The circuit changes that mediate parkinsonian tremor, while likely differing from those underlying akinesia and rigidity, are not precisely known. In this study, to identify a specific metabolic brain network associated with this disease manifestation, we used FDG PET to scan nine tremor dominant Parkinson's disease (PD) patients at baseline and during ventral intermediate (Vim) thalamic nucleus deep brain stimulation (DBS). Ordinal trends canonical variates analysis (OrT/CVA) was performed on the within-subject scan data to detect a significant spatial covariance pattern with consistent changes in subject expression during stimulation-mediated tremor suppression. The metabolic pattern was characterized by covarying increases in the activity of the cerebellum/dentate nucleus and primary motor cortex, and, to a less degree, the caudate/putamen. Vim stimulation resulted in consistent reductions in pattern expression (p<0.005, permutation test). In the absence of stimulation, pattern expression values (subject scores) correlated significantly (r=0.85, p<0.02) with concurrent accelerometric measurements of tremor amplitude. To validate this spatial covariance pattern as an objective network biomarker of PD tremor, we prospectively quantified its expression on an individual subject basis in independent PD populations. The resulting subject scores for this PD tremor-related pattern (PDTP) were found to exhibit: (1) excellent test-retest reproducibility (p<0.0001); (2) significant correlation with independent clinical ratings of tremor (r=0.54, p<0.001) but not akinesia-rigidity; and (3) significant elevations (p<0.02) in tremor dominant relative to atremulous PD patients. Following validation, we assessed the natural history of PDTP expression in early stage patients scanned longitudinally with FDG PET over a 4-year interval. Significant increases in PDTP expression (p<0.01) were evident in this cohort over time; rate of progression, however, was slower than for the PD-related akinesia/rigidity pattern (PDRP). We also determined whether PDTP expression is modulated by interventions specifically directed at parkinsonian tremor. While Vim DBS was associated with changes in PDTP (p<0.001) but not PDRP expression, subthalamic nucleus (STN) DBS reduced the activity of both networks (p<0.05). PDTP expression was suppressed more by Vim than by STN stimulation (p<0.05). These findings suggest that parkinsonian tremor is mediated by a distinct metabolic network involving primarily cerebello-thalamo-cortical pathways. Indeed, effective treatment of this symptom is associated with significant reduction in PDTP expression. Quantification of treatment-mediated changes in both PDTP and PDRP scores can provide an objective means of evaluating the differential effects of novel antiparkinsonian interventions on the different motor features of the disorder.
