Neural circuit modulation during deep brain stimulation at the subthalamic nucleus for Parkinson's disease: what have we learned from neuroimaging studies?

Abstract

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.

FIG. 1.

Simplified model of the cortico-basal ganglia-thalamo-cortical loop. Both STN and GPi are common targets for Parkinson's therapy. Glu, glutamatatergic; GABA, GABAergic; GPe, globus pallidus external segment; GPi, globus pallidus internal segment; STN, subthalamic nucleus; VA/VL, ventral anterior/ventrolateral. Important circuit elements not shown include cortical innervation of STN (hyperdirect pathway), dopaminergic inputs to striatum and extrastriatal areas via the substantia nigra pars compacta, and the substantia nigra pars reticulata as a basal ganglia output nucleus.

FIG. 2.

Lack of effect of STN-DBS on endogenous striatal dopamine release within the putamen, as detected by positron emission tomography imaging of ¹¹C-raclopride (D2/D3 receptor agonist) displacement. Figure displays raclopride displacement volume ratio (DVR) averaged within the putamen for each of six advanced Parkinson's patients, both during bilateral STN-deep brain stimulation (DBS) and after a nonstimulation period of at least 12 h. Figure modified from Hilker et al. (2003).

FIG. 3.

STN-DBS evokes frequency-dependent blood-oxygen-level-dependent (BOLD) activation in sensorimotor cortex of normal rats. The amplitude of DBS-induced activation peaked at 130 Hz, and was largest in the ipsilateral motor cortex during unilateral stimulation. (A) BOLD activation maps in different brain slices with reference to bregma; (B) averaged traces of BOLD response profiles in cortical subregions depicted in A. Figure modified from Lai et al. (2013).

FIG. 4.

Detection of prefrontal hypometabolism during STN-DBS for treatment-refractory obsessive-compulsive disorder. Bilateral STN-DBS (targeting the associative and limbic STN subregions) induced reduced glucose metabolism in the cingulate gyrus and left frontal lobe (among other regions) when compared with a within-subject DBS-OFF baseline. Figure modified from Le Jeune et al. (2010).