Martine R. van Schouwenburg

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.

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.

Establishing the Dopamine Dependency of Human Striatal Signals During Reward and Punishment Reversal Learning

Drugs that alter dopamine transmission have opposite effects on reward and punishment learning. These opposite effects have been suggested to depend on dopamine in the striatum. Here, we establish for the first time the neurochemical specificity of such drug effects, during reward and punishment learning in humans, by adopting a coadministration design. Participants (N = 22) were scanned on 4 occasions using functional magnetic resonance imaging, following intake of placebo, bromocriptine (dopamine-receptor agonist), sulpiride (dopamine-receptor antagonist), or a combination of both drugs. A reversal-learning task was employed, in which both unexpected rewards and punishments signaled reversals. Drug effects were stratified with baseline working memory to take into account individual variations in drug response. Sulpiride induced parallel span-dependent changes on striatal blood oxygen level-dependent (BOLD) signal during unexpected rewards and punishments. These drug effects were found to be partially dopamine-dependent, as they were blocked by coadministration with bromocriptine. In contrast, sulpiride elicited opposite effects on behavioral measures of reward and punishment learning. Moreover, sulpiride-induced increases in striatal BOLD signal during both outcomes were associated with behavioral improvement in reward versus punishment learning. These results provide a strong support for current theories, suggesting that drug effects on reward and punishment learning are mediated via striatal dopamine.

Bromocriptine Does Not Alter Speed–Accuracy Tradeoff

Being quick often comes at the expense of being accurate. This speed–accuracy tradeoff is a central feature of many types of decision making. It has been proposed that dopamine plays an important role in adjusting responses between fast and accurate behavior. In the current study we investigated the role of dopamine in perceptual decision making in humans, focusing on speed–accuracy tradeoff. Using a cued version of the random dot motion task, we instructed subjects to either make a fast or an accurate decision. We investigated decision making behavior in subjects who were given bromocriptine (a dopamine receptor agonist) or placebo. We analyzed the behavioral data using two accumulator models, the drift diffusion model, and the linear ballistic accumulator model. On a behavioral level, there were clear differences in decision threshold between speed and accuracy focus, but decision threshold did not differ between the drug and placebo sessions. Bayesian analyses support the null hypothesis that there is no effect of bromocriptine on decision threshold. On the neural level, we replicate previous findings that the striatum and pre-supplementary motor area are active when preparing for speed, compared with accurate decisions. We do not find an effect of bromocriptine on this activation. Therefore, we conclude that bromocriptine does not alter speed–accuracy tradeoff.

Selective attentional enhancement and inhibition of fronto-posterior connectivity by the basal ganglia during attention switching

The prefrontal cortex and the basal ganglia interact to selectively gate a desired action. Recent studies have shown that this selective gating mechanism of the basal ganglia extends to the domain of attention. Here, we investigate the nature of this action-like gating mechanism for attention using a spatial attention-switching paradigm in combination with functional neuroimaging and dynamic causal modeling. We show that the basal ganglia guide attention by focally releasing inhibition of task-relevant representations, while simultaneously inhibiting task-irrelevant representations by selectively modulating prefrontal top-down connections. These results strengthen and specify the role of the basal ganglia in attention. Moreover, our findings have implications for psychological theorizing by suggesting that inhibition of unattended sensory regions is not only a consequence of mutual suppression, but is an active process, subserved by the basal ganglia.

Anatomical connection strength predicts dopaminergic drug effects on fronto-striatal function

RationaleThe neurotransmitter dopamine plays a key role in cognitive functions that are associated with fronto-striatal circuitry and has been implicated in many neuropsychiatric disorders. However, there is a large variability in the direction and extent of dopaminergic drug effects across individuals.ObjectivesWe investigated whether individual differences in dopaminergic drug effects on human fronto-striatal functioning are associated with individual differences in white matter tracts.MethodsThe effects of the dopamine receptor agonist bromocriptine were assessed using functional magnetic resonance imaging in 22 healthy volunteers in a placebo-controlled, double-blind, within-subject design. Human psychopharmacology and functional neuroimaging were combined with functional connectivity analyses and structural connectivity analyses to establish a link between dopaminergic drug effects on fronto-striatal function and fronto-striatal anatomy.ResultsWe demonstrate that bromocriptine alters functional signals associated with attention switching in the basal ganglia. Crucially, individual differences in the drug’s effect on these signals could be predicted from individual differences in fronto-striato-thalamic white matter tracts, as indexed by diffusion tensor imaging. Anatomical fronto-striatal connectivity also predicted drug effects on switch-related functional connectivity between the basal ganglia and the prefrontal cortex.ConclusionsThese data reinforce the link between dopamine, cognition and the basal ganglia and have implications for the individual tailoring of dopaminergic drug therapy based on anatomical fronto-striatal connection strength.

Alpha activity reflects individual abilities to adapt to the environment

Recent findings suggest that oscillatory alpha activity (7-13Hz) is associated with functional inhibition of sensory regions by filtering incoming information. Accordingly the alpha power in visual regions varies in anticipation of upcoming, predictable stimuli which has consequences for visual processing and subsequent behavior. In covert spatial attention studies it has been demonstrated that performance correlates with the adaptation of alpha power in response to explicit spatial cueing. However it remains unknown whether such an adaptation also occurs in response to implicit statistical properties of a task. In a covert attention switching paradigm, we here show evidence that individuals differ on how they adapt to implicit statistical properties of the task. Subjects whose behavioral performance reflects the implicit change in switch trial likelihood show strong adjustment of anticipatory alpha power lateralization. Most importantly, the stronger the behavioral adjustment to the switch trial likelihood was, the stronger the adjustment of anticipatory posterior alpha lateralization. We conclude that anticipatory spatial attention is reflected in the distribution of posterior alpha band power which is predictive of individual detection performance in response to the implicit statistical properties of the task.

Dopaminergic drug effects during reversal learning depend on anatomical connections between the orbitofrontal cortex and the amygdala

Dopamine in the striatum is known to be important for reversal learning. However, the striatum does not act in isolation and reversal learning is also well-accepted to depend on the orbitofrontal cortex (OFC) and the amygdala. Here we assessed whether dopaminergic drug effects on human striatal BOLD signaling during reversal learning is associated with anatomical connectivity in an orbitofrontal-limbic-striatal network, as measured with diffusion tensor imaging (DTI). By using a fiber-based approach, we demonstrate that dopaminergic drug effects on striatal BOLD signal varied as a function of fractional anisotropy (FA) in a pathway connecting the OFC with the amygdala. Moreover, our experimental design allowed us to establish that these white-matter dependent drug effects were mediated via D2 receptors. Thus, white matter dependent effects of the D2 receptor agonist bromocriptine on striatal BOLD signal were abolished by co-administration with the D2 receptor antagonist sulpiride. These data provide fundamental insight into the mechanism of action of dopaminergic drug effects during reversal learning. In addition, they may have important clinical implications by suggesting that white matter integrity can help predict dopaminergic drug effects on brain function, ultimately contributing to individual tailoring of dopaminergic drug treatment strategies in psychiatry.

Spatial attention and the effects of frontoparietal alpha band stimulation

A frontoparietal network has long been implicated in top-down control of attention. Recent studies have suggested that this network might communicate through coherence in the alpha band. Here we aimed to test the effect of coherent alpha (8–12 Hz) stimulation on the frontoparietal network. To this end, we recorded behavioral performance and electroencephalography (EEG) data while participants were engaged in a spatial attention task. Furthermore, participants received transcranial alternating current stimulation (tACS) over the right frontal and parietal cortex, which oscillated coherently in-phase within the alpha band. Compared to a group of participants that received sham stimulation, we found that coherent frontoparietal alpha band stimulation altered a behavioral spatial attention bias. Neurally, the groups showed hemispheric-specific differences in alpha coherence between the frontal and parietal-occipital cortex. These results provide preliminary evidence that alpha coherence in the frontoparietal network might play a role in top-down control of spatial attention.

Enhancement of multitasking performance and neural oscillations by transcranial alternating current stimulation

Multitasking is associated with the generation of stimulus-locked theta (4–7 Hz) oscillations arising from prefrontal cortex (PFC). Transcranial alternating current stimulation (tACS) is a non-invasive brain stimulation technique that influences endogenous brain oscillations. Here, we investigate whether applying alternating current stimulation within the theta frequency band would affect multitasking performance, and explore tACS effects on neurophysiological measures. Brief runs of bilateral PFC theta-tACS were applied while participants were engaged in a multitasking paradigm accompanied by electroencephalography (EEG) data collection. Unlike an active control group, a tACS stimulation group showed enhancement of multitasking performance after a 90-minute session (F1,35 = 6.63, p = 0.01, ηp2 = 0.16; effect size = 0.96), coupled with significant modulation of posterior beta (13–30 Hz) activities (F1,32 = 7.66, p = 0.009, ηp2 = 0.19; effect size = 0.96). Across participant regression analyses indicated that those participants with greater increases in frontal theta, alpha and beta oscillations exhibited greater multitasking performance improvements. These results indicate frontal theta-tACS generates benefits on multitasking performance accompanied by widespread neuronal oscillatory changes, and suggests that future tACS studies with extended treatments are worth exploring as promising tools for cognitive enhancement.