Dopamine and reward hypersensitivity in Parkinson's disease with impulse control disorder.

Impulse control disorders in Parkinson's disease are common neuropsychiatric complications associated with dopamine replacement therapy. Some patients treated with dopamine agonists develop pathological behaviours, such as gambling, compulsive eating, shopping, or disinhibited sexual behaviours, which can have a severe impact on their lives and that of their families. In this study we investigated whether hypersensitivity to reward might contribute to these pathological behaviours and how this is influenced by dopaminergic medication. We asked participants to shift their gaze to a visual target as quickly as possible, in order to obtain reward. Critically, the reward incentive on offer varied over trials. Motivational effects were indexed by pupillometry and saccadic velocity, and patients were tested ON and OFF dopaminergic medication, allowing us to measure the effect of dopaminergic medication changes on reward sensitivity. Twenty-three Parkinson's disease patients with a history of impulse control disorders were compared to 26 patients without such behaviours, and 31 elderly healthy controls. Intriguingly, behavioural apathy was reported alongside impulsivity in the majority of patients with impulse control disorders. Individuals with impulse control disorders also exhibited heightened sensitivity to exogenous monetary rewards cues both ON and OFF (overnight withdrawal) dopamine medication, as indexed by pupillary dilation in anticipation of reward. Being OFF dopaminergic medication overnight did not modulate pupillary reward sensitivity in impulse control disorder patients, whereas in control patients reward sensitivity was significantly reduced when OFF dopamine. These effects were independent of cognitive impairment or total levodopa equivalent dose. Although dopamine agonist dose did modulate pupillary responses to reward, the pattern of results was replicated even when patients with impulse control disorders on dopamine agonists were excluded from the analysis. The findings suggest that hypersensitivity to rewards might be a contributing factor to the development of impulse control disorders in Parkinson's disease. However, there was no difference in reward sensitivity between patient groups when ON dopamine medication, suggesting that impulse control disorders may not emerge simply because of a direct effect of dopaminergic drug level on reward sensitivity. The pupillary reward sensitivity measure described here provides a means to differentiate, using a physiological measure, Parkinson's disease patients with impulse control disorder from those who do not experience such symptoms. Moreover, follow-up of control patients indicated that increased pupillary modulation by reward can be predictive of the risk of future emergence of impulse control disorders and may thereby provide the potential for early identification of patients who are more likely to develop these symptoms.

MEMS-Actuated Carbon Fiber Microelectrode for Neural Recording.

Microwire and microelectrode arrays used for cortical neural recording typically consist of tens to hundreds of recording sites, but often only a fraction of these sites are in close enough proximity to firing neurons to record single-unit activity. Recent work has demonstrated precise, depth-controllable mechanisms for the insertion of single neural recording electrodes, but these methods are mostly only capable of inserting electrodes which elicit an adverse biological response. We present an electrostatic-based actuator capable of inserting individual carbon fiber microelectrodes which elicit minimal to no adverse biological response. The device is shown to insert a carbon fiber recording electrode into an agar brain phantom and can record an artificial neural signal in saline. This technique provides a platform generalizable to many microwire-style recording electrodes.

Dopamine guides competition for cognitive control: Common effects of haloperidol on working memory and response conflict.

Several lines of evidence suggest that dopamine modulates working memory (the ability to faithfully maintain and efficiently manipulate information over time) but its specific role has not been fully defined. Nor is it clear whether any effects of dopamine are specific to memory processes or whether they reflect more general cognitive mechanisms that extend beyond the working memory domain. Here, we examine the effect of haloperidol, principally a dopamine D2 receptor antagonist, on the ability of humans to ignore distracting information or update working memory contents. We compare these effects to performance on an independent measure of cognitive control (response conflict) which has minimal memory requirements. Haloperidol did not selectively affect the ability to ignore or update, but instead reduced the overall quality of recall. In addition, it impaired the ability to overcome response conflict. The deleterious effect of haloperidol on response conflict was selectively associated with the negative effect of the drug on ignoring - but not updating - suggesting that dopamine affects protection of working memory contents and inhibition in response conflict through a common mechanism. These findings provide new insights into the role of dopamine D2 receptors on human cognition. They suggest that D2 receptor effects on protecting the memory contents from distraction might be related to a more general process that supports inhibitory control in contexts that do not require working memory.

Apathy in rapid eye movement sleep behaviour disorder is associated with serotonin depletion in the dorsal raphe nucleus.

Apathy is a common and under-recognized disorder that often emerges in the prodromal phase of Parkinsonian diseases. The mechanism by which this occurs is not known, but recent evidence from patients with established Parkinson's disease suggests that serotonergic dysfunction may play a role. The integrity of the raphe serotonergic system can be assessed alongside dopaminergic basal ganglia imaging using the radioligand 123I-ioflupane, which binds both serotonin and dopamine transporters. To investigate the relative roles of these neurotransmitters in prodromal parkinsonism, we imaged patients with idiopathic rapid eye movement sleep behaviour disorder, the majority of whom will develop a parkinsonian disorder in future. Forty-three patients underwent brain imaging with 123I-ioflupane single photon emission computed tomography and structural MRI. Apathy was quantified using the Lille Apathy Rating Scale. Other clinical parkinsonian features were assessed using standard measures. A negative correlation was observed between apathy severity and serotonergic 123I-ioflupane signal in the dorsal raphe nucleus (r = -0.55, P < 0.001). There was no significant correlation between apathy severity and basal ganglia dopaminergic signal, nor between dorsal raphe signal and other neuropsychiatric scores. This specific association between apathy and raphe 123I-ioflupane signal suggests that the serotonergic system might represent a target for the treatment of apathy.