Nelleke C. van Wouwe

Subthalamic nucleus stimulation influences expression and suppression of impulsive behaviour in Parkinson's disease

Past studies show beneficial as well as detrimental effects of subthalamic nucleus deep-brain stimulation on impulsive behaviour. We address this paradox by investigating individuals with Parkinsons disease treated with subthalamic nucleus stimulation (n = 17) and healthy controls without Parkinsons disease (n = 17) on performance in a Simon task. In this reaction time task, conflict between premature response impulses and goal-directed action selection is manipulated. We applied distributional analytic methods to separate the strength of the initial response impulse from the proficiency of inhibitory control engaged subsequently to suppress the impulse. Patients with Parkinsons disease were tested when stimulation was either turned on or off. Mean conflict interference effects did not differ between controls and patients, or within patients when stimulation was on versus off. In contrast, distributional analyses revealed two dissociable effects of subthalamic nucleus stimulation. Fast response errors indicated that stimulation increased impulsive, premature responding in high conflict situations. Later in the reaction process, however, stimulation improved the proficiency with which inhibitory control was engaged to suppress these impulses selectively, thereby facilitating selection of the correct action. This temporal dissociation supports a conceptual framework for resolving past paradoxical findings and further highlights that dynamic aspects of impulse and inhibitory control underlying goal-directed behaviour rely in part on neural circuitry inclusive of the subthalamic nucleus.

Dopamine and inhibitory action control: evidence from spontaneous eye blink rates

The inhibitory control of actions has been claimed to rely on dopaminergic pathways. Given that this hypothesis is mainly based on patient and drug studies, some authors have questioned its validity and suggested that beneficial effects of dopaminergic stimulants on response inhibition may be limited to cases of suboptimal inhibitory functioning. We present evidence that, in carefully selected healthy adults, spontaneous eyeblink rate, a marker of central dopaminergic functioning, reliably predicts the efficiency in inhibiting unwanted action tendencies in a stop-signal task. These findings support the assumption of a modulatory role for dopamine in inhibitory action control.

Positive affect modulates flexibility and evaluative control

The ability to interact with a constantly changing environment requires a balance between maintaining the currently relevant working memory content and being sensitive to potentially relevant new information that should be given priority access to working memory. Mesocortical dopamine projections to frontal brain areas modulate working memory maintenance and flexibility. Recent neurocognitive and neurocomputational work suggests that dopamine release is transiently enhanced by induced positive affect. This ERP study investigated the role of positive affect in different aspects of information processing: in proactive control (context maintenance and updating), reactive control (flexible adaptation to incoming task-relevant information), and evaluative control in an AX-CPT task. Subjects responded to a target probe if it was preceded by a specific cue. Induced positive affect influenced the reactive and evaluative components of control (indexed by the N2 elicited by the target and by the error-related negativity elicited after incorrect responses, respectively), whereas cue-induced proactive preparation and maintenance processes remained largely unaffected (as reflected in the P3b and the contingent negative variation components of the ERP).

Feature binding and affect : Emotional modulation of visuo-motor integration

The primate cortex represents the external world in a distributed fashion, which calls for a mechanism that integrates and binds the features of a perceived or processed event. Animal and patients studies provide evidence that feature binding in the visual cortex is driven by the muscarinic-cholinergic system, whereas visuo-motor integration may be under dopaminergic control. Consistent with this scenario, we present indication that the binding of visual and action features is modulated by emotions through the probable stimulation of the dopaminergic system. Interestingly, the impact of emotions on binding was restricted to tasks in which shape was task-relevant, suggesting that extracting affective information is not automatic but requires attention to shape.

Intelligence and cognitive flexibility: Fluid intelligence correlates with feature “unbinding” across perception and action

People integrate the features of perceived events and of action plans, as well as of episodic stimulus—response relations, intoevent files. We investigated whether the management of event files, and particularly the speed of updating the binding between the task-relevant stimulus feature and the response, correlates with fluid intelligence. Indeed, the performance of participants scoring high on Raven’s Standard Progressive Matrices test was less impaired by a mismatch between the stimulus—response relation in the current and the previous trial. This result suggests that high intelligence is accompanied by a higher degree of flexibility in handling event files—that is, by higher efficiency in updating episodic representations.

Spontaneous eyeblink rate predicts the strength of visuomotor binding.

The primate cortex represents the external world in a distributed way, which requires for a mechanism that integrates the features of a processed event. Animal and patients studies suggest that feature binding in the visual cortex is under muscarinic-cholinergic control, whereas visuomotor integration is driven by the dopaminergic system. Consistent with this picture, we present evidence that the binding of visual and action features is modulated by spontaneous eyeblink rate (EBR), which is a functional marker of central dopaminergic function. Remarkably, the impact of EBR was restricted to the task-relevant visuomotor binding, suggesting that dopamine increased the maintenance of task-relevant information.

Perceiving blocks of emotional pictures and sounds: effects on physiological variables

Most studies on physiological effects of emotion-inducing images and sounds examine stimulus locked variables reflecting a state of at most a few seconds. We here aimed to induce longer lasting emotional states using blocks of repetitive visual, auditory, and bimodal stimuli corresponding to specific valence and arousal levels. The duration of these blocks enabled us to reliably measure heart rate variability as a possible indicator of arousal. In addition, heart rate and skin conductance were determined without taking stimulus timing into account. Heart rate was higher for pleasant and low arousal stimuli compared to unpleasant and high arousal stimuli. Heart rate variability and skin conductance increased with arousal. Effects of valence and arousal on cardiovascular measures habituated or remained the same over 2-min intervals whereas the arousal effect on skin conductance increased. We did not find any effect of stimulus modality. Our results indicate that blocks of images and sounds of specific valence and arousal levels consistently influence different physiological parameters. These parameters need not be stimulus locked. We found no evidence for differences in emotion induction between visual and auditory stimuli, nor did we find bimodal stimuli to be more potent than unimodal stimuli. The latter could be (partly) due to the fact that our bimodal stimuli were not optimally congruent.

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.

Dissociable effects of dopamine on the initial capture and the reactive inhibition of impulsive actions in parkinson's disease

Dopamine plays a key role in a range of action control processes. Here, we investigate how dopamine depletion caused by Parkinson disease (PD) and how dopamine restoring medication modulate the expression and suppression of unintended action impulses. Fifty-five PD patients and 56 healthy controls (HCs) performed an action control task (Simon task). PD patients completed the task twice, once withdrawn from dopamine medications and once while taking their medications. PD patients experienced similar susceptibility to making fast errors in conflict trials as HCs, but PD patients were less proficient compared with HCs at suppressing incorrect responses. Administration of dopaminergic medications had no effect on impulsive error rates but significantly improved the proficiency of inhibitory control in PD patients. We found no evidence that dopamine precursors and agonists affected action control in PD differently. Additionally, there was no clear evidence that individual differences in baseline action control (off dopamine medications) differentially responded to dopamine medications (i.e., no evidence for an inverted U-shaped performance curve). Together, these results indicate that dopamine depletion and restoration therapies directly modulate the reactive inhibitory control processes engaged to suppress interference from the spontaneously activated response impulses but exert no effect on an individuals susceptibility to act on impulses.

Dopaminergic modulation of the updating of stimulus-response episodes in Parkinson's disease.

Increasing evidence suggests that the control of retrieval of episodic feature bindings is modulated by the striatal dopaminergic pathway. The present study investigated whether this may reflect a contribution from the ventral or the dorsal part of the striatum. Along the lines of the overdose hypothesis in Parkinsons disease (PD), functions known to rely on the dorsal striatum are enhanced with dopaminergic medication, while operations relying on the ventral circuitry are impaired. We found that partial mismatches between present and previous stimulus-response relations are, compared to control participants, abnormally low OFF DA medication and normalized ON DA medication. The results suggest that the dorsal striatum, but not (or not so much) the ventral striatum, is driving the flexible control of retrieval of stimulus-response episodes.