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Review | Circuits and Circuit Disorders

Basal Ganglia Circuits as Targets for Neuromodulation in Parkinson Disease

Mahlon R. DeLong, MD1; Thomas Wichmann, MD1,2
[+] Author Affiliations
1Department of Neurology, School of Medicine, Emory University, Atlanta, Georgia
2Yerkes National Primate Research Center, Emory University, Atlanta, Georgia
JAMA Neurol. 2015;72(11):1354-1360. doi:10.1001/jamaneurol.2015.2397.
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Importance  The revival of stereotactic surgery for Parkinson disease (PD) in the 1990s, with pallidotomy and then with high-frequency deep brain stimulation (DBS), has led to a renaissance in functional surgery for movement and other neuropsychiatric disorders.

Objective  To examine the scientific foundations and rationale for the use of ablation and DBS for treatment of neurologic and psychiatric diseases, using PD as the primary example.

Evidence Review  A summary of the large body of relevant literature is presented on anatomy, physiology, pathophysiology, and functional surgery for PD and other basal ganglia disorders.

Findings  The signs and symptoms of movement disorders appear to result largely from signature abnormalities in one of several parallel and largely segregated basal ganglia thalamocortical circuits (ie, the motor circuit). The available evidence suggests that the varied movement disorders resulting from dysfunction of this circuit result from propagated disruption of downstream network activity in the thalamus, cortex, and brainstem. Ablation and DBS act to free downstream networks to function more normally. The basal ganglia thalamocortical circuit may play a key role in the expression of disordered movement, and the basal ganglia–brainstem projections may play roles in akinesia and disturbances of gait. Efforts are under way to target circuit dysfunction in brain areas outside of the traditionally implicated basal ganglia thalamocortical system, in particular, the pedunculopontine nucleus, to address gait disorders that respond poorly to levodopa and conventional DBS targets.

Conclusions and Relevance  Deep brain stimulation is now the treatment of choice for many patients with advanced PD and other movement disorders. The success of DBS and other forms of neuromodulation for neuropsychiatric disorders is the result of the ability to modulate circuit activity in discrete functional domains within the basal ganglia circuitry with highly focused interventions, which spare uninvolved areas that are often disrupted with drugs.

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Figure 1.
Anatomy of Cortex–Basal Ganglia–Thalamocortical Circuits

ACA indicates anterior cingulate area; CMA, cingulate motor area; DLPFC, dorsolateral prefrontal cortex; FEF, frontal eye fields; LOFC, lateral orbitofrontal cortex; M1, primary motor cortex; MD, mediodorsal; MDpl, mediodorsal nucleus of thalamus, pars lateralis; MOFC, medial orbitofrontal cortex; PMC, premotor cortex; SEF, supplementary eye field; SMA, supplementary motor area; SNr, substantia nigra pars reticulata; VAmc, ventral anterior nucleus of thalamus, pars magnocellularis; VApc, ventral anterior nucleus of thalamus, pars parvocellularis; VLa, anterior ventrolateral nucleus of the thalamus; VLcr, ventrolateral nucleus of thalamus, pars caudalis, rostral division; VLm, ventrolateral nucleus of thalamus, pars medialis; and VS, ventral striatum. Reprinted with permission from Elsevier Limited.10

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Figure 2.
Parkinsonism-Related Activity Changes in the Basal Ganglia–Thalamocortical Motor Circuit and Targets of Medical and Surgical and Interventions

A, Parkinsonism-related changes in overall activity in the basal ganglia–thalamocortical motor circuit. Black arrows indicate inhibitory connections; gray arrows, excitatory connections. The thickness of the arrows corresponds to their presumed activity. B, Potential and actual targets of antiparkinsonian therapeutic interventions and signs and symptoms addressed with each target (arrows with open arrowheads). Deep brain stimulation (DBS) is approved by the US Food and Drug Administration only at the subthalamic nucleus (STN), internal pallidal segment (GPi), and nucleus ventralis intermedius targets for the treatment of Parkinson disease. CM indicates centromedian nucleus; D1 and D2, dopamine receptor subtypes; GPe, external segment of the globus pallidus; PPN, pedunculopontine nucleus; SNc, substantia nigra pars compacta; VA, ventral anterior nucleus of the thalamus; and VL, ventrolateral nucleus of the thalamus. For other abbreviations, see the legend to Figure 1. Reprinted with permission from Elsevier Limited.14

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