Subthalamic nucleus stimulation-induced regional blood flow responses correlate with improvement of motor signs in Parkinson disease

Abstract

Deep brain stimulation of the subthalamic nucleus (STN DBS) improves motor symptoms in idiopathic Parkinson's disease, yet the mechanism of action remains unclear. Previous studies indicate that STN DBS increases regional cerebral blood flow (rCBF) in immediate downstream targets but does not reveal which brain regions may have functional changes associated with improved motor manifestations. We studied 48 patients with STN DBS who withheld medication overnight and underwent PET scans to measure rCBF responses to bilateral STN DBS. PET scans were performed with bilateral DBS OFF and ON in a counterbalanced order followed by clinical ratings of motor manifestations using Unified Parkinson Disease Rating Scale 3 (UPDRS 3). We investigated whether improvement in UPDRS 3 scores in rigidity, bradykinesia, postural stability and gait correlate with rCBF responses in a priori determined regions. These regions were selected based on a previous study showing significant STN DBS-induced rCBF change in the thalamus, midbrain and supplementary motor area (SMA). We also chose the pedunculopontine nucleus region (PPN) due to mounting evidence of its involvement in locomotion. In the current study, bilateral STN DBS improved rigidity (62%), bradykinesia (44%), gait (49%) and postural stability (56%) (paired t-tests: P < 0.001). As expected, bilateral STN DBS also increased rCBF in the bilateral thalami, right midbrain, and decreased rCBF in the right premotor cortex (P < 0.05, corrected). There were significant correlations between improvement of rigidity and decreased rCBF in the SMA (r(s) = -0.4, P < 0.02) and between improvement in bradykinesia and increased rCBF in the thalamus (r(s) = 0.31, P < 0.05). In addition, improved postural reflexes correlated with decreased rCBF in the PPN (r(s) = -0.38, P < 0.03). These modest correlations between selective motor manifestations and rCBF in specific regions suggest possible regional selectivity for improvement of different motor signs of Parkinson's disease.

Fig. 1

Overlay of the average MRI of participants with available MRIs (n = 11) and PPN region defined using Paxinos and Huang Atlas of the Human Brainstem. (A) Superior cerebellar peduncle, (B) Medial lemniscus, (C) PPN AND (D) central tegmental tract.

Fig. 2

A priori defined VOIs: (A) bilateral thalami, (B) bilateral SMA, (C) bilateral SMC, (D) bilateral PPN region. The VOIs are overlaid on Talairach atlas co-registered average MRI of 11 participants.

Fig. 3

(A) Bilateral DBS STN leads to significant rCBF increase in bilateral thalami and right midbrain, corrected P < 0.05 at cluster level, n = 31. (B) Bilateral DBS STN leads to significant rCBF decrease in the right premotor region, corrected P < 0.05 at cluster level, n = 30.

Fig 4

(A) Improvement of bradykinesia correlates with thalamic rCBF increase; r_s = 0.31, corrected P < 0.05, n = 28. (B) Improvement of rigidity correlates with SMA rCBF decrease in: r_s = −0.381, corrected P < 0.038, n = 30. (C) Improvement in postural stability correlates with rCBF decrease in the PPN region: r_s = −0.38, corrected P < 0.03, n = 31.