# Task-based effective connectivity finds alterations in frontoparietal network in Duchenne muscular dystrophy

## TL;DR

This study finds altered brain connectivity in Duchenne muscular dystrophy, linking it to working memory challenges and potential targets for treatment.

## Contribution

The study identifies atypical task-based effective connectivity in the frontoparietal network in Duchenne muscular dystrophy using dynamic causal modeling.

## Key findings

- Task-based hypoactivation of frontoparietal–occipital regions was observed in Duchenne muscular dystrophy.
- Group differences in effective connectivity during working memory tasks were statistically lower in Duchenne muscular dystrophy.
- Right posterior parietal → dorsolateral prefrontal connectivity correlated negatively with working memory performance in Duchenne muscular dystrophy.

## Abstract

Duchenne muscular dystrophy is a monogenic X-linked genetic disorder that is caused due to the absence of dystrophin. In addition to the skeletal and cardiac manifestations, challenges in executive function are pervasive and persistent, affecting a majority of young individuals with Duchenne muscular dystrophy. Executive function-related disability is linked to chronic stress, academic under-achievement and poor vocational attainment. Of the executive function domains, inhibitory control and working memory are disproportionately affected, and linked to academic under-achievement in Duchenne muscular dystrophy. Despite its consequential importance to the quality-of-life in affected individuals, the neural substrates underpinning working memory challenges are poorly understood in this disease. The dynamic interactions of bilateral dorsolateral prefrontal cortex as part of the frontoparietal network is critical for working memory. Atypical neural connectivity within the frontoparietal network may underlie the neural basis of working memory challenges in Duchenne muscular dystrophy. Effective (directional) connectivity analysis of brain functional MRI is an advanced analytical approach that quantitates the directionality and the nature (facilitatory or inhibitory) causal interactions between brain regions. The strength of effective connectivity in Hertz—stronger (facilitatory) versus weaker (inhibitory)—within the frontoparietal network was analysed using dynamic causal modelling in 11 right-handed male participants with Duchenne muscular dystrophy and 9 right-handed male neurotypicals while they completed an n-back working memory task. Participants also completed standardized neurocognitive assessments out-of-scanner. Age-corrected working memory scores were comparable in Duchenne muscular dystrophy (mean 100.0, standard deviation 16.0) and neurotypicals (mean 109.0, standard deviation 8.0) (P = 0.15). Task-based hypoactivation of frontoparietal–occipital regions was observed in Duchenne muscular dystrophy. The group difference in mean frontoparietal effective connectivity during the in-scanner n-back working memory tasks was statistically lower by Bayes factor of 3 in Duchenne muscular dystrophy, compared to neurotypicals. The right posterior parietal → dorsolateral prefrontal connectivity correlated negatively to out-of-scanner working memory performance in Duchenne muscular dystrophy. Median reaction times during the 0-back and 2-back working memory tasks were longer in Duchenne muscular dystrophy compared to neurotypicals, but the difference did not reach statistical significance (P = 0.2). Median reaction time during the 0-back fearful facial condition was longer in Duchenne muscular dystrophy compared to neurotypicals (P = 0.01). Our work implicates atypical task-based effective connectivity within the frontoparietal network and impaired perceptual processing in Duchenne muscular dystrophy. Dynamic neural network signatures can serve as mechanistic targets for pharmacological and non-pharmacological interventions to mitigate executive function impairment in Duchenne muscular dystrophy.

Thangarajh et al. detected hypoactivation of bilateral frontoparietal brain regions during task-based functional MRI in Duchenne Muscular Dystrophy. Effective connectivity analysis revealed mutually inhibitory interactions between the right posterior parietal cortex and dorsolateral prefrontal cortex, supporting a functional diaschisis between perceptual processing and information encoding. Dystrophin-deficiency alters neural connectivity.

Graphical Abstract