Distinct Brain Drivers and Shared Cerebello-Cortical Input in ADCY5 and SGCE Hyperkinetic Movements

Area of Science:

• Neuroscience
• Movement Disorders
• Brain Imaging

Background:

• Hyperkinetic movement disorders involve cortico-basal ganglia-cerebellar loop dysfunction, often presenting with psychiatric and cognitive symptoms.
• ADCY5 (MxMD-ADCY5) and SGCE (MYC/DYT-SGCE) disorders are childhood-onset conditions characterized by myoclonus, dystonia, and psychiatric issues.
• Evidence suggests basal ganglia involvement in MxMD-ADCY5 and cerebellar involvement in MYC/DYT-SGCE.

Purpose of the Study:

• To investigate how basal ganglia and cerebellar dysfunction contribute to cortical dysregulation in hyperkinetic movement disorders.
• To differentiate the neural circuit mechanisms underlying ADCY5 and SGCE related disorders.

Main Methods:

• Resting-state functional MRI (fMRI) was employed to analyze effective connectivity within motor and non-motor cortico-basal ganglia-cerebellar loops.
• Diffusion-weighted imaging assessed microstructural properties using neurite orientation dispersion and density measures.
• Findings were validated using leave-one-out cross-validation.

Main Results:

• Both patient groups showed high rates of psychiatric comorbidities.
• In MxMD-ADCY5, basal ganglia dysfunction impacted the cerebellum, which then modulated cortical activity; reduced neurite density was found in the subthalamic nucleus.
• In MYC/DYT-SGCE, the cerebellum primarily influenced cortical activity, with downstream effects on basal ganglia, and no microstructural alterations were detected.

Conclusions:

• Both disorders exhibit abnormal cortical modulation converging on a cerebellar-cortical pathway.
• In MxMD-ADCY5, basal ganglia influence on the cortex is mediated through the cerebellum.
• In MYC/DYT-SGCE, the cerebellum directly influences cortical activity.