Brain, Spinal Stimulation Combo May Improve Rare Ataxias

Damian McNamara

August 23, 2018

Noninvasive neurostimulation delivered to the brain and spinal cord significantly reduces symptoms of rare, neurodegenerative ataxias, a new first-in-humans trial shows.

Cerebellar anodal and spinal cathodal transcranial direct-current stimulation (tDCS) produced significant improvements on the Scale for the Assessment and Rating of Ataxia (SARA), the International Cooperative Ataxia Rating Scale (ICARS), the 9-hole peg test (9HPT), the 8-meter walk test, and more.

In contrast, none of these measures significantly improved after the sham intervention.

"We believe that the treatment with concurrent cerebellar and spinal electrical stimulation in patients with ataxia may reduce clinical symptoms, improve quality of life, and restore the physiological inhibition, mediated by the cerebellum, on the motor cortex," principal investigator Alberto Benussi, MD, of the Neurology Unit at the Centre for Aging Brain and Neurodegenerative Disorders at the University of Brescia in Italy, told Medscape Medical News.

"This is of particular relevance in the light of limited pharmacologic and nonpharmacologic treatment options for patients with ataxia," he said.

The study was published online August 22 in Neurology.  

Dual Approach

The new study expands on previous findings by the same investigators showing that cerebellar stimulation improves posture, gait, and kinetic functions.  

In the current study, the investigators added spinal cord stimulation, an area often compromised in neurodegenerative ataxias.

"It is now well known that cerebellar ataxias frequently present with a significant involvement of the spinal cord, as in the spino-cerebellar ataxias," Benussi said.

"Very recent studies have shown that the stimulation of the spinal cord is feasible, while studies from our group have shown that cerebellar stimulation is effective in these types of patients. It seemed logical to try and stimulate both the cerebellum and spinal cord and obtain a synergic effect by stimulating both structures," he added.

Investigators assessed 20 participants recruited from December 2016 to April 2017. Participants were randomly assigned to active or sham tDCS 5 days a week for 2 weeks.

Response was assessed at 14 days, 1 month, and 3 months. Following a 3-month washout phase, patients switched group assignment. Researchers again assessed treatment response at the three time points.

The cohort included multiple ataxia types: seven patients with spinocerebellar ataxia (SCA) type 2; six with the cerebellar variant of multiple system atrophy (MSA-C); four with sporadic adult-onset ataxia; and one each with SCA 38, SCA 14, Friedreich ataxia, and ataxia with oculomotor apraxia type 2.

Investigators examined the main effects of treatment and time for the active intervention and sham cohorts vs baseline, and compared to each other.

The main treatment effect associated with active stimulation was significant for improvements in SARA scores at all follow-up time points (P < .001) but not at baseline (P = .042). Similarly, the main effect associated with time significantly favored tDCS (P < .001) over sham tDCS (all P > .05).

Statistically Significant Gains

For overall ICARS scores, the main effect of treatment was significantly greater for active tDCS than for sham tDCS (all P < .001) but not at baseline (P = .613).

The main effect of time also revealed a significant difference in the tDCS group compared with baseline (P < .001) but not in the sham group (P > .050).

In terms of ICARS subscores, researchers reported statistically significant time and treatment interactions for posture and gait (P = .011) and kinetic limb coordination (P < .001).

In contrast, the interactions were not significant for dysarthria (P = .235) or oculomotor movement (P = 1.00). Again, these observations favored active over sham tDCS.

Performance on the 9HPT, where participants pick up pegs one at a time, insert them into a board and then remove them one by one as quickly as possible, was significantly faster following active stimulation.

The average time dropped from 53 seconds at baseline to 47 seconds after active stimulation. The main effect of treatment was better at all time points (P < .010) vs sham in both dominant and nondominant hands but not at baseline (P = .670 and P = .926, respectively).

The 9PHT main effect of time also revealed significant gains associated with active treatment (P < .050) compared with baseline. However, the same did not hold true after sham tDCS (P > .050).

Results for the 8-meter walk test improved from an average 9.4 seconds to 7.8 second after stimulation. This test also showed a significant interaction between time and treatment.

The main effect of treatment showed a significant gain in the active tDCS group at all time points compared with baseline (P < .05), but not in the sham group (P > .50).   

Early Treatment Optimal?

To assess cerebellar brain inhibition, the investigators also compared 18 of the participants with ataxia to 10 age-matched healthy controls by using transcranial magnetic stimulation (TMS). They excluded 2 of the 20 participants who could not maintain constant muscle relaxation.

The TMS findings demonstrated sustained restoration of cerebellar brain inhibition associated with real tDCS.

Again, they found a significant interaction between time and treatment for TMS resting motor threshold findings favoring active stimulation. The main effect of treatment was significantly greater at all follow-up assessments following real tDCS (P < .001) vs sham, but not at baseline. The main effect of time also was significantly greater for active tDCS compared with baseline (P < .050), but not for the sham group (P > .050).

The investigators also reported significant associations between restoration of cerebellar brain inhibition and the percentage improvement in SARA (P = .009) and ICARS (P = .036) scores.

Interestingly, the patients with less severe ataxia appeared to gain the most benefit from the active tDCS combination.

"If we consider that repeated sessions of electrical stimulation have shown to induce and enhance neuronal plasticity with long-term after-effects, it is reasonable to believe that patients who were least affected, and thus with an increased 'plasticity potential,' might be the ones to benefit the most after this treatment," Benussi said.

The finding suggests that stimulation might be most effective when administered at early stages of disease. "This is a very important aspect to bear in mind, considering that most of these diseases are rare disorders and the final diagnosis is reached only many years after the onset of symptoms." 

"Another important aspect to evaluate is if we can generalize these findings to other types of ataxias," Benussi said. Large trials are needed to answer this question.

"Another frequently neglected aspect in ataxias is the role of the cerebellum in cognitive domains, such as executive functions, spatial cognition and language, with patients frequently manifesting the so-called 'cerebellar cognitive affective syndrome,'" Benussi said.

To address this, the investigators intend to characterize and evaluate cerebellar stimulation on cognitive domains in patients with ataxias.

Clinically Meaningful?

Commenting on the findings for Medscape Medical News, Elizabeth A. Coon, MD, associate professor of neurology at the Mayo Clinic in Rochester, Minnesota, said it was "encouraging to see positive results in the degenerative ataxia patient population."

"Overall, the numbers are small and the heterogeneous causes of ataxia causes one to question the mechanism of benefit. The improvement in subjective and objective rating scales is good to see but many of those effects waned 2.5 months from the end of stimulation," she said.

The practicality of treating patients with tDCS is still uncertain, Coon added. The therapy is limited to a few centers and, although each session is typically short, treatment in this study was delivered 5 days a week for 2 weeks.

"It would be useful to see this replicated by other groups in larger numbers and perhaps compared to a control group that undergoes comprehensive rehabilitation exercises," Coon said.

Having biomarkers of disease progression would be very useful to determine whether this approach slows disease or is solely a symptomatic treatment, she added.

Also commenting on the study for Medscape Medical News, Paola Sandroni, MD, PhD, professor of neurology at Mayo Clinic and a fellow of the American Academy of Neurology, said that because of the heterogeneity of degenerative ataxias, it's difficult to know exactly what the stimulation does. She added that the inclusion of two stimulation sites makes it even more difficult to determine how it works.

"Nonetheless, I applaud the effort and creativity and trying to be as strict as possible from a methodological standpoint."

Sandroni added that somatosensory evoked potentials data could have helped. She also questioned whether the statistically significant findings would be clinically meaningful and durable.

"On the other hand, having a noninvasive option for a population with no good options is a plus."

Questions Remain

In an accompanying editorial, Shinsuke Fujioka, MD, and Yoshio Tsuboi, MD, from the Department of Neurology at Fukuoka University in Japan, and Joseph H. Friedman, MD, from the Department of Neurology at the Warren Alpert Medical School of Brown University in Providence, Rhode Island, note that "although it was a bit surprising that there is no placebo effect, cerebello-spinal tDCS is apparently effective in ameliorating motor signs of ataxic disorders."

A remaining question is whether the combination of cerebellar and spinal stimulation is superior to cerebellar stimulation alone, they note, suggesting future research should include a cerebellar stimulation–only group.

"Further studies are warranted to confirm the long-term safety and effectiveness of this treatment in a prospective manner for specific ataxic disorders, and further improvements in stimulators are needed to make this practical in everyday clinical practice," they write.

The Italian Alzheimer's Disease Foundation supported the study. Benussi, Coon, and Sandroni have disclosed no relevant financial relationships. Fujioka serves on the editorial board of Parkinsonism and Related Disorders and the Polish Journal of Neurology and Neurosurgery and disclosed research support in the form of JSPS KAKENHI grant 15K19501. Tsuboi receives research support from JSPS KAKENHI grant KA290001. Friedman serves on the editorial board of the Rhode Island Medical Journal; receives publishing royalties from Springer Press and Cambridge University Press; has been a consultant for Acadia Pharmaceuticals, Gerson Lerhman, and Coleman Research Group; and has received research support from the National Institutes of Health and the Michael J. Fox Foundation.

Neurology. Published online August 22, 2018. Abstract, Editorial

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