Gray matter volume in cerebellum predicts therapy efficacy
Higher volume tied to greater motor, cognitive gains after neuromodulation
The volume of gray matter in the brain region known as the cerebellum helps predict motor and cognitive benefits for Friedreich’s ataxia patients after noninvasive neuromodulation, a therapy that delivers mild electric currents to brain regions, a study found.
Gray matter contains a high concentration of nerve cell bodies and their extensions that receive or send information. The cerebellum is essential for motor coordination and is also involved in cognition.
Study participants with higher volumes of gray matter showed greater improvements in motor and cognitive performances induced by a neuromodulation technique called transcranial direct current stimulation (ctDCS), suggesting “that individualizing ctDCS parameters based on cerebellar structure could enhance therapeutic outcomes,” the researchers wrote.
The study, “Cerebellar grey matter volume predicts cerebellar tDCS efficacy in individuals with Friedreich ataxia,” was published in Clinical Neurophysiology.
FA is caused by mutations in the FXN gene, which impair the production of frataxin, a protein required for the proper function of mitochondria, cellular structures responsible for producing energy. This leads to mitochondrial dysfunction and impairments in cell energy production, resulting in progressive neurodegeneration and loss of muscle strength and coordination.
New approaches
Skyclarys (omaveloxolone), the only approved treatment for FA, is intended to promote mitochondrial function and antioxidant responses and to prevent inflammation. But despite improvement and symptom stabilization, the disease eventually progresses, the scientists said. While approaches to restore frataxin levels are being pursued, they remain in early development stages.
“There is therefore a need to explore alternative interventions that, even if unable to restore frataxin, could modulate its physiological consequences and yield faster clinical benefits,” the investigators wrote.
Previous studies have shown that neuromodulation with ctDCS may ease motor and cognitive issues in people with FA, but substantial variability has been noted among patients.
The researchers, in Belgium, assessed whether atrophy, or shrinkage, of the cerebellum could be associated with response to ctDCS.
They analyzed 24 people with FA, with a median age of 32 and a mean disease duration of 15 years, and compared them with 24 age- and sex-matched healthy controls. The FA patients had significantly lower volumes of cerebellar gray matter than the controls (87 cubic centimeters vs. 97 cubic centimeters), as determined by MRI scans. The cerebellum’s distance to the skin was similar in both groups.
Patients received a five-day ctDCS intervention, administered daily for 20 minutes, at a current of 3.3 milliamps (mA), and a density of 0.057 mA per square centimeter.
Neuromodulation led to a significant improvement in motor function, demonstrated by a reduction in the Scale for the Assessment and Rating of Ataxia (SARA) mean score from 23.1 points before treatment to 21.6 points after treatment. This score assesses motor function parameters including gait, sitting, stance, and upper limb coordination, with higher values indicating more severe symptoms.
Further analysis indicated that a lower gray matter volume in the anterior (front) part of the cerebellum was associated with the variation in SARA scores. A lower cerebellar volume correlated with lower clinical improvement.
A similar effect was seen in the cerebellar cognitive affective syndrome (CCAS) scale of cognition. In this case, a higher volume of the posterior (back) cerebellum was associated with higher CCAS scores.
These effects may be associated with the loss of Purkinje cells, nerve cells in the cerebellum that are the target cells for ctDCS, according to the researchers. “Such findings underscore the importance of both [nerve cell] density and connectivity in mediating the therapeutic effects of ctDCS,” they wrote.
Other parameters, including cerebellum-skin distance and the diameter of the superior cerebellar peduncle, one of the nerve fiber bundles that connect the cerebellum to the brainstem, were not associated with treatment response.
“Tailoring ctDCS protocols to account for cerebellar atrophy could improve treatment response and reduce variability in degenerative ataxia interventions,” the researchers wrote. “Future research should further explore parameter adjustments to maximize ctDCS benefits.”
