Some device-based non-invasive brain stimulation methods have been recommended as probably effective for cognitive treatment in Alzheimer disease. New targets and novel transcranial electrical stimulation techniques enable physiology-inspired modulation of oscillatory activity and precise targeting of deep brain structures.

Various methods of non-invasive brain stimulation (NIBS) have been studied for the treatment of mild cognitive impairment (MCI) and dementia in people with Alzheimer disease (AD). Device-based NIBS techniques modulate brain function by inducing electric fields in the brain. Most studies have tested multiple sessions of repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS); however, other emerging approaches have shown promising results, including transcranial alternating current stimulation (tACS) and temporal interference stimulation (TIS). Here, I summarize the various techniques and their individual benefits.

rTMS enables specific targeting of cortical areas close to the scalp and induces action potentials in the targeted neuronal population1. Distant effects can also be observed in brain regions structurally or functionally connected with the stimulated region, as shown by electroencephalography (EEG), TMS–EEG, PET and functional (f)MRI1,2,3. The method is powerful; however, it can be applied only in a laboratory setting, as the device is not easily portable. By contrast, transcranial electrical stimulation (tES) techniques such as tDCS and tACS use a very low current intensity (~1–2 mA) that does not directly induce neuronal firing, but modulates neuronal membranes towards hypopolarization or hyperpolarization. Performance of concurrent activity such as cognitive training with the stimulation has been suggested to enhance the potential cognitive after-effects. One great advantage of tES techniques is their potential implementation as home-based treatments, because the device is easily portable. Furthermore, both rTMS and tDCS protocols are overall well tolerated with very good safety profiles1,4.

A review and a meta-analysis1,4 demonstrated that most randomized controlled trials (RCTs) of rTMS in AD have focused on two types of high-frequency (~10–20 Hz) stimulation protocol. In one protocol, rTMS is applied over the left dorsolateral prefrontal cortex (DLPFC), whereas in the other, the certified NeuroAD system, stimulation is applied over multiple cortical sites of both hemispheres, including Broca’s and Wernicke’s areas, the bilateral parietal somatosensory association cortices and the bilateral DLPFC, in conjunction with cognitive training. The rationale for targeting the DLPFC is its involvement in attention, executive function and working memory. The NeuroAD system targets the DLPFC alongside additional regions that are involved particularly in language processing, attention and somatosensory functions.

“therapeutic effects in people with more severe dementia can be mitigated by pronounced cortical atrophy”

The RCTs showed that, in people with AD, rTMS applied over the DLPFC improved global cognition and associative memory, and the NeuroAD system improved global cognition1,4. Both protocols revealed a medium effect size in mild AD–dementia and MCI, and were recommended as probably effective (B-level of clinical evidence) for AD–dementia4. The effects seem to last for at least one month and vary between different session protocols1,4. Evidence suggests that therapeutic effects in people with more severe dementia can be mitigated by pronounced cortical atrophy5.

Among other brain regions, the precuneus was successfully targeted in a 24-week RCT of rTMS in people with mild-to-moderate AD2, showing improvement in global cognition and activities of daily living. The precuneus is engaged in episodic memory and visuospatial processing and constitutes a major hub of the default mode network (DMN), which is disrupted early during the course of AD. The left inferior parietal lobule is another DMN site that has been targeted in trials of rTMS: in people with mild-to-moderate AD, ten sessions of high-frequency stimulation over the region improved global cognition and dynamic functional connectivity of the DMN compared with sham treatment6. Beyond targets in the DMN, 5 Hz rTMS of the bilateral cerebellar crus II region also shows promising results in people with AD, both in terms of improvement of multiple cognitive domains and enhancement of cerebellar–cortical connectivity, particularly to the DLPFC7.

In tDCS protocols, anodal DLPFC stimulation led to significant improvements in overall cognition and working memory (probably effective, level-B evidence), with a medium effect size for the group with AD–dementia and a small effect size for MCI4. Notably, the meta-analysis did not reveal a major enhancement of tDCS by concomitant cognitive training, although a small significant enhancing effect of combined treatment was demonstrated in the MCI subgroup4. The limited effect might be because cognitive training combined with stimulation is not feasible in individuals with full-blown dementia.

In people with amnestic MCI, one study tested an intensified stimulation protocol of anodal tDCS of the left DLPFC applied twice per day for five consecutive days combined with cognitive training8. Performance in a working memory task was not enhanced by the treatment, suggesting that intensified stimulation, with more stimulation sessions per day, is not superior to the standard protocols that use one stimulation session per day. On the other hand, high-definition tDCS applied over multiple cortical sites might prove efficacious.

Other promising protocols for the treatment of MCI and AD-dementia include tACS protocols. For example, tACS was applied at a physiology-inspired gamma frequency over the precuneus of people with AD9. One hour of treatment improved auditory verbal and associative memory and cholinergic transmission (assessed by short latency afferent inhibition). Moreover, clinical improvement was associated with increased gamma frequency activity and an increased electric field in the stimulated region, suggesting that the cognitive after-effects were linked to successful entrainment of gamma oscillations by tACS9. Studies in healthy volunteers suggest that more sophisticated protocols might be required for boosting working memory performance, for example by enhancing theta–gamma cross-frequency phase amplitude coupling10. Monitoring and adjusting tACS to the individual’s ongoing background oscillatory brain activity should be addressed in future research.

tES currents can reach deeper brain regions than rTMS, although at the expense of focality11. TIS is a new tES method that can precisely target deep brain structures without modulating surrounding brain tissues. TIS involves two or more differing high-frequency signals (>1 kHz) emitted by at least two pairs of electrodes that temporally interfere at the targeted area deep in the brain. Overlap of the waves at the targeted region causes the electric fields to combine through the principle of superposition, creating an amplitude-modulated signal envelope at a frequency pattern equal to the difference between the two source signals.

The first TIS studies in young healthy adults have been published; one study targeted the anterior hippocampus, which is involved in memory encoding and is affected in AD. The results showed a trending improvement in associative memory performance and significant task-induced blood-oxygen-level-dependent (BOLD) signal decreases in the stimulated region, as assessed by online fMRI11. One possible explanation for this observation is that by augmenting endogenous theta synchronization in the hippocampus, TIS decreases underlying metabolic demand, resulting in reduced BOLD signal11.

“NIBS can potentially serve as long-term home-based treatments”

In conclusion, device-based NIBS techniques have attracted much attention owing to their good safety profiles and their ability to enhance specific cognitive functions for several weeks or months and to modulate brain networks and even deep brain structures. Further adding to their appeal, NIBS can potentially serve as long-term home-based treatments. Pre-stimulation optimization, at least by current modelling, might be necessary in future trials in people with AD.