Gray matter density loss in essential tremor: A lobule by lobule analysis of the cerebellum

Background: The pathophysiological basis for essential tremor (ET) remains unclear, although evidence increasingly links it to a disordered and perhaps degenerative cerebellum. Prior imaging studies have treated the cerebellum en bloc. Our hypothesis was that regional differences in cerebellar gray matter (GM) density may better distinguish ET cases from controls. Forty-seven ET cases and 36 control subjects were imaged using magnetic resonance imaging (MRI). The cerebellum was segmented into 34 lobes using a Spatially Unbiased Infra-Tentorial Template (SUIT) atlas within the Statistical Parametric Mapping (SPM) analysis package. Age, gender and Montreal Cognitive Assessment (MoCA) scores were regressed out from the statistical models to isolate group effects. ET cases were further stratified into phenotypically-defined subgroups. The Benjamini-Hochberg False Discovery Rate procedure (BH FDR) (α = 0.1) was used to correct for multiple comparisons. Results: When all ET cases and controls were compared, none of the regions met the BH FDR criteria for significance. When compared with controls, ET cases with head or jaw tremor (n = 27) had significant changes in GM density in nine cerebellar lobules, with a majority in the left cerebellar region, and each meeting the BH FDR criteria. Likewise, ET cases with voice tremor (n = 22) exhibited significant changes in 11 lobules in both left and right regions and the vermis. These analyses, in sum, indicated decreases in GM density in lobules I-IV, V, VI, VII and VIII as well as the vermis. ET cases with severe tremor (n = 20) did not show regions of change that survived the BH FDR procedure when compared to controls. Conclusions: We showed that ET cases with various forms of cranial tremor differed from controls with respect to cerebellar GM density, with evidence of GM reduction across multiple cerebellar regions. Additional work, using a lobule-by-lobule approach, is needed to confirm these results and precisely map the regional differences in ET cases, subgroups of ET cases, and controls.