Dopamine promotes cognitive effort by biasing the benefits versus costs of cognitive work.

Stimulants such as methylphenidate are increasingly used for cognitive enhancement but precise mechanisms are unknown. We found that methylphenidate boosts willingness to expend cognitive effort by altering the benefit-to-cost ratio of cognitive work. Willingness to expend effort was greater for participants with higher striatal dopamine synthesis capacity, whereas methylphenidate and sulpiride, a selective D2 receptor antagonist, increased cognitive motivation more for participants with lower synthesis capacity. A sequential sampling model informed by momentary gaze revealed that decisions to expend effort are related to amplification of benefit-versus-cost information attended early in the decision process, whereas the effect of benefits is strengthened with higher synthesis capacity and by methylphenidate. These findings demonstrate that methylphenidate boosts the perceived benefits versus costs of cognitive effort by modulating striatal dopamine signaling.

Reward learning deficits in Parkinson's disease depend on depression.

BACKGROUND: Depression is one of the most common and debilitating non-motor symptoms of Parkinson's disease (PD). The neurocognitive mechanisms underlying depression in PD are unclear and treatment is often suboptimal. METHODS: We investigated the role of striatal dopamine in reversal learning from reward and punishment by combining a controlled medication withdrawal procedure with functional magnetic resonance imaging in 22 non-depressed PD patients and 19 PD patients with past or present depression. RESULTS: PD patients with a depression (history) exhibited impaired reward v. punishment reversal learning as well as reduced reward v. punishment-related BOLD signal in the striatum (putamen) compared with non-depressed PD patients. No effects of dopaminergic medication were observed. CONCLUSIONS: The present findings demonstrate that impairments in reversal learning from reward v. punishment and associated striatal signalling depend on the presence of (a history of) depression in PD.

The specificity of Pavlovian regulation is associated with recovery from depression.

BACKGROUND: Changes in reflexive emotional responses are hallmarks of depression, but how emotional reflexes make an impact on adaptive decision-making in depression has not been examined formally. Using a Pavlovian-instrumental transfer (PIT) task, we compared the influence of affectively valenced stimuli on decision-making in depression and generalized anxiety disorder compared with healthy controls; and related this to the longitudinal course of the illness. METHOD: A total of 40 subjects with a current DSM-IV-TR diagnosis of major depressive disorder, dysthymia, generalized anxiety disorder, or a combination thereof, and 40 matched healthy controls performed a PIT task that assesses how instrumental approach and withdrawal behaviours are influenced by appetitive and aversive Pavlovian conditioned stimuli (CSs). Patients were followed up after 4-6 months. Analyses focused on patients with depression alone (n = 25). RESULTS: In healthy controls, Pavlovian CSs exerted action-specific effects, with appetitive CSs boosting active approach and aversive CSs active withdrawal. This action-specificity was absent in currently depressed subjects. Greater action-specificity in patients was associated with better recovery over the follow-up period. CONCLUSIONS: Depression is associated with an abnormal influence of emotional reactions on decision-making in a way that may predict recovery.

Cognitive flexibility depends on white matter microstructure of the basal ganglia.

Ample evidence shows that the basal ganglia play an important role in cognitive flexibility. However, traditionally, cognitive processes have most commonly been associated with the prefrontal cortex. Indeed, current theoretical models of basal ganglia function suggest the basal ganglia interact with the prefrontal cortex and thalamus, via anatomical fronto-striato-thalamic circuits, to implement cognitive flexibility. Here we aimed to assess this hypothesis in humans by associating individual differences in cognitive flexibility with white matter microstructure of the basal ganglia. To this end we employed an attention switching paradigm in adults with ADHD and controls, leading to a broad range in task performance. Attention switching performance could be predicted based on individual differences in white matter microstructure in/around the basal ganglia. Crucially, local white matter showing this association projected to regions in the prefrontal cortex and thalamus. Our findings highlight the crucial role of the basal ganglia and the fronto-striato-thalamic circuit for cognitive flexibility.

Feedback-related negativity codes outcome valence, but not outcome expectancy, during reversal learning.

Optimal behavior depends on the ability to assess the predictive value of events and to adjust behavior accordingly. Outcome processing can be studied by using its electrophysiological signatures--that is, the feedback-related negativity (FRN) and the P300. A prominent reinforcement-learning model predicts an FRN on negative prediction errors, as well as implying a role for the FRN in learning and the adaptation of behavior. However, these predictions have recently been challenged. Notably, studies so far have used tasks in which the outcomes have been contingent on the response. In these paradigms, the need to adapt behavioral responses is present only for negative, not for positive feedback. The goal of the present study was to investigate the effects of positive as well as negative violations of expectancy on FRN amplitudes, without the usual confound of behavioral adjustments. A reversal-learning task was employed in which outcome value and outcome expectancy were orthogonalized; that is, both positive and negative outcomes were equally unexpected. The results revealed a double dissociation, with effects of valence but not expectancy on the FRN and, conversely, effects of expectancy but not valence on the P300. While FRN amplitudes were largest for negative-outcome trials, irrespective of outcome expectancy, P300 amplitudes were largest for unexpected-outcome trials, irrespective of outcome valence. These FRN effects were interpreted to reflect an evaluation along a good-bad dimension, rather than reflecting a negative prediction error or a role in behavioral adaptation. By contrast, the P300 reflects the updating of information relevant for behavior in a changing context.

Decomposing effects of dopaminergic medication in Parkinson's disease on probabilistic action selection--learning or performance?

Dopamine has long been implicated in reward-based learning and the expression of such learned associations on performance. Robust evidence supports its effects on learning and performance, but teasing these apart has proved challenging. Here we have adapted a classic test of value-based learning, the probabilistic selection task, to disentangle effects of dopamine on value-based performance from effects on value-based learning. Valence-specific effects of dopamine on this specific task cannot be accounted for by modulation of learning, and therefore must reflect modulation of performance. We found that dopaminergic medication, consisting of levodopa and/or dopamine agonists taken at own dose, in 18 patients with mild Parkinson's disease (Hoehn and Yahr < 2.5) potentiated reward-based approach in terms of both accuracy and reaction times, while leaving punishment-based avoidance unaffected. These data demonstrate that the effects of dopamine on probabilistic action selection are at least partly mediated by effects on the expression of learned associations rather than on learning itself, and help refine current models of dopamine's role in reward.

Enhanced frontal function in Parkinson's disease.

We investigated the role of dopamine in working memory by examining effects of withdrawing dopaminergic medication in patients with Parkinson's disease. Resistance to distraction during a delayed response task was abnormally enhanced in Parkinson's disease patients OFF medication relative to controls. Conversely, performance on a backward digit span test was impaired in these same Parkinson's disease patients OFF medication. Dopaminergic medication reinstated susceptibility to distraction and backward digit span performance, so that performance of Parkinson's disease patients ON medication did not differ from that of controls. We hypothesize that the enhanced distractor resistance and impaired backward digit span in Parkinson's disease reflects low dopamine levels in the striatum, and perhaps upregulated frontal dopamine levels. Dopaminergic medication may reinstate distractibility by normalizing the balance between striatal and prefrontal dopamine transmission.

Mood state moderates the role of serotonin in cognitive biases.

Reduction of the monoamine serotonin (5-HT) via the dietary manipulation of tryptophan (acute tryptophan depletion; ATD) has been shown to induce negative cognitive biases similar to those found in depression in healthy individuals. However, evidence also indicates that there can be positive effects of ATD on both mood and reinforcement processing. Here, we present two separate studies, with remarkably similar findings, which may help explain these discrepancies. In both experiments, we assessed cognitive biases following experimentally induced mood states under both a balanced amino acid drink (BAL) and ATD. A significant interaction between treatment, mood state and cognitive bias was observed in both experiments. In the first experiment, subjects undergoing positive mood induction demonstrated a positive cognitive bias on BAL, which was abolished by ATD. The same effect was observed in subjects undergoing neutral mood induction in the second experiment. These effects replicate findings in healthy individuals undergoing ATD. Subjects undergoing negative mood induction, by contrast, demonstrated the opposite pattern of results; in both experiments, they showed no bias under BAL but induction of a positive cognitive bias by ATD. These results mimic previous findings in currently depressed patients undergoing ATD. We therefore suggest that mood state moderates the effect of ATD on cognitive biases. This, in turn, has important implications for the understanding of the role of 5-HT in psychiatric disorders.

Biological changes associated with healthy versus pathological aging: a symposium review.

The Douglas Mental Health University Institute, in collaboration with the McGill Centre for Studies in Aging, organized a 2-day symposium entitled "Biological Changes Associated with Healthy Versus Pathological Aging" that was held in 13 and 14 December 2007 on the Douglas campus. The symposium involved presentations on current trends in aging and dementia research across several sub-disciplines: genetics, neurochemistry, structural and functional neuroimaging and clinical treatment and rehabilitation. The goal of this symposium was to provide a forum for knowledge-transfer between scientists and clinicians with different specializations in order to promote cross-fertilization of research ideas that would lead to future collaborative neuroscience research in aging and dementia. In this review article, we summarize the presentations made by the 13 international scientists at the symposium and highlight: (i) past research, and future research trends in neuroscience of aging and dementia and (ii) links across levels of analysis that can lead to fruitful transdisciplinary research programs that will advance knowledge about the neurobiological changes associated with healthy aging and dementia.

The human striatum is necessary for responding to changes in stimulus relevance.

Various lines of evidence suggest that the striatum is implicated in cognitive flexibility. The neuropsychological evidence has, for the most part, been based on research with patients with Parkinson's disease, which is accompanied by chemical disruption of both the striatum and the prefrontal cortex. The present study examined this issue by testing patients with focal lesions of the striatum on a task measuring two forms of cognitive switching. Patients with striatal, but not frontal lobe lesions, were impaired in switching between concrete sensory stimuli. By contrast, both patient groups were unimpaired when switching between abstract task rules relative to baseline nonswitch trials. These results reveal a dissociation between two distinct forms of cognitive flexibility, providing converging evidence for a role of the striatum in flexible control functions associated with the selection of behaviorally relevant stimuli.

Stop signal response inhibition is not modulated by tryptophan depletion or the serotonin transporter polymorphism in healthy volunteers: implications for the 5-HT theory of impulsivity.

RATIONALE: Reduced serotonin neurotransmission is implicated in disorders of impulse control, but the involvement of serotonin in inhibitory processes in healthy human subjects remains unclear. OBJECTIVES: To investigate the effects of an acute manipulation of serotonin and genotype at a functional polymorphism in a gene coding for the serotonin transporter (5-HTT) on an established measure of response inhibition. METHODS: Serotonin function was reduced by the acute tryptophan depletion (ATD) procedure in a double-blind, crossover design in 42 healthy subjects. The Stop Signal Task (SST) was administered 5-7 h after drink administration. The influences of 5-HTT polymorphism, gender and trait impulsivity were investigated. RESULTS: ATD was associated with significant depletion of plasma tryptophan levels but did not increase the stop signal reaction time in comparison to the balanced (placebo) amino acid mixture. Subjects possessing the short allele of the 5-HTT polymorphism were not more impulsive on the SST than subjects homozygous for the long allele under placebo conditions and were not disproportionately sensitive to the effects of ATD. There was no effect of gender or trait impulsivity on ATD-induced change. CONCLUSIONS: We find no support for the involvement of brain serotonin neurotransmission in this form of inhibitory control in healthy human subjects.

The neuropsychology of ventral prefrontal cortex: decision-making and reversal learning.

Converging evidence from human lesion, animal lesion, and human functional neuroimaging studies implicates overlapping neural circuitry in ventral prefrontal cortex in decision-making and reversal learning. The ascending 5-HT and dopamine neurotransmitter systems have a modulatory role in both processes. There is accumulating evidence that measures of decision-making and reversal learning may be useful as functional markers of ventral prefrontal cortex integrity in psychiatric and neurological disorders. Whilst existing measures of decision-making may have superior sensitivity, reversal learning may offer superior selectivity, particularly within prefrontal cortex. Effective decision-making on existing measures requires the ability to adapt behaviour on the basis of changes in emotional significance, and this may underlie the shared neural circuitry with reversal learning.

Enhanced or impaired cognitive function in Parkinson's disease as a function of dopaminergic medication and task demands.

We investigated how dopamine (DA) systems contribute to cognitive performance in the domain of learning and attentional flexibility by examining effects of withdrawing DA-ergic medication in patients with Parkinson's disease (PD). Medication remediated impairments in switching between two tasks, thought to depend on circuitry connecting the dorsolateral prefrontal cortex and the posterior parietal cortex to the dorsal caudate nucleus, which is profoundly DA-depleted in PD. By contrast, the same medication impaired probabilistic reversal learning that implicates orbitofrontal cortex- ventral striatal circuitry, which is relatively spared of DA loss in PD. Hence, DA-ergic medication improves or impairs cognitive performance depending on the nature of the task and the basal level of DA function in underlying cortico-striatal circuitry.

Mechanisms of cognitive set flexibility in Parkinson's disease.

Previous research on cognitive set shifting in patients with Parkinson's disease has often been confounded by concept formation, rule learning, working memory and/or general slowing of cognitive processes. To circumvent this problem, the present study used the task-set switching procedure in which good performance was independent of rule learning, and in which working memory load was reduced by explicitly cueing the task switches. Our results provide strong evidence for a specific cognitive set shifting deficit in patients with mild Parkinson's disease in a non-learning context, which also cannot be explained by general slowing of cognitive processes. Moreover, the deficit was robust in a small sample of patients at the earliest stages of the disease. Finally, the impairment in task-set switching was only apparent when competing information was present, i.e. when the load on selection mechanisms was increased.

Flexibility, inhibition, and planning: frontal dysfunctioning in schizophrenia.

Neuropsychological tests known to reveal abnormalities in patients with frontal lobe damage were used to explore cognitive function in 20 chronic schizophrenic patients. Eleven control subjects, matched on age and NLV-IQ (NLV is the Dutch version of the NART) were also tested. No impairments of planning ability were found on either the Action Program test or the Zoomap test, both subtests from the BADS (Behavioural Assessment of the Dysexecutive Syndrome). No abnormalities were apparent on tests of reactive flexibility, measured by task-switching and by the Rule Shift Cards test, also a subtest of the BADS. Patients with schizophrenia, however, had significantly greater difficulty in inhibiting irrelevant information and in generating words in a verbal fluency task, a measure of spontaneous flexibility.

Goal neglect and inhibitory limitations: dissociable causes of interference effects in conflict situations.

Interference effects on task performance in conflict situations might reflect real limitations in inhibitory capabilities or failures to fully or consistently utilize such capabilities in executive control of task performance. We propose that useful clues regarding the actual cause of interference effects may be obtained from examination of their robustness within and between experimental conditions. We illustrate this approach for two major types of interference effects that have commonly been attributed to fundamental inhibitory limitations: Stroop-type interference and residual switch costs. We present results that indicate that these effects may not be unavoidable consequences of fundamental inhibitory limitations but may stem from goal neglect, i.e., failures to fully or effectively deploy inhibitory capabilities. These results indicate that, in addition to mean performance levels, variability of task performance may provide a valuable source of evidence regarding the actual cause of performance limitations or deficits in conflict situations.