Cognitive Effect of Transcranial Direct Current Stimulation on Left Dorsolateral Prefrontal Cortex in Mild Alzheimer’s Disease: A Randomized,Double-Blind,Cross-Over Small-Scale Exploratory Study

Abstract

Background:

Transcranial direct current stimulation (tDCS) is considered a potential therapeutic instrument for Alzheimer’s disease (AD) because it affects long-term synaptic plasticity through the processes of long-term potentiation and long-term depression, thereby improving cognitive ability. Nevertheless, the efficacy of tDCS in treating AD is still debated. Dorsal lateral prefrontal cortex is the main role in executive functions.

Objective:

We investigate the cognitive effects of tDCS on AD patients.

Methods:

Thirty mild AD patients aged 66–86 years (mean = 75.6) were included in a double-blind, randomized, sham-controlled crossover study. They were randomly assigned to receive 10 consecutive daily sessions of active tDCS (2 mA for 30 min) or a sham intervention and switched conditions 3 months later. The anodal and cathodal electrodes were placed on the left dorsal lateral prefrontal cortex and the right supraorbital area, respectively. Subjects underwent various neuropsychological assessments before and after the interventions.

Results:

The results showed that tDCS significantly improved Cognitive Abilities Screening Instrument scores, especially on the items of “concentration and calculation”, “orientation”, “language ability”, and “categorical verbal fluency”. Mini-Mental State Examination and Wisconsin Card Sorting Test scores in all domains of “concept formation”, “abstract thinking”, “cognitive flexibility”, and “accuracy” also improved significantly after tDCS. For the sham condition, no difference was found between the baseline scores and the after-intervention scores on any of the neuropsychological tests.

Conclusion:

>: Using tDCS improves the cognition of AD patients. Further large size clinical trials are necessary to validate the data.

Keywords

Alzheimer’s disease cognitive function effect left dorsal lateral prefrontal cortex transcranial direct currentstimulation

INTRODUCTION

Needs for the therapeutic strategies of Alzheimer’s disease

Alzheimer’s disease (AD) is the most common type of dementia, accounting for 60% –80% of all cases [1]. Current therapies for AD have a limited efficacy to improve patients’ cognitive impairments. Furthermore, the use of currently available drugs for AD is controversial, and none of the standard treatments (ChE inhibitors and N-methyl-D-aspartate receptor antagonists) has been shown to be effective at slowing or halting its progression [2 –4]. AD is associated with the deposition of amyloid-β (Aβ) plaque and the hyperphosphorylation of intraneuronal tau protein, leading to mitochondrial dysfunction, inflammatory damage, synaptic failure, neurotrophin depletion, neurotransmitter deficit, vascular injury, and neuronal loss [5 –7]. So far, however, therapies targeting Aβ have failed to show clinical efficacy in phase III trials, and most anti-tau agents are in early clinical development [8]. Because no effective, disease-modifying drugs for AD yet exist [9 –11], there is an urgent need to find alternative or complementary therapeutic strategies.

tDCS: A promising approach for enhancing cognitive function in AD

In AD neuropathology, Aβ and downstream hyperphosphorylated tau synergistically drive the cognitive decline by disrupting synaptic plasticity, mediating synaptic toxicity [12], inducing mitochondrial dysfunction [12], depleting brain-derived neurotrophic factors (BDNFs) [13], evoking a reduction in cerebral blood flow [14], and inducing the alternation in functional connectivity [15]. In particular, they may lead to the suppression of long-term potentiation (LTP) and the enhancement of long-term depression (LTD) in AD [12 , 16–18]. LTP and LTD are the two main forms of synaptic plasticity that are recognized as the biological basis for learning and memory activities at the cellular level [19, 20]. Because soluble Aβ oligomers significantly inhibit LTP and facilitate LTD [18], conditions that induce LTD, such as the elevated Aβ levels seen in early-onset AD, potentially lead to synapse loss. Furthermore, facilitating LTP, which is known to inhibit LTD, potentially preserves synaptic plasticity and brain connectivity [21].

As the quest for new drugs with enhanced clinical efficacy continues, there is a growing emphasis on disease-modifying strategies designed to redirect the course of AD toward favorable neurocognitive outcomes [22]. Non-invasive brain stimulations, notably transcranial direct current stimulation (tDCS), positively impact AD treatment, indicating significant potential for augmenting cognitive function in affected individuals [23]. Compared to other non-invasive brain stimulations methods, tDCS is a simple, safe, convenient, well-tolerated, and affordable tool. It modifies neurotransmitter systems, with anodal tDCS enhancing excitatory synaptic transmissions by altering the glutamate-GABA balance [24 –31]. Anodal tDCS is thought to promote the induction of LTP, while cathodal tDCS is believed to lead to the induction of LTD. In terms of its mechanism, tDCS is thought to be able to alter the synaptic environment and calcium regulation, affect protein synthesis and the release of BDNF, regulate LTP and LTD, and subsequently impact regional cerebral blood flow and functional connectivity [23 , 32–35]. Additionally, an animal study indicates that anodal tDCS may enhance Aβ clearance in the early stages of AD, directly impacting Aβ production and degradation, and ultimately lowering Aβ deposits [36]. These mechanisms may hold significant promise in ameliorating the cognitive decline associated with AD [23].

Human studies on tDCS in AD

The ability of tDCS to mitigate cognitive symptoms in AD has been tested [37 –44]. In a clinical study, it was shown that applying tDCS with a weak constant current of 1.5 mA to stimulate the temporoparietal areas in a single 15-minute session yielded positive effects on recognition memory performance among 10 patients diagnosed with probable AD [37]. The other study adjusted the parameters to a current of 2 mA and a 30-min session for anodal tDCS on the temporal and prefrontal areas, and the results also demonstrated a significant effect on the visual recognition memory task [38]. In another single session of the tDCS study, anodal current of 1.5 mA and 15 min of stimulation were delivered bilaterally over the temporal-parietal lobe to 7 patients with probable AD, revealing benefits in working memory tasks for AD patients [39]. Several studies have explored the efficacy of multiple sessions of tDCS on AD cognition, with positive results [40, 41]. In a study involving 15 AD patients, anodal tDCS targeted the temporal region with a 2 mA intensity, lasting 30 min per session per day for 5 consecutive days [40]. The participants experienced improvement in visual recognition memory, and this enhancement endured for at least 4 weeks following the therapy. In a double-blind randomized study with 34 patients diagnosed with AD, the left dorsolateral prefrontal cortex (LDLPFC) was targeted and stimulated at 2 mA for 25 min daily over ten consecutive days, revealing significant improvement in cognitive function [41]. Although several studies have shown positive effects of tDCS on AD-related symptoms, negative findings have also been reported [42 –44]. One study involved 2 weeks of tDCS stimulation over the LDLPFC, with daily sessions for 5 days a week, each lasting 25 minutes per session and using a current of 2 mA [42]. This study failed to observe a significant additional effect of anodal tDCS on memory performance in AD. The other randomized double-blind study, which included six sessions of intervention over 2 weeks, with each session lasting 20 min and a current of 2 mA for anodal tDCS stimulation over the LDLPFC, also showed a lack of effect on global cognition in patients with moderate AD [43]. The additional study, comprising six tDCS sessions over a 10-day period, employing a 2 mA current and a 30-min stimulation duration per session, with anodal stimulation targeted at the left temporal lobe, revealed no notable enhancement in verbal memory function for individuals with AD [44].

Furthermore, a literature review [45] and a meta-analysis [46] suggest that the efficacy of tDCS in treating AD is under debate. This lack of agreement may be due to differences among the studies examined in terms of the sample size, the evaluation criteria, the number and length of stimulation sessions, the intensity and type of stimulation, the targeted brain area, and the use of sham stimulation. Consequently, further research is needed to explore under what circumstances tDCS can be beneficial in treating AD [45]. These conventional studies explore the impact of varying anodal and cathodal electrode placements on the electric field’s direction and distribution during similar neuropsychological tasks.

tDCS targeting the LDLPFC demonstrates cognitive enhancement benefits

During the early stages of AD, episodic memory and executive deficits manifest prior to the onset of impairments in constructional praxis, language, and sustained attention [47]. In studies investigating the effects of tDCS for AD, the temporoparietal areas, temporal lobes, and dorsal lateral prefrontal cortex (DLPFC) are the main targeted brain regions because of the role of the temporal lobe in memory processes and that of the DLPFC in executive functions. A review article has found that using tDCS to target the left temporal cortex showed no changes in global cognition, verbal learning, attention, or executive functions [45]. Studies showed that brain stimulation on DLPFC can lead to increased neuron activity and synaptic connections, ultimately enhancing cognitive function and working memory, which could potentially be used as a treatment approach for AD patients. [48, 49]. The process involves promoting synaptic plasticity, resulting in improved efficiency in the frontal cortex and subsequent cognitive benefits. Furthermore, the reduced cholinergic terminal integrity in the cortex is an important factor underlying the observed cognitive decline in early dementia [50]. Study showed that the stimulation of DLPFC restored the rich cholinergic innervation from the basal forebrain [51]. A recent study demonstrated that applying bilateral anodal tDCS to both the left and right DLPFC did not lead to enhancements in working memory, cognitive flexibility, or response inhibition abilities [52]. tDCS or repetitive transcranial magnetic stimulation of the LDLPFC has also been associated with improvements in memory, language, processing speed, global cognitive symptoms, and apathy after a period of treatment [41 , 46–59]. The LDLPFC remains the preferred region for using non-invasive brain stimulation [45], based on empirical evidence and the fact that this region is responsible for executive functions and working memory [60].

The aim of this study

The escalating elderly demographic in Taiwan has led to a notable upsurge in AD cases. Timely advancement of strategies to ameliorate AD holds significance in enhancing health outcomes and curtailing societal expenses. tDCS serves as a modality of choice in the investigation of cognitive function effects in AD. The aim of this study was to evaluate, with the help of pre- and post-intervention assessments of cognitive functions, the cognitive effects in AD patients of stimulating the LDLPFC using anodal tDCS for 10 sessions.

MATERIALS AND METHODS

Study design and flow chart

This clinical trial was conducted as a double-blind, block randomized, sham-controlled, crossover small-scale exploratory study. Participants were randomly assigned to different arms of the study (see Fig. 1), and they and raters were blind to the stimulation conditions (tDCS versus sham). Though the washout period determined in past tDCS studies lasted 1–4 weeks, we chose a 12-week duration because the effects of tDCS have been reported to continue for 4 weeks in AD patients [61, 62]. In the process of condition allocation, meticulous efforts were made to mitigate substantial demographic and cognitive divergence between the two conditions, which could potentially impact the outcomes of the assessments. To achieve this, participants were subjected to random assignment into either the AD(1) condition or AD(2) condition, taking into account variables such as age, gender, education level, and Clinical Dementia Rating (CDR) level. In the AD(1) condition, participants underwent the tDCS procedure initially, followed by a sham procedure after a three-month interval. Conversely, in the AD(2) condition, participants received the sham procedure initially, with the tDCS process administered three months later. The instrument uses coded settings for tDCS and sham processes to ensure participant and rater blinding. The screen dashboard displays similar signals during both processes, preventing self-identification. Group assignments remain undisclosed until the blinds are lifted at the study’s conclusion.

Fig. 1

Flow chart of tDCS study.

Participants

According to a previous study and sample size calculation, an estimated 30 participants with AD, aged between 50 and 90 years old, were recruited from neurologic or geropsychiatric clinics in a general hospital [41]. The effect size (e) was 0.77 if the difference between tDCS and sham was 3, with standard deviation (SD) of pair difference = 5.5 (e = 3/5.5/ $\sqrt{2}$ = 0.77, for crossover study, the e should be difference/SD/ $\sqrt{2}$ . The sample size was 30 with type I error α= 0.05 and power = 82% . All had been diagnosed with AD according to the DSM-5 and all had been given a series of neuropsychological screening tests, including the CDR scale, the Mini-Mental State Examination (MMSE), and the Cognitive Abilities Screening Instrument (CASI, 2.0), in order to corroborate the diagnosis of cognitive dysfunction [63 –65]. In this study, patients with very mild to mild AD were selected because neuro-psychological testing may not have been completed for patients with moderate to severe AD. The CDR rating of each participant was 0.5 to 1. None of the cases had moderate to severe systemic diseases, significant neurological diseases (other than the suspected AD), intracranial space occupying lesions, scalp lesions, foreign objects in the head, pacemaker implants, or moderate to severe visual or hearing impairments at the time of this study.

The study enrolled subjects from neurologic and geropsychiatric clinics within a general hospital. A range of comprehensive investigations, encompassing patient medical records, thorough physical and neurologic evaluations, mental status assessments, laboratory experiments, and brain MRI analyses, collectively corroborated the accurate diagnosis of AD among the participants. In the course of the research undertaking, a minimum of 100 eligible participants were extended invitations to engage in the trial. However, the pervasive impact of the COVID-19 pandemic along with logistical impediments associated with human mobility resulted in a winnowed cohort, with a total of 42 individuals undergoing preliminary screening for potential inclusion in the trial. Subsequently, from this subset, a total of 32 individuals diagnosed with AD met the eligibility criteria to proceed into the trial. Unfortunately, two participants withdrew midway, leaving 30 who successfully completed the trial.

Outcome measures

All participants were evaluated with the MMSE, CASI, and Wisconsin Card Sorting Test (WCST). Their cognitive functions and neuropsychological symptoms were assessed before and after undergoing the 10 sessions of tDCS or sham interventions (see Fig. 1). The CASI and MMSE are the standard tools for diagnosing dementia in neurology and geropsychiatry clinics in Taiwan. The MMSE is a short and effective test that is used extensively in clinical and research settings to evaluate cognitive function [66]. The CASI has high sensitivity and specificity for detecting dementia and sufficiently good test-retest reliability [67]. Its scores range from 0 to 100, providing a quantitative assessment of nine cognitive domains: “long-term memory”, “short-term memory”, “attention”, “mental manipulation” (concentration and calculation), “orientation”, “abstract thinking and judgment”, “language ability”, “drawing” (visual construction), and “animal-name fluency” (categorical verbal fluency).

The WCST is a problem-solving test that measures both the ability to identify abstract categories and cognitive flexibility understood as the ability to change one’s strategies in response to environmental contingencies [68]. It is an extensively used neuropsychological tool designed to measure frontal lobe impairment and has long been considered the gold-standard measure of executive functioning [69, 70]. It has also been used to investigate the executive functions of patients with AD [71].

Intervention: Active tDCS and sham process

Participants were randomly assigned to receive either the active tDCS treatment or the sham intervention, and after a washout period of 3 months they were given the other treatment. The tDCS was delivered with a wireless tDCS neurostimulator (Neuroelectrics STARSTIM^®) connected to saline-soaked 25 cm² synthetic sponge electrodes placed on the scalp. A 2 mA current was delivered for 30 min on 10 consecutive days (excluding weekends). The ramp-up and ramp-down periods were 30 s each [40, 41]. The anode was placed over the LDLPFC (region F3 of the international 10–20 electroencephalography system), with the cathode over the right supraorbital region (RSOR) [41, 72]. Sham mode is implemented by delivering a 30-s ramping up and down of the current envelope at the beginning and end of stimulation, respectively. This was performed to mimic the tactile sensations commonly reported with tDCS. Within the sham protocol, a computer screen emulates a signal feigning the presence of current flow.

Statistical analyses

All statistical analyses were performed with SPSS 20.0 (IBM Corp. Armonk, NY) and SAS 9.4 (SAS Institute, Cary, NC). The Chi-square test and the Mann-Whitney U test were used to assess the differences in demographic characteristics between conditions of participants. The Wilcoxon Signed Rank Test (WSRT) was used to compare changes in cognitive abilities between pre- and post-intervention within each intervention type. The same WSRT approach was then applied to evaluate whether these changes differed between the active tDCS and sham intervention types.

RESULTS

In this study, a cohort of 32 individuals diagnosed with CDR 0.5 to 1 AD was recruited for investigation. Ultimately, a total of 30 participants successfully completed all designated research sessions. Two instances of participant attrition were observed in the study, wherein one withdrawal resulted from familial concerns regarding the potential for COVID-19 infection, while the second withdrawal stemmed from logistical constraints, specifically the absence of available familial resources and time allocation to facilitate the transportation of the case to the laboratory. Both of the identified CDR 0.5 cases successfully concluded the tDCS phase of the study. Post-intervention cognitive test scores exhibited substantial improvement in comparison to baseline scores. However, these two cases were excluded from the statistical analysis due to the unavailability of sham data for comparative purposes. The 12 male and 18 female participants in this study had an average age of 75.6 years old (range: 66–86 years of age) and an average of 9.5 years of formal education (range: 0–16 years) (See Table 1). There were 15 cases with a score of 0.5 on the CDR and 15 with a score of 1. All participants tolerated tDCS well, with no adverse effects recorded, although 12 patients (40%) transiently complained of mild tingling or itching during the experimental procedures.

Table 1

The baseline demographic characteristics and neuropsychological tests in two conditions

Condition	Randomized condition		Mean (Min–Max)
Demographic data	(total 30 persons)
	AD1(1st tDCS; 2nd sham) 14 persons Mean (Min–Max)	AD2(1st sham; 2nd tDCS)16 persons Mean (Min–Max)
Age (y)	76.5 (66–86)	74.9 (67–84)	75.6 (66–86)
Sex (M/F)	6/8	6/10	12/18
Education (y)	9.5 (0–16)	9.4 (0–16)	9.5 (0–16)
CDR (0.5/1)	6/8	9/7	15/15
MMSE–total scores: 30	17.4 (3–27)	22.5 (4–28)	20.1 (3–28)
Years of disease	3.4 (1–8)	2.9 (1–6)	3.1 (1–8)

Effects in CASI and MMSE

Statistical analysis of WSRT pre- and post-tDCS intervention revealed significant differences in both CASI and MMSE (Figs. 2 and 3, Supplementary Table 1). In terms of CASI score presentation, the mean value pre-tDCS intervention was 68.75, while post-tDCS intervention, it showed an average of 72.73, signifying a significant improvement (p = 0.000). Specifically, within the sub-elements of CASI, notable improvements were observed in “concentration and calculation” (p = 0.035), “orientation” (p = 0.002), “language ability” (p = 0.046), and “categorical verbal fluency” (p = 0.003) subsequent to the tDCS intervention. Regarding MMSE scores, the mean value before tDCS was 20.27, and after tDCS, it averaged 21.17, indicating a significant improvement (p = 0.006) too. When examining the impact of tDCS and sham conditions on CASI and MMSE, notable distinctions emerge between the two conditions. The improvements in CASI and MMSE scores were more significant for tDCS than sham (p = 0.010 and p = 0.007, respectively). In CASI sub-items, tDCS intervention led to notable improvements in “orientation”, “categorical verbal fluency”, and “visual construction” compared to sham intervention (p = 0.004, p = 0.015, and p = 0.040, respectively). The results of the analyses of all CASI and MMSE data are presented in Supplementary Table 1. As for the sham condition, no differences in CASI scores were identified between pre-and post-intervention.

Fig. 2

CASI presentations pre- and post-intervention: (1) The WSRT showed significant differences on CASI presentations between tDCS and sham conditions (p = 0.010). (2) The WSRT showed a significant difference for CASI between pre-and post-active tDCS (p = <0.001). No difference was found between pre- and post-intervention in the sham condition. Note: Red dash line –significant difference between both means.

Fig. 3

MMSE presentations pre- and post-intervention: (1) The WSRT showed a significant difference on MMSE presentations between tDCS and sham conditions (p = 0.007). (2) The WSRT showed post-intervention (p = 0.006) was significantly higher than the pre-intervention in the tDCS condition. No difference was found between pre- and post-intervention in the sham condition. Note: Red dash line –with significant difference between both means.

Effects in WCST (Fig. 4)

During the experiment, 29 patients completed the WCST, and one patient refused to take part in the test. The WSRT showed significant differences between the tDCS and sham conditions in their performance on “total correct” (p = 0.038), “conceptual level responses” (p = 0.022), and “failure to maintain set” (FMS) (p = 0.048). The disparity between the pre- and post-intervention scores on those items was better for the tDCS condition than for the sham condition.

Fig. 4

Presentations of WCST items pre- and post-intervention in the tDCS and sham conditions. (1) Statistics showed significant differences between the conditions on: “total correct”, “conceptual level responses”, and “failure to maintain set”. (2) In active condition, “conceptual level responses”, “categories completed”, and “failure to maintain set” increased. No difference was found between pre- and post-intervention in the sham condition. Note: Red dash line –significant difference between both means.

The analysis of the pre- and post-intervention differences in scores on each WCST item showed an increase for the tDCS condition on “conceptual level responses” (p = 0.026), “categories completed” (CAT) (p = 0.048), and “failure to maintain set” (FMS) (p = 0.037). In the case of the sham condition, no difference was noted between the baseline and after intervention in the scores on all WCST items.

DISCUSSION

This investigation demonstrated that administering 10 sessions of tDCS, each lasting 30 min, with an intensity of 2 mA and utilizing the anode at the LDLPFC and cathode at the RSOR, yielded a favorable impact on overall cognitive function in individuals with AD. The application of anodal tDCS to the left DLPFC emerged as a promising and secure method for the noninvasive modulation of cortical excitability. Notably, favorable outcomes, such as memory enhancement, were observed when the anode was situated over the left temporal parietal area or bilateral temporal area, coupled with the cathode placed on the right deltoid muscle, as supported by references [37 , 40]. However, the arrangement involving anodal stimulation of the left temporal parietal area and cathodal stimulation of the RSOR did not yield a significant improvement in verbal memory function in individuals with AD, as indicated by reference [44]. Conversely, the implementation of anodal tDCS on LDLPFC with cathodal stimulation on the right deltoid muscle did not yield a statistically significant additional impact on memory performance in individuals with AD [42]. A recent research endeavor examined the effectiveness of tDCS for addressing the neuropsychiatric symptoms associated with AD. The study involved placing the anode over the bilateral angular gyrus and administering a current of 2 mA. Each treatment session lasted 30 min, and this protocol was repeated three times per week over a span of four weeks [59]. The outcome demonstrated enhanced cognitive function as a consequence of tDCS stimulation. In our study, akin to prior research, the cathode was situated over the contralateral prefrontal area [38 , 59]. Our findings, consistent with prior research, support that the application of anodal tDCS on the LDLPFC coupled with cathodal stimulation on the RSOR has been demonstrated to yield noteworthy enhancements in cognitive function among individuals with AD [38, 73].

Confirming the findings of past studies, this clinical trial showed that applying anodal tDCS to the LDLPFC offers a noninvasive and safe means of modulating cortical excitability. Our finding that using tDCS to stimulate the LDLPFC potentially improves the cognitive functions of AD patients is consistent with Khedr’s study [41]. Our results showed that scores on the items of the CASI, including “concentration and calculation”, “orientation”, “visual construction”, “language ability”, and “categorical verbal fluency”, improved after treatment with tDCS. The LDLPFC is thought to be associated with the executive functions of abstract reasoning, perceptual decision making, regulating working memory, cognitive flexibility, planning, inhibition, organization, and regulation in the human brain [74 –79]. It should be noted at this point that imaging studies have shown that the LDLPFC enhances concentration and calculation abilities [80, 81]. Furthermore, it has been shown that mental orientation in relation to space, time, and people is managed by a specific brain system characterized by a highly ordered internal organization and closely related to the default-mode network which is associated with self-referential mental activity [82]. Another relevant study concluded that using tDCS with the same anodal and cathodal positions as in our study increased resting-state functional connectivity, particularly within the default-mode network [83]. Therefore, it is possible that “orientation” was improved by the anodal tDCS over the LDLPFC.

Brain stimulation seems to have a beneficial effect on the language skills of AD patients. In a study of patients at the early stages of AD, the administration of active tDCS to the LDLPFC over a period of 6 months, compared to a sham intervention, was shown to improve not only global cognition, as measured with the MMSE, but also language function, assessed by means of the Boston Naming Test [84]. The “language ability” domain of the CASI assesses the ability to read, write, name, and perform commands. Our results for this instrument showed that tDCS applied to the DLPFC improved the language skills of the patients. According to the Memory, Unification, and Control model, the LDLPFC is involved in the control mechanism in language processing [85, 86]. Language comprehension and production require control and working memory abilities involving the DLPFC. In fact, one study has demonstrated that the LDLPFC is part of the complex cortical network associated with language processing and so may be involved in both language comprehension and production [87].

An imaging study showed activation of the LDLPFC in people doing the WCST [88]. This suggests that taking part in the WCST directly activates this region of the brain. According to previous studies, completing the WCST involves three primary cognitive factors in both normal and clinical samples: (I) concept formation, cognitive flexibility, and accuracy; (II) problem solving and learning; (III) response maintenance and distractibility [89 –91]. The capabilities included in Factor I can be assessed by several items on the WCST, including “total errors”, “perseverative responses”, “percentage of conceptual level responses”, “conceptual level responses”, “trails to complete first category”, “perseverative errors”, and “total number correct”, and they are reflected in the CAT score. The capabilities included in Factor II can be evaluated primarily by the “nonperseverative errors” item, and to a lesser extent the “trials to complete first category” item. Finally, the capabilities included in Factor III are reflected in the FMS score. The CAT score, which primarily loads onto Factor I, also serves as an overall measure of strategy development and execution. The improvements in WCST scores observed in our study suggest that applying anodal tDCS to the LDLPFC improved the executive functions of AD patients, including concept formation, abstract thinking, cognitive flexibility, and accuracy. This use of tDCS has been shown to lead to a significant improvement in reaction time [92], while another study has suggested that it may improve executive function and dual tasking in older adults with functional limitations [93]. Finally, a number of studies have shown that the tDCS of the LDLPFC can modulate the cognitive functions of the prefrontal cortex, especially attention control and executive function [94 –96].

Although numerous studies have suggested that anodal tDCS over the LDLPFC has beneficial effects on working memory [97 –101], our data did not show such an effect on memory, and neither did other studies. In addition, a meta-analysis has shown that stimulation of the temporal areas caused better cognitive improvement compared with the stimulation of the LDLPFC [46]. Furthermore, whereas parts of the medial temporal cortex, especially the hippocampus, play a critical role in memory performance, the DLPFC plays a compensatory role in memory tasks in AD patients [102]. A possible explanation for this is that there are no direct fiber projections or only indirect connections between the prefrontal cortex and the hippocampus, which may result in a limited effect on memory performance of applying tDCS to the DLPFC [46].

In our study, scores on the FMS item of the WCST increased after the tDCS and sham conditions presented no significant difference. Although the FMS scores of most participants fell within the normal range (0–2), this increase implies a level of distractibility and a weak response maintenance in the tDCS condition. Applying cathodal tDCS to the ROSR requires stimulating the area directly in front of the right frontopolar cortex (rFPC), which has been associated with tracking alternate options, strategies, and goals and is selectively engaged in monitoring and integrating subgoals during working memory tasks [103 –105]. An imaging study has shown that the rFPC is critically involved in executive control processes that are required by the WCST by identifying a loss of response inhibition and a decreased set-maintenance ability in patients with rFPC lesions [106]. In general, cathodal tDCS is thought to reduce the excitability of the targeted cortical region, whereas anodal tDCS has the opposite effect [107]. Thus, it is possible that the function of the rFPC was inhibited by the use of cathodal tDCS, which led to the limited presentation of “failure to maintain set” and “working memory” in this study.

The effects of tDCS were observed not only during the stimulation but also after the end of stimulation (after-effects) [108]. For example, a study on the effect of tDCS on object-location learning and its retention demonstrated no immediate effect on learning. However, recall of the information improved after 1 week [61]. It was noted that the after-effects of tDCS depended on glutamatergic mechanisms, and the tDCS-induced reduction of GABA might serve as a “gating” mechanism [109]. Furthermore, the long-lasting after-effects of tDCS might result from changes in the connections between neurons, such as LTP or LTD, which are known to be induced [110]. However, the relationship between stimulation duration and the duration of after-effects was not linear under all conditions. This research did not include an assessment of the after-effects (duration of effects) of tDCS. A subsequent evaluation was conducted one month after the intervention, revealing a decline in scores compared to post-intervention levels. While the assessment of tDCS after-effects is considered significant, these findings have been omitted from the current report due to the need for a more robust experimental design.

Conclusions and limitations

Our findings show that 10 sessions of tDCS had a positive effect on global cognitive functioning in AD. Several limitations of this study should be mentioned. The first consideration is the small sample size. Further large size clinical trials are necessary to validate the data. Though only 30 subjects took part, this study can be considered statistically efficient since it was designed as a double-blind, randomized, crossover trial. Because patients in a crossover study serve as their own controls, the confounding effects of covariates are reduced. However, the possibility of carryover effects from tDCS treatment to the sham intervention needs to be considered in the study design and statistical evaluation during the crossover period. It has been reported that the effects of tDCS in AD patients may be delayed for up to 4 weeks [40]. A 12-week washout period was chosen for this study to minimize carryover effects of tDCS. We also statistically assessed the likelihood of carryover effects using WSRT. No significant carryover effects were found in this study (p > 0.05).

The second consideration is whether a learning effect may come into play the longer a patient participates in the study, impacting results regardless of the treatment used. The scores on the CASI, MMSE and WCST showed no significant improvements in the sham condition. Because the majority of AD patients have a deficit in the learning and retention of new information [111], a learning effect probably did not impact the data of the sham conditions. On the other hand, the clinical hallmark of AD is a gradual decline in cognitive function. If a carry-over effect of tDCS existed, it is reasonable to suggest that the protective effects of tDCS would have prevented the neuropsychological assessments from deteriorating for the sham conditions after 3 months.

The third consideration is the impact of the confounding factors of pharmacotherapy and non-pharmacotherapy on the participants during the experimental procedure. We controlled the use of neuropsychiatric medicines by each patient as much as possible throughout the study, but we did not control non-pharmacological interventions.

The fourth consideration is the possible inhomogeneous distribution of the electric field in different cases since this distribution depends on several anatomical factors such as the thickness and composition of the overlying skull, the thickness of the cerebrospinal fluid layer between the cortex and the skull, and the sulcal depth [112]. The tDCS-induced homogeneous electric fields do not uniformly modulate all neurons in the stimulated area [46].

The fifth consideration is the existence of typical and atypical variants of AD. Atypical variants account for 6% of the cases of late-onset AD [113]. Differences have been identified in the extent and regional deposition of the neuropathologic hallmarks of typical and atypical AD [114]. The atypical phenotypes of AD broadly correspond to regional atrophy and tau deposition [115]. Thus, the phenotypic heterogeneity that patients with AD present with may influence the effect of tDCS when it is applied to the same regions of the brains of different patients. In our study, we did not exclude phenotypic variants.

The sixth consideration is the absence of a biopathological biomarker for AD in this study. Regarding the biomarker utilized for AD diagnosis in this investigation, the brain MRI of each AD participant exhibited evidence of medial temporal atrophy. Nevertheless, evaluating the advantageous effects of tDCS based on short-term structural MRI alterations remains challenging. Ongoing research leads to evolving diagnostic criteria for AD, reflecting progress. A stepwise method is currently employed to develop new diagnostic standard. The validated core biomarkers, encompassing bodily fluids (cerebrospinal fluid and blood) and PET imaging, serve as indicators of the Aβ or tau pathophysiology present in AD across its early and late stage; however, their availability is not extensive [116]. They can also serve as indicators for monitoring the impact of intervention. Employing core biomarkers to assess and monitor the effectiveness of tDCS will provide a more objective demonstration of its advantages. Therefore, there is a need for further research to be conducted in the future with the goal of identifying homogeneous conditions in order to elucidate the effect of tDCS on various target brain regions.

AUTHOR CONTRIBUTIONS

Carol Sheei-Meei Wang (Conceptualization; Data curation; Formal analysis; Funding acquisition; Investigation; Methodology; Project administration; Writing – original draft; Writing – review & editing); Po See Chen (Conceptualization; Methodology; Supervision; Visualization; Writing – review & editing); Tsung-Yu Tsai (Conceptualization; Formal analysis; Investigation); Nien-Tsen Hou, MD (Data curation; Investigation); Chia-Hung Tang (Data curation; Investigation); Pai-Lien Chen (Formal analysis; Methodology; Software); Ying-Che Huang (Data curation; Investigation); Kuo-Sheng Cheng (Conceptualization; Project administration; Supervision; Visualization; Writing – original draft; Writing – review & editing).

Footnotes

ACKNOWLEDGMENTS

This work was supported by National Cheng Kung University Hospital (NCKUH-11001003). The authors wish to thank Prof. Michael Nitsche and Dr. Min-Fang Kuo for their reminding the study design. We thank Chien-Ting Lin and Chia-Hung Hu for their excellent technical assistance in this study. We also want to thank Andy Cormier for his English editorial assistance. The study was supported by research grants from Ministry of Science and Technology and Tainan hospital, Ministry of Health and Welfare, Taiwan. It had been approved by the Institute Review Board of National Cheng Kung University Hospital for publication [protocol number = B-BR-106-090 and date of approval = June. 21, 2019].

FUNDING

This work was supported by the Ministry of Science and Technology and Tainan Hospital, Department of Health Executive Yuan, Tainan city, Taiwan

CONFLICT OF INTEREST

The authors have no conflict of interest to report.

DATA AVAILABILITY

All data relevant to the study are available on reasonable request.

The supplementary material is available in the electronic version of this article: .

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