Neural substrates of motor and cognitive dysfunctions in SCA2 patients: A network based statistics analysis

Abstract

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disease characterized by a progressive cerebellar syndrome, which can be isolated or associated with extracerebellar signs. It has been shown that patients affected by SCA2 present also cognitive impairments and psychiatric symptoms.The cerebellum is known to modulate cortical activity and to contribute to distinct functional networks related to higher-level functions beyond motor control. It is therefore conceivable that one or more networks, rather than isolated regions, may be dysfunctional in cerebellar degenerative diseases and that an abnormal connectivity within specific cerebello-cortical regions might explain the widespread deficits typically observed in patients.In the present study, the network-based statistics (NBS) approach was used to assess differences in functional connectivity between specific cerebellar and cerebral “nodes” in SCA2 patients. Altered inter-nodal connectivity was found between more posterior regions in the cerebellum and regions in the cerebral cortex clearly related to cognition and emotion. Furthermore, more anterior cerebellar lobules showed altered inter-nodal connectivity with motor and somatosensory cerebral regions. The present data suggest that in SCA2 a cerebellar dysfunction affects long-distance cerebral regions and that the clinical symptoms may be specifically related with connectivity changes between motor and non-motor cerebello-cortical nodes.

The Cerebellar Cognitive Affective/Schmahmann Syndrome: a Task Force Paper

“…CB atrophy was also associated with altered diffusivity of the middle and superior CB peduncles, the main cerebro-CB afferent and efferent white matter tracts, respectively, indicating that cerebro-CB dysregulation may account for the CCAS in SCA2 [215]. Network-based statistics reveals that altered internodal connectivity between the CB posterior lobe and the cerebral cortex correlated with assessments of cognition and emotion, consistent with the view that CB dysfunction in SCA2 affects cerebral regions at a distance and that the clinical symptoms may be related to connectivity changes in both the cerebral and CB nodes of motor and nonmotor cerebro-CB circuits [104]. These findings are consistent with the observations that there are distinct and topographically precise CB contributions to cerebral intrinsic connectivity networks [24,25,39] and that rTMS applied to distinct CB regions can selectively modulate network functional connectivity in healthy individuals [145,216].…”

“…These tasks depend on multisensory integration, sequencing, prediction of events, and inhibition of inappropriate responses, all of which are affected by CB damage. Further, divided and sustained attention correlated with lobules VIIB/VIIIA which have been proposed to be part of the dorsal attention network [104,223], and selective attention correlated with vermis lobule VI. These findings provide support for the involvement of specific CB regions in the attention impairments seen in the CCAS and for the inclusion of the CB within the dorsal attention network.…”

“…Significantly poorer ataxia symptoms were associated with damage to the anterior CB and lobule VI (top), whereas poorer performance on the Boston Naming Test was associated with right-lateralized damage to posterior CB regions, including Crus II, VIIB, and VIII (bottom). Adapted with permission from [17] regions supporting cognition and emotion, including the superior and middle frontal gyri [104]. Such changes in cerebro-CB network connectivity have also been associated with clinical impairments in visual-spatial processing and executive function in SCA6 [105].…”

Functional Changes of Mentalizing Network in SCA2 Patients: Novel Insights into Understanding the Social Cerebellum

“…From an anatomical point of view, the presence of extensive reciprocal connections between the cerebellum and higher-level cerebral regions has been widely demonstrated [60][61][62] as well as the functional contribution of the cerebellum, especially Crus I/II, to functional networks that are relevant to cognitive functions and social abilities, also including DMN [16;41]. Generally speaking, cognitive deficits in SCA2 patients have been previously described and related to both structural [36] and functional alterations [63] in the cerebello-cerebral networks.…”

Neuroimaging Biomarkers in SCA2 Gene Carriers

“…MRI exploiting BOLD contrast is a major tool to non-invasively investigate the brain function in patients with neurological diseases. As in other neurodegenerative diseases [44], clinical impairment hinders assessment of symptomatic SCA2 gene carriers with fMRI during execution of tasks [45], and justifies that resting state fMRI has been the preferred method to investigate brain physiopathology in SCA2 using a variety of analytical approaches [46][47][48][49].…”