Combined Effect of tDCS and Motor or Cognitive Activity in Patients With Alzheimer's Disease: A Proof-of-Concept Pilot Study
Phase: NA
Conditions: Alzheimer Disease (AD)
Sponsor: Universita di Verona

02/10/2024 
 
TITLE: Combined e昀昀ect of tDCS and motor or cogni}ve ac}vity in pa}ents 
with Alzheimer’s Disease: a proof-of-concept pilot study   
 
NCT Number: NCT06619795 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

02/10/2024 
The aim of this study will be to evaluate the e昀昀ec}veness of combining tDCS with motor or cogni}ve 
ac}vi}es on cogni}ve func}ons in pa}ents with AD. A secondary aim will be to inves}gate whether 
tDCS will have a di昀昀erent impact when combined with motor versus cogni}ve ac}vi}es. 
 
Materials and Methods  
The study will be a double-blind randomized controlled trial (RCT) that will compare the e昀昀ects of 
anodal and sham tDCS combined with motor or cogni}ve ac}vity on cogni}ve performance in AD 
pa}ents. The research team will consist of "evaluators" and "treatment providers." The 
neuropsychologist evaluator will be responsible for measuring outcomes and will remain unaware 
of the group assignments. Addi}onally, to assess the presence of a placebo e昀昀ect or the absence of 
an e昀昀ect from the anodal s}mula}on, and to reduce poten}al bias, par}cipants will also be kept 
unaware of the type of s}mula}on being administered. In contrast, the treatment providers, 
including neuropsychologists and physiotherapists, will be informed about the treatment but will 
not know the type of tDCS s}mula}on used (anodal or sham) (Cotelli et al., 2014). 
 
Par琀椀cipants   
Pa}ents with AD will be recruited from the Mons. A. Mazzali Founda}on (Mantua). The inclusion 
criteria will be: Mini Mental State Examina}on (MMSE) >15, good level of compliance, treatment 
with acetylcholinesterase inhibitors (e.g., donepezil, rivas}gmine), and no modi昀椀ca}ons to 
medica}on in the last four months. The exclusion criteria will be: behavioral disorders (e.g., 
aggressiveness), alcohol abuse, orthopedic condi}ons with a risk of falls, respiratory disorders, 
uncorrected severe auditory or visual de昀椀cits, history of epilep}c 昀椀ts, use of an}-epilep}c 
medica}on, metallic body implants, pacemaker, and psychiatric, neurological, systemic, or metabolic 
disorders. 
Following a simple so昀琀ware-generated randomiza}on scheme (www.randomiza}on.org), pa}ents 
will be allocated to one of four groups a昀琀er the baseline evalua}on. Unbalanced randomiza}on will 
be applied. The randomiza}on list will not be disclosed to the assessors or treatment providers but 
will be known only to the principal inves}gator (CF). 
 
Treatment procedures   
The real tDCS groups will receive anodal s}mula}on combined with either motor ac}vity (MotA) or 
cogni}ve ac}vity (CogA). The sham tDCS groups will receive sham s}mula}on combined with motor 
ac}vity (MotS) or cogni}ve ac}vity (CogS). 
Each group will undergo 45 minutes of ac}vity, with the 昀椀rst 15 minutes performed simultaneously 
with tDCS s}mula}on. Treatments (45 minutes) will be administered for two weeks, 昀椀ve }mes per 
week (Cotelli et al., 2014).. 
During the study, par}cipants will not engage in any other motor or cogni}ve ac}vi}es. 
Motor ac琀椀vity 
A standardized sequence of motor exercises will be established. A physiotherapist will conduct the 
individual motor ac}vity, which will include moderate-intensity endurance and resistance training. 
Each session will begin with a 5-minute warm-up and conclude with a 5-minute cool-down, including 
ac}ve joint mobiliza}on. Subsequently, pa}ents will engage in endurance exercises, which will be 

02/10/2024 
randomly ordered and divided among cycling on a cycle ergometer, walking on a plavorm, and arm 
cranking on a specialized ergometer (Fonte et al., 2019). 
Cogni琀椀ve ac琀椀vity 
A neuropsychologist will conduct individual cogni}ve ac}vi}es, focusing on s}mula}ng residual 
cogni}ve abili}es, par}cularly memory. The cogni}ve s}mula}on will be tailored to the severity of 
each pa}ent's cogni}ve decline. Each session will begin with an orienta}on exercise, followed by 
oral and paper-and-pencil tasks targe}ng speci昀椀c cogni}ve func}ons. These exercises will aim to 
encourage natural reminiscence processes while also focusing on the present, enhancing social 
interac}on and mood. Mul}sensory s}mula}on will also be incorporated. 
The structure of the neuropsychological treatment will be modeled a昀琀er a study conducted by 
Spector et al. in 2003, which involved 201 demen}a pa}ents (Spector et al., 2003). This approach 
demonstrated posi}ve outcomes in several cogni}ve domains, as well as improvements in quality of 
life, while maintaining a high level of feasibility and adaptability (Fonte et al., 2019; Spector et al., 
2003). 
 
tDCS procedure   
The tDCS s}mula}on will be performed using a BrainSTIM s}mulator (EMS). A pair of saline-soaked 
electrodes will be placed and secured on the pa}ents. The anode (25 cm², 5x5 cm) will be posi}oned 
over the le昀琀 dorsolateral prefrontal cortex (DLPFC) following the 10–20 system (F3-F7 posi}on), and 
the cathode (35 cm², 7x5 cm) will be placed above the shoulder on the opposite side. The s}mula}on 
procedure will be adapted to align with the prevalent literature, as the DLPFC montage is widely 
used (Pilloni et al., 2022; Fonte et al.,2021). The intensity of the s}mula}on will be set at 2mA and 
applied for the 昀椀rst 15 minutes of either cogni}ve or motor ac}vity (45 minutes total). 
The electrode placement and parts of the s}mula}on procedure will follow the protocol described 
by Cotelli and colleagues in 2014 (Cotelli et al., 2014). To ensure safety, the current density of the 
ac}ve electrode will be kept within the limits established by Poreisz and collaborators in 2007 and 
Nitsche and collaborators in 2008. In the sham condi}on, the current will be turned o昀昀 10 seconds 
a昀琀er the s}mula}on starts and turned back on during the 昀椀nal 10 seconds, so that par}cipants will 
be unable to discern whether the s}mula}on is real or sham (Poreisz et al., 2007; Nitsche et al., 
2008). 
 
Evalua琀椀on procedures   
Primary and secondary outcomes will be measured by the same blinded examiner. Pa}ents will be 
evaluated before treatment (T0), immediately a昀琀er treatment (T1), and at a one-week follow-up 
(T2). Cogni}ve assessments will be conducted in a single session las}ng one hour. The tests used in 
the assessment are described below. 
• Primary Outcome 
The primary outcome will be the Mini Mental State Examina}on (MMSE), used to assess global 
cogni}ve impairment (Folstein et al., 1975). 
• Secondary Outcomes 
The secondary outcomes will include: 

02/10/2024 
• Picture Recogni}on (PR) is a subtest of the Rivermead Behavioral Memory Test-3, an 
ecological memory ba琀琀ery resembling everyday tasks, with the aim to measure daily 
memory func}on (Beschin et al., 2013).  
• Digit Span Test- Forward (DSF), used to measure span of immediate verbal recall. The 
examiner presents digits verbally at a rate of one per second (Monaco et al., 2013).  
• Digit Span Test- Backward (DSB), used to measure working memory (Monaco et al., 2013).  
• Phonemic Fluency Test (PFT), used to measure processing speed, language produc}on and 
execu}ve func}ons (Zappalà et al., 1995).  
• Visual Search Test (VST), to assess visual-selec}ve a琀琀en}on (Spinnler & Tognoni, 1987).  
• Sustained A琀琀en}on to Response Test (SART): used to evaluate sustained a琀琀en}on and 
control inhibi}on. In the test, par}cipants view a computer monitor on which a random 
series of single digits are presented at the regular rate of 1 per 1.15 seconds (Robertson et 
al., 1997).  
• Neuropsychiatric Inventory (NPI) to evaluate the presence, frequency and severity of 
behavioral disorders (Cummings et al., 1994). 
 
Sta琀椀s琀椀cal analysis   
 
Data from all randomized pa}ents will be assessed. The Kruskal-Wallis test will be used to measure 
baseline homogeneity for all outcome measures across the four groups. The Mann-Whitney U test 
will be employed to examine the e昀昀ects of tDCS by comparing MotA+CogA versus MotS+CogS 
between T1 and T0 (T1-T0) and between T2 and T0 (T2-T0). Further analysis will inves}gate 
di昀昀erences in performance between the MotA and CogA groups from T1 to T0 (T1-T0) and from T2 
to T0 (T2-T0). The alpha level for signi昀椀cance will be set at P < 0.05. 
Sta}s}cal analysis will be conducted using the Sta}s}cal Package for Social Science (SPSS) for 
Macintosh, version 26.0 (IBM SPSS Inc, Armonk, NY, USA). 
To determine the sample size, based on the study by Khedr and colleagues, an e昀昀ect size of 1.15 will 
be calculated using G*Power 3.1.9.4 so昀琀ware. With an e昀昀ect size of 1.15, an alpha of 0.01, and a 
power of 0.90, a total of 48 pa}ents will be required to detect a signi昀椀cant treatment e昀昀ect Khedr 
et al., 2019). 
 
 
 
 
 
 
 

02/10/2024 
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