Sensory and motor cortex function contributes to symptom severity in spinocerebellar ataxia type 6

Abstract

Spinocerebellar ataxia type 6 (SCA6) is a genetic disease that causes degeneration of Purkinje cells, and recent evidence points to degeneration of Betz cells in the motor cortex. The relation between functional activity of motor cortex and symptom severity during a hand-grip motor control in vivo has not yet been investigated. This study explored both functional changes in the sensorimotor cortex and cerebellar regions and structural alterations in the cerebellum for SCA6 patients as compared to age-matched healthy controls using a multimodal imaging approach (task-based fMRI, task-based functional connectivity, and free-water diffusion MRI). Further, we tested their relation with the severity of ataxia symptoms. SCA6 patients had reduced functional activity in the sensorimotor cortex, supplementary motor area (SMA), cerebellar vermis, and cerebellar lobules I-VI (corrected P < 0.05). Reduced task-based functional connectivity between cortical motor regions (i.e., primary motor cortex and SMA) and cerebellar regions (i.e., vermis and lobules I–VI) was found in SCA6 (corrected P < 0.05). SCA6 had elevated free-water values throughout the cerebellum as compared with controls (corrected P < 0.05). Importantly, reduced functional activity in the sensorimotor cortex and SMA and increased free-water in the superior cerebellar peduncle and cerebellar lobule V were related to more severe symptoms in SCA6 (all pairs: R2 ≥ 0.4 and corrected P < 0.05). Current results demonstrate that impaired functional activity in sensorimotor cortex and SMA and elevated free-water of lobule V and superior cerebellar peduncle are both related to symptom severity, and may provide candidate biomarkers for SCA6.

Spinocerebellar ataxias: prospects and challenges for therapy development

“…Among the many MRI modalities, morphometric MRI, diffusion MRI and magnetic resonance spectroscopy (MRS) have been evaluated as biomarkers in SCAs by a number of groups worldwide 141 . In addition, the utility of task-based and resting-state functional MRI 142,143 is gathering increased interest for monitoring of functional abnormalities.…”

Temporal Invariance in SCA6 Is Related to Smaller Cerebellar Lobule VI and Greater Disease Severity

“…Given that the both the CNS and the cerebellum are intact in healthy musicians, the reduced variability of the individual components due to a selective reduction in size of lobule VI, likely enhances the coordination to achieve motor proficiency. In contrast, ataxia results in pancerebellar degeneration with concomitant changes in other brain areas (Kang et al, 2017;Therrien and Bastian, 2019), affecting the timing of motor actions (Ivry and Keele, 1989;Spencer et al, 2003). Indeed, the loss of motor control is likely affected by the loss of Purkinje cells in additional areas of the cerebellum, as we demonstrate with the prediction of disease severity using the ICARS (Fig.…”

International Classification of Functioning, Health and Disability (ICF) Conceptual Approach towards Spinocerebellar Ataxia

“…The focus of body structure in spinocerebellar ataxia is obviously the cerebellum, in the spinocerebellum (center) portion. It is known that the spinocerebellum gathers a large volume of sensory information from the peripheral organs, as well as relaying information from the motor cortex [12,13]. Etiologically this is caused by autosomal dominant mutation on the SCA gene, and this would disrupt the connection between multiple layers of cerebellum [1].…”

“…The main environmental factor issues that was addressed for SCA is the difficulty to walk on varying level terrains [13,29,30]. It should be remembered that stable walking in varying level terrains require several functions ranging from cognition, vision, limb control, and balance.…”

“…Postural exercise approach are generally based on "re-learning" strategies of destabilizing responses, that anticipatory movements are trained in various environments, as well as honing of sensorimotor reflexes in the light of preserved plasticity [9,13]. Postural instability would also lead to chronic low back pain, and thus stretching must also be given in order to alleviate these before and after training sessions [9].…”