Neuroscience research questions traditional markers for cerebellar movement disorders

A new finding by a Virginia Tech neuroscientist at the Fralin Biomedical Research Institute at VTC is challenging the way investigators study chronic neurological disorders such as dystonia, ataxia, and tremor.

All three disorders, which cause involuntary movements such as painful contortions, awkward postures, and shaking, stem from dysfunction in the brain's cerebellum.

Neuroscientists often focus on activity between two cell types as both a cause and a target for treating these diseases. In the cerebellum, Purkinje cells are known to inhibit activity in cells located in the deep cerebellar nuclei. Neuroscientists have assumed that knowing what's happening with Purkinje cells indicates what's going on with the deep nuclei cells.

But a new study by Meike van der Heijden challenges that assumption. The finding, published in the Journal of Physiology, suggests that despite their anatomical connection, the activity of one cell type is a poor biomarker for understanding the other.

We see that there's not a clear linear relationship between activity in the Purkinje cells and in the deep nuclei cells. So there's very limited predictive power in monitoring one to understand what's going on in the other."

Van der Heijden, Assistant Professor, Fralin Biomedical Research Institute at VTC

The finding is important to both understanding and treating cerebellar movement disorders.

"Purkinje and cerebellar deep nuclei cell activity is disrupted in a disease state, and a better understanding of the relationship between these neuron types will ultimately help optimize treatments for diseases such as dystonia, ataxia, and tremor," said Alyssa Lyon, a doctoral candidate in Virginia Tech's Translational Biology, Medicine, and Health Graduate Program and the paper's first author.

Purkinje cells are found in the outer layer of the cerebellum, making their activity easier to measure than deep nuclei cells, which are found at greater depths from the surface within the brain. Neuroscientists have considered the more accessible Purkinje cells a reliable biomarker for activity in the deep nuclei cells.

Typically, the Purkinje cells inhibit the deep nuclei cells. When Purkinje cells are more active, deep nuclei cells should be less active, and the reverse should also be true.

The lab team studied a database of electrophysiology recordings from pre-clinical models for cerebellar diseases and found no significant correlation between activity in the two cell types.

"We suggest that if you want to know how the cerebellum is behaving in a disease state, you have to look at the deep nuclei neurons, not just the Purkinje cells," said Van der Heijden, who also holds an appointment in Virginia Tech's School of Neuroscience.

Likewise, she added, regulating the Purkinje cells as a treatment and expecting a change in the deep nuclei cells is not advised.

"This is a cautionary tale for understanding cerebellar activity in disease, but also for treating these challenging diseases," Van der Heijden said. "We need to be very careful in making assumptions, and to actually do experiments to test our hypotheses."