Changes and imbalances that occur in connectivity in the basal ganglia motor loop are associated with common motor signs as well as apathy observed in patients with Huntington disease (HD), a study in Brain suggests.

HD is a rare, inherited neurodegenerative disease caused by a defective gene, the huntingtin gene on chromosome 4. Although the cause of HD is clear, the pathogenesis of the core clinical motor, cognitive, and behavioral features of HD remains unknown. Researchers have hypothesized changes in connectivity within the indirect pathway may be associated with the onset of motor signs in HD. Moreover, they suspect altered basal ganglia connectivity in the pathogenesis of HD may have more clinical implications than just motor signs, for example, psychiatric disturbances like apathy.

The objective of the current study was to assess whether motor signs in HD are associated with altered indirect pathway connectivity, and whether apathy in early HD is tied to change in direct pathway connectivity.


Continue Reading

Researchers used data collected in the TRACK-ON HD study, which included patients with prodromal HD. Data from the third study visit were used in the analysis. The Unified Huntington’s Disease Rating total motor score (TMS) and the self-rated Baltimore apathy scale (BAS) were the 2 primary outcomes for the study. The study cohort was peri-manifest and included 34 out of 94 HD gene carrier patients with a diagnosis of early HD. In patients with early stage disease, the mean Total Motor Score was 17.9±9.2.

A Bayesian framework called dynamic causal modeling was used to study effective connectivity based on a simplified model of pathways of interest. At the group level, the researchers also used Parametric Empirical Bayes to model how within-subject connections are associated with between-subject factors (e.g., motor scores). A Bayesian Model Reduction was used to determine whether hypothesized connections between connectivity parameters and clinical scores could emerge from the data.

The researchers hypothesized that motor signs and apathy in HD “may be selectively correlated with indirect and direct pathway dysfunction, respectively.” They reportedly found “very strong evidence” to support these hypotheses. Specifically, the researchers noted that the more severe HD-associated motor signs correlated with altered connectivity in the indirect pathway components of the studied model. Additionally, there was an association between loss of goal-direct behavior or apathy and changes in the direct pathway component.

They “found modest effect sizes” in both of the analyses, which may limit the findings. In addition, the researchers noted that they were unable to resolve other neurologic mechanisms that could have contributed to apathy in patients with HD, including white matter changes and involvement of cortical structures. They explained that they “therefore do not claim, based on the data presented here that changes in connectivity that we present are sufficient to generate clinical features.” Rather, the researchers suggest, “that changes in basal ganglia connectivity may contribute to their development in patients” with HD.

The findings for this study not only inform the pathogenesis of HD clinical features, but they may also help support the development of future therapeutics, according to the researchers. “For apathy in particular, our findings may suggest that medications which manipulate the relative activity of basal ganglia pathways, in particular those that modulate direct pathway activity, may be a fruitful way forward,” they concluded.

Reference

Nair A, Razi A, Gregory S, Rutledge RR, Rees G, Tabrizi SJ. Imbalanced basal ganglia connectivity is associated with motor deficits and apathy in Huntington’s disease. Brain. Published online October 11, 2021. doi:10.1093/brain/awab367