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

Pallido-putaminal connectivity predicts outcomes of deep brain stimulation for cervical dystonia

Cervical dystonia is a non-degenerative movement disorder characterised by dysfunction of both motor and sensory cortico-basal ganglia networks. Deep brain stimulation targeted to the internal pallidum (GPi) is an established treatment, but its specific mechanisms remain elusive, and response to therapy is highly variable. Modulation of key dysfunctional networks via axonal connections is likely important. Fifteen patients underwent pre-operative diffusion-MRI acquisitions and then progressed to bilateral DBS targeting the posterior GPi. Severity of disease was assessed pre-operatively and later at follow-up. Scans were used to generate tractography-derived connectivity estimates between the bilateral regions of stimulation and relevant structures. Connectivity to the putamen correlated with clinical improvement, and a series of cortical connectivity-based putaminal parcellations identified the primary motor (M1) putamen as the key node (r = 0.70, p = 0.004). A regression model with this connectivity and electrode coordinates explained 68% of variance in outcomes (r = 0.83, p = 0.001), with both as significant explanatory variables. We conclude that modulation of the M1 putamen—posterior GPi limb of the cortico-basal ganglia loop is characteristic of successful DBS treatment of cervical dystonia. Pre-operative diffusion imaging contains additional information that predicts outcomes, implying utility for patient selection and/or individualised targeting

Longitudinal changes of early motor and cognitive symptoms in progressive supranuclear palsy: the OxQUIP study

Background Progressive supranuclear palsy (PSP) is a rare neurodegenerative condition characterised by a range of motor and cognitive symptoms. Very little is known about the longitudinal change in these symptoms over time. Moreover, the effectiveness of clinical scales to detect early changes in PSP is still a matter of debate. Objective We aimed to determine longitudinal changes in PSP features using multiple closely spaced follow-up time points over a period of 2 years. Methods 28 healthy control and 28 PSP participants, with average time since onset of symptoms of 1.9 years, were prospectively studied every 3 months for up to 24 months. Changes from baseline scores were calculated at each follow-up time point using multiple clinical scales to identify longitudinal progression of motor and cognitive symptoms. Results The Montreal Cognitive Assessment, but not the Mini-Mental State Examination, detected cognitive decline at baseline. Both scales revealed poor longitudinal sensitivity to clinical change in global cognitive symptoms. Conversely, the Movement Disorders Society Unified Parkinson’s disease Rating Scale – part III and the PSP Rating Scale (PSPRS) reliably detected motor decline less than 2 years after disease onset. The ‘Gait/Midline’ PSPRS subscore consistently declined over time, with the earliest change being observed 6 months after baseline assessment. Conclusion While better cognitive screening tools are still needed to monitor cognitive decline in PSP, motor decline is consistently captured by clinical rating scales. These results support the inclusion of multiple follow-up time points in longitudinal studies in the early stages of PSP

Clinical Outcome of Asleep Deep Brain Stimulation for Parkinson Disease Using Robot-Assisted Delivery and Anatomic Targeting of the Subthalamic Nucleus: A Series of 152 Patients.

BACKGROUND: Recent advances in methods used for deep brain stimulation (DBS) include subthalamic nucleus electrode implantation in the asleep patient without the traditional use of microelectrode recordings or intraoperative test stimulation. OBJECTIVE: To examine the clinical outcome of patients who have undergone asleep DBS for the treatment of Parkinson disease using robot-assisted electrode delivery. METHODS: This is a retrospective review of clinical outcomes of 152 consecutive patients. Their outcomes at 1 yr postimplantation are reported; these include Unified Parkinson\u27s Disease Rating Scale (UPDRS) assessment, Tinetti Mobility Test, Parkinson\u27s Disease Questionnaire (PDQ)-39 quality of life assessment, Mattis Dementia Rating Scale, Beck Depression Inventory, and Beck Anxiety. We also report on a new parietal trajectory for electrode implantation. RESULTS: A total of 152 patients underwent assessment at 1 yr. UPDRS III improved from 39 to 20.5 (47%, P \u3c .001). The total UPDRS score improved from 67.6 to 36.4 (46%, P \u3c .001). UPDRS II scores improved from 18.9 to 10.5 (44%, P \u3c .001) and UPDRS IV scores improved from 7.1 to 3.6 (49%, P \u3c .001). There was a significant reduction in levodopa equivalent daily dose after surgery (mean: 35%, P \u3c .001). PDQ-39 summary index improved by a mean of 7.1 points. There was no significant difference found in clinical outcomes between the frontal and parietal approaches. CONCLUSION: Asleep robot-assisted DBS of the subthalamic nucleus demonstrates comparable outcomes with traditional techniques in the treatment of Parkinson disease