Exploring the cortical and subcortical functional magnetic resonance imaging changes associated with freezing in Parkinson's disease.
ABSTRACT Freezing of gait is a devastating symptom of advanced Parkinson's disease yet the neural correlates of this phenomenon remain poorly understood. In this study, severity of freezing of gait was assessed in 18 patients with Parkinson's disease on a series of timed 'up and go' tasks, in which all patients suffered from episodes of clinical freezing of gait. The same patients also underwent functional magnetic resonance imaging with a virtual reality gait paradigm, performance on which has recently been shown to correlate with actual episodes of freezing of gait. Statistical parametric maps were created that compared the blood oxygen level-dependent response associated with paroxysmal motor arrests (freezing) to periods of normal motor output. The results of a random effects analysis revealed that these events were associated with a decreased blood oxygen level-dependent response in sensorimotor regions and an increased response within frontoparietal cortical regions. These signal changes were inversely correlated with the severity of clinical freezing of gait. Motor arrests were also associated with decreased blood oxygen level-dependent signal bilaterally in the head of caudate nucleus, the thalamus and the globus pallidus internus. Utilizing a mixed event-related/block design, we found that the decreased blood oxygen level-dependent response in the globus pallidus and the subthalamic nucleus persisted even after controlling for the effects of cognitive load, a finding which supports the notion that paroxysmal increases in basal ganglia outflow are associated with the freezing phenomenon. This method also revealed a decrease in the blood oxygen level-dependent response within the mesencephalic locomotor region during motor arrests, the magnitude of which was positively correlated with the severity of clinical freezing of gait. These results provide novel insights into the pathophysiology underlying freezing of gait and lend support to models of freezing of gait that implicate dysfunction across coordinated neural networks.
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ABSTRACT: Background. Patients with freezing of gait (FOG) have more difficulty with switching tasks as well as controlling the spatiotemporal parameters of gait than patients without FOG. Objective. To compare the ability of patients with and without FOG to adjust their gait to sudden speed switching and to prolonged walking in asymmetrical conditions. Methods. Gait characteristics of 10 freezers, 12 non-freezers, and 12 controls were collected during tied-belt conditions (3 and 4 km/h), motor switching and reswitching (increase of speed in one belt from 3 to 4 km/h and vice versa), and adaptation (adjustment to asymmetrical gait) and re-adaptation (returning to symmetrical gait) on a split-belt treadmill. Results. Following switching, freezers showed the largest increase of step length asymmetry (P = .001). All groups gradually adapted their gait to asymmetrical conditions, but freezers were slower and demonstrated larger final asymmetry than the other 2 groups (P = .001). After reswitching, freezers again showed the largest step length asymmetry (P = .01). During re-adaptation, both controls and non-freezers reached symmetrical levels, but freezers did not. Interestingly, only immediately after switching did one episode of FOG and one episode of festination occur in 2 different patients. Conclusions. Freezers have more difficulties adapting their gait during both suddenly triggered and continued gait speed asymmetry. The impaired ability of freezers during both switching and reswitching would suggest that they have an adaptive deficit rather than difficulties with asymmetry per se. Future work needs to address whether these adaptation problems can be ameliorated with rehabilitation. © The Author(s) 2014.Neurorehabilitation and neural repair 11/2014; 29(2). DOI:10.1177/1545968314545175 · 4.62 Impact Factor
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ABSTRACT: Gait disturbances, including freezing of gait, are frequent and disabling symptoms of Parkinson's disease. They often respond poorly to dopaminergic treatments. Although recent studies have shed some light on their neural correlates, their modulation by dopaminergic treatment remains quite unknown. Specifically, the influence of levodopa on the networks involved in motor imagery (MI) of parkinsonian gait has not been directly studied, comparing the off and on medication states in the same patients. We therefore conducted an [H2150] Positron emission tomography study in eight advanced parkinsonian patients (mean disease duration: 12.3 ± 3.8 years) presenting with levodopa-responsive gait disorders and FoG, and eight age-matched healthy subjects. All participants performed three tasks (MI of gait, visual imagery and a control task). Patients were tested off, after an overnight withdrawal of all antiparkinsonian treatment, and on medication, during consecutive mornings. The order of conditions was counterbalanced between subjects and sessions. Results showed that imagined gait elicited activations within motor and frontal associative areas, thalamus, basal ganglia and cerebellum in controls. Off medication, patients mainly activated premotor-parietal and pontomesencephalic regions. Levodopa increased activation in motor regions, putamen, thalamus, and cerebellum, and reduced premotor-parietal and brainstem involvement. Areas activated when patients are off medication may represent compensatory mechanisms. The recruitment of these accessory circuits has also been reported for upper-limb movements in Parkinson's disease, suggesting a partly overlapping pathophysiology between imagined levodopa-responsive gait disorders and appendicular signs. Our results also highlight a possible cerebellar contribution in the pathophysiology of parkinsonian gait disorders through kinesthetic imagery. Hum Brain Mapp, 2014. © 2014 Wiley Periodicals, Inc.Human Brain Mapping 11/2014; 36(3). DOI:10.1002/hbm.22679 · 6.92 Impact Factor
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ABSTRACT: The brainstem pedunculopontine nucleus has a likely, although unclear, role in gait control, and is a potential deep brain stimulation target for treating resistant gait disorders. These disorders are a major therapeutic challenge for the ageing population, especially in Parkinson's disease where gait and balance disorders can become resistant to both dopaminergic medication and subthalamic nucleus stimulation. Here, we present electrophysiological evidence that the pedunculopontine and subthalamic nuclei are involved in distinct aspects of gait using a locomotor imagery task in 14 patients with Parkinson's disease undergoing surgery for the implantation of pedunculopontine or subthalamic nuclei deep brain stimulation electrodes. We performed electrophysiological recordings in two phases, once during surgery, and again several days after surgery in a subset of patients. The majority of pedunculopontine nucleus neurons (57%) recorded intrasurgically exhibited changes in activity related to different task components, with 29% modulated during visual stimulation, 41% modulated during voluntary hand movement, and 49% modulated during imaginary gait. Pedunculopontine nucleus local field potentials recorded post-surgically were modulated in the beta and gamma bands during visual and motor events, and we observed alpha and beta band synchronization that was sustained for the duration of imaginary gait and spatially localized within the pedunculopontine nucleus. In contrast, significantly fewer subthalamic nucleus neurons (27%) recorded intrasurgically were modulated during the locomotor imagery, with most increasing or decreasing activity phasically during the hand movement that initiated or terminated imaginary gait. Our data support the hypothesis that the pedunculopontine nucleus influences gait control in manners extending beyond simply driving pattern generation. In contrast, the subthalamic nucleus seems to control movement execution that is not likely to be gait-specific. These data highlight the crucial role of these two nuclei in motor control and shed light on the complex functions of the lateral mesencephalus in humans. http://www.ncbi.nlm.nih.gov/pubmed/25765327Brain 05/2015; DOI:10.1093/brain/awv047 · 10.23 Impact Factor