Transcranial direct current stimulation as a memory enhancer in patients with Alzheimer’s disease: a randomized, placebo-controlled trial

Study design and participants

A randomized, placebo-controlled trial with a parallel group design was performed.
Two groups were included in the intervention: an active tDCS group and a placebo tDCS
group. The allocation ratio was 1:1.

Patients diagnosed with Alzheimer’s disease were invited to participate in the study
via a letter from the Department of Geriatric Medicine at the University Hospital
of North Norway, and healthy participants were recruited through a newspaper advertisement.
The eligibility criteria were living at home and fulfillment of the research criteria
for the likelihood of having Alzheimer’s disease according to the revised criteria
of the National Institute of Neurological and Communicative Disorders and Stroke and
Alzheimer’s Disease and Related Disorders Association criteria 7]. We followed section 4.2 in these criteria: “Probable Alzheimer’s disease with increased
level of certainty.” This determination of eligibility for the study requires evidence
of a progressive cognitive decline based on information from informants (relatives)
and a cognitive and/or neuropsychological evaluation 7].

We excluded patients who scored 18 on the Mini Mental State Examination (MMSE) 8]. Other exclusion criteria included serious somatic disorders (cancer, chronic obstructive
pulmonary disease, and heart failure) or neuropsychiatric disorders (e.g., severe
depression and psychosis) that might reduce cognitive abilities. The patients with
comorbid cerebral conditions, such as cerebrovascular injuries and/or stroke, brain
tumor, or Parkinson’s disease, were not eligible to participate in the study. Patients
using cholinesterase inhibitors had to have been using them for at least 3 months
before enrolling in the study. A total of 25 patients with Alzheimer’s disease were
included in the study.

A total of 22 healthy elderly volunteers, aged 59–83 years, served as controls for
the neuropsychological test performance at baseline. None of them had cognitive impairment
or other serious diseases. These healthy volunteers were recruited through an advertisement.
The control group did not receive any tDCS stimulation. They completed the Hospital
Anxiety and Depression Scale 9], a questionnaire used to screen for depression and anxiety.

The neuropsychological test battery used for healthy volunteers and patients with
Alzheimer’s disease was identical. The study was executed in a research laboratory
at the University of Tromsø Institute of Psychology. The study was ethically approved
by the regional committee for medical and health research ethics (2012/1890) and was
registered in the ClinicalTrials.gov database with the identifier NCT02518412. All
of the patients and healthy control subjects signed a written informed consent form
in line with the Declaration of Helsinki before participating in the study. Each patient
received a gift card worth 600 NOK (67 EUR, 75 USD) for their participation. Figure
1 contains a flow diagram of the trial.

Fig. 1. Flow diagram of trial profile

Outcome measures

The primary outcome measure was verbal memory function. We used a validated and standardized
Norwegian version of the California Verbal Learning Test–Second Edition (CVLT-II)
to assess three aspects of verbal memory function: immediate recall, delayed recall,
and recognition 10]. CVLT-II is normed by age and gender and is widely used to assess patients with Alzheimer’s
disease 10]. To reduce test-retest effects, the CVLT-II consists of two parallel versions: the
CVLT-II standard and alternate forms, which contain two different and independent
word lists. We used the standard form at baseline and the alternative form in the
posttest.

The secondary outcome measures included the MMSE, clock-drawing test, and Trail Making
Test parts A and B (TMT A and B). The MMSE is a screening tool used for assessing
cognitive impairment (e.g., orientation, recall, arithmetic, language, and ability
to follow simple instructions) 8]. The clock-drawing test is another screening tool used for detecting cognitive impairment
and is also used to assess visuoconstructive ability 11]. The TMT consists of part A and part B. TMT A measures sustained attention, whereas
TMT B assesses executive function 12].

To control for general cognitive abilities, we used the Wechsler Abbreviated Scale
of Intelligence with the matrix reasoning and vocabulary subtests 13]. To screen for depressive symptoms, we used the Cornell Scale for Depression in Dementia
14], which is a questionnaire completed by an informant (i.e., a relative). A score above
13 indicates depression, which was an exclusion criterion in the present study. We
documented progressive decline using the Informant Questionnaire on Cognitive Decline
in the Elderly (IQCODE) 15], which was also completed by an informant. To assess for potential confusion during
neuropsychological testing, the Confusion Assessment Method 16] was applied by a research assistant. This questionnaire is based on the observation
of core symptoms of confusion (e.g., inattention, disorganized thinking, and altered
level of consciousness).

Intervention

The intervention was treatment with tDCS using a direct current stimulator (neuroConn,
Ilmenau, Germany), which is battery-driven and delivers a direct current. The current
intensity was 2 mA, and the stimulation duration was 30 minutes. A pair of 35-cm
²
rubber electrodes transferred the direct current. These electrodes were inserted into
sponge pads soaked with 10 ml of sterile water. To stimulate the left temporal lobe,
the anode (positive electrode) was placed at the T3 position in the 10–20 system for
electroencephalographic electrode positioning. The cathode (negative electrode) was
placed on the right frontal lobe at the Fp2 position. For the placebo tDCS, the electrode
placement and session duration were identical to those for active tDCS. However, in
the placebo tDCS, the current was delivered for 30 seconds at the beginning of the
stimulation, then the current was turned off automatically.

Randomization and blinding

The patients were assigned to a list with five-digit codes provided by the manufacturer
of the tDCS stimulator. Each patient had his or her own code. The codes instructed
the stimulator to deliver either placebo or active stimulation. The order of the codes
was randomized using the Random.org website (https://www.random.org/). To ensure double-blinding, the list of code assignments was not disclosed during
the entire tDCS intervention. The list was decoded when the study was completed to
identify the patients in the active and placebo groups. The tDCS stimulator did not
display information that could be used to identify the placebo or active stimulation.

Procedure

After their inclusion in the study, the patients and their relatives visited the research
laboratory and received information regarding the project. During this meeting, the
patient completed an informed consent form. Subsequently, the patient underwent neuropsychological
testing (baseline). The neuropsychological assessment lasted for approximately 60 minutes,
including several short breaks. After the neuropsychological assessment was completed,
the first tDCS stimulation commenced. Each patient underwent six sessions of tDCS
or placebo tDCS stimulation for 10 days. Each tDCS stimulation session lasted 30 minutes.
An experienced research assistant administered the tDCS stimulation. When the last
tDCS stimulation was completed, the patient performed the neuropsychological posttesting
and received a gift certificate. Figure 2 gives an overview of the procedure.

Fig. 2. Overview of the procedure

Power and statistical analyses

In previous studies in which tDCS was used to stimulate memory functions in patients
with Alzheimer’s disease, researchers reported significant results (p??0.05) with a total of ?15 patients 3]–5] in a within-group design. Thus, we aimed to include a larger sample than those described
in previous studies 3]–5] to ensure accurate analysis of the effects of the intervention.

We used IBM SPSS version 22 software (IBM, Armonk, NY, USA) to perform the statistical
analysis. Because of a violation of the assumption of a normal distribution, a nonparametric
Mann-Whitney U test was conducted to compare the placebo tDCS and active tDCS groups at baseline.
A nonparametric Kruskal-Wallis test was used to assess the baseline characteristics
for all three groups (placebo tDCS, active tDCS, and healthy control subjects at baseline).

For the primary analyses, the data had a normal distribution. However, because of
a small sample size and a large variance, we decided to use a nonparametric Mann-Whitney
U test for the analysis. With the Mann-Whitney U test, we examined the change from baseline to posttest. The raw scores for the neuropsychological
tests (CVLT-II and WASI) were scaled according to standardized norm tables 13], 17]. The significance level was set at p??0.05.