Cerebello-Spinal tDCS as Rehabilitative Intervention in Neurodegenerative Ataxias: a Randomized, Double-blind, Sham-controlled Trial Followed by an Open-label Phase
Phase: NA
Conditions: Ataxia, Spinocerebellar Ataxias, Spinocerebellar Ataxia Type 1, Spinocerebellar Ataxia Type 2, Spinocerebellar Ataxia 3, Multiple System Atrophy, Ataxia With Oculomotor Apraxia, CANVAS
Sponsor: Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia

 
 
CLINICA NEUROLOGICA - UNIVERSITA’ DEGLI STUDI DI BRESCIA 
UO Neurologia 2 - AZIENDA SOCIO SANITARIA TERRITORIALE degli SPEDALI CIVILI DI BRESCIA 
Direttore: Prof. Alessandro Padovani 
 
 
Title of the study: “Cerebello-Spinal tDCS as Rehabilitative Intervention in 
Neurodegenerative Ataxia” 
NCT number: NCT04153110 
Date: September 4th, 2018  
 
 
 

 
 
CLINICA NEUROLOGICA - UNIVERSITA’ DEGLI STUDI DI BRESCIA 
UO Neurologia 2 - AZIENDA SOCIO SANITARIA TERRITORIALE degli SPEDALI CIVILI DI BRESCIA 
Direttore: Prof. Alessandro Padovani 
 
 
EXPERIMENTAL CLINICAL PROTOCOL 
 
TITLE OF THE STUDY: “Cerebello-Spinal tDCS as Rehabilitative Intervention 
in Neurodegenerative Ataxia” 
 
ACRONYM: SCA02 
 
VERSION AND DATE: Version 2 of September 4, 2018 
 
DIVISION WHERE THE RESEARCH IS PERFORMED: Clinica Neurologica, 
Università di Brescia, Spedali Civili di Brescia  
 
MAIN EXPERIMENTATOR: Prof. Barbara Borroni 
 
INTRODUCTION AND RATIONAL: Transcranial stimulation with direct currents 
or transcranial direct current stimulation, tDCS is a neurophysiological method of non-
invasive modulation of the central nervous system excitability, which is having an 
increasing diffusion and an increasingly numerous spectrum of potentials 
therapeutic applications such as, for example, post-stroke rehabilitation, depression 
and pain, already consolidated. This method, being non-invasive, low-cost and simple 
to carry out, has the potential to be widely used both as a research tool and as a support 
tool for rehabilitation treatment, as in the case of Spinocerebellar Ataxias, a group of 
neurodegenerative pathologies based on genetics, characterized by slowly progressive 
ataxia of walking, posture and limbs, associated with dysarthria and / or alteration of 
oculomotion, for which no treatments are currently available. This method also finds 
application in Cerebellar Ataxias of neurodegenerative origin, such as in Multisystem 
Atrophy (MSA), in Friedreich Ataxia and in other Central Nervous System pathologies 
with selective involvement of cerebellar structures. Indeed, a positive effect of tDCS 
has been demonstrated in modulating cerebellar excitability in humans (Galea 2009) 
with a favorable effect of cerebellar anodic stimulation by tDCS on motor learning and 
walking (Jayaram 2012). Based on these premises, the treatment of patients with 
Cerebellar Ataxias of neurodegenerative origin is proposed (for example SCA, MSA, 
Friedreich's Ataxia). 
Transcranial magnetic stimulation (TMS) techniques have been widely used in the 
study of neurodegenerative diseases, particularly in Parkinson's disease and dementia 
due to Alzheimer's disease. Over the years, numerous transcranial magnetic stimulation 
protocols have been developed to obtain information on neurophysiological parameters 

 
 
CLINICA NEUROLOGICA - UNIVERSITA’ DEGLI STUDI DI BRESCIA 
UO Neurologia 2 - AZIENDA SOCIO SANITARIA TERRITORIALE degli SPEDALI CIVILI DI BRESCIA 
Direttore: Prof. Alessandro Padovani 
 
with the aim of investigating both the pathogenesis and the evolution of some 
neurodegenerative pathologies. 
The study of the cerebellar-brain inhibition (CBI) allows us to investigate the 
physiological inhibitory activity of the cerebellar cortex on motor circuits. This 
stimulation protocol is evaluated through the simultaneous magnetic stimulation of the 
cerebellar cortex and of the motor cortex with two separate coils (Carrillo 2014; Koch 
2014). Some studies have in fact highlighted an alteration of cerebello-motor 
connectivity, assessed by CBI protocol, in patients suffering from cerebellar ataxias of 
degenerative origin (Ugawa 1994; Ugawa 1997; Conde 2013; Bonnì 2014). 
 
OBJECTIVES: The aim of the study is to evaluate the long-term effects on cognitive 
performance, quality of life and motor performance, in particular coordination and 
balance, of tDCS applied at the level of the cerebellar cortex and at the spinal level in 
patients suffering from cerebellar ataxias of degenerative origin to identify a possible 
rehabilitation protocol. The effect of tDCS on cerebello-motor connectivity will also 
be evaluated by CBI TMS protocol. 
 
PROCEDURES: Patients already enrolled at the Neurological Clinic recognized as 
suffering from cerebellar ataxia of degenerative origin according to the current clinical 
criteria will be enrolled, with a disorder of motor coordination, walking or a mild to 
moderate balance, which are due to regular clinical controls. Patients will be divided 
into two groups. The first group will undergo stimulation protocol by means of tDCS, 
while the second group will be subjected to placebo (sham) treatment. Each session 
will consist of the application of ten sessions of tDCS at 2mA, at the level of the 
cerebellar cortex and at the spinal level (2 cm caudally at T11) for the duration of 20 
min each. The effects will be evaluated before stimulation with tDCS, two weeks after 
treatment and three months. In particular, the effects on cognitive performance, quality 
of life and performance of motor coordination and balance will be evaluated by using 
dedicated scales. Finally, the effects on neurophysiological parameters of CBI will be 
evaluated by TMS. 
 
INCLUSION / EXCLUSION CRITERIA: Patients with spino-cerebellar ataxia, 
Friedreich's ataxia, multisystem atrophy, sporadic ataxia in adult onset will be 
included. Patients affected by: i) cerebrovascular diseases, hydrocephalus, expansive 
intracranial processes ii) significant medical problems (eg diabetes and arterial 
hypertension poorly controlled; cancer in the past 5 years) will be excluded iii) major 
depressive disorders, bipolar disorders, schizophrenia, abuse of substances, mental 
retardation according to DSM-IV criteria) implanted metal objects or history of 
epilepsy. Patients should not suspend any ongoing therapy. 

 
 
CLINICA NEUROLOGICA - UNIVERSITA’ DEGLI STUDI DI BRESCIA 
UO Neurologia 2 - AZIENDA SOCIO SANITARIA TERRITORIALE degli SPEDALI CIVILI DI BRESCIA 
Direttore: Prof. Alessandro Padovani 
 
 
STUDY DESIGN: this is a randomized, double-blind, non-pharmacologic, placebo-
controlled clinical trial, since neither patients nor those who will administer the 
evaluation tests will be aware of the type of treatment carried out, real-tDCS or sham 
(anodic tDCS: placebo tDCS = 1: 1) with cerebellar tDCS 5 days a week for 2 
consecutive weeks in 40 patients with neurodegenerative ataxia. 
A randomized stratification by type of pathology will be implemented, so as to balance 
the patients with the same pathology between the two groups (real and sham). 
Subsequently, a randomization in blocks will be implemented, in order to balance the 
quantitative asymmetry of the patients assigned to the two groups, guaranteeing a 
similar number of patients enrolled in the two groups, even if the trial should be 
interrupted early. 
Patients with spinocerebellar ataxia, Friedreich's ataxia, multisystem atrophy, sporadic 
ataxia in adult onset will be included. Each patient will undergo a clinical evaluation 
(cognitive performance, quality of life and performance of motor coordination and 
balance), evaluation of CBI connectivity by transcranial magnetic stimulation at 
baseline (T0), after 2 weeks of treatment with tDCS (T1) and follow -up to 3 months 
(T2). 
An open phase will follow and all patients will receive an anodic tDCS stimulation at 
the cerebellar and cathodic levels at the spinal level (5 days / week for 2 weeks) and 
will receive the same standardized evaluation after the 2-week treatment (T3), at the 
follow- up to 3 months (T4) and 6-month follow-up (T5). 
 
END POINTS: 
Primary Outcome Measures: 
1. Change in the International Cooperative Ataxia Rating Scale (ICARS) Score 
(Baseline – 2 Weeks). 
2. Change in the Scale for the Assessment and Rating of Ataxia (SARA) Score 
(Baseline – 2 Weeks). 
3. Change in the Cerebellar cognitive affective syndrome (CCAS) Scale (Baseline – 2 
Weeks). 
 
Secondary Outcome Measures: 
4. Change in the International Cooperative Ataxia Rating Scale (ICARS) Score 
(Baseline - 2 weeks - 3 month - 6 months - 9 months). 
5. Change in the Scale for the Assessment and Rating of Ataxia (SARA) Score 
(Baseline - 2 weeks - 3 month - 6 months - 9 months). 
6. Change in the Cerebellar cognitive affective syndrome (CCAS) Scale (Baseline - 2 
weeks - 3 month - 6 months - 9 months). 

 
 
CLINICA NEUROLOGICA - UNIVERSITA’ DEGLI STUDI DI BRESCIA 
UO Neurologia 2 - AZIENDA SOCIO SANITARIA TERRITORIALE degli SPEDALI CIVILI DI BRESCIA 
Direttore: Prof. Alessandro Padovani 
 
7. Change in Cerebellar Brain Inhibition (CBI) Measurements (Baseline - 2 weeks - 3 
month - 6 months - 9 months). 
8. Change in the Short-Form Health Survey 36 (SF36) Score (Baseline - 2 weeks - 3 
month - 6 months - 9 months). 
 
STATISTICAL PLAN: we will use parametric analyzes (t tests) to compare the 
demographic variables (age and education) of the two groups at the baseline. A P <0.05 
will be considered significant. To evaluate the effect of the stimulation protocol by 
means of tDCS on cognitive performances, of motor coordination and balance and 
quality of life, at T 2-3-4-5 we will use a mixed-model ANOVA. 
We performed a "power analysis" to estimate the sample size, based on some 
previously published studies (Benussi A, Brain Stimul, 2017) using methods similar to 
those applied in the study in question. The "effect size" f (V) was calculated by direct 
method. Taking into account the aforementioned studies an effect size equal to a partial 
η2 of 0.037, equal to an "effect size" f (V) of 0.195 and, considering alpha = 0.05 and 
the power (1-β) = 0.80, the expected sample size is 54 subjects using a repeated 
measures ANOVA study. The proposed sample size of 60 subjects should be adequate 
to achieve the main objective of the study. 
 
ETHICAL CONSIDERATIONS (RISK-BENEFIT): tDCS is a non-invasive, low-
cost and easy-to-implement method which is having an increasing diffusion and an 
increasingly numerous spectrum of potential therapeutic applications such as, for 
example, post-stroke rehabilitation, depression and pain, already consolidated. 
Recently its efficacy in modulating cerebellar excitability in humans (Galea 2009) has 
been demonstrated with favorable effect of cerebellar anodic stimulation by tDCS on 
motor learning and walking (Jayaram 2012). 
We therefore hypothesize that tDCS may have a positive effect on the performance of 
motor coordination and balance in patients with Spinocerebellar Atrophy, a group of 
neurodegenerative pathologies characterized by slowly progressive ataxia of walking, 
posture and limbs, associated with dysarthria and / or alteration of oculomotor , for 
which currently no treatments are available. 
Literature data show that the application of the method according to the current safety 
guidelines (Iyer, 2005; Nitsche, 2003; Wassermann 2005) has little relevant side 
effects, including mild tingling sensation during or after stimulation , moderate fatigue, 
slight sensation of itching at the electrode application points, slight burning or pain, 
headache, nervousness, nausea, appearance of vesicles at the electrode application 
points in more rare cases. 

 
 
CLINICA NEUROLOGICA - UNIVERSITA’ DEGLI STUDI DI BRESCIA 
UO Neurologia 2 - AZIENDA SOCIO SANITARIA TERRITORIALE degli SPEDALI CIVILI DI BRESCIA 
Direttore: Prof. Alessandro Padovani 
 
Regarding the TMS method, it is a non-invasive brain stimulation that allows the study 
of 
neurophysiological 
parameters 
that 
can 
provide 
information 
on 
the 
pathophysiological mechanisms involved in neurodegenerative diseases. 
Literature data show that the application of the method according to the current safety 
guidelines has little relevant side effects: a certain number of subjects participating in 
TMS experiments (up to 20%) suffer headaches or back pain, due to probably due to 
excessive muscle tension and a rigid position of the head and / or neck during the 
application of the TMS. These effects are temporary and in most cases do not require 
any treatment. 
Since the TMS produces a magnetic field, people with fixed electrical stimulators (for 
example, cardiac stimulators, nerve stimulators, auditory implants) that would not 
work or would be damaged by the magnetic field cannot participate in the study. 
Examination is also excluded for people with particular metallic foreign bodies (such 
as splinters, some prostheses, screws and nails) that could move if placed inside the 
magnetic field. Since the effects of TMS on the developing fetus are not known, 
pregnant women cannot participate in the study. 
 
DETECTION OF ADVERSE EVENTS: The Principal Investigator will promptly 
communicate to the Provincial Ethics Committee of the Province of Brescia any 
adverse event induced by the method. 
 
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CLINICA NEUROLOGICA - UNIVERSITA’ DEGLI STUDI DI BRESCIA 
UO Neurologia 2 - AZIENDA SOCIO SANITARIA TERRITORIALE degli SPEDALI CIVILI DI BRESCIA 
Direttore: Prof. Alessandro Padovani 
 
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