Regional, not global, functional connectivity contributes to isolated focal dystonia

Abstract

Objective:To test the hypothesis that there is shared regional or global functional connectivity dysfunction in a large cohort with isolated focal dystonia affecting different body regions compared to control participants. In this case-control study we obtained resting-state MRI scans (3-4 7.3 minute runs) with eyes closed in participants with focal dystonia (cranial [17], cervical [13], laryngeal [18], limb [10]) and age- and sex-matched controls.Methods:Rigorous preprocessing for all analyses was performed to minimize effect of head motion during scan acquisition (dystonia N=58, control N=47 analyzed). We assessed regional functional connectivity by computing a seed-correlation map between putamen, pallidum, and sensorimotor cortex and all brain voxels. We assessed significant group differences on a cluster-wise basis. In a separate analysis, we applied 300 seed regions across the cortex, cerebellum, basal ganglia and thalamus to comprehensively sample the whole brain. We obtained participant whole-brain correlation matrices by computing the correlation between seed average time courses for each seed pair. Weighted object-oriented data analysis assessed group-level whole-brain differences.Results:Participants with focal dystonia had decreased functional connectivity at the regional level, within the striatum and between lateral primary sensorimotor cortex and ventral intraparietal area, whereas whole-brain correlation matrices did not differ between focal dystonia and control groups. Rigorous quality control measures eliminated spurious large-scale functional connectivity differences between groups.Conclusion:Regional functional connectivity differences, not global network level dysfunction, contributes to common pathophysiological mechanisms in isolated focal dystonia. Rigorous quality control eliminated spurious large-scale network differences between focal dystonia and control participants.

The Central Effects of Botulinum Toxin in Dystonia and Spasticity

“…Additional insight into the central effects of BoNT-A may be obtained by analysing data at rest, which are unaffected by the a priori selected stimulation or task. While multiple studies evaluated resting state brain function in dystonia to determine disease traits (e.g., [ 95 , 96 , 97 ]), this section focuses on studies specifically evaluating the effects of BoNT-A intervention. A fluoro-deoxy-glucose PET study [ 83 ] evaluated resting state metabolism in patients with blepharospasm at a single time point following BoNT-A injections.…”

“…Similarly, the central effects of BoNT-A may hinge upon dynamic modulatory changes in multiple nodes of the sensorimotor network, which could be differently weighted in various patient cohorts, explaining both the variability of clinical manifestations and the individual responses to treatment. The network-wide hypothesis of pathophysiology of dystonia has recently been challenged, however, as more focal differences in FC have been reported in the striatum and sensorimotor cortex after more rigorous approaches had been applied [ 97 ]. Hence, regionally specific effects of BoNT-A are plausible if similar rigorous methods are used.…”

Botulinum toxin injection changes resting state cerebellar connectivity in cervical dystonia

“…However, functional MRI (fMRI) evidence demonstrates changes in multiple resting state networks (e.g., 12 , which partly normalize with botulinum neurotoxin A (BoNT) therapy, suggesting primarily functional disruption of the motor control 25 , 34 . Nevertheless, there are only a few publications discussing resting state fMRI in CD 9 , 11 , 12 , 30 , 35 , 40 , 51 . These studies demonstrate functional connectivity changes at either cortical or subcortical levels thought to reflect defective planning, disturbed spatial cognition, and compensatory executive control of accurate movements 12 .…”

“…The only studies assessing the effect of BoNT-A on resting state connectivity either did not evaluate any cerebellar regions of interest 6 or evaluated the cerebellum as a single region of interest (ROI) 12 . The remaining studies of resting-state connectivity in CD did not assess the effects of treatment and included patients with different times since their previous BoNT-A injection 35 , 40 . The lack of detailed analysis of treatment-related changes in cerebellar functional connectivity thus poses a surprisingly significant knowledge gap, especially considering the potentially important role of the cerebellum in the pathophysiology of dystonia.…”

Late cortical disinhibition in focal hand dystonia

“…It associates motor disorders caused by dysfunction in the basal ganglia loop and sensory disorders as attested by abnormalities in spatial (Bara‐Jimenez et al., 2000; Molloy et al., 2003; Sanger et al., 2001; Tinazzi et al., 2000) and temporal (Frasson et al., 2001; Sanger et al., 2001) sensory discrimination. Anatomically, patients with different forms of focal dystonia exhibit altered regional functional connectivity within the striatum and between the lateral primary sensorimotor cortex and the ventral intraparietal area (Norris et al., 2020). Recent data suggest that rather than a pure basal ganglia disorder, dystonia is a network disorder involving the basal ganglia, cerebellum, thalamus and sensorimotor cortex (for a review, see Latorre et al., 2020).…”