Brain Connectomics’ Modification to Clarify Motor and Nonmotor Features of Myotonic Dystrophy Type 1

Abstract

The adult form of myotonic dystrophy type 1 (DM1) presents with paradoxical inconsistencies between severity of brain damage, relative preservation of cognition, and failure in everyday life. This study, based on the assessment of brain connectivity and mechanisms of plasticity, aimed at reconciling these conflicting issues. Resting-state functional MRI and graph theoretical methods of analysis were used to assess brain topological features in a large cohort of patients with DM1. Patients, compared to controls, revealed reduced connectivity in a large frontoparietal network that correlated with their isolated impairment in visuospatial reasoning. Despite a global preservation of the topological properties, peculiar patterns of frontal disconnection and increased parietal-cerebellar connectivity were also identified in patients' brains. The balance between loss of connectivity and compensatory mechanisms in different brain networks might explain the paradoxical mismatch between structural brain damage and minimal cognitive deficits observed in these patients. This study provides a comprehensive assessment of brain abnormalities that fit well with both motor and nonmotor clinical features experienced by patients in their everyday life. The current findings suggest that measures of functional connectivity may offer the possibility of characterizing individual patients with the potential to become a clinical tool.

Altered levels of the splicing factor muscleblind modifies cerebral cortical function in mouse models of myotonic dystrophy

“…Given that there was no change in the ipsilateral response, the decreased contralateral response may reflect altered corpus callosum function. As reviewed earlier (see Introduction), white matter and functional connectivity changes in DM1 and DM2 patients, including in the corpus callosum, have been a common finding in anatomical and DTI studies (Fukuda et al 2005;Ota et al 2006;Wozniak et al 2011;Minnerop et al 2011;Franc et al 2012;Serra et al 2014;Serra et al 2016). However, we would emphasize that the decreased flavoprotein response in the contralateral hemisphere is not definitive for abnormal corpus callosum function, with additional experiments needed to test other possibilities.…”

“…Gray matter cell loss has also been reported, although less so in DM2 than DM1 patients (Ono et al 1996;Kassubek et al 2003;Antonini et al 2004;Minnerop et al 2011). Furthermore, resting state fMRI studies in DM1 patients report changes in resting state connectivity (Serra et al 2014;Serra et al 2016). These findings suggest that cerebral cortical circuits are altered in DM, particularly white matter tracts (Minnerop et al 2011).…”

Abnormal Cortical Thickness Is Associated With Deficits in Social Cognition in Patients With Myotonic Dystrophy Type 1

“…This study is part of broader research program that investigates the neural correlates of various aspects of SC in patients with DM1. We first investigated the association between ToM abilities and functional connectivity, as reported in Serra et al (16). Then, we extended this investigation to emotion attribution, social situation, and moral-non-moral judgment abilities in a cohort of subjects that includes a large part of those already included in the former study (n = 26) (16), and we focused our investigation on the cortical thickness.…”

“…Social cognition deficits have been consistently reported not only in patients with frontal brain lesions but also in patients with neurodevelopmental disorders such as autism or neurodegeneration such as the behavioral variant of the frontotemporal dementia (18). In DM1 patients, we recently identified functional brain abnormalities within networks implicated in ToM ability (16). Emotion recognition-wise, specific deficits have also been reported in patients with DM1 (19), although there are no available studies exploring their neurobiological substrate.…”

“…Importantly, a strict relationship has been reported not only between structural brain abnormalities and DM1 patients' cognitive profile (e.g., executive functions, reasoning and visuospatial abilities) (7,9) but also with patients' CTG triplet expansion (6,8,13). When looking at functional brain connectivity, abnormalities in specific networks have been identified to account for DM1 patients' personality traits (14), as well as for some complex cognitive impairments (8,15) in the domain of social cognition (SC) (16). This is particularly relevant considering that higher-order neuropsychological dysfunctions, including SC, dominate the cognitive profile of DM1 patients who, conversely, perform relatively well on tests exploring single neuropsychological domains (e.g., memory, language, etc).…”