Interventional Cross-over Study to Evaluate the Efficacy on Cognitive Performance of Alternating Current Brain Stimulation (tACS) in Patients Suffering From Neurodegenerative Diseases
Phase: NA
Conditions: Alzheimer Disease
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: “Interventional cross-over study to evaluate the efficacy on 
cognitive performance of alternating current brain stimulation (tACS) in patients 
suffering from neurodegenerative diseases” 
NCT number: Not yet assigned  
Date: December 17th, 2019  
 
 
 

 
 
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: “Interventional cross-over study to evaluate the 
efficacy on cognitive performance of alternating current brain stimulation (tACS) 
in patients suffering from neurodegenerative diseases” 
 
ACRONYM: GammAD 
 
VERSION AND DATE: Version 1.1 of December 17th, 2019 
 
DIVISION WHERE THE RESEARCH IS PERFORMED: Clinica Neurologica, 
Università di Brescia, Spedali Civili di Brescia  
 
MAIN EXPERIMENTATOR: Prof. Barbara Borroni 
 
INTRODUCTION AND RATIONAL: Brain oscillations are ubiquitous in the 
human brain and have been implicated in cognitive and behavioral states defined in 
precisely tuned neural networks. In neurodegenerative disorders, neurodegeneration is 
accompanied by changes in oscillatory activity leading to the emerging concept of 
neurological and psychiatric disorders as "oscillopathies". Alzheimer's disease, which 
accounts for the vast majority of age-related dementias, is characterised by a prominent 
disruption of oscillations in the gamma frequency band. The restoration of gamma 
oscillations by neural entrainment in animal models of Alzheimer's disease have shown 
a remarkable decrease in the pathological burden of amyloid and tau via increased 
microglial activity, resulting in a significant increase of cognitive performances. 
Transcranial alternating current brain stimulation (tACS), is a neurophysiological 
method of non-invasive modulation of the excitability of the central nervous system 
that is having an increasingly numerous spectrum of potential therapeutic applications. 
Recent studies have demonstrated the effectiveness of this method in modulating the 
natural frequencies of cerebral oscillation, underlying multiple cognitive processes 
such as verbal memory, perception and working memory. 
On the basis of these premises, the treatment with gamma tACS is proposed in patients 
affected by Alzheimer's disease. 
In this randomized, double-blind, sham-controlled, cross-over study, the investigators 
will evaluate whether a single stimulation with gamma tACS on the posterior parietal 
cortex can improve symptoms in patients with Mild Cognitive Impairment due to 
Alzheimer's disease. 

 
 
CLINICA NEUROLOGICA - UNIVERSITA’ DEGLI STUDI DI BRESCIA 
UO Neurologia 2 - AZIENDA SOCIO SANITARIA TERRITORIALE degli SPEDALI CIVILI DI BRESCIA 
Direttore: Prof. Alessandro Padovani 
 
Subjects will be randomized in two groups, one receiving a single treatment with 
gamma tACS (40 Hz) first and the other receiving sham stimulation. After one week 
the treatments will be exchanged. Patients will be evaluated with neuropsychological 
tests and neurophysiological measures of cholinergic transmission. 
 
OBJECTIVES: The aim of the study is to evaluate the effects on cognitive 
performance of tACS in patients suffering from Alzheimer's disease (AD) to identify 
a possible rehabilitation protocol. The effect of tACS on intracortical connectivity will 
also be evaluated using the and SAI TMS protocols. 
 
PROCEDURES: Patients followed at the Neurological Clinic with a diagnosis of 
Alzheimer’s disease will be enrolled according to current clinical criteria. Patients will 
be randomized into two groups: 
 
The first group will undergo a stimulation protocol by means of tACS (real), 
the second group will undergo a placebo treatment (sham). 
 
Treatment group: 
Each session will consist in the application of a tACS session (real at 3 mA) at the 
cortical level for the duration of 60 minutes each, during which patients will be 
subjected to an experimental cognitive task (Face Naming Task). The pre- and post-
stimulation effects with tACS will be evaluated; in particular, the effects on cognitive 
performance will be assessed through the use of dedicated tests (Rey Auditory Verbal 
Learning Test - RAVLT) and the effects on the neurophysiological parameters of SAI 
using TMS. 
 
Placebo group: 
In the placebo group, the assembly will be kept the same as that of the real stimulation, 
however the electric current will be automatically interrupted about 5 seconds after the 
start of the stimulation, so as to make the placebo stimulation indistinguishable from 
the real one. The same tests and assessments used during real stimulation will be used. 
 
After 1 week (after a single session of real stimulation or placebo stimulation) the two 
groups will be inverted (cross over). 
 
INCLUSION CRITERIA:  
- Mild Cognitive Impairment due to Alzheimer's disease (according to Albert et 
al., Alzheimers Dement 2011). 
 

 
 
CLINICA NEUROLOGICA - UNIVERSITA’ DEGLI STUDI DI BRESCIA 
UO Neurologia 2 - AZIENDA SOCIO SANITARIA TERRITORIALE degli SPEDALI CIVILI DI BRESCIA 
Direttore: Prof. Alessandro Padovani 
 
EXCLUSION CRITERIA:  
- Cerebrovascular disorders, previous stroke, hydrocephalus, and intra-cranial 
mass documented by MRI. 
- History of traumatic brain injury or other neurological diseases. 
- Serious medical illness other than FTD 
- History of seizures 
- Pregnancy 
- Metal implants in the head (except dental fillings) 
- Electronic implants (i.e. pace-maker, implanted medical pump) 
- Age <18 years 
 
STUDY DESIGN: this is a placebo-controlled, randomized, double-blind, non-
pharmacological interventional clinical trial, as neither the patients nor the person who 
will administer the evaluation tests will be aware of the type of treatment performed, 
real-tACS or placebo (tACS: placebo tACS = 1 : 1). This is a crossover study, in fact 
the patients who will carry out the first real stimulation session will carry out a second 
session with placebo stimulation after 1 week and vice versa. An experimental task 
(Face Naming Task) will be performed in both sessions. 
In consideration of the transient effects of tACS, with a duration of cognitive effects of 
a few hours after the interruption of stimulation, the study does not provide a long-term 
follow-up. 
Patients diagnosed with Alzheimer's Disease will be included. Each patient will 
undergo a cognitive assessment with the administration of a dedicated test (Rey 
Auditory Verbal Learning Test - RAVLT) and analysis of neurophysiological 
parameters of SAI by TMS before treatment and immediately after. All measures will 
be repeated after a week by reversing the stimulation from real to placebo and vice 
versa. In both sessions, a task, the Face Naming Task, will be carried out during the 
stimulation with tACS, both real and placebo. 
 
END POINTS: The effect of tACS alternating current brain stimulation on the Face 
Naming Task and RAVLT will be primary outcome measures. The effect of tCAS on 
SAI measures will be considered as secondary outcome measure. 
 
STATISTICAL PLAN: we will use parametric analyzes (t test) to compare the 
demographic variables (age and education) of the two groups at baseline. A p <0.05 
will be considered significant. To evaluate the effect of the stimulation protocol using 
tACS on cognitive performance we will use an ANOVA model. 
Power analysis: considering that similar studies have not been published, we used data 
from slightly different studies (both by population and by method of stimulation), 

 
 
CLINICA NEUROLOGICA - UNIVERSITA’ DEGLI STUDI DI BRESCIA 
UO Neurologia 2 - AZIENDA SOCIO SANITARIA TERRITORIALE degli SPEDALI CIVILI DI BRESCIA 
Direttore: Prof. Alessandro Padovani 
 
always remaining within the established safety limits (Antal 2017). The "effect size" f 
(V) was calculated using the direct method. Taking into consideration from the 
aforementioned studies an effect size equal to a partial η2 of 0.205, equal to an "effect 
size" f (V) of 0.5078 and, considering alpha = 0.05 and the power (1-β) = 0.80, the 
expected sample size is 18 subjects using a repeated measures ANOVA study with two 
within-subjects factors: both treatment (real vs placebo - crossover study) and time (T0 
and T1). The proposed sample size of 20 subjects should be adequate to achieve the 
main objective of the study. 
 
ETHICAL CONSIDERATIONS (RISK-BENEFIT): tACS is a non-invasive, low-
cost and simple to perform method that is having a growing diffusion and an ever-
increasing spectrum of potential therapeutic applications. 
We hypothesize that tACS can have a positive effect on naming performances in 
patients suffering from neurodegenerative diseases, such as Alzheimer's disease and 
frontotemporal dementia, and that tACS can have a positive effect on the normalization 
of neurophysiological parameters that have been altered in subjects affected by these 
diseases. neurodegenerative, for which there is still no treatment. 
Literature data show that the application of the method according to the current safety 
guidelines (Iyer, 2005; Nitsche, 2003; Wassermann 2005; Antal 2017) has little 
relevant side effects, including mild tingling sensation during or after stimulation, 
moderate fatigue, mild itching sensation at the electrode application points, mild 
burning or pain, headache, nervousness, nausea, blistering at the electrode application 
points in more rare cases. 
As for 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 pathologies. 
Literature data show that the application of the method according to the current safety 
guidelines has minor side effects: a certain number of subjects participating in TMS 
experiments (up to 20%) suffer from headache or back pain, due to likely to excessive 
muscle tension and stiff head and / or neck position during TMS application. These 
effects are temporary and in most cases do not require any treatment. 
Since TMS produces a magnetic field, people with fixed electrical stimulators (e.g. 
heart stimulators, nerve stimulators, hearing implants) that would not function or be 
damaged by the magnetic field cannot participate in the study. Also excluded from the 
examination are those with particular metal foreign bodies (for example splinters, some 
prostheses, screws and nails) that could move if placed within the magnetic field. 
Because the effects of TMS on the developing fetus are not known, pregnant women 
cannot participate in the study. 
 

 
 
CLINICA NEUROLOGICA - UNIVERSITA’ DEGLI STUDI DI BRESCIA 
UO Neurologia 2 - AZIENDA SOCIO SANITARIA TERRITORIALE degli SPEDALI CIVILI DI BRESCIA 
Direttore: Prof. Alessandro Padovani 
 
PERSONAL DATA PROCESSING: 
The data will be processed in compliance with Legislative Decree 196/2003 and 
subsequent authorizations and additions and with the European Regulation n. 679/2016 
relating to the protection of privacy and used for the purposes pursued by 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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