cues only, indicating ACC involvement in actual control adjustments. Together, these findings argue strongly for a role of the ACC in anticipatory control independent of anticipated conflict and error likelihood, and also show that such control can eliminate conflict-related ACC activity during target processing. Models of frontal cortex conflict-detection and conflict-resolution mechanisms require modification to include consideration of these anticipatory control properties of the ACC.

Striatal Dopamine Mediates the Interface between Motivational and Cognitive Control in Humans: Evidence from Genetic Imaging

Dopamine has been hypothesized to provide the basis for the interaction between motivational and cognitive control. However, there is no evidence for this hypothesis in humans. We fill this gap by using fMRI, a novel behavioral paradigm and a common polymorphism in the DAT1 gene (SLC6A3). Carriers of the 9-repeat (9R) allele of a 40 base pair repeat polymorphism in the 3′ untranslated region of DAT1, associated with high striatal dopamine, showed greater activity in the ventromedial striatum during reward anticipation than homozygotes for the 10-repeat allele, replicating previous genetic imaging studies. The crucial novel finding is that 9R carriers also exhibited a greater influence of anticipated reward on switch costs, as well as greater activity in the dorsomedial striatum during task switching in anticipation of high reward relative to low reward. These data establish a crucial role for human striatal dopamine in the modulation of cognitive flexibility by reward anticipation, thus, elucidating the neurochemical mechanism of the interaction between motivation and cognitive control.

Dopaminergic Modulation of Cognitive Control: Distinct Roles for the Prefrontal Cortex and the Basal Ganglia

Evidence from psychopharmacological functional neuroimaging begins to elucidate the neurochemical mechanisms of cognitive control. The role of dopamine in two subcomponent processes of cognitive control is discussed: the active maintenance and the flexible updating of goal-relevant representations. A range of studies have highlighted a role for the prefrontal cortex (pFC) and its modulation by dopamine in the active maintenance of distractor-resistant goal-relevant representations. This work suggests that dopamine might modulate top-down signals from the pFC, thereby increasing the activity of posterior cortical regions that process goal-relevant representations and rendering them distractor-resistant. Conversely, other studies highlight a role for dopamine in the basal ganglia in cognitive switching, which might reflect a modulation of the selective gating of cortical cognitive and motor programs. We present a working hypothesis that integrates these two disparate literatures and states that the flexible adaptation of current goal-relevant representations is mediated by modulatory influences of activity in the dopamine-sensitive basal ganglia on connectivity between the prefrontal cortex and posterior cortex.

Nitric Oxide Synthase genotype modulation of impulsivity and ventral striatal activity in adult ADHD patients and healthy comparison subjects

OBJECTIVE Attention deficit hyperactivity disorder (ADHD) is a highly heritable disorder. The NOS1 gene encoding nitric oxide synthase is a candidate gene for ADHD and has been previously linked with impulsivity. In the present study, the authors investigated the effect of a functional variable number of tandem repeats (VNTR) polymorphism in NOS1 (NOS1 exon 1f-VNTR) on the processing of rewards, one of the cognitive deficits in ADHD. METHOD A sample of 136 participants, consisting of 87 adult ADHD patients and 49 healthy comparison subjects, completed a reward-related impulsivity task. A total of 104 participants also underwent functional magnetic resonance imaging during a reward anticipation task. The effect of the NOS1 exon 1f-VNTR genotype on reward-related impulsivity and reward-related ventral striatal activity was examined. RESULTS ADHD patients had higher impulsivity scores and lower ventral striatal activity than healthy comparison subjects. The association between the short allele and increased impulsivity was confirmed. However, independent of disease status, homozygous carriers of the short allele of NOS1, the ADHD risk genotype, demonstrated higher ventral striatal activity than carriers of the other NOS1 VNTR genotypes. CONCLUSIONS The authors suggest that the NOS1 genotype influences impulsivity and its relation with ADHD is mediated through effects on this behavioral trait. Increased ventral striatal activity related to NOS1 may be compensatory for effects in other brain regions.

Human cognitive flexibility depends on dopamine D2 receptor signaling

RationaleAccumulating evidence indicates that the cognitive effects of dopamine depend on the subtype of dopamine receptor that is activated. In particular, recent work with animals as well as current theorizing has suggested that cognitive flexibility depends on dopamine D2 receptor signaling. However, there is no evidence for similar mechanisms in humans.ObjectivesWe aim to demonstrate that optimal dopamine D2 receptor signaling is critical for human cognitive flexibility.MethodsTo this end, a pharmacological pretreatment design was employed. This enabled us to investigate whether effects of the dopamine receptor agonist bromocriptine on task-set switching were abolished by pretreatment with the D2 receptor antagonist sulpiride. To account for individual (genetic) differences in baseline levels of dopamine, we made use of a common variable number of tandem repeat (VNTR) polymorphism in the 3′-untranslated region of the dopamine transporter gene, DAT1.ResultsBromocriptine improved cognitive flexibility relative to placebo, but only in subjects with genetically determined low levels of dopamine (n = 27). This beneficial effect of bromocriptine on cognitive flexibility was blocked by pretreatment with the selective dopamine D2 receptor antagonist sulpiride (n = 14).ConclusionsThese results provide strong evidence in favor of the hypothesis that human cognitive flexibility implicates dopamine D2 receptor signaling.

Attentional control of task and response in lateral and medial frontal cortex: Brain activity and reaction time distributions

It is unclear whether task conflict is reflected in the anterior cingulate cortex (ACC) or in more dorsal regions of the medial frontal cortex (MFC). When participants switch between tasks involving incongruent, congruent, and neutral stimuli, it is possible to examine both response conflict (incongruent vs. congruent) and task conflict (congruent vs. neutral). Here, we report an event-related functional magnetic resonance imaging (fMRI) study that examined which areas in frontal cortex, including MFC, are implicated in response conflict, task conflict, or both. Stimuli were incongruent and congruent arrow-word combinations, or arrows and words only in a neutral condition. Participants responded manually to the arrow or word. The task varied every second trial. The behavioral data revealed response conflict (incongruent>congruent) and task conflict (congruent>neutral) in mean reaction times and ex-Gaussian latency distribution components. The imaging data revealed activity in both the ACC and a more dorsal region in the MFC (the medial superior frontal gyrus) related to response conflict as well as task conflict. These conflict effects were observed independent of the task performed (arrow or word) or the trial type (repeat or switch). In lateral prefrontal cortex (LPFC), response conflict was associated with activity in ventral LPFC, whereas task conflict activated both ventral and dorsal regions. Thus, whereas the type of conflict (response vs. task) was differentiated in LPFC, no such differentiation was found in MFC, including the ACC. Models of ACC functioning may require modification to take account of these findings.

Attentional control in anterior cingulate cortex based on probabilistic cueing

In Stroop-like tasks, conflict effects in behavioral measures and ACC activity are smaller on trials following an incongruent trial than following a congruent one. Researchers have found no agreement on whether these sequential effects in ACC can be driven by experienced incongruency only or also by expectations about target types. In the present fMRI experiment, we specifically manipulated the expectancies by using symbolic cues predicting with 75% or 50% certainty the incongruent or congruent targets in a Stroop-like task. Both behavioral and dorsal ACC data replicated previous sequential effects, with conflict effects being smallest for targets following the cues that predicted with 75% certainty the incongruent targets. However, these effects were not driven by experienced conflict but by symbolic cues. These results demonstrate differential attentional control activity in ACC after probabilistic cueing, providing evidence for control adjustments driven by changes in expectation.

Dopamine and the Cognitive Downside of a Promised Bonus

It is often assumed that the promise of a monetary bonus improves cognitive control. We show that in fact appetitive motivation can also impair cognitive control, depending on baseline levels of dopamine-synthesis capacity in the striatum. These data not only demonstrate that appetitive motivation can have paradoxical detrimental effects for cognitive control but also provide a mechanistic account of these effects.

Aberrant reward processing in Parkinson's disease is associated with dopamine cell loss.

Dopamine has been implicated in reward-related impulsivity, but the exact relationship between dopamine, reward and impulsivity in humans remains unknown. We address this question in Parkinsons disease (PD), which is characterized by severe dopamine depletion. PD is associated primarily with motor and cognitive inflexibility, but can also be accompanied by reward-related impulsivity. This paradoxical symptom of PD has often been attributed to dopaminergic overstimulation by antiparkinson medication, which is necessary to relieve the motor and cognitive inflexibility. However, factors other than medication may also contribute to aberrant impact of reward. Here we assess whether cognitive inflexibility and aberrant reward impact in PD are two sides of the same coin, namely dopamine cell loss. To measure dopamine cell loss, we employed (123)I-FP-CIT Single Photon Emission Computed Tomography (SPECT) in 32 PD patients (10 never-medicated patients and 22 patients after withdrawal of all medication for >12h) and related the values to behavior on a rewarded task-switching paradigm. Dopamine cell loss was associated not only with cognitive inflexibility (under low reward), but also with aberrant impact of reward. These effects could not be attributed to medication use. Relative to controls (n=26), aberrant reward processing in PD was particularly expressed as reduced capacity to maintain (i.e., repeat) the current task-set under high reward. Our findings demonstrate that factors intrinsically related to PD may underlie the paradoxical symptoms of inflexibility and reward-related impulsivity in PD. The present results concur with observations that low baseline dopamine states predispose to drug and other addictions.

Influence of Motivation on Control Hierarchy in the Human Frontal Cortex

The frontal cortex mediates cognitive control and motivation to shape human behavior. It is generally observed that medial frontal areas are involved in motivational aspects of behavior, whereas lateral frontal regions are involved in cognitive control. Recent models of cognitive control suggest a rostro-caudal gradient in lateral frontal regions, such that progressively more rostral (anterior) regions process more complex aspects of cognitive control. How motivation influences such a control hierarchy is still under debate. Although some researchers argue that both systems work in parallel, others argue in favor of an interaction between motivation and cognitive control. In the latter case it is yet unclear how motivation would affect the different levels of the control hierarchy. This was investigated in the present functional MRI study applying different levels of cognitive control under different motivational states (low vs high reward anticipation). Three levels of cognitive control were tested by varying rule complexity: stimulus-response mapping (low-level), flexible task updating (mid-level), and sustained cue-task associations (high-level). We found an interaction between levels of cognitive control and motivation in medial and lateral frontal subregions. Specifically, flexible updating (mid-level of control) showed the strongest beneficial effect of reward and only this level exhibited functional coupling between dopamine-rich midbrain regions and the lateral frontal cortex. These findings suggest that motivation differentially affects the levels of a control hierarchy, influencing recruitment of frontal cortical control regions depending on specific task demands.