Abstract
Alzheimer's disease (AD) is an age-related neurodegenerative disorder for which there are currently rarely effective drug treatments available to halt or slow down its progression. With the aging of the world population, AD as the primary cause of dementia, is rapidly becoming one of the most expensive, lethal, and burdening diseases of this century. In recent years, the new method used to treat nervous system diseases including AD is transcranial electrical stimulation (tES) with non-invasive and for regulating the flexibility of neural circuits operation and behaviors. The rationale of tES for AD neuromodulation is derived from research on animal and clinical trials. In the present paper, we review the current uses of the tES including transcranial direct current stimulation, transcranial alternating current stimulation, and transcranial pulsed electrical stimulation in rehabilitation for AD's core clinical symptom with cognitive dysfunctions, as well as the relevant data from AD animal models have also been discussed. Finally, the regarding applied challenges of tES in AD therapy have been referred for further improvement.
Introduction
Dementia is diagnosed in an estimated 10 million people annually, and 60～70% of those are attributed to Alzheimer's disease (AD). 1 AD is a chronic, progressive, and severe disease that affects the central nervous system and is commonly characterized by memory loss, personality changes, and a deterioration in cognitive functions. 2 The International Alzheimer's Association reports that an estimated 55 million people with dementia worldwide in 2021, and the number of AD patients is predicted to rise to 78 million in ten years. 3 AD has emerged as a significant worldwide health issue in the century.
According to the predominant theory of AD pathogenesis, aberrant aggregation of the amyloid-β protein (Aβ) triggers a harmful cascade that includes tau pathology and neurodegeneration. However, it has also shown that tau protein and Aβ can cause neuronal damage independently. 4 Meanwhile, it is noteworthy that AD's pathology breaks down functional connections in various parts of the brain. Cognitive networks, including the limbic systems, salience network and default mode, have been demonstrated to malfunction in AD patients by functional magnetic resonance imaging (MRI). 5 In the early stages of AD, a single-photon emission computed tomography study revealed distinct patterns of hypometabolism and hypoperfusion in the posterior cingulate cortex and precuneus, then bilateral and frequently asymmetric reductions in the posterior temporoparietal cortex, the frontal cortex was found to be impacted in advanced stages. 6 Focusing on regulating the damaged brain networks may offer an innovative and promising treatment for AD.
Transcranial electrical stimulation (tES) is a non-invasive brain stimulation technology, such as transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), and transcranial pulsed electrical stimulation (tPCS). For individuals with AD and mild cognitive impairment (MCI), tES has been becoming a potential non-pharmacological intervention. 7 The basic principle of tES is that weak electrical currents are applied to the brain specific area, which could interact with neural processing, modify neural plasticity, and entrain brain networks, all of which result in changes in human behavior. 8
tDCS special applications in AD therapy
tDCS typically entails positioning electrodes on the scalp to apply a mild direct current for the modulation of cortical excitability. 9 The stimulation current is usually in the range of 1～2 mA for 20 up to 40 min, which can be administered as an outpatient procedure without anesthesia. 10 As skin, skull, and intracranial structures’ resistance, the current that effectively reaches neuronal tissues is low. 11 In the tDCS literature, “anodal-tDCS” and “cathodal-tDCS” are used to describe electrode placement in relation to the brain region primarily targeted along with the direction of the intended effect (e.g. “anodal motor cortical tDCS” is intended to increase motor cortical excitability and “cathodal motor cortical tDCS” is supposed to decrease motor cortical excitability). But these expressions should be used with discretion. Under either polarity electrode, the direction of measured excitability changes can vary with brain state and dose parameters such as stimulation intensity and duration. 12 The 2 mA “cathodal-tDCS” enhanced cortical activity has been reported compared to 1 mA “cathodal-tDCS”. 13 tDCS has been widely applied in many kinds of neuropsychiatric diseases, particularly in AD, stroke, and depression.14–16
Meta-analysis have reported the efficacy of tDCS stimulation in improving cognition in whole with AD patients, 17 AD patients with mild to moderate stage, 18 and MCI patients with anodal application. 19 In preclinical AD, the tDCS exhibited its beneficial role in alleviating neurovascular unit dysfunction and reducing Aβ plaques, indicating that the effect of tDCS on Aβ deposition may partly depend on blood-brain barrier-mediated clearance of Aβ. 20 The patients with MCI underwent tDCS stimulation over the left dorsolateral prefrontal cortex (DLPFC) with a current intensity of 2 mA for 30 min in 10 sessions, it has shown that anodal-tDCS is superior to sham-tDCS for improvement in memory recall, verbal fluency, and executive functioning. 21 A meta-analysis showed that the stimulation of temporal-lobe-related brain regions, the number of stimulations ≥10, and the current density of 2.5 mA/cm2 were better than for the stimulation of left DLPFC. 19 It has been found that transcranial random noise stimulation in the lateral temporal lobe can significantly improve epileptic-related memory deficits. 22 This may mean that tDCS can also improve cognitive function by producing neural noise in the temporal lobe. Meanwhile, the anodal-tDCS over the temporoparietal region bilaterally produces significant improvement in the cognitive rating scores, whereas there was no effect of sham. A study recruited 46 AD participants received a current intensity of 2 mA over the left and right temporoparietal for 20 min on each side, with the cathode placed on the left arm. The results have shown that a total of 10 sessions of bilateral anodal-tDCS applied over the temporoparietal regions can improve cognitive function in AD and reduce social costs. 23
We also observed the tDCS in MCI clinic trial. Das et al. enrolled 22 patients with MCI, which were randomized into three groups as anodal-tDCS + reasoning training (SMART) group, advanced SMART group, and sham-tDCS + SMART group. 24 The anodal-tDCS group received the stimulation over the left inferior frontal gyrus (IFG) for 20 min (10 s fade-in and 10 s fade-out). The sham-tDCS group received stimulation for a total of 20 s (10 s fade-in and 10 s fade-out) to mimic the sensation of the stimulation. SMART training was delivered to all participants in both groups in sessions involving small groups of 2–5 individuals over 4 weeks, consisting of two 1-h sessions per week for a total of 8 h of training. Participants received anodal-tDCS or sham-tDCS stimulation immediately prior to each of the SMART training sessions. Anodal-tDCS to left IFG combined with SMART increased blood flow to the right middle frontal cortex were observed by resting pseudo-continuous arterial spin labeling MRI. However, the stimulation seemingly blocked the cognitive benefits of SMART on inhibition, innovation and episodic memory compared to the sham-tDCS + SMART group.
A combined protocol of anodal-tDCS with repetitive transcranial magnetic stimulation(rTMS) over bilateral angular gyrus (AG, P5/P6 electrode site) for AD-related neuropsychiatric symptoms has been tried. 25 84 participants with moderate AD were recruited, and the findings demonstrated that rTMS–tDCS application to bilateral AG can effectively improve AD-related symptoms, cognitive function, and sleep quality with considerable safety. Contrasting results have emerged from patients with MCI and AD, which reported no significant efficacy of tDCS.26,27 A recent review reported that evidence of a positive effect on memory is inconclusive in AD and weak in MCI. 28 The inconsistency may be caused by the lack of standard parameters and measurements of current intensity, stimulation time, electrode placement, as well as the number and frequency of sessions that hinder the general of the results. There is a pressing need for further trials that survey various experiment designs, stimulation protocols, and standardized neuropsychological cognitive assessments, which are crucial for gaining a more comprehensive understanding of tDCS in the treatment of cognitive decline associated with MCI and AD (Table 1).29–32
Clinical trials using tDCS as therapeutic tool in AD.
LDLPFC: left dorsolateral prefrontal cortex; IFG: inferior frontal gyrus; AG: angular gyrus; CS: cognitive stimulation; a-tDCS: anodal-tDCS; s-tDCS: Sham-tDCS; L: left; R: right; MMSE: Mini-Mental State Examination; MCI, mild cognitive impairment.
L/R DLPFC (F3 and F4), Broca's area (F5), Wernicke's area (CP5), L/R somatosensory association cortex (P3 and P4).
tACS's potential therapy for AD
By entraining neurons under particular cortical rhythms based on the applied stimulation frequency (e.g. 40 Hz), tACS, a unique form of tES, modifies cortical oscillations and may be a promising alternative for neuronal illness. 33 The targeted region and particular oscillatory activity are believed to enhance cognitive or sensory functioning through neural entrainment, which stimulates oscillatory activity at the stimulation frequency.34,35 Weak oscillating electric currents, usually between 1 and 4 mA in humans, are applied to the scalp during tACS. Due to limited skull conductivity, the currents largely shunt via tissues around the brain, including skin and cerebrospinal fluid, before reaching the brain.
Recent preclinical work has demonstrated that exogenously-induced 40 Hz gamma oscillations can reduce Aβ deposition via microglia activation and may also reduce p-Tau levels in a mouse model of AD (5XFAD). 36 Thus, gamma induction might be a new and effective therapeutic frequency. 37 Meanwhile, γ-tACS might help with a number of cognitive processes in patients with AD.38,39 Dhaynaut et al. conducted a further trial of 40 Hz-tACS treatment on AD patients for a period of four weeks. The patients were subjected to positron emission tomography scans, which revealed that 75% of AD patients exhibited a reduction in p-tau load in the brain. 40 A study involving 15 participants with mild to moderate AD, and assigned participants equally into three subgroups. 38 The first group underwent ten sessions for 2 weeks of 40 Hz (gamma) tACS over the unilateral temporo-frontal. The second group received ten sessions for 2 weeks of γ-tACS over the bitemporal, and the third group underwent twenty sessions for 4 weeks of γ-tACS over the bitemporal. The results showed a significant increase in blood perfusion in the bilateral temporal lobes after the tACS treatment.
In addition to the temporal regions, Benussi et al. applied γ-tACS over the precuneus. 39 60 participants with AD were randomized into two groups of γ-tACS and sham-tACS.γ-tACS group receives an alternating sinusoidal current of 1.5 mA peak-to-baseline (3.0 mA peak-to-peak, current density: 0.09 mA/cm2) at a frequency of 40 Hz for 60 min. After 1 week of stimulation, a significant correlation between episodic memory and cholinergic neurotransmission (evaluated indirectly with transcranial magnetic stimulation) has been measured with enhancement, which suggests a potential beneficial effect of precuneus γ-tACS on memory in AD patients.
Another study has recruited eighty-seven eligible patients with mild to moderate AD, which were randomized into three groups received a three-week (15 sessions) treatment of tACS combined with sound stimulation, tACS, and sound stimulation. tACS group received tACS with gamma frequency (40 Hz) and a peak-to-peak amplitude of 1.5 mA 15 times, 20-min sessions across 3 weeks (21 days). The two electrodes (4 × 6 cm2) are placed in the DLPFC and the contralateral supraorbital area, which was located at F3 and F4 based on the 10–20 EEG. 20 min (stimulate for 5 min, rest for 5 min, stimulate for 5 min, rest for 1 min, and stimulate for 4 min), 40 Hz, 60 dB sound stimulation was applied in the sound group. For tACS combined with the sound stimulation group, the tACS and sound stimulation started and ended simultaneously. The results have shown that compared with tACS alone or sound alone, the combination group had a significant long-term effect on cognitive improvement. 41
40 Hz-tACS has the potential to improve cognitive function in AD patients with well-tolerance. The subsequent performance was insufficient with cognition capacities declining gradually. 42 The optimal tACS protocol in clinic has still urgent to be surveyed with large sample size of multi-center study.
tPCS's application analysis on AD
Another type of tES with a non-constant current is tPCS. In this paradigm, a unique stimulation form is produced by interrupting the stimulation at regular intervals and adding the definitions of pulse duration, frequency, and inter-pulse intervals (either short or long) to the current output. 43 tPCS can improve frontal and interhemispheric neural connections by altering the electrical activity of cortical and subcortical regions.44–46 Thus, it has been hypothesized that tPCS could reach deeper brain structures compared to tDCS.
Fifty-six Sprague-Dawley male rats of the AD model were randomly divided into seven groups (n = 8 per each group), the control group (cage control), the sham group, the Aβ group, the Aβ combined with tDCS group, the Aβ and tACS group, the Aβ and transcranial random noise stimulation (tRNS) group, and the Aβ and tPCS group. The tES was applied to the awake and freely moving rats’ right frontal cortex for 6 days, 20 min per session, with current intensities of 200 μA, the current intensity was ramped for 10 s. Aβ25−35 (5 μg/2.5 µL/day) or its vehicle (distilled water) was injected bilaterally in the four doses on days 1 and 4. Animal cognitive capacity was evaluated on days 11 and 12 by a novel object recognition (NOR) test. In the study, it was found that the different tES paradigms could improve Aβ-induced memory impairment in the NOR test. The effect of tRNS on the improvement of the performance of memory-impaired rats in NOR test was shown and had significant differences in total exploration time compared to other groups, and in this case, it seems more effective than other paradigms. tPCS did not significant difference compared to the other paradigm but could improve the Aβ-induced deficit in NOR test. Therefore, it can be expected that in addition to using tDCS, other stimulatory paradigms may also be considered in the treatment of AD. 47
Another study investigated the effects of theta tACS and phase-locked tPCS on learning and cognitive control. Twenty healthy volunteers participated in the study. Each volunteer partook in four sessions, receiving one stimulation type at random (theta-tACS, peak tPCS, trough tPCS or sham) while undergoing a learning game, followed by an unstimulated test based on learned material. Stimulation electrodes (2 cm × 2 cm) were placed on the scalp at F3 (anode) and F4 (cathode).Each session lasted approximately 1.5 h, with an interval of at least 2 days to allow for washout and to avoid cross-over effects. The results demonstrated that no statistically significant effect of stimulation on the event related potential recordings, EEG, and the performance of the volunteers. While stimulation effects were not apparent in this study, the nominal performance of the phase-locking algorithm offers a technical foundation for further research in determining effective stimulation paradigms and conditions. 48 And a significant number of basic and clinical trials are still needed to demonstrate the efficacy and safety of tPCS in enhancing cognitive function in individuals with AD in future.
Future challenges
At present, a mechanistic understanding of tES has lagged behind its widespread adoption. While it remains unclear how typical tES protocols affect neural activity and the lack of knowledge hampering the optimization and effectiveness of tES in treating AD, it is proposed that validated models of current flow should guide study design and artifacts should be carefully excluded during signal recording and analysis. Potential indirect effects of tES (e.g. peripheral stimulation) should be investigated in more detail and further explored in experimental designs. Novel technologies of tES with deeper brain tissue stimulation for enhancing validity, specificity, and reproducibility, as well as optimal therapeutic parameters, should be investigated.
AD's pathology is complicated, and its dynamic brain network activity mechanism is damaged in various disease stages. The mechanisms underlying brain cell senescence and by which cell senescence contributes to neurodegeneration and memory loss in AD, however, remain largely unknown. There are graph analysis implicates less efficient interaction between brain regions and supports the disconnection hypothesis of AD.49,50 Thus, it may be difficult to obtain normal brain remodeling and rehabilitation effects by relying only on a single target and neural regulation of brain region. The multiple brain regions modulation is a trend based on AD's brain network characteristics. This requires precise neuromodulation techniques that can target specific brain regions and pathological processes. As the EEG assessments, neural oscillation in AD brain regions was observed.49,51 The precise multiple brain regions neuromodulation would be a concern, and it is hoped that better clinical trials to achieve the benefits of large-scale, controlled studies using EEG biomarker-based diagnostic characterization of AD participants, development of neurophysiological markers to verify brain target engagement, and standardization of parameters were also concerned for challenges.
The common brain region targets of tES for AD neuromodulation.
Conclusions
tES has emerged as a promising approach for the treatment of AD with more safety and acceptability compared to invasive techniques. Meanwhile, tES operation is flexible with low cost. However, it seems hard to get the deeper brain area, which is important for AD neuromodulation, such as the hippocampus. Currently, tDCS has achieved more research in AD animals and patients than tACS and tPCS. tACS as a particular electrical frequency-adjusted character has attracted more attention for cognitive impairment treatment. In addition, tES combined with other therapies, such as acupuncture and functional training, may further enhance its therapeutic effects. However, due to the complications of AD, the optimized brain area regulation needs to be further revealed. Meanwhile, the nervous modulation mechanism underlying tES is still unclear and remains to be elucidated, as well as multi-clinical centers with a large number of AD and MCI participants to acquire appropriate parameters and assess therapeutic effects. With the development of brain imaging technology, individualized brain assessments and accurate neuromodulation are becoming a trend for AD rehabilitation.
Footnotes
Acknowledgments
The authors have no acknowledgments to report.
Author contributions
Huan Wang (Investigation; Supervision; Writing – original draft; Writing – review & editing); Yuanli Li (Writing – original draft; Writing – review & editing); Ning Qin (Resources; Supervision); Dilinuer Maimaitiaili (Resources); Jiali Wu (Investigation; Methodology); Shuangqin Wang (Investigation); Yixin Zhou (Methodology; Resources); Jingjue Lu (Supervision; Visualization).
Funding
The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the 2023 Science and Technology Development project of Shanghai University of Traditional Chinese Medicine (No.23KFL022) and the Discipline Construction of Pudong Health Bureau of Shanghai (Grant No. PWZzb2022-11).
Declaration of competing interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.