Isolated Focal Dystonia as a Disorder of Large-Scale Functional Networks

Abstract

Isolated focal dystonias are a group of disorders with diverse symptomatology but unknown pathophysiology. Although recent neuroimaging studies demonstrated regional changes in brain connectivity, it remains unclear whether focal dystonia may be considered a disorder of abnormal networks. We examined topology as well as the global and local features of large-scale functional brain networks across different forms of isolated focal dystonia, including patients with task-specific (TSD) and nontask-specific (NTSD) dystonias. Compared with healthy participants, all patients showed altered network architecture characterized by abnormal expansion or shrinkage of neural communities, such as breakdown of basal ganglia-cerebellar community, loss of a pivotal region of information transfer (hub) in the premotor cortex, and pronounced connectivity reduction within the sensorimotor and frontoparietal regions. TSD were further characterized by significant connectivity changes in the primary sensorimotor and inferior parietal cortices and abnormal hub formation in insula and superior temporal cortex, whereas NTSD exhibited abnormal strength and number of regional connections. We suggest that isolated focal dystonias likely represent a disorder of large-scale functional networks, where abnormal regional interactions contribute to network-wide functional alterations and may underline the pathophysiology of isolated focal dystonia. Distinct symptomatology in TSD and NTSD may be linked to disorder-specific network aberrations.

Functional and structural neural bases of task specificity in isolated focal dystonia

“…Stratifying patients on the basis of the affected body region further showed that the pathophysiological complexity of each TSFD phenotype may be accounted for by different, albeit spatially neighboring, functional and structural aberrations of the parietal cortex. These areas have been previously shown to be altered in focal dystonias, linked to their polygenic risk, and considered as one of the objective diagnostic biomarkers of this disorder …”

“…Recent neuroimaging studies have shown that, compared to other focal dystonias (e.g., blepharospasm and cervical dystonia), TSFD patients present not only with abnormalities in the basal ganglia, cerebellum, and primary sensorimotor cortex, but also in higher‐order motor and associative cortical regions . Overall greater involvement of cortical alterations in TSFD is thought to reflect impairments of highly learned, complex sequences of voluntary motor actions, whereas other dystonias are characterized by loss of control of more stereotyped movements (e.g., eye blinking, neck posture).…”

Neuroimaging Applications in Dystonia

“…This concept has been recently experimentally substantiated in a study that used a graph theoretical approach to probe the organization of large-scale functional networks across different forms of focal dystonia. Compared to healthy subjects, patients showed altered network architecture, which was characterized by an abnormal breakdown of the basal gangliathalamo-cerebellar community, a loss of pivotal regions of information transfer (hubs) in the premotor cortex, and a pronounced decline in sensorimotor and inferior parietal cortical connectivity (Battistella, Termsarasab, Ramdhani, Fuertinger, & Simonyan, 2017) (Fig. 5A).…”

“…6/17, area 6/17; 7A/7P, subdivisions of area 7; CbI-I/IV/Cbl-V/Cbl-VI, cerebellar lobules I/IV/V/VI; Cu/PCu, cuneus/precuneus; FG, fusiform gyrus; Ig1, part Ig1 of the insula; LG, lingual gyrus; MCC/PCC, middle/posterior cingulate cortex; SOG, superior orbital gyrus; Tp/Tpf/Ts/Tt, parietal/prefrontal/somatosensory/temporal subdivisions of the thalamus; hOC4v, ventral part of area hOC4; L, left; R, right. Panel (A): Adapted from Battistella, G., Termsarasab, P., Ramdhani, R. A., Fuertinger, S., & Simonyan, K. (2017). Isolated focal dystonia as a disorder of large-scale functional networks .…”

Forebrain knock-out of torsinA reduces striatal free-water and impairs whole-brain functional connectivity in a symptomatic mouse model of DYT1 dystonia

“…Understanding how striatal pathology affects network-level FC in preclinical models is important for dissecting pathophysiology and providing readouts for disease modifying interventions. Further, understanding network-level connectivity in a translational model of generalized dystonia is opportune because motor impairment in human subjects with focal dystonia points to disturbances in FC (Battistella et al, 2015; 2016). …”