Polestriding Intervention Improves Gait and Axial Symptoms in Mild to Moderate Parkinson Disease.

OBJECTIVE: To evaluate the effects of 12-week polestriding intervention on gait and disease severity in people with mild to moderate Parkinson disease (PD). DESIGN: A-B-A withdrawal study design. SETTING: Outpatient movement disorder center and community facility. PARTICIPANTS: Individuals (N=17; 9 women [53%] and 8 men [47%]; mean age, 63.7±4.9y; range, 53-72y) with mild to moderate PD according to United Kingdom brain bank criteria with Hoehn & Yahr score ranging from 2.5 to 3.0 with a stable medication regimen and ability to tolerate "off" medication state. INTERVENTIONS: Twelve-week polestriding intervention with 12-week follow-up. MAIN OUTCOME MEASURES: Gait was evaluated using several quantitative temporal, spatial, and variability measures. In addition, disease severity was assessed using clinical scales such as Unified Parkinson's Disease Rating Scale (UPDRS), Hoehn & Yahr scale, and Parkinson's Disease Questionnaire-39. RESULTS: Step and stride lengths, gait speed, and step-time variability were improved significantly (P<.05) because of 12-week polestriding intervention. Also, the UPDRS motor score, the UPDRS axial score, and the scores of UPDRS subscales on walking and balance improved significantly after the intervention. CONCLUSIONS: Because increased step-time variability and decreased step and stride lengths are associated with PD severity and an increased risk of falls in PD, the observed improvements suggest that regular practice of polestriding may reduce the risk of falls and improve mobility in people with PD.

Alpha-Synuclein Pathology in Sensory Nerve Terminals of the Upper Aerodigestive Tract of Parkinson's Disease Patients.

Dysphagia is common in Parkinson's disease (PD) and causes significant morbidity and mortality. PD dysphagia has usually been explained as dysfunction of central motor control, much like other motor symptoms that are characteristic of the disease. However, PD dysphagia does not correlate with severity of motor symptoms nor does it respond to motor therapies. It is known that PD patients have sensory deficits in the pharynx, and that impaired sensation may contribute to dysphagia. However, the underlying cause of the pharyngeal sensory deficits in PD is not known. We hypothesized that PD dysphagia with sensory deficits may be due to degeneration of the sensory nerve terminals in the upper aerodigestive tract (UAT). We have previously shown that Lewy-type synucleinopathy (LTS) is present in the main pharyngeal sensory nerves of PD patients, but not in controls. In this study, the sensory terminals in UAT mucosa were studied to discern the presence and distribution of LTS. Whole-mount specimens (tongue-pharynx-larynx-upper esophagus) were obtained from 10 deceased human subjects with clinically diagnosed and neuropathologically confirmed PD (five with dysphagia and five without) and four age-matched healthy controls. Samples were taken from six sites and immunostained for phosphorylated α-synuclein (PAS). The results showed the presence of PAS-immunoreactive (PAS-ir) axons in all the PD subjects and in none of the controls. Notably, PD patients with dysphagia had more PAS-ir axons in the regions that are critical for initiating the swallowing reflex. These findings suggest that Lewy pathology affects mucosal sensory axons in specific regions of the UAT and may be related to PD dysphagia.

Motor learning in essential tremor.

Classical conditioning is abnormal in patients with cerebellar degeneration. Pathological studies have recently demonstrated the finding of Purkinje cell loss in a subset of essential tremor (ET). We studied 10 subjects with long duration ET using a blink reflex conditioning paradigm and compared them with nine controls. A 55.6% reduction in motor learning was seen in the first block of stimulation and this finding persisted across all subsequent trials. We conclude that motor learning is significantly abnormal in subjects with advanced ET and likely reflects pathological involvement of the cerebellum.

A multicentre study on suicide outcomes following subthalamic stimulation for Parkinson's disease.

Subthalamic nucleus deep brain stimulation improves motor symptoms and quality of life in advanced Parkinson's disease. As after other life-altering surgeries, suicides have been reported following deep brain stimulation for movement disorders. We sought to determine the suicide rate following subthalamic nucleus deep brain stimulation for Parkinson's disease by conducting an international multicentre retrospective survey of movement disorder and surgical centres. We further sought to determine factors associated with suicide attempts through a nested case-control study. In the survey of suicide rate, 55/75 centres participated. The completed suicide percentage was 0.45% (24/5311) and attempted suicide percentage was 0.90% (48/5311). Observed suicide rates in the first postoperative year (263/100,000/year) (0.26%) were higher than the lowest and the highest expected age-, gender- and country-adjusted World Health Organization suicide rates (Standardized Mortality Ratio for suicide: SMR 12.63-15.64; P < 0.001) and remained elevated at the fourth postoperative year (38/100,000/year) (0.04%) (SMR 1.81-2.31; P < 0.05). The excess number of deaths was 13 for the first postoperative year and one for the fourth postoperative year. In the case-control study of associated factors, 10 centres participated. Twenty-seven attempted suicides and nine completed suicides were compared with 70 controls. Postoperative depression (P < 0.001), being single (P = 0.007) and a previous history of impulse control disorders or compulsive medication use (P = 0.005) were independent associated factors accounting for 51% of the variance for attempted suicide risk. Attempted suicides were also associated (P < 0.05) with being younger, younger Parkinson's disease onset and a previous suicide attempt. Completed suicides were associated with postoperative depression (P < 0.001). Postoperative depression remained a significant factor associated with attempted and completed suicides after correction for multiple comparisons using the stringent Bonferroni correction. Mortality in the first year following subthalamic nucleus deep brain stimulation has been reported at 0.4%. Suicide is thus one of the most important potentially preventable risks for mortality following subthalamic nucleus deep brain stimulation for Parkinson's disease. Postoperative depression should be carefully assessed and treated. A multidisciplinary assessment and follow-up is recommended.

Parkinson's disease outcomes after intraoperative CT-guided "asleep" deep brain stimulation in the globus pallidus internus.

OBJECTIVE: Recent studies show that deep brain stimulation can be performed safely and accurately without microelectrode recording ortest stimulation but with the patient under general anesthesia. The procedure couples techniques for direct anatomical targeting on MRI with intraoperative imaging to verify stereotactic accuracy. However, few authors have examined the clinical outcomes of Parkinson's disease (PD) patients after this procedure. The purpose of this study was to evaluate PD outcomes following "asleep" deep brain stimulation in the globus pallidus internus (GPi). METHODS: The authors prospectively examined all consecutive patients with advanced PD who underwent bilateral GPi electrode placement while under general anesthesia. Intraoperative CT was used to assess lead placement accuracy. The primary outcome measure was the change in the off-medication Unified Parkinson's Disease Rating Scale motor score 6 months after surgery. Secondary outcomes included effects on the 39-Item Parkinson's Disease Questionnaire (PDQ-39) scores, on-medication motor scores, and levodopa equivalent daily dose. Lead locations, active contact sites, stimulation parameters, and adverse events were documented. RESULTS: Thirty-five patients (24 males, 11 females) had a mean age of 61 years at lead implantation. The mean radial error off plan was 0.8 mm. Mean coordinates for the active contact were 21.4 mm lateral, 4.7 mm anterior, and 0.4 mm superior to the midcommissural point. The mean off-medication motor score improved from 48.4 at baseline to 28.9 (40.3% improvement) at 6 months (p < 0.001). The PDQ-39 scores improved (50.3 vs 42.0; p = 0.03), and the levodopa equivalent daily dose was reduced (1207 vs 1035 mg; p = 0.004). There were no significant adverse events. CONCLUSIONS: Globus pallidus internus leads placed with the patient under general anesthesia by using direct anatomical targeting resulted in significantly improved outcomes as measured by the improvement in the off-medication motor score at 6 months after surgery.

A System for Real-Time Feedback to Improve Gait and Posture in Parkinson's Disease.

For people with Parkinson's disease (PD), gait and postural impairments can significantly affect their ability to perform activities of daily living. Presentation of appropriate cues has been shown to improve gait in PD. Based on this, a treadmill-based system and experimental paradigm were developed to determine if people with PD can utilize real-time feedback (RTFB) of step length or back angle (uprightness) to improve gait and posture. Eleven subjects (mean age 67 ± 8 years) with mild-to-moderate PD (Hoehn and Yahr stage I-III) were evaluated regarding their ability to successfully utilize RTFB of back angle or step length during quiet standing and treadmill walking tasks during a single session in their medication-on state. Changes in back angle and step length due to feedback were compared using Friedman nonparametric tests with Wilcoxon Signed-Rank tests for post-hoc comparisons. Improvements in uprightness were observed as an increase in back angle during quiet standing (p = 0.005) and during treadmill walking (p = 0.005) with back angle feedback when compared to corresponding tasks without feedback. Improvements in gait were also observed as an increase in step length (p = 0.005) during step length feedback compared to tasks without feedback. These results indicate that people with mild-to-moderate PD can utilize RTFB to improve upright posture and gait. Future work will investigate the long-term effects of this RTFB paradigm and the development of systems for clinical or home-based use.

Physiology and pathophysiology of cortico-basal ganglia-thalamocortical loops: theoretical and practical aspects.

A new theoretical framework is used to analyze functions and pathophysiological processes of cortico-basal ganglia-thalamocortical loops and to demonstrate the hierarchical relationships between various loops. All hierarchical levels are built according to the same functional principle: Each loop is a neural optimal control system (NOCS) and includes a model of object behavior and an error distribution system. The latter includes dopaminergic neurons and is necessary to tune the model to a controlled object (CO). The regularities of pathophysiological processes in NOCSs are analyzed. Mechanisms of current functional neurosurgical procedures like lesioning and deep brain stimulation (DBS) of various basal ganglia structures and neurotransplantation are described based on proposed theoretical ideas. Parkinson's disease (PD) is used to exemplify clinical applications of the proposed theory. Within the proposed theoretical framework, PD must be considered as a disease of the error distribution system. The proposed theoretical views have broad fundamental and clinical applications.

Alpha-synuclein pathology and axonal degeneration of the peripheral motor nerves innervating pharyngeal muscles in Parkinson disease.

Parkinson disease (PD) is a neurodegenerative disease primarily characterized by cardinal motor manifestations and CNS pathology. Current drug therapies can often stabilize these cardinal motor symptoms, and attention has shifted to the other motor and nonmotor symptoms of PD that are resistant to drug therapy. Dysphagia in PD is perhaps the most important drug-resistant symptom because it leads to aspiration and pneumonia, the leading cause of death. Here, we present direct evidence for degeneration of the pharyngeal motor nerves in PD. We examined the cervical vagal nerve (cranial nerve X), pharyngeal branch of nerve X, and pharyngeal plexus innervating the pharyngeal muscles in 14 postmortem specimens, that is, from 10 patients with PD and 4 age-matched control subjects. Synucleinopathy in the pharyngeal nerves was detected using an immunohistochemical method for phosphorylated α-synuclein. Alpha-synuclein aggregates were revealed in nerve X and the pharyngeal branch of nerve X, and immunoreactive intramuscular nerve twigs and axon terminals within the neuromuscular junctions were identified in all of the PD patients but in none of the controls. These findings indicate that the motor nervous system of the pharynx is involved in the pathologic process of PD. Notably, PD patients who have had dysphagia had a higher density of α-synuclein aggregates in the pharyngeal nerves than those without dysphagia. These findings indicate that motor involvement of the pharynx in PD is one of the factors leading to oropharyngeal dysphagia commonly seen in PD patients.

Parkinson disease affects peripheral sensory nerves in the pharynx.

Dysphagia is very common in patients with Parkinson disease (PD) and often leads to aspiration pneumonia, the most common cause of death in PD. Current therapies are largely ineffective for dysphagia. Because pharyngeal sensation normally triggers the swallowing reflex, we examined pharyngeal sensory nerves in PD patients for Lewy pathology.Sensory nerves supplying the pharynx were excised from autopsied pharynges obtained from patients with clinically diagnosed and neuropathologically confirmed PD (n = 10) and healthy age-matched controls (n = 4). We examined the glossopharyngeal nerve (cranial nerve IX), the pharyngeal sensory branch of the vagus nerve (PSB-X), and the internal superior laryngeal nerve (ISLN) innervating the laryngopharynx. Immunohistochemistry for phosphorylated α-synuclein was used to detect Lewy pathology. Axonal α-synuclein aggregates in the pharyngeal sensory nerves were identified in all of the PD subjects but not in the controls. The density of α-synuclein-positive lesions was greater in PD patients with dysphagia versus those without dysphagia. In addition, α-synuclein-immunoreactive nerve fibers in the ISLN were much more abundant than those in cranial nerve IX and PSB-X. These findings suggest that pharyngeal sensory nerves are directly affected by pathologic processes in PD. These abnormalities may decrease pharyngeal sensation, thereby impairing swallowing and airway protective reflexes and contributing to dysphagia and aspiration.

Deep brain stimulation amplitude alters posture shift velocity in Parkinson's disease.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is now widely used to alleviate symptoms of Parkinson's disease (PD). The specific aim of this study was to identify posture control measures that may be used to improve selection of DBS parameters in the clinic and this was carried out by changing the DBS stimulation amplitude. A dynamic posture shift paradigm was used to assess posture control in 4 PD STN-DBS subjects. Each subject was tested at 4 stimulation amplitude settings. Movements of the center of pressure and the position of the pelvis were monitored and several quantitative indices were calculated. The presence of any statistically significant changes in several normalized indices due to reduced/no stimulation was tested using the one-sample t test. The peak velocity and the average movement velocity during the initial and mid phases of movement towards the target posture were substantially reduced. These results may be explained in terms of increased akinesia and bradykinesia due to altered stimulation conditions. Thus, the dynamic posture shift paradigm may be an effective tool to quantitatively characterize the effects of DBS on posture control and should be further investigated as a tool for selection of DBS parameters in the clinic.

Altered pharyngeal muscles in Parkinson disease.

Dysphagia (impaired swallowing) is common in patients with Parkinson disease (PD) and is related to aspiration pneumonia, the primary cause of death in PD. Therapies that ameliorate the limb motor symptoms of PD are ineffective for dysphagia. This suggests that the pathophysiology of PD dysphagia may differ from that affecting limb muscles, but little is known about potential neuromuscular abnormalities in the swallowing muscles in PD. This study examined the fiber histochemistry of pharyngeal constrictor and cricopharyngeal sphincter muscles in postmortem specimens from 8 subjects with PD and 4 age-matched control subjects. Pharyngeal muscles in subjects with PD exhibited many atrophic fibers, fiber type grouping, and fast-to-slow myosin heavy chain transformation. These alterations indicate that the pharyngeal muscles experienced neural degeneration and regeneration over the course of PD. Notably, subjects with PD with dysphagia had a higher percentage of atrophic myofibers versus with those without dysphagia and controls. The fast-to-slow fiber-type transition is consistent with abnormalities in swallowing, slow movement of food, and increased tone in the cricopharyngeal sphincter in subjects with PD. The alterations in the pharyngeal muscles may play a pathogenic role in the development of dysphagia in subjects with PD.

Subthalamic nucleus stimulation reverses mediofrontal influence over decision threshold.

It takes effort and time to tame one's impulses. Although medial prefrontal cortex (mPFC) is broadly implicated in effortful control over behavior, the subthalamic nucleus (STN) is specifically thought to contribute by acting as a brake on cortico-striatal function during decision conflict, buying time until the right decision can be made. Using the drift diffusion model of decision making, we found that trial-to-trial increases in mPFC activity (EEG theta power, 4-8 Hz) were related to an increased threshold for evidence accumulation (decision threshold) as a function of conflict. Deep brain stimulation of the STN in individuals with Parkinson's disease reversed this relationship, resulting in impulsive choice. In addition, intracranial recordings of the STN area revealed increased activity (2.5-5 Hz) during these same high-conflict decisions. Activity in these slow frequency bands may reflect a neural substrate for cortico-basal ganglia communication regulating decision processes.

Duodenal levodopa infusion for the treatment of Parkinson's disease.

Motor fluctuations are a common problem in the long-term management of Parkinson's disease (PD), resulting in disability and impaired quality of life. The relatively short serum half-life (approximately 90 min) of oral levodopa/carbidopa and its erratic absorption due to delayed and inconsistent gastric emptying (a non-motor feature of PD) are thought to be important factors in the development of motor fluctuations. Continuous infusion of levodopa/carbidopa directly into the small intestine of PD patients results in marked reduction of motor fluctuations by reducing plasma levodopa variability by an order of magnitude over oral therapy. Previously, the use of long-term intraduodenal infusion of levodopa/carbidopa was limited by the relatively large volumes of infusate necessitated by the low solvency of levodopa. The development of a micronized levodopa (20 mg/ml) and carbidopa (5 mg/ml) suspension utilizing a methylcellulose gel provides the high levodopa concentration and physical and chemical stability necessary for long-term enteral therapy. Clinical evidence indicates that a marked reduction of motor fluctuations and dyskinesias can be achieved and maintained by intraduodenal administration of this suspension. This article reviews the published data describing the efficacy and safety of duodenal levodopa, and discusses its current and potential role in meeting the needs of PD patients.

Hold your horses: impulsivity, deep brain stimulation, and medication in parkinsonism.

Deep brain stimulation (DBS) of the subthalamic nucleus markedly improves the motor symptoms of Parkinson's disease, but causes cognitive side effects such as impulsivity. We showed that DBS selectively interferes with the normal ability to slow down when faced with decision conflict. While on DBS, patients actually sped up their decisions under high-conflict conditions. This form of impulsivity was not affected by dopaminergic medication status. Instead, medication impaired patients' ability to learn from negative decision outcomes. These findings implicate independent mechanisms leading to impulsivity in treated Parkinson's patients and were predicted by a single neurocomputational model of the basal ganglia.