Top-down alteration of functional connectivity within the sensorimotor network in focal dystonia

Abstract

Objectives: To determine the directionality of regional interactions and influences of one region on another within the functionally abnormal sensorimotor network in isolated focal dystonia.

Methods: A total of 40 patients with spasmodic dysphonia with and without dystonic tremor of voice and 35 healthy controls participated in the study. Independent component analysis (ICA) of resting-state fMRI was used to identify 4 abnormally coupled brain regions within the functional sensorimotor network in all patients compared to controls. Follow-up spectral dynamic causal modeling (DCM) estimated regional effective connectivity between patients and controls and between patients with spasmodic dysphonia with and without dystonic tremor of voice to expand the understanding of symptomatologic variability associated with this disorder.

Results: ICA found abnormally reduced functional connectivity of the left inferior parietal cortex, putamen, and bilateral premotor cortex in all patients compared to controls, pointing to a largely overlapping pathophysiology of focal dystonia and dystonic tremor. DCM determined that the disruption of the sensorimotor network was both top-down, involving hyperexcitable parieto-putaminal influence, and interhemispheric, involving right-to-left hyperexcitable premotor coupling in all patients compared to controls. These regional alterations were associated with their abnormal self-inhibitory function when comparing patients with spasmodic dysphonia patients with and without dystonic tremor of voice.

Conclusions: Abnormal hyperexcitability of premotor-parietal-putaminal circuitry may be explained by altered information transfer between these regions due to underlying deficient connectivity. Identification of brain regions involved in processing of sensorimotor information in preparation for movement execution suggests that complex network disruption is staged well before the dystonic behavior is produced by the primary motor cortex.

Figure 1. Analytical pipeline

Analytical pipeline of resting-state (rs) fMRI data processing for examination of functional and structural connectivity of the dystonic network. Data processing can be subdivided into 4 main steps, highlighted at the top. BMA = bayesian model averaging; DCM = dynamic causal modeling; DCT = discrete cosine transform; f = frequency; GLM = general linear model; HV = healthy volunteers; ICA = independent component analysis; PEB = parametric empirical Bayes; PT = patients; ROI = region of interest; SD = spasmodic dysphonia; SD/DTv = spasmodic dysphonia combined with dystonic tremor of voice; WM = white matter.

Figure 2. Identification of the brain regions used to build the DCM model

(A) Independent component analysis of resting-state fMRI data identified regional decreases in functional connectivity within the sensorimotor network between healthy controls (HVs) and patients (PT) with spasmodic dysphonia and dystonic tremor of voice at family-wise error–corrected p ≤ 0.05. (B) These regions were used to construct the dynamic causal model (DCM). The fully connected model was built to estimate effective connectivity between the abnormal regions within the functional sensorimotor network. IPC = inferior parietal cortex; PrM = premotor cortex; Put = putamen.

Figure 3. Results of the bayesian dynamic model comparison in HVs and patients with SD and SD/DTv

Panels A.a–A.c show the within-group effect for the effect size of each of the parameter in the model after bayesian model averaging (A.a), the corresponding posterior probabilities (PP; A.b), and a schematic representation of the significant excitatory connections (red), inhibitory connections (blue), and nonsignificant connections (gray). Panels B.a–B.c show the connections with strength that differed significantly between healthy controls and patients in terms of the effect size (B.a) and PPs (B.b). Panel B.c highlights between-group significant connections in purple and nonsignificant connections in gray. Panels C.a–C.c show connections with strength that differed significantly between patients with spasmodic dysphonia (SD) and those with SD/ dystonic tremor of voice (DTv) in terms of the effect size (C.a) and PPs (C.b). Panel C.c highlights between-group significant connections in purple and nonsignificant connections in gray. HV = healthy volunteers; IPC = inferior parietal cortex; PrM = premotor cortex; Put = putamen.