Milestones in research on the pathophysiology of Parkinson's disease

Wichmann, Thomas; DeLong, Mahlon R.; Guridi, Jorge; Obeso, José A.

doi:10.1002/mds.23695

Cited by 177 publications

(142 citation statements)

References 104 publications

(1 reference statement)

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“…This expectation is supported by theoretical assumptions describing the functional organization of the basal-ganglia-thalamocortical circuits, 1,13 including the proposed direct, indirect, and hyperdirect pathways. 1,13,22,35 The STN has been suggested to be a central nucleus in the indirect and hyperdirect pathways and to have a substantial effect on the control of basal ganglia output.…”

mentioning

confidence: 99%

A randomized double-blind crossover trial comparing subthalamic and pallidal deep brain stimulation for dystonia

Schjerling

Hjermind

Jespersen

et al. 2013

JNS

105

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Object The authors' aim was to compare the subthalamic nucleus (STN) with the globus pallidus internus (GPi) as a stimulation target for deep brain stimulation (DBS) for medically refractory dystonia. Methods In a prospective double-blind crossover study, electrodes were bilaterally implanted in the STN and GPi of 12 patients with focal, multifocal, or generalized dystonia. Each patient was randomly selected to undergo initial bilateral stimulation of either the STN or the GPi for 6 months, followed by bilateral stimulation of the other nucleus for another 6 months. Preoperative and postoperative ratings were assessed by using the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) and video recordings. Quality of life was evaluated by using questionnaires (36-item Short Form Health Survey). Supplemental Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) scores were assessed for patients with focal dystonia (torticollis) by examining the video recordings. Results On average for all patients, DBS improved the BFMDRS movement scores (p < 0.05) and quality of life physical scores (p < 0.01). After stimulation of the STN, the mean 6-month improvement in BFMDRS movement score was 13.8 points; after stimulation of the GPi, this improvement was 9.1 points (p = 0.08). Quality of life did not differ significantly regardless of which nucleus was stimulated. All 12 patients accepted 6 months of stimulation of the STN, but only 7 accepted 6 months of stimulation of the GPi. Among those who rejected stimulation of the GPi, 3 accepted concomitant stimulation of both the STN and GPi for 6 months, resulting in improved quality of life physical and mental scores and BFMDRS movement scores. Among the 4 patients who were rated according to TWSTRS, after 6 months of stimulation of both the STN and GPi, TWSTRS scores improved by 4.7% after stimulation of the GPi and 50.8% after stimulation of the STN (p = 0.08). Conclusions The STN seems to be a well-accepted, safe, and promising stimulation target in the treatment of dystonia, but further studies are necessary before the optimal target can be concluded. Simultaneous stimulation of the STN and GPi should be further investigated. Clinical trial registration no.: KF 01-110/01 (Committees on Biomedical Research Ethics of the Capital Region of Denmark).

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mentioning

confidence: 99%

A randomized double-blind crossover trial comparing subthalamic and pallidal deep brain stimulation for dystonia

Schjerling

Hjermind

Jespersen

et al. 2013

JNS

105

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“…Interest in the GPi within the context of Parkinson's disease arises from many sources, including the therapeutic effects exerted from lesioning (pallidotomy) or DBS at this target (Follett and Torres-Russotto, 2012;Obeso et al, 2001;Pizzolato and Mandat, 2012;Rouaud et al, 2010). In classical models of Parkinson's disease, loss of striatal dopamine is predicted to result in hyperactivity within the GPi with consequent over-inhibition of thalamocortical motor relays (Obeso et al, 2008b;Wichmann et al, 2011). One possible mechanism of STN-DBS action may be the attenuation of such pathological GPi hyperactivity, and consequent restoration of thalamic motor relay fidelity (see next section).…”

Section: Internal Globus Pallidusmentioning

confidence: 99%

Neural Circuit Modulation During Deep Brain Stimulation at the Subthalamic Nucleus for Parkinson's Disease: What Have We Learned from Neuroimaging Studies?

Albaugh

Shih²

2013

Brain Connectivity

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Deep brain stimulation (DBS) targeting the subthalamic nucleus (STN) represents a powerful clinical tool for the alleviation of many motor symptoms that are associated with Parkinson's disease. Despite its extensive use, the underlying therapeutic mechanisms of STN-DBS remain poorly understood. In the present review, we integrate and discuss recent literature examining the network effects of STN-DBS for Parkinson's disease, placing emphasis on neuroimaging findings, including functional magnetic resonance imaging, positron emission tomography, and single-photon emission computed tomography. These techniques enable the noninvasive detection of brain regions that are modulated by DBS on a whole-brain scale, representing a key experimental strength given the diffuse and far-reaching effects of electrical field stimulation. By examining these data in the context of multiple hypotheses of DBS action, generally developed through clinical and physiological observations, we define a multitude of consistencies and inconsistencies in the developing literature of this rapidly moving field.

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“…Other factors were the growing understanding of the pathophysiology of basal ganglia disorders, including the development of circuit models of basal ganglia function and circuit dysfunction in movement disorders and studies in the newly introduced 1-methyl-1,2,3,6-phenyl-tetrahydropyridine (MPTP) primate model of parkinsonism [2]. Collectively, these advances provided a clear rationale and impetus for the revival of ablative procedures.…”

Section: Introductionmentioning

confidence: 99%

Deep Brain Stimulation for Movement Disorders of Basal Ganglia Origin: Restoring Function or Functionality?

2016

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Deep brain stimulation (DBS) is highly effective for both hypo-and hyperkinetic movement disorders of basal ganglia origin. The clinical use of DBS is, in part, empiric, based on the experience with prior surgical ablative therapies for these disorders, and, in part, driven by scientific discoveries made decades ago. In this review, we consider anatomical and functional concepts of the basal ganglia relevant to our understanding of DBS mechanisms, as well as our current understanding of the pathophysiology of two of the most commonly DBS-treated conditions, Parkinson's disease and dystonia. Finally, we discuss the proposed mechanism(s) of action of DBS in restoring function in patients with movement disorders. The signs and symptoms of the various disorders appear to result from signature disordered activity in the basal ganglia output, which disrupts the activity in thalamocortical and brainstem networks. The available evidence suggests that the effects of DBS are strongly dependent on targeting sensorimotor portions of specific nodes of the basal gangliathalamocortical motor circuit, that is, the subthalamic nucleus and the internal segment of the globus pallidus. There is little evidence to suggest that DBS in patients with movement disorders restores normal basal ganglia functions (e.g., their role in movement or reinforcement learning). Instead, it appears that high-frequency DBS replaces the abnormal basal ganglia output with a more tolerable pattern, which helps to restore the functionality of downstream networks.

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Milestones in research on the pathophysiology of Parkinson's disease

Cited by 177 publications

References 104 publications

A randomized double-blind crossover trial comparing subthalamic and pallidal deep brain stimulation for dystonia

A randomized double-blind crossover trial comparing subthalamic and pallidal deep brain stimulation for dystonia

Neural Circuit Modulation During Deep Brain Stimulation at the Subthalamic Nucleus for Parkinson's Disease: What Have We Learned from Neuroimaging Studies?

Deep Brain Stimulation for Movement Disorders of Basal Ganglia Origin: Restoring Function or Functionality?

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