rTMS for the treatment of Alzheimer’s disease: where should we be stimulating?

KEYWORDS:

• Alzheimer’s disease
• brain stimulation
• cognition
• cortical changes
• neuroplasticity
• rTMS
• targeted treatment

1. Introduction

Alzheimer’s disease (AD) is a neurodegenerative disorder affecting over 40 million individuals worldwide [1]. It is characterized by a debilitating progressive loss of cognitive function, and although the underlying cause of the disease is complex, the corresponding brain atrophy and loss of neuroplasticity have been well documented [1,2]. Recently, there has been a focus on treating AD with brain stimulation techniques that facilitate neuroplasticity and target large-scale neurocircuits, such as the hippocampal-parietal and central-executive networks, which are dysfunctional in AD [3–5]. One form of brain stimulation of interest is repetitive transcranial magnetic stimulation (rTMS) as it can be applied non-invasively and painlessly to patients [6].

The faciliatory effects of rTMS on cognition in healthy adults provided the rationale for its first use in AD [7]. Overall, studies have shown that rTMS can significantly improve cognition in patients with AD (for the meta-analysis see [6]), but it is not clear what brain areas are the most appropriate to target. Structures which are important for memory, such as the hippocampus, are affected early in the pathology [2]. Yet, it is difficult to target deep brain structures with traditional rTMS coils, deep rTMS coils could achieve this but with a loss of focality. As this editorial is focused on targeted rTMS, in which cortical targets near the scalp have primarily been studied, deep rTMS methods have not been reviewed.

The most commonly targeted cortical region is the dorsolateral prefrontal cortex (DLPFC), but there is a lack of research into other regions that could prove effective for treating cognitive decline. It is important to understand what aspects of the disease should be considered when determining these regions.

2. Dorsolateral prefrontal cortex

Studies which targeted the DLPFC, a key node of the central-executive network, with rTMS have shown improvements in cognitive scores using both short- and long-term stimulation paradigms [7–11]. In patients with AD, disrupted DLPFC plasticity is linked to worsened working memory and language comprehension [12], so targeting the DLPFC could alleviate these deficits. Interestingly, rTMS targeting the DLPFC is also an FDA-approved treatment for patients suffering from Major Depressive Disorder. Depression has a high comorbidity with AD and impaired cognition is closely linked to depressive symptoms [13,14]. In an AD study where patients had depressive symptoms, stimulating the DLPFC improved cognitive performance whilst also reducing depression [11]. Currently, there exists a discrepancy between studies, with some excluding patients with depressive symptoms [7–10] and others not disclosing whether neuropsychological testing was considered [15,16]. This makes it difficult to dissect the effects of rTMS on improving cognition, as decreasing depressive symptoms could be contributing to the improvements [14].

The DLPFC has also been linked to other neuropsychiatric symptoms, including apathy [9,17]. Apathy is a negative symptom where patients have a failure to initiate behaviors and experience retardation of emotional expression [18]. It has a high prevalence in AD, often contributing to worsening quality of life, and like depression, is associated with cognitive deficits [18]. Recently, studies which stimulated the DLPFC reported reductions in apathy alongside improvements in cognition [9,15]. Therefore, improvements in apathy may also contribute to the DLPFC targeted rTMS effects in non-depressed patients.

In summary, the DLPFC is associated with many brain functions, including both memory and mood regulation. With a lack of effective treatments for depression and apathy in AD, rTMS targeting the DLPFC could be an alternative treatment for these negative psychological symptoms [13]. Therefore, it is important to understand how improvements in such symptoms contribute to cognitive functioning in AD and to determine if other areas may be more appropriate stimulation targets for the deficits documented in AD.

3. Multisite stimulation

Recently, a multisite rTMS approach has been developed for treating AD. Known as NeuroAD, it involves alternating between stimulating the DLPFC, Broca’s area, Wernickes area, and the parietal somatosensory association cortex, in conjunction with cognitive training [4]. Studies examining the effects of NeuroAD have demonstrated significant improvements in cognition for months after the end of stimulation [4,15,16]. The effect has only been explored in combination with cognitive training, so it is unclear the exact contributions of rTMS, as cognitive training on its own is beneficial for improving overall cognition [19]. However, the NeuroAD protocol does highlight the importance of other brain regions for improving cognition in AD.

4. Other targets

There have been three studies in AD which examined targeting other brain areas with rTMS, each with their own specialization and significance. Firstly, a study by Anderkova et al. [20] targeted the right inferior frontal gyrus and superior temporal gyrus. These brain regions are involved in attention and cognitive speed [20], and patients with AD exhibit disturbances in attention from early in the condition [17]. In this study rTMS improved performance on attention-related tasks, though overall cognition was not assessed [20]. Zhao et al. [3] stimulated the parietal cortex, which is part of the hippocampal-parietal network [5]. After long-term rTMS stimulation to the parietal cortex, participants had improved overall cognition in mild, but not in moderate AD [3]. Finally, Koch et al. [21] targeted the dorsal precuneus which undergoes atrophy and loss of functional connectivity in AD [21,22]. Following two weeks of rTMS treatment, episodic memory deficits were alleviated and the connectivity of the precuneus improved [21]. These studies show that targeting brain areas other than the DLPFC can also improve cognition in AD patients. But what may influence the choice of region in future studies?

5. Choice of the region for treating Alzheimer’s disease

There are benefits to choosing specific areas of the brain to stimulate. Targeting specific structures has the potential to influence cognitive and emotional behaviors; as previously demonstrated by studies stimulating the frontal gyrus to improve attention, or the DLPFC for language comprehension and neuropsychiatric symptoms such as depression or apathy [8,9,11,20]. An alternative strategy is to attempt to repair brain areas and connections which are negatively affected in AD, for example, stimulating the precuneus to rescue abnormal functional connectivity [21].

Assessing regions involved in specific memory functions could indicate new areas to target in AD. Episodic memory is of interest as it is profoundly impaired in AD and involves the hippocampus. Though it cannot be stimulated directly, targeting cortical areas associated with the hippocampus and episodic memory; such as the posterior parietal cortex or the angular gyrus [23], could improve this function in AD. However, it remains unclear if stimulating brain areas to affect specific memory functions is the most effective use of rTMS to treat AD or whether the underlying pathology should be examined.

The main mechanism of rTMS is through inducing plasticity and strengthening brain connections, and as demonstrated in healthy adults, rTMS can alter cortico-hippocampal connectivity and improve cognition [5]. Therefore, identifying areas which present a loss of functional connectivity in AD could provide potential targets for rTMS. In one AD study, various cortical areas were all found to have disrupted connectivity to the hippocampus, including the medial prefrontal cortex, cingulate cortex, inferotemporal cortex, and the superior and temporal gyrus [24]. Another study showed that decreased connectivity in default mode network cortical structures was correlated to cognitive decline, including the median- and paracingulate gyrus, precuneus, and superior temporal lobe [25]. Targeting these areas has the potential to directly influence disrupted connectivity, but more research is needed to determine which specific brain area is key to effectively improve cognition in patients with AD.

One caveat of investigating new stimulation sites are the neuronavigational techniques which should be employed during clinical development, as new stimulation sites involve MRI navigated rTMS [20,21]. Once targets are validated as efficacious, the 10–20 system is likely to provide reliable coil positioning (as it has with the DLPFC [7,26]) and enable larger-scale research and clinical use.

Another aspect to consider is the stage of the disorder, as AD typically follows a well-documented progression affecting many brain regions. From Mild Cognitive Impairment (MCI) to severe AD, regions undergo atrophy, neuroplastic changes, and increasing plaque and tangle burden [1]. Discerning the changes in specific brain areas over the progression of the disorder is important as they could be targets to slow the development of MCI to AD. Research has identified progressing cortical atrophy in the precuneus, medial temporal and posterior parietal regions at the earliest stages of the disease, extending later to the prefrontal, sensory and motor cortices [2,22]. Interestingly, studies found that the stage of the disorder does influence the outcome after rTMS; MCI and mild AD patients often have greater improvements than severe AD [3,9,11,16]. The difference in severe patients may be due to targeting the wrong area but it is more likely rTMS is not effective in severely developed AD as the widespread brain atrophy is irreversible [20].

6. Conclusion

There is extensive evidence that rTMS can have benefits for patients with AD. Therefore, research should focus on how these benefits can be maximised. This may involve addressing fundamental questions such as how specific areas and pathways contribute to memory processes or which cortical connections disrupted in AD need strengthening. Additionally, one target alone may not achieve success within a population; multiple targets or individualised analysis could serve to develop a well-planned tailored treatment for individuals at different disease states. Such basic understanding will be significant to inform the optimal rTMS targets in the future.

Declaration of interest

The authors have nothing to declare.

Additional information

Funding

This paper was not funded.