Identification of a metabolic brain network characterizing essential tremor

Abstract

The neuronal correlate of tremor genesis and cognitive function in essential tremor (ET) and its modulation by deep brain stimulation (DBS) are poorly understood. To explore the underlying metabolic topography of motor and cognitive symptoms, sixteen ET patients (age 63.6 ± 49.1 years) and 18 healthy controls (HC) (61.1 ± 6.3 years) underwent tremor and cognitive assessments and¹⁸F-fluorodeoxyglucose PET of the brain. Multivariate spatial covariance analysis was applied for identifying ET related metabolic brain networks. For network validation and to explore DBS effects, 8 additional ET patients (68.1 ± 8.2 years) treated with DBS were assessed in both the ON and OFF state, respectively. The ET related metabolic spatial covariance pattern (ETRP) was characterized by relatively increased metabolism in the cerebellum, brainstem, and temporo-occipital cortices, accompanied by relative metabolic decreases mainly in fronto-temporal and motor cortices. Network expression showed inverse correlations with tremor severity and disease duration and positive correlations with cognitive dysfunction. DBS substantially alleviated tremor, but had only marginal effects on cognitive performance. There were no significant DBS effects on ETRP expression at the group level, but all but one subject showed higher scores in the ON state. Our findings suggest ET is characterized by an abnormal brain network associated with disease phenotype.

Keywords: Brain metabolism; Deep brain stimulation; Essential tremor; FDG PET; Spatial covariance analysis.

Fig. 1

Cognitive performance across groups. STROOP: Stroop test (color: color naming, word: word reading, color-word: color-word interference task); TMT = Trail making test; RWT = Regensburger Wortfluessigkeitstest; CVLT = California verbal learning test; DGS = digit span test; PR = Percentile rank. Bars present group means, error mars indicate the standard deviation.

Fig. 2

(A) Essential tremor related metabolic spatial covariance pattern (ETRP) identified in FDG-PET scans. Regions of relative metabolic increases are displayed in red, relative metabolic decreases in blue. Only regions surviving bootstrapping (1000 iterations) at a CI of 95% are displayed. Blobs are superimposed on a standard T1 template, coordinates are displayed in MNI standard space. (B) ETRP subject scores were significantly increased compared with HC in the derivation cohort (ET1) and an independent validation cohort (ET2). Error bars present the SEM. ET: essential tremor; HC: healthy controls; MNI: Montreal Neurological Institute; FDG-PET:F-fluorodeoxyglucose positron emission tomography.

Fig. 3

Correlations of disease duration, tremor severity, and cognitive performance with ETRP expression. ET1 subjects are displayed as gray diamonds, ET2 subjects are shown in black. ETRP: Essential tremor related metabolic spatial covariance pattern; FTM: Fahn-Tolosa-Marin scale, STROOP: Stroop test (color-word interference task); Complex figure: Complex figure test (copy task).