Abnormal development of cerebellar-striatal circuitry in Huntington disease

Abstract

Objective: To test the hypothesis that the trajectory of functional connections over time of the striatum and the cerebellum differs between presymptomatic patients with the Huntington disease (HD) gene expansion (GE) and patients with a family history of HD but without the GE (GNE), we evaluated functional MRI data from the Kids-HD study.

Methods: We utilized resting-state, functional MRI data from participants in the Kids-HD study between 6 and 18 years old. Participants were divided into GE (CAG 36-59) and GNE (CAG <36) groups. Seed-to-seed correlations were calculated among 4 regions that provide input signals to the anterior cerebellum: (1) dorsocaudal putamen, (2) globus pallidus externa, (3) subthalamic nucleus, and (4) pontine nuclei; and 2 regions that represented output from the cerebellum: the dentate nucleus to the (1) ventrolateral thalamus and (2) dorsocaudal putamen. Linear mixed effects regression models evaluated differences in developmental trajectories of these connections over time between groups.

Results: Four of the six striatal-cerebellum correlations showed significantly different trajectories between groups. All showed a pattern where in the early age ranges (6-12 years) there was hyperconnectivity in the GE compared to the GNE, with those trajectories showing linear decline in the latter half of the age range.

Conclusion: These results parallel previous findings showing striatal hypertrophy in children with GE as early as age 6. These findings support the notion of developmentally higher connectivity between the striatum and cerebellum early in the life of the child with HD GE, possibly setting the stage for cerebellar compensatory mechanisms.

Figure 1. Cerebellar integration with indirect pathway

The portion of the figure in the green box represents the direct pathway (promotes movement) and the section in the blue box represents the indirect pathway (inhibits movement). In Huntington disease, it is the indirect pathway that degenerates first, leading to lack of inhibition and involuntary movements (chorea). The cerebellum is integrated into striatal circuity through the indirect pathway. Thus the cerebellum could compensate for a faulty indirect pathway, restoring balance and preventing the development of involuntary movements. Red arrows indicate where the cerebellum is integrated into the indirect pathway. GPe = globus pallidus externa; GPi = globus pallidus interna; STN = subthalamic nucleus. Figure adapted from references 13 and 14.

Figure 2. Striatal input to cerebellum

(A–C) Predicted values from a linear mixed effects regression model of the functional connectivity (R2) between the striatal–cerebellar regions of interest (dependent variables) over time between groups (age × group interaction term). The model controlled for age, sex, and scanner, and included a sex × group interaction term and a random effect term per the participant's slope of age, and a random effect term per family to account for participants who were siblings. aCB = anterior lobe of the cerebellum; dPU = dorsocaudal putamen; GE = gene-expanded; GNE = gene nonexpanded; GPE = globus pallidus externus; PN = pontine nucleus; STN = subthalamic nucleus.

Figure 3. Cerebellar output to striatum

This figure represents the predicted values from a linear mixed effects regression model of the functional connectivity (R²) between the dentate nucleus and ventrolateral nucleus of the thalamus (dependent variable) over time between groups (age × group interaction term). The model controlled for age, sex, and scanner, and included a sex × group interaction term and a random effect term per participant's slope of age, and a random effect term per family to account for participants who were siblings. GE = gene expanded; GNE = gene nonexpanded.

Figure 4. CAG effect over time in functional correlations between anterior lobe of the cerebellum and subthalamic nucleus

CAG = cytosine-adenine-guanine.