Paul Silberstein

Dopamine dysregulation syndrome, impulse control disorders and punding after deep brain stimulation surgery for Parkinson's disease

Data regarding the effect of deep brain stimulation (DBS) surgery on the dopamine dysregulation syndrome (DDS), impulse control disorders (ICDs) and punding in Parkinsons disease (PD) are limited. We present a case series of 21 operated PD patients who had exhibited DDS, ICDs or punding at some stage during the disease. DDS remained unimproved or worsened post-operatively in 12/17 patients with pre-operative DDS (71%) (nine bilateral subthalamic nucleus [STN], one right-sided STN, two bilateral globus pallidus internus [GPi] DBS). DDS improved or resolved after bilateral STN DBS in 5/17 patients with pre-operative DDS. DDS apparently developed for the first time after bilateral STN DBS in two patients, although only after a latency of eight years in one case. One patient without reported pre-operative DDS or ICDs developed pathological gambling post-STN DBS. One patient had pathological gambling which resolved pre-operatively, and did not recur post-DBS. Thus, DDS, ICDs and punding may persist, worsen or develop for the first time after DBS surgery, although a minority of patients improved dramatically. Predictive factors may include physician vigilance, motor outcome and patient compliance.

Frequency dependent effects of subthalamic nucleus stimulation in Parkinson's disease.

Excessive synchronisation of basal ganglia activity at frequencies < 30 Hz is a hallmark of the parkinsonian state, and may contribute to bradykinesia. Accordingly, we electrically stimulated chronically implanted subthalamic macroelectrodes in 10 Parkinsons disease patients, after overnight withdrawal of anti-parkinsonian medication. We compared the effects of stimulation at 0, 5, 10, 15, 20, 25, 30, and ca. 130 Hz by measuring kinesia time (KT) in a tapping task. Although the effects of direct stimulation were small, frequency-response curves demonstrated local peaks at 5-10 Hz and at 20-25 Hz, superimposed upon an overall tendency for KT to reduce with increasing stimulation frequency. This is consistent with the hypothesis that spontaneous activities in these bands might promote bradykinesia.

Activation of the subthalamic region during emotional processing in Parkinson disease.

Objective: To elucidate the involvement of the human subthalamic nucleus (STN) region in the processing or transmission of emotional information. Methods: Local field potentials (LFPs) were recorded from this region in 10 patients with Parkinson disease (PD) undergoing bilateral implantation of the STN for high-frequency stimulation. LFP recordings were made while patients viewed pleasant and unpleasant emotionally arousing and neutral pictures. Results: A significant decrease (event-related desynchronization [ERD]) in the local alpha power (8 to 12 Hz) was found for all stimulus categories starting at about 0.5 seconds after stimulus presentation. However, 1 to 2 seconds poststimulus, the ERD was larger in trials of pleasant (mean ERD: 21.6 ± 2.8%; p < 0.009) and unpleasant (mean ERD: 15.0 ± 4.2%; p = 0.018) stimuli compared with neutral stimuli (mean ERD: 4.4 ± 4.2%). Conclusion: The delayed modulation of alpha activity recorded from the area of the subthalamic nucleus in PD may reflect the processing or transmission of information related to emotional stimuli. “Limbic” activation in the region of the subthalamic nucleus may explain why high-frequency stimulation of the subthalamic nucleus alters affect in some patients with PD.

Oscillatory pallidal local field potential activity inversely correlates with limb dyskinesias in Parkinson's disease.

Levodopa induced dyskinesias (LIDs) are poorly understood and yet are a major cause of disability in Parkinsons disease (PD). The activity of neurons in the basal ganglia of patients with PD tends to be strongly synchronized at frequencies under 30 Hz, leading to oscillatory local field potentials (LFPs). As dopaminergic therapy acutely suppresses this synchronization, we investigated whether this suppression may contribute to LIDs. Accordingly, we sought an inverse correlation between oscillatory synchronization and dyskinesia activity across time. To this end, we recorded pallidal LFPs in two Parkinsonian subjects exhibiting LIDs following surgery for deep brain stimulation. We correlated LFP power with simultaneously recorded EMG from the dyskinetic contralateral upper limb. We found highly significant inverse correlations between the oscillatory LFP activity under 30 Hz and dyskinetic EMG (maximum r = -0.65, P < 0.001 and r = -0.33, P < 0.001 for activities over 13-30 Hz in each subject). The inverse relationship between oscillatory pallidal LFP activity and dyskinetic EMG was maintained over time periods of a few seconds and was focal. This observation links the suppression of oscillatory synchronization in the pallidum with dyskinetic muscle activity in PD.

Globus Pallidus Internus Deep Brain Stimulation as Rescue Therapy for Refractory Dyskinesias following Effective Subthalamic Nucleus Stimulation

Background: Deep brain stimulation (DBS) at the subthalamic nucleus (STN) or globus pallidus internus (GPi) can effectively treat the motor symptoms of Parkinsons disease, but dual implantation is rare. We report the first cases of additional GPi stimulation as rescue therapy for disabling dyskinesias following successful STN stimulation. Methods: Two patients, initially treated with bilateral STN DBS, underwent subsequent bilateral GPi DBS after the development of refractory dyskinesias within 1 and 6 years of STN surgery. Patients were evaluated with the Unified Parkinsons Disease Rating Scale (UPDRS) before and after surgeries for STN and GPi DBS. Results: GPi DBS effectively suppressed dyskinesias in these patients and improved their quality of life, as demonstrated by their videos and UPDRS scores. Conclusions: Additional bilateral GPi DBS may be considered in the rare instance of patients who develop refractory dyskinesias early or late after bilateral STN DBS.

Balance control systems in Parkinson’s disease and the impact of pedunculopontine area stimulation

See Xiang et al. (doi:10.1093/brain/awy250) for a scientific commentary on this article. Balance impairment in Parkinsons disease decreases quality of life and is often refractory to treatment. Perera et al. report that balance impairment relates to deficits in intermittent and continuous control systems proposed to maintain upright stance. The deficits may be reversible with the experimental therapy, pedunculopontine nucleus deep brain stimulation.