W.P.M. van den Wildenberg

Electrophysiological correlates of anterior cingulate function in a go/no-go task: effects of response conflict and trial type frequency.

Neuroimaging and computational modeling studies have led to the suggestion that response conflict monitoring by the anterior cingulate cortex plays a key role in cognitive control. For example, response conflict is high when a response must be withheld (no-go) in contexts in which there is a prepotent tendency to make an overt (go) response. An event-related brain potential (ERP) component, the N2, is more pronounced on no-go than on go trials and was previously thought to reflect the need to inhibit the go response. However, the N2 may instead reflect the high degree of response conflict on no-go trials. If so, an N2 should also be apparent when subjects make a go response in conditions in which nogo events are more common. To test this hypothesis, we collected high-density ERP data from subjects performing a go/no-go task, in which the relative frequency of go versus no-go stimuli was varied. Consistent with our hypothesis, an N2 was apparent on both go and no-go trials and showed the properties expected of an ERP measure of conflict detection on correct trials: (1) It was enhanced for low-frequency stimuli, irrespective of whether these stimuli were associated with generating or suppressing a response, and (2) it was localized to the anterior cingulate cortex. This suggests that previous conceptions of the no-go N2 as indexing response inhibition may be in need of revision. Instead, the results are consistent with the view that the N2 in go/no-go tasks reflects conflict arising from competition between the execution and the inhibition of a single response.

Effective connectivity reveals important roles for both the hyperdirect (fronto-subthalamic) and the indirect (fronto-striatal-pallidal) fronto-basal ganglia pathways during response inhibition.

Fronto-basal ganglia pathways play a crucial role in voluntary action control, including the ability to inhibit motor responses. Response inhibition might be mediated via a fast hyperdirect pathway connecting the right inferior frontal gyrus (rIFG) and the presupplementary motor area (preSMA) with the subthalamic nucleus or, alternatively, via the indirect pathway between the cortex and caudate. To test the relative contribution of these two pathways to inhibitory action control, we applied an innovative quantification method for effective brain connectivity. Functional magnetic resonance imaging data were collected from 20 human participants performing a Simon interference task with an occasional stop signal. A single right-lateralized model involving both the hyperdirect and indirect pathways best explained the pattern of brain activation on stop trials. Notably, the overall connection strength of this combined model was highest on successfully inhibited trials. Inspection of the relationship between behavior and connection values revealed that fast inhibitors showed increased connectivity between rIFG and right caudate (rCaudate), whereas slow inhibitors were associated with increased connectivity between preSMA and rCaudate. In compliance, connection strengths from the rIFG and preSMA into the rCaudate were correlated negatively. If participants failed to stop, the magnitude of experienced interference (Simon effect), but not stopping latency, was predictive for the hyperdirect–indirect model connections. Together, the present results suggest that both the hyperdirect and indirect pathways act together to implement response inhibition, whereas the relationship between performance control and the fronto-basal ganglia connections points toward a top-down mechanism that underlies voluntary action control.

GENETIC MARKERS OF STRIATAL DOPAMINE PREDICT INDIVIDUAL DIFFERENCES IN DYSFUNCTIONAL, BUT NOT FUNCTIONAL IMPULSIVITY

Various psychiatric disorders are characterized by elevated levels of impulsivity. Although extensive evidence supports a specific role of striatal, but not frontal dopamine (DA) in human impulsivity, recent studies on genetic variability have raised some doubts on such a role. Importantly, impulsivity consists of two dissociable components that previous studies have failed to separate: functional and dysfunctional impulsivity. We compared participants with a genetic predisposition to have relatively high striatal DA levels (DAT1 9-repeat carriers, DRD2 C957T T/T homozygotes, and DRD4 7-repeat carriers) with participants with other genetic predispositions. We predicted that the first group would show high scores of dysfunctional, but not functional, self-reported impulsivity and greater difficulty in inhibiting a behavioral response to a stop-signal, a behavioral measure of impulsivity. In a sample of 130 healthy adults, we studied the relation between DAT1, DRD4, and C957T polymorphism at the DRD2 gene (polymorphisms related to striatal DA) and catechol-Omethyltransferase (COMT) Val158Met (a polymorphism related to frontal DA) on self-reported dysfunctional and functional impulsivity, assessed by the Dickman impulsivity inventory (DII), and the efficiency of inhibitory control, assessed by the stop-signal paradigm. DRD2 C957T T/T homozygotes and DRD4 7-repeat carriers indeed had significantly higher scores on self-reported dysfunctional, but not functional, impulsivity. T/T homozygotes were also less efficient in inhibiting prepotent responses. Our findings support the claim that dopaminergic variation affects dysfunctional impulsivity. This is in line with the notion that the over-supply of striatal DA might weaken inhibitory pathways, thereby enhancing the activation of, and the competition between responses.

The effect of Parkinson's disease on interference control during action selection

Basal ganglia structures comprise a portion of the neural circuitry that is hypothesized to coordinate the selection and suppression of competing responses. Parkinsons disease (PD) may produce a dysfunction in these structures that alters this capacity, making it difficult for patients with PD to suppress interference arising from the automatic activation of salient or overlearned responses. Empirical observations thus far have confirmed this assumption in some studies, but not in others, due presumably to considerable inter-individual variability among PD patients. In an attempt to help resolve this controversy, we measured the performance of 50 PD patients and 25 healthy controls on an arrow version of the Eriksen flanker task in which participants were required to select a response based on the direction of a target arrow that was flanked by arrows pointing in the same (congruent) or opposite (incongruent) direction. Consistent with previous findings, reaction time (RT) increased with incongruent flankers compared to congruent or neutral flankers, and this cost of incongruence was greater among PD patients. Two novel findings are reported. First, distributional analyses, guided by dual-process models of conflict effects and the activation-suppression hypothesis, revealed that PD patients are less efficient at suppressing the activation of conflicting responses, even when matched to healthy controls on RT in a neutral condition. Second, this reduced efficiency was apparent in half of the PD patients, whereas the remaining patients were as efficient as healthy controls. These findings suggest that although poor suppression of conflicting responses is an important feature of PD, it is not evident in all medicated patients.

Estrogen modulates inhibitory control in healthy human females: evidence from the stop-signal paradigm.

Animal studies point to a role of estrogen in explaining gender differences in striatal dopaminergic functioning, but evidence from human studies is still lacking. Given that dopamine is crucial for controlling and organizing goal-directed behavior, estrogen may have a specific impact on cognitive control functions, such as the inhibition of prepotent responses. We compared the efficiency of inhibitory control (as measured by the stop-signal task) in young women across the three phases of their menstrual cycle (salivary estradiol and progesterone concentrations were assessed) and in young men. Women were less efficient in inhibiting prepotent responses in their follicular phase, which is associated with higher estradiol levels and with higher dopamine turnover rates, than in their luteal or menstruation phase. Likewise, women showed less efficient inhibitory control than men in their follicular phase but not in their luteal or menstruation phase. Our results are consistent with models assuming that the over-supply of striatal dopamine in the follicular phase weakens inhibitory pathways, thus leading to enhanced competition between responses. We conclude that gender differences in response inhibition are variable and state dependent but not structural.

The effect of speed-accuracy strategy on response interference control in Parkinson's disease

Studies that used conflict paradigms such as the Eriksen Flanker task show that many individuals with Parkinsons disease (PD) have pronounced difficulty resolving the conflict that arises from the simultaneous activation of mutually exclusive responses. This finding fits well with contemporary views that postulate a key role for the basal ganglia in action selection. The present experiment aims to specify the cognitive processes that underlie action selection deficits among PD patients in the context of variations in speed-accuracy strategy. PD patients (n=28) and healthy controls (n=17) performed an arrow version of the flanker task under task instructions that either emphasized speed or accuracy of responses. Reaction time (RT) and accuracy rates decreased with speed compared to accuracy instructions, although to a lesser extent for the PD group. Differences in flanker interference effects among PD and healthy controls depended on speed-accuracy strategy. Compared to the healthy controls, PD patients showed larger flanker interference effects under speed stress. RT distribution analyses suggested that PD patients have greater difficulty suppressing incorrect response activation when pressing for speed. These initial findings point to an important interaction between strategic and computational aspects of interference control in accounting for cognitive impairments of PD. The results are also compatible with recent brain imaging studies that demonstrate basal ganglia activity to co-vary with speed-accuracy adjustments.

The role of the left inferior frontal gyrus in social perception: an rTMS study.

Perceiving and interpreting social information richness is something that humans do automatically whenever they engage in social interactions. Numerous studies have identified neural substrates, including mirror neurons that may enable such social perception. In this study, we temporarily disrupted activity in the left inferior frontal gyrus (LIFG) using repetitive transcranial magnetic stimulation (rTMS). We investigated whether this cortical region, that is hypothesized to include mirror neurons, plays a central role in social perception. The LIFG was stimulated in the experimental condition (n=18), the vertex was targeted in the control condition (n=19). Disrupting LIFG, but not vertex, increased reaction times during an emotion recognition task, and eliminated the suppression of the 8-12Hz EEG μ rhythm, postulated as an index of mirroring activity. The results of this study provide further evidence for the role of the human mirror neuron system (MNS) in social perception, and indicate that the MNS can be measured with EEG.

Controlling your impulses: electrical stimulation of the human supplementary motor complex prevents impulsive errors.

To err is human. However, an inappropriate urge does not always result in error. Impulsive errors thus entail both a motor system capture by an urge to act and a failed inhibition of that impulse. Here we show that neuromodulatory electrical stimulation of the supplementary motor complex in healthy humans leaves action urges unchanged but prevents them from turning into overt errors. Subjects performed a choice reaction-time task known to trigger impulsive responses, leading to fast errors that can be revealed by analyzing accuracy as a function of poststimulus time. Yet, such fast errors are only the tip of the iceberg: electromyography (EMG) revealed fast subthreshold muscle activation in the incorrect response hand in an even larger proportion of overtly correct trials, revealing covert response impulses not discernible in overt behavior. Analyzing both overt and covert response tendencies enables to gauge the ability to prevent these incorrect impulses from turning into overt action errors. Hyperpolarizing the supplementary motor complex using transcranial direct current stimulation (tDCS) preserves action impulses but prevents their behavioral expression. This new combination of detailed behavioral, EMG, and tDCS techniques clarifies the neurophysiology of impulse control, and may point to avenues for improving impulse control deficits in various neurologic and psychiatric disorders.

Lifespan changes in motor activation and inhibition during choice reactions: A Laplacian ERP study

Response speed improves from childhood to early adulthood and declines steadily with advancing age. The present event-related brain potential (ERP) study explored the contribution of the primary motor cortex (M1) to lifespan changes in response speed and accuracy using a choice reaction time (RT) task. Two groups of children (8 and 12 years) and two groups of adults (21 and 76 years) responded to left- or right-pointing arrows. RTs showed a typical U-shaped lifespan pattern. RT was segmented into pre-selection time, pre-motor time, and motor time by using the onset of the central motor command (i.e., LRP, and the negative Laplacian potential) and the onset of response-related EMG. Pre-motor time was most sensitive to age-related change. In addition, the positive Laplacian potential, assumed to be associated with inhibition of the incorrect response alternative, was absent in children. In adults, the onset of the ipsilateral positivity started before the onset of the contralateral negativity but in elderly the onsets occurred approximately at the same time. This pattern of findings is consistent with the observed differences in choice error rates between age groups. Taken together, the lifespan changes in motor potentials point to suboptimal motor response control in children and the elderly compared to young adults.

Deep Brain Stimulation of the Subthalamic Nucleus Improves Reward-Based Decision-Learning in Parkinson's Disease

Recently, the subthalamic nucleus (STN) has been shown to be critically involved in decision-making, action selection, and motor control. Here we investigate the effect of deep brain stimulation (DBS) of the STN on reward-based decision-learning in patients diagnosed with Parkinsons disease (PD). We determined computational measures of outcome evaluation and reward prediction from PD patients who performed a probabilistic reward-based decision-learning task. In previous work, these measures covaried with activation in the nucleus caudatus (outcome evaluation during the early phases of learning) and the putamen (reward prediction during later phases of learning). We observed that stimulation of the STN motor regions in PD patients served to improve reward-based decision-learning, probably through its effect on activity in frontostriatal motor loops (prominently involving the putamen and, hence, reward prediction). In a subset of relatively younger patients with relatively shorter disease duration, the effects of DBS appeared to spread to more cognitive regions of the STN, benefiting loops that connect the caudate to various prefrontal areas importantfor outcome evaluation. These results highlight positive effects of STN stimulation on cognitive functions that may benefit PD patients in daily-life association-learning situations.