Role of dopamine and clinical heterogeneity in cognitive dysfunction in Parkinson's disease.

Parkinson's disease (PD) is commonly treated with dopaminergic medication, which enhances some, while impairing other cognitive functions. It can even contribute to impulse control disorder and addiction. We describe the history of research supporting the dopamine overdose hypothesis, which accounts for the large within-patient variability in dopaminergic medication effects across different tasks by referring to the spatially non-uniform pattern of dopamine depletion in dorsal versus ventral striatum. However, there is tremendous variability in dopaminergic medication effects not just within patients across distinct tasks, but also across different patients. In the second part of this chapter we review recent studies addressing the large individual variability in the negative side effects of dopaminergic medication on functions that implicate dopamine, such as value-based learning and choice. These studies begin to unravel the mechanisms of dopamine overdosing, thus revising the strict version of the overdose hypothesis. For example, the work shows that the canonical boosting of reward-versus punishment-based choice by medication is greater in patients with depression and a non-tremor phenotype, which both implicate, among other pathology, more rather than less severe dysregulation of the mesolimbic dopamine system. Future longitudinal cohort studies are needed to identify how to optimally combine different clinical, personality, cognitive, neural, genetic and molecular predictors of detrimental medication effects in order to account for as much of the relevant variability as possible. This will provide a useful tool for precision neurology, allowing individual and contextual tailoring of (the dose of) dopaminergic medication in order to maximize its cognitive benefits, yet minimize its side effects.

Enhanced motivation of cognitive control in Parkinson's disease.

Motor and cognitive deficits in Parkinson's disease (PD) have been argued to reflect motivational deficits. In prior work, however, we have shown that motivation of cognitive control is paradoxically potentiated rather than impaired in Parkinson's disease. This is particularly surprising given the fact that Parkinson's disease is often accompanied by depression, a prototypical disorder of motivation. To replicate our previous finding and assess the effects of depression, we investigated performance of PD patients with (n = 22) and without depression (history) (n = 23) and age-matched healthy controls (n = 23) on a task specifically designed to measure the effect of reward motivation on task-switching. We replicated previous findings by showing contrasting effects of reward motivation on task-switching in PD patients and age-matched healthy controls. While the promise of high versus low reward improved task-switching in PD, it tended to impair task-switching in age-matched healthy controls. There were no effects of a depression (history) diagnosis in PD patients. These findings reinforce prior observations that Parkinson's disease is accompanied by enhanced incentive motivation of cognitive control and highlight the potential of incentive motivational strategies for overcoming cognitive deficits in Parkinson's disease.

Mechanisms Underlying Dopamine-Induced Risky Choice in Parkinson's Disease With and Without Depression (History).

Patients with Parkinson's disease (PD) are often treated with dopaminergic medication. Dopaminergic medication is known to improve both motor and certain nonmotor symptoms, such as depression. However, it can contribute to behavioral impairment, for example, by enhancing risky choice. Here we characterize the computational mechanisms that contribute to dopamine-induced changes in risky choice in PD patients with and without a depression (history). We adopt a clinical-neuroeconomic approach to investigate the effects of dopaminergic medication on specific components of risky choice in PD. Twenty-three healthy controls, 21 PD patients with a depression (history), and 22 nondepressed PD patients were assessed using a well-established risky choice paradigm. Patients were tested twice: once after taking their normal dopaminergic medication and once after withdrawal of their medication. Dopaminergic medication increased a value-independent gambling propensity in nondepressed PD patients, while leaving loss aversion unaffected. By contrast, dopaminergic medication effects on loss aversion were associated with current depression severity and with drug effects on depression scores. The present findings demonstrate that dopaminergic medication increases a value-independent gambling bias in nondepressed PD patients. Moreover, the current study raises the hypothesis that dopamine-induced reductions in loss aversion might underlie previously observed comorbidity between depression and medication-related side effects in PD, such as impulse control disorder.

Dopaminergic Drug Effects on Probability Weighting during Risky Decision Making.

Dopamine has been associated with risky decision-making, as well as with pathological gambling, a behavioral addiction characterized by excessive risk-taking behavior. However, the specific mechanisms through which dopamine might act to foster risk-taking and pathological gambling remain elusive. Here we test the hypothesis that this might be achieved, in part, via modulation of subjective probability weighting during decision making. Human healthy controls (n = 21) and pathological gamblers (n = 16) played a decision-making task involving choices between sure monetary options and risky gambles both in the gain and loss domains. Each participant played the task twice, either under placebo or the dopamine D2/D3 receptor antagonist sulpiride, in a double-blind counterbalanced design. A prospect theory modelling approach was used to estimate subjective probability weighting and sensitivity to monetary outcomes. Consistent with prospect theory, we found that participants presented a distortion in the subjective weighting of probabilities, i.e., they overweighted low probabilities and underweighted moderate to high probabilities, both in the gain and loss domains. Compared with placebo, sulpiride attenuated this distortion in the gain domain. Across drugs, the groups did not differ in their probability weighting, although gamblers consistently underweighted losing probabilities in the placebo condition. Overall, our results reveal that dopamine D2/D3 receptor antagonism modulates the subjective weighting of probabilities in the gain domain, in the direction of more objective, economically rational decision making.

What a neurologist should know about depression in Parkinson's disease.

Depression is a frequent non-motor symptom of Parkinson's disease. Its prevalence varies widely across studies (between 2.7% and 90%); around 35% have clinically significant depressive symptoms. Although depression can have an immense impact on the quality of life of affected patients and their caregivers, depressive symptoms in Parkinson's disease frequently remain unrecognised and, as a result, remain untreated. Here we overview the diagnostic challenges and pitfalls, including the factors contributing to the underdiagnosis of depression. We also discuss current ideas on the underlying pathophysiology. Finally, we offer a treatment approach based on currently available evidence.

Dopamine controls Parkinson's tremor by inhibiting the cerebellar thalamus.

Parkinson's resting tremor is related to altered cerebral activity in the basal ganglia and the cerebello-thalamo-cortical circuit. Although Parkinson's disease is characterized by dopamine depletion in the basal ganglia, the dopaminergic basis of resting tremor remains unclear: dopaminergic medication reduces tremor in some patients, but many patients have a dopamine-resistant tremor. Using pharmacological functional magnetic resonance imaging, we test how a dopaminergic intervention influences the cerebral circuit involved in Parkinson's tremor. From a sample of 40 patients with Parkinson's disease, we selected 15 patients with a clearly tremor-dominant phenotype. We compared tremor-related activity and effective connectivity (using combined electromyography-functional magnetic resonance imaging) on two occasions: ON and OFF dopaminergic medication. Building on a recently developed cerebral model of Parkinson's tremor, we tested the effect of dopamine on cerebral activity associated with the onset of tremor episodes (in the basal ganglia) and with tremor amplitude (in the cerebello-thalamo-cortical circuit). Dopaminergic medication reduced clinical resting tremor scores (mean 28%, range -12 to 68%). Furthermore, dopaminergic medication reduced tremor onset-related activity in the globus pallidus and tremor amplitude-related activity in the thalamic ventral intermediate nucleus. Network analyses using dynamic causal modelling showed that dopamine directly increased self-inhibition of the ventral intermediate nucleus, rather than indirectly influencing the cerebello-thalamo-cortical circuit through the basal ganglia. Crucially, the magnitude of thalamic self-inhibition predicted the clinical dopamine response of tremor. Dopamine reduces resting tremor by potentiating inhibitory mechanisms in a cerebellar nucleus of the thalamus (ventral intermediate nucleus). This suggests that altered dopaminergic projections to the cerebello-thalamo-cortical circuit have a role in Parkinson's tremor.aww331media15307619934001.

Unmasking levodopa resistance in Parkinson's disease.

Some motor and nonmotor features associated with Parkinson's disease (PD) do not seem to respond well to levodopa (or other forms of dopaminergic medication) or appear to become resistant to levodopa treatment with disease progression and longer disease duration. In this narrative review, we elaborate on this issue of levodopa resistance in PD. First, we discuss the possibility of pseudoresistance, which refers to dopamine-sensitive symptoms or signs that falsely appear to be (or have become) resistant to levodopa, when in fact other mechanisms are at play, resulting in suboptimal dopaminergic efficacy. Examples include interindividual differences in pharmacodynamics and pharmacokinetics and underdosing because of dose-limiting side effects or because of levodopa phobia. Moreover, pseudoresistance can emerge as not all features of PD respond adequately to the same dosage of levodopa. Second, we address that for several motor features (eg, freezing of gait or tremor) and several nonmotor features (eg, specific cognitive functions), the response to levodopa is fairly complex, with a combination of levodopa-responsive, levodopa-resistant, and even levodopa-induced characteristics. A possible explanation relates to the mixed presence of underlying dopaminergic and nondopaminergic brain lesions. We suggest that clinicians take these possibilities into account before concluding that symptoms or signs of PD are totally levodopa resistant. © 2016 International Parkinson and Movement Disorder Society.

Amplified Striatal Responses to Near-Miss Outcomes in Pathological Gamblers.

Near-misses in gambling games are losing events that come close to a win. Near-misses were previously shown to recruit reward-related brain regions including the ventral striatum, and to invigorate gambling behavior, supposedly by fostering an illusion of control. Given that pathological gamblers are particularly vulnerable to such cognitive illusions, their persistent gambling behavior might result from an amplified striatal sensitivity to near-misses. In addition, animal studies have shown that behavioral responses to near-miss-like events are sensitive to dopamine, but this dopaminergic influence has not been tested in humans. To investigate these hypotheses, we recruited 22 pathological gamblers and 22 healthy controls who played a slot machine task delivering wins, near-misses and full-misses, inside an fMRI scanner. Each participant played the task twice, once under placebo and once under a dopamine D2 receptor antagonist (sulpiride 400 mg), in a double-blind, counter-balanced design. Participants were asked about their motivation to continue gambling throughout the task. Across all participants, near-misses elicited higher motivation to continue gambling and increased striatal responses compared with full-misses. Crucially, pathological gamblers showed amplified striatal responses to near-misses compared with controls. These group differences were not observed following win outcomes. In contrast to our hypothesis, sulpiride did not induce any reliable modulation of brain responses to near-misses. Together, our results demonstrate that pathological gamblers have amplified brain responses to near-misses, which likely contribute to their persistent gambling behavior. However, there is no evidence that these responses are influenced by dopamine. These results have implications for treatment and gambling regulation.

Predicting osteoporosis in patients with a low-energy fracture.

The multicenter cross-sectional study was designed to develop a simple rule to predict the risk of osteoporosis in the patients with a low-energy fracture (LEF). Furthermore, we aimed to investigate the incidence of fall-related risk factors. We included 206 patients with age over 50 and an LEF at the emergency room. All patients underwent osteoporosis and fall risk assessment and dual-energy X-ray absorptiometry (DEXA) of both hips and the lumbar spine. The incidence of osteoporosis in our study population was 41% (84 cases of 206). Fifty-four percent of the patients reported at least one fall-related risk factor. Mobility problems occurred in 31% and osteoarthritis in 19%. The final osteoporosis prediction rule included age, positive family history, immobility, and low-body weight. The discrimination of the rule after correction for over-optimism was good (receiver operating curve (ROC)=ROC area=0.79). This simple rule may be helpful to select patients who need further osteoporosis assessment.