Article

Spinal Cord Stimulation Restores Locomotion in Animal Models of Parkinson's Disease

Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, USA.
Science (Impact Factor: 33.61). 04/2009; 323(5921):1578-82. DOI: 10.1126/science.1164901
Source: PubMed

ABSTRACT

Dopamine replacement therapy is useful for treating motor symptoms in the early phase of Parkinson's disease, but it is less effective in the long term. Electrical deep-brain stimulation is a valuable complement to pharmacological treatment but involves a highly invasive surgical procedure. We found that epidural electrical stimulation of the dorsal columns in the spinal cord restores locomotion in both acute pharmacologically induced dopamine-depleted mice and in chronic 6-hydroxydopamine-lesioned rats. The functional recovery was paralleled by a disruption of aberrant low-frequency synchronous corticostriatal oscillations, leading to the emergence of neuronal activity patterns that resemble the state normally preceding spontaneous initiation of locomotion. We propose that dorsal column stimulation might become an efficient and less invasive alternative for treatment of Parkinson's disease in the future.

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    • "From 1999 to 2004, clinical cases showed that the therapeutic effect lasts about 4–6 months on average [2]. To make treatments more permanent, implantable neural electrical stimulation systems have been developed to make the system more viable to treat various disorders, such as for Parkinson's disease [3] and sciatica [4] [5]. To address the invasiveness of implanting surgeries, minimally invasive surgery (MIS) procedures have been developed, which aim to reduce the size of incisions as well as a patient's discomfort after an operation [6]. "
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    ABSTRACT: A bipolar electrode probe used for implantable nerve stimulation treatments in minimally invasive surgeries is presented. The probe is composed of a flexible printed circuit substrate and a patterned SU-8 film. This probe features a three-dimensional (3D) tweezer-like mechanism opened by residual stress from the SU-8 film, designed to fix the probe in the tissue surrounding a target nerve. Stripes on the SU-8 film direct the net residual stress in a single direction to form a curve. The holding strengths of the probes with different deformations are defined and measured by a tensile test. Results show that the fixing ability of a 3D probe is better than a plane probe. The probes with curvature heights between 13 and 14 mm have a maximum average breaking force of 0.258 N, which is 16.3 and 13.1% higher than the probes with curvature heights between 9 and 10 mm and between 10 and 11 mm, respectively. In addition, a film of gelatin fibrous membrane, produced by electrospinning, covers the fixed ends of the probe's anchors and acts as cell scaffolds to induce cell growth, which help to ensure long-term fixation in the body. 3T3 fibroblast cells are grown to verify the scaffold effect of the fibrous membrane.
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    • "To avoid SCS current intensities that could be experienced as uncomfortable, before each stimulation session the intensity of each stimulation frequency was adjusted and set to 1.7 times the minimum intensity at which any behavioral response could be consistently detected (small postural changes, head or neck movements). Overall, as previously reported in rodents (Fuentes et al., 2009), we observed that SCS induced a clear alleviation of motor impairment in monkeys who exhibited severe clinical PD signs. Because the stimulation frequencies used in this study (range, 4–300 Hz) proved equally effective, the analysis of the SCS effects, both behavioral and electrophysiological, were performed by pooling all the frequencies, unless otherwise stated. "
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    ABSTRACT: Although deep brain electrical stimulation can alleviate the motor symptoms of Parkinson disease (PD), just a small fraction of patients with PD can take advantage of this procedure due to its invasive nature. A significantly less invasive method — epidural spinal cord stimulation (SCS) — has been suggested as an alternative approach for symptomatic treatment of PD. However, the mechanisms underlying motor improvements through SCS are unknown. Here, we show that SCS reproducibly alleviates motor deficits in a primate model of PD. Simultaneous neuronal recordings from multiple structures of the cortico-basal ganglia-thalamic loop in parkinsonian monkeys revealed abnormal highly synchronized neuronal activity within each of these structures and excessive functional coupling among them. SCS disrupted this pathological circuit behavior in a manner that mimics the effects caused by pharmacological dopamine replacement therapy or deep brain stimulation. These results suggest that SCS should be considered as an additional treatment option for patients with PD.
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    • "Dopamine signaling can modulate the dynamic synchronization of neural activity within and between brain structures (Dzirasa et al. 2009). Disruption of these circuits through the degeneration of dopaminergic neurons in the substantia nigra in PD potentially results in widespread changes in brain activity and connectivity (e.g., Costa et al. 2006; Fuentes et al. 2009; Martinu and Monchi 2013; Poston and Eidelberg 2012). Functional connectivity neuroimaging has been used in cognitively unimpaired PD to examine the brain's intrinsic functional architecture at a resting state. "
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    ABSTRACT: Parkinson's disease (PD) is associated with abnormal synchronization in basal ganglia-thalamo-cortical loops. We tested whether early PD patients without demonstrable cognitive impairment exhibit abnormal modulation of functional connectivity at rest, while engaged in a task, or both. PD and healthy controls underwent two functional MRI scans: a resting-state scan and a Stroop Match-to-Sample task scan. Rest-task modulation of basal ganglia (BG) connectivity was tested using seed-to-voxel connectivity analysis with task and rest time series as conditions. Despite substantial overlap of BG-cortical connectivity patterns in both groups, connectivity differences between groups had clinical and behavioral correlates. During rest, stronger putamen-medial parietal and pallidum-occipital connectivity in PD than controls was associated with worse task performance and more severe PD symptoms suggesting that abnormalities in resting-state connectivity denote neural network dedifferentiation. During the executive task, PD patients showed weaker BG-cortical connectivity than controls, i.e., between caudate-supramarginal gyrus and pallidum-inferior prefrontal regions, that was related to more severe PD symptoms and worse task performance. Yet, task processing also evoked stronger striatal-cortical connectivity, specifically between caudate-prefrontal, caudate-precuneus, and putamen-motor/premotor regions in PD relative to controls, which was related to less severe PD symptoms and better performance on the Stroop task. Thus, stronger task-evoked striatal connectivity in PD demonstrated compensatory neural network enhancement to meet task demands and improve performance levels. fMRI-based network analysis revealed that despite resting-state BG network compromise in PD, BG connectivity to prefrontal, premotor, and precuneus regions can be adequately invoked during executive control demands enabling near normal task performance.
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