[Show abstract][Hide abstract] ABSTRACT: Subthalamic nucleus (STN) deep brain stimulation is a successful intervention for medically refractory Parkinson disease, although its efficacy depends on optimal electrode placement. Even though the predominant effect is observed contralaterally, modest improvements in ipsilateral and midline symptoms are also observed.
To elucidate the role of contact location of unilateral deep brain stimulation on contralateral, ipsilateral, and axial subscores of Parkinson disease motor symptoms.
Eighty-six patients receiving first deep brain stimulation STN electrode placements were identified, yielding 73 patients with 3-month follow-up. Total preoperative and postoperative Unified Parkinson Disease Rating Scale Part III scores were obtained and divided into contralateral, ipsilateral, and midline subscores. Contact location was determined on immediate postoperative magnetic resonance imaging. A3-dimensional ordinary "kriging" algorithm generated spatial interpolations for total, ipsilateral, contralateral, and midline symptom categories. Interpolative reconstructions were performed in the axial planes (z = -0.5, -1.0, -1.5, -3.5, -4.5, -6.0) and a sagittal plane (x = 12.0). Interpolation error and significance were quantified by use of a cross-validation technique and quantile-quantile analysis.
There was an overall reduction in Unified Parkinson Disease Rating Scale Part III symptoms: total = 37.0 ± 24.11% (P < .05), ipsilateral = 15.9 ± 51.8%, contralateral = 56.2 ± 26.8% (P < .05), and midline = 26.5 ± 34.7%. Kriging interpolation was performed and cross-validated with quantile-quantile analysis with high correlation (R > 0.92) and demonstrated regions of efficacy for each symptom category. Contralateral symptoms demonstrated broad regions of efficacy across the peri-STN area. The ipsilateral and midline regions of efficacy were constrained and located along the dorsal STN and caudal zona incerta.
We provide evidence for a unique functional topographic window in which contralateral, ipsilateral, and midline structures may achieve the best efficacy. Although there are overlapping regions, laterality demonstrates distinct topographies. Surgical optimization should target the intersection of optimal regions for these symptom categories.
AC, anterior commissureDBS, deep brain stimulationPC, posterior commissureROE, region of efficacySTN, subthalamic nucleusSW, Schaltenbrand-WahrenUPDRS, Unified Parkinson Disease Rating Scale.
[Show abstract][Hide abstract] ABSTRACT: Importance
Coenzyme Q10 (CoQ10), an antioxidant that supports mitochondrial function, has been shown in preclinical Parkinson disease (PD) models to reduce the loss of dopamine neurons, and was safe and well tolerated in early-phase human studies. A previous phase II study suggested possible clinical benefit.Objective
To examine whether CoQ10 could slow disease progression in early PD.Design, Setting, and Participants
A phase III randomized, placebo-controlled, double-blind clinical trial at 67 North American sites consisting of participants 30 years of age or older who received a diagnosis of PD within 5 years and who had the following inclusion criteria: the presence of a rest tremor, bradykinesia, and rigidity; a modified Hoehn and Yahr stage of 2.5 or less; and no anticipated need for dopaminergic therapy within 3 months. Exclusion criteria included the use of any PD medication within 60 days, the use of any symptomatic PD medication for more than 90 days, atypical or drug-induced parkinsonism, a Unified Parkinson’s Disease Rating Scale (UPDRS) rest tremor score of 3 or greater for any limb, a Mini-Mental State Examination score of 25 or less, a history of stroke, the use of certain supplements, and substantial recent exposure to CoQ10. Of 696 participants screened, 78 were found to be ineligible, and 18 declined participation.Interventions
The remaining 600 participants were randomly assigned to receive placebo, 1200 mg/d of CoQ10, or 2400 mg/d of CoQ10; all participants received 1200 IU/d of vitamin E.Main Outcomes and Measures
Participants were observed for 16 months or until a disability requiring dopaminergic treatment. The prospectively defined primary outcome measure was the change in total UPDRS score (Parts I-III) from baseline to final visit. The study was powered to detect a 3-point difference between an active treatment and placebo.Results
The baseline characteristics of the participants were well balanced, the mean age was 62.5 years, 66% of participants were male, and the mean baseline total UPDRS score was 22.7. A total of 267 participants required treatment (94 received placebo, 87 received 1200 mg/d of CoQ10, and 86 received 2400 mg/d of CoQ10), and 65 participants (29 who received placebo, 19 who received 1200 mg/d of CoQ10, and 17 who received 2400 mg/d of CoQ10) withdrew prematurely. Treatments were well tolerated with no safety concerns. The study was terminated after a prespecified futility criterion was reached. At study termination, both active treatment groups showed slight adverse trends relative to placebo. Adjusted mean changes (worsening) in total UPDRS scores from baseline to final visit were 6.9 points (placebo), 7.5 points (1200 mg/d of CoQ10; P = .49 relative to placebo), and 8.0 points (2400 mg/d of CoQ10; P = .21 relative to placebo).Conclusions and Relevance
Coenzyme Q10 was safe and well tolerated in this population, but showed no evidence of clinical benefit.Trial Registration
clinicaltrials.gov Identifier: NCT00740714
[Show abstract][Hide abstract] ABSTRACT: We conducted, in persons with Parkinson's disease (PD), a thorough assessment of neuromotor function and performance in conjunction with phenotypic analyses of skeletal muscle tissue, and further tested the adaptability of PD muscle to high-intensity exercise training. Fifteen participants with PD (Hoehn & Yahr stage 2-3) completed 16 wk of high-intensity exercise training designed to simultaneously challenge strength, power, endurance, balance, and mobility function. Skeletal muscle adaptations (p<0.05) to exercise training in PD included: myofiber hypertrophy (type I:+14%, type II:+36%); shift to less fatigable myofiber type profile; and increased mitochondrial complex activity in both subsarcolemmal and intermyofibrillar fractions (I: +45-56%, IV: +39-54%). These adaptations were accompanied by a host of functional and clinical improvements (p<0.05): total body strength (+30-56%); leg power (+42%); single leg balance (+34%); sit-to-stand motor unit activation requirement (-30%); 6-min walk (+43m), Parkinson's Disease Quality of Life Scale (PDQ-39, -7.8pts); Unified Parkinson's Disease Rating Scale (UPDRS) total (-5.7pts) and motor (-2.7pts); and fatigue severity (-17%). Additionally, PD subjects in the pre-training state were compared to a group of matched, non-PD controls (CON; did not exercise). A combined assessment of muscle tissue phenotype and neuromuscular function revealed a higher distribution and larger cross sectional area of type I myofibers, and greater type II myofiber size heterogeneity in PD vs. CON (p<0.05). In conclusion, persons with moderately advanced PD adapt to high-intensity exercise training with favorable changes in skeletal muscle at the cellular and subcellular levels that are associated with improvements in motor function, physical capacity, and fatigue perception.
No preview · Article · Jan 2014 · Journal of Applied Physiology
[Show abstract][Hide abstract] ABSTRACT: Object:
While many centers place bilateral deep brain stimulation (DBS) systems simultaneously, unilateral subthalamic nucleus (STN) DBS followed by a staged contralateral procedure has emerged as a treatment option for many patients. However, little is known about whether the preoperative phenotype predicts when staged placement of a DBS electrode in the opposite STN will be required. The authors aimed to determine whether preoperative clinical phenotype predicts early staged placement of a second STN DBS electrode in patients who undergo unilateral STN DBS for Parkinson disease (PD).
Eighty-two consecutive patients with advanced PD underwent unilateral STN DBS contralateral to the most affected hemibody and had at least 2 years of follow-up. Multivariate logistic regression analysis determined preoperative characteristics that predicted staged placement of a second electrode in the opposite STN. Preoperative measurements included aspects of the Unified Parkinson's Disease Rating Scale (UPDRS), motor asymmetry index, and body weight.
At 2-year follow-up, 28 (34%) of the 82 patients had undergone staged placement of a contralateral electrode while the remainder chose to continue with unilateral stimulation. Statistically significant improvements in UPDRS total and Part 3 scores were retained at the end of the 2-year follow-up period in both subsets of patients. Multivariate logistic regression analysis showed that the most important predictors for early staged placement of a second subthalamic stimulator were low asymmetry index (OR 13.4, 95% CI 2.8-64.9), high tremor subscore (OR 7.2, CI 1.5-35.0), and low body weight (OR 5.5, 95% CI 1.4-22.3).
This single-center study provides evidence that elements of the preoperative PD phenotype predict whether patients will require early staged bilateral STN DBS. These data may aid in the management of patients with advanced PD who undergo STN DBS.
Full-text · Article · Sep 2013 · Journal of Neurosurgery
[Show abstract][Hide abstract] ABSTRACT: Financial capacity (FC) is an instrumental activity of daily living (IADL) critical to independent functioning and sensitive to cognitive impairment in dementia. Little is known about FC in cognitively impaired patients with Parkinson's disease (PD). The present study investigated FC in PD patients with prodromal and clinical dementia.
Participants were 20 older controls and 35 PD patients who met consensus criteria for either mild cognitive impairment (PD-MCI, n = 18) or PD dementia (PDD, n = 17). FC was assessed using a standardized performance based measure consisting of 9 domain and two global scores (Financial Capacity Instrument; FCI) (1). FCI domain and global performance scores were compared across groups. Capacity impairment ratings (no impairment, mild/moderate impairment, severe impairment) were calculated for each PD patient's domain and global scores.
Relative to controls, PD-MCI patients were impaired on both FCI global scores and domains of basic monetary skills, financial concepts, and investment decision-making. Relative to both controls and PD-MCI patients, PDD patients were impaired on virtually all FCI variables. With respect to impairment ratings, greater than 50% of PD-MCI patients and greater than 90% of PDD patients were classified as either mild/moderate or severely impaired on the two FCI global scores.
Impairment of financial capacity is already present in PD-MCI and is advanced in PDD. Complex cognitively-mediated IADLs such as financial capacity appear to be impaired early in the course of PD dementia.
[Show abstract][Hide abstract] ABSTRACT: Subthalamic deep brain stimulation (DBS) is superior to medical therapy for the motor symptoms of advanced Parkinson's disease (PD), and additional evidence suggests that it improves refractory symptoms of essential tremor, primary generalized dystonia, and obsessive-compulsive disorder. Despite this, its therapeutic mechanism is unknown. We hypothesized that subthalamic stimulation activates the cerebral cortex at short latencies after stimulus onset during clinically effective stimulation for PD. In 5 subjects (six hemispheres), EEG measured the response of cortex to subthalamic stimulation across a range of stimulation voltages and frequencies. Novel analytical techniques reversed the anode and cathode electrode contacts and summed the resulting pair of event-related potentials to suppress the stimulation artifact. We found that subthalamic brain stimulation at 20 Hz activates the somatosensory cortex at discrete latencies (mean latencies: 1.0 ± 0.4, 5.7 ± 1.1, and 22.2 ± 1.8 ms, denoted as R1, R2, and R3, respectively). The amplitude of the short latency peak (R1) during clinically effective high-frequency stimulation is nonlinearly dependent on stimulation voltage (P < 0.001; repeated-measures analysis of variance), and its latency is less variable than that of R3 (1.02 versus 19.46 ms; P < 0.001, Levene's test). We conclude that clinically effective subthalamic brain stimulation in humans with PD activates the cerebral cortex at 1 ms after stimulus onset, most likely by antidromic activation. These findings suggest that alteration of the precise timing of action potentials in cortical neurons with axonal projections to the subthalamic region may be an important component of the therapeutic mechanism of subthalamic brain stimulation.
Full-text · Article · Jun 2012 · Movement Disorders
[Show abstract][Hide abstract] ABSTRACT: Deep brain stimulation is effective for a wide range of neurological disorders; however, its mechanisms of action remain unclear. With respect to Parkinson's disease, the existence of multiple effective targets suggests that putamen stimulation also may be effective and raises questions as to the mechanisms of action. Are there as many mechanisms of action as there are effective targets or some single or small set of mechanisms common to all effective targets? During the course of routine surgery of the globus pallidus interna in patients with Parkinson's disease, the deep brain stimulation lead was placed in the putamen en route to the globus pallidus interna. Recordings of hand opening and closing during high-frequency and no stimulation were made. Speed of the movements, based on the amplitude and frequency of the repetitive hand movements as well as the decay in amplitude, were studied. Hand speed in 6 subjects was statistically significantly faster during active deep brain stimulation than the no-stimulation condition. There were no statistically significant differences in decay in the amplitude of hand movements. High-frequency deep brain stimulation of the putamen improves bradykinesia in a hand-opening and -closing task in patients with Parkinson's disease. Consequently, high-frequency deep brain stimulation of virtually every structure in the basal ganglia-thalamic-cortical system improves bradykinesia. These observations, together with microelectrode recordings reported in the literature, argue that deep brain stimulation effects may be system specific and not structure specific.
No preview · Article · Oct 2011 · Movement Disorders
[Show abstract][Hide abstract] ABSTRACT: Sleep disturbances are common in Parkinson's disease (PD). Bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) is superior to best medical therapy in the treatment of motor symptoms in advanced PD, and observational studies suggest that bilateral STN DBS improves sleep in these patients as well. Unilateral STN DBS also improves motor function in PD, but its effects on sleep have not been extensively investigated.
We report the effects of unilateral STN DBS on subjective sleep quality as measured by the Pittsburgh Sleep Quality Index (PSQI) in 53 consecutive PD patients. These subjects completed the PSQI prior to surgery and at 3 and 6 months post-operatively. The primary outcome measure was the change in the global PSQI at 6 months post-operatively versus the pre-operative baseline, measured with repeated measures analysis of variance (ANOVA).
Patients with PD who underwent unilateral STN DBS had a significant improvement in PSQI at 6 months post-operatively (baseline 9.30 ± 0.56 (mean ± SEM), 6 months: 7.93 ± 0.56, p = 0.013). Supplemental analyses showed that subjects selected for STN DBS placed on the right had worse baseline subjective sleep quality and more improvement in PSQI at 6 months compared to patients who received left STN DBS.
This prospective case series study provides evidence that unilateral STN DBS improves subjective sleep quality in patients with PD at up to 6 months post-operatively as measured by the PSQI.
[Show abstract][Hide abstract] ABSTRACT: Unilateral and bilateral subthalamic nucleus deep brain stimulation (STN DBS) in Parkinson's disease (PD) result in weight gain in the initial postoperative months, but little is known about the changes in weight following unilateral and staged bilateral STN DBS over longer time intervals. A case-control comparison evaluated weight changes over 2 years in 43 consecutive unilateral STN DBS patients, among whom 25 elected to undergo staged bilateral STN DBS, and 21 age-matched and disease severity matched PD controls without DBS. Regression analyses incorporating age, gender, and baseline weight in case or control were conducted to assess weight changes 2 years after the initial unilateral surgery. Unilateral STN DBS and staged bilateral STN DBS patients gained 3.9 ± 2.0 kg and 5.6 ± 2.1 kg versus their preoperative baseline weight (P < 0.001, respectively) while PD controls without DBS lost 0.8 ± 1.1 kg. Although bilateral STN DBS patients gained 1.7 kg more than unilateral STN DBS patients at 2 years, this difference was not statistically significant (P = 0.885). Although there was a trend toward greater weight gain in staged bilateral STN DBS patients versus unilateral patients, we found no evidence for an equivalent or synergistic increase in body weight following placement of the second DBS electrode.
Full-text · Article · Sep 2011 · Brain and Behavior
[Show abstract][Hide abstract] ABSTRACT: Sleep dysfunction is a common nonmotor symptom experienced by patients with Parkinson's disease (PD). Symptoms, including excessive daytime sleepiness, sleep fragmentation, rapid eye movement (REM) sleep behavior disorder and others, can significantly affect quality of life and daytime functioning in these patients. Recent studies have evaluated the effects of deep brain stimulation (DBS) at various targets on sleep in patients with advanced PD. Several of these studies have provided evidence that subthalamic nucleus DBS improves subjective and objective measures of sleep, including sleep efficiency, nocturnal mobility, and wake after sleep onset (minutes spent awake after initial sleep onset). Although fewer studies have investigated the effects of bilateral internal globus pallidus and thalamic ventral intermedius DBS on sleep, pallidal stimulation does appear to improve subjective sleep quality. Stimulation of the pedunculopontine nucleus has recently been proposed for selected patients with advanced PD to treat severe gait and postural dysfunction. Owing to the role of the pedunculopontine nucleus in modulating behavioral state, the impact of stimulation at this target on sleep has also been evaluated in a small number of patients, showing that pedunculopontine nucleus DBS increases REM sleep. In this review, we discuss the effects of stimulation at these various targets on sleep in patients with PD. Studying the effects of DBS on sleep can enhance our understanding of the pathophysiology of sleep disorders, provide strategies for optimizing clinical benefit from DBS, and may eventually guide novel therapies for sleep dysfunction.
Full-text · Article · Jan 2011 · Therapeutic Advances in Neurological Disorders
[Show abstract][Hide abstract] ABSTRACT: Multiple studies have shown bilateral improvement in motor symptoms in Parkinson disease (PD) following unilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) and internal segment of the globus pallidus, yet the mechanism(s) underlying this phenomenon are poorly understood. We hypothesized that STN neuronal activity is altered by contralateral STN DBS. This hypothesis was tested intraoperatively in humans with advanced PD using microelectrode recordings of the STN during contralateral STN DBS. We demonstrate alterations in the discharge pattern of STN neurons in response to contralateral STN DBS including short latency, temporally precise, stimulation frequency-independent responses consistent with antidromic activation. Furthermore, the total discharge frequency during contralateral high frequency stimulation (160 Hz) was greater than during low frequency stimulation (30 Hz) and the resting state. These findings demonstrate complex responses to DBS and imply that output activation throughout the basal ganglia-thalamic-cortical network rather than local inhibition is a therapeutic mechanism of DBS.
Full-text · Article · Dec 2010 · Journal of Neurophysiology
[Show abstract][Hide abstract] ABSTRACT: Long-term dopamine replacement therapy in Parkinson's disease leads to the development of disabling involuntary movements named dyskinesias that are related to adaptive changes in striatal signaling pathways. The chronic transcription factor DeltaFosB, which is overexpressed in striatal neurons after chronic dopaminergic drug exposure, is suspected to mediate these adaptive changes. Here, we sought to demonstrate the ability of DeltaFosB to lead directly to the abnormal motor responses associated with chronic dopaminergic therapy. Using rAAV (recombinant adenoassociated virus) viral vectors, high levels of DeltaFosB expression were induced in the striatum of dopamine-denervated rats naive of chronic drug administration. Transgenic DeltaFosB overexpression reproduced the entire spectrum of altered motor behaviors in response to acute levodopa tests, including different types of abnormal involuntary movements and hypersensitivity of rotational responses that are typically associated with chronic levodopa treatment. JunD, the usual protein partner of DeltaFosB binding to AP-1 (activator protein-1) sites of genes, remained unchanged in rats with high DeltaFosB expression induced by viral vectors. These findings demonstrate that the increase of striatal DeltaFosB in the evolution of chronically treated Parkinson's disease may be a trigger for the development of abnormal responsiveness to dopamine and the emergence of involuntary movements.
Full-text · Article · May 2010 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
[Show abstract][Hide abstract] ABSTRACT: Levodopa-induced dyskinesia can result in significant functional disability and reduced quality of life in patients with Parkinson's disease (PD). The goal of this study was to determine if the addition of once-daily ropinirole 24-hour prolonged-release (n = 104) in PD patients not optimally controlled with levodopa after up to 3 years of therapy with less than 600 mg/d delays the onset of dyskinesia compared with increasing doses of levodopa (n = 104). During the study, 3% of the ropinirole prolonged-release group (mean dose 10 mg/d) and 17% of the levodopa group (mean additional dose 284 mg/d) developed dyskinesia (P < 0.001). There were no significant differences in change in Unified Parkinson's Disease Rating Scale activities of daily living or motor scores, suggesting comparable efficacy between the two treatments. Adverse events were comparable in the two groups with nausea, dizziness, insomnia, back pain, arthralgia, somnolence, fatigue, and pain most commonly reported. Ropinirole prolonged-release delayed the onset of dyskinesia with comparable efficacy to increased doses of levodopa in early PD patients not optimally controlled with levodopa.
Full-text · Article · May 2010 · Movement Disorders
[Show abstract][Hide abstract] ABSTRACT: To examine changes in quality of life (QOL) and global clinical status after 30 days of adjunctive treatment with tolcapone, a revers-ible inhibitor of catechol-O-methyltransferase, in patients with fluctuating Parkinson's disease.
This 30-day, multicenter, open-label, community-based study enrolled fluctuating Parkinson's disease patients to receive tolcapone 100 mg TID as an adjunct to levodopa/carbidopa. The primary end point was QOL change assessed using the Parkinson's Disease Questionnaire (PDQ)-8. Clinical change was assessed using the investigator-rated Clinical Global Impression of Improvement Scale (CGI-I).
Fifty-six physicians enrolled 202 patients; 138 (68%) were > or = 65 years of age and 116 (57%) had Parkinson's disease for > or = 5 years. The mean PDQ-8 total score improved from 42.1 to 34.8 after 30 days of tolcapone (P<.0001). Sixty-nine percent of patients improved on the CGI-I. Physicians planned to continue tolcapone beyond the 30 days in 72%, most commonly because of positive changes in motor function and overall general improvement. No patient discontinued because of liver adverse events.
Adjunctive tolcapone treatment was associated with statistically significant improvement in QOL in fluctuating Parkinson's disease patients. A majority of patients experienced clinical benefits and continued treatment beyond the end of this study. No liver-related adverse events were reported.