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 Table of Contents  
REVIEW ARTICLE
Year : 2020  |  Volume : 4  |  Issue : 2  |  Page : 122-125

Role of repetitive transcranial magnetic stimulation in management of alzheimer's disease


Department of Psychiatry, T.N.M.C and B.Y.L. Nair Ch Hospital, Mumbai, Maharashtra, India

Date of Submission04-Jun-2020
Date of Decision28-Jun-2020
Date of Acceptance09-Jul-2020
Date of Web Publication24-Sep-2020

Correspondence Address:
Dr. Hrishikesh B Nachane
63, Sharmishtha, Tarangan, Thane – West, Thane 400 606, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/aip.aip_44_20

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  Abstract 


Management strategies in Alzheimer's disease (AD) are challenging and limited in several aspects. Repetitive transcranial magnetic stimulation (rTMS), being a noninvasive brain stimulation method, has recently been studied in the management of AD. The literature available is different on several aspects such as patient enrollment, site of stimulation, outcome measures, and follow-up. We present a narrative review highlighting important aspects of rTMS in AD. We searched the databases of Google Scholar and PubMed using the search terms: rTMS and Alzheimer's disease; rTMS and cognition; rTMS and dementia; and brain stimulation and Alzheimer's disease. Original research, case reports and series, other narrative reviews, systematic reviews, and meta-analyses were included, and studies where only abstracts were available were excluded. Majority of the studies present a modest benefit of rTMS in mild–moderate AD and some in normal aging and mild cognitive impairment. Improvement is marked in high-frequency rTMS as compared to low frequency. The favorite site of stimulation appears to be the dorsolateral prefrontal cortex (DLPFC). Studies chiefly assessed cognitive function, while sparingly involving other areas of impairment such as psychopathology and global functioning. Improvement in cognition is mainly in the weeks ensuring rTMS, and studies assessing improvement in a long-term follow-up are needed. There appears to be minimal to no side effects reported in most studies. Future implications of rTMS in AD are suggested.

Keywords: Alzheimer's disease, cognition, repetitive transcranial magnetic stimulation


How to cite this article:
Nachane HB, Kedare JS. Role of repetitive transcranial magnetic stimulation in management of alzheimer's disease. Ann Indian Psychiatry 2020;4:122-5

How to cite this URL:
Nachane HB, Kedare JS. Role of repetitive transcranial magnetic stimulation in management of alzheimer's disease. Ann Indian Psychiatry [serial online] 2020 [cited 2021 Apr 20];4:122-5. Available from: https://www.anip.co.in/text.asp?2020/4/2/122/295906




  Introduction Top


Alzheimer's disease (AD), a chronic progressive neurodegenerative disorder, has met with limited success in its management.[1] It is usually associated with changes in cognitive processes, beginning particularly with memory and then extending to other cognitive domains, such as language and praxis.[1] Behavioral and psychological symptoms of dementia (BPSD) constitute a major clinical component of AD that usually accompany cognitive changes and are a source of suffering for the patients as well as caregivers.[2] They have a deeper impact on the patient's lifestyle and management, more than the cognitive changes, at times.[2] With an increasing understanding of the pathophysiology behind AD, newer modalities of treatment are being tried.[3],[4] However, most have met with limited success.[5] AD puts a tremendous financial stress not only on the patient's family but also on the health-care system as well, and hence, it is imperative to develop effective management strategies.[6]

Given the limited effectiveness of pharmacological therapies, nonpharmacological interventions in AD have gained attention in recent years, particularly various brain stimulation techniques.[1],[7] Noninvasive brain stimulation such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation have proven valuable in research and therapeutics and are currently being tried in several stages of AD.[1],[8] rTMS is a novel brain stimulation technique that delivers rapid sequences of several magnetic pulses up to frequencies of 100 Hz.[1] rTMS is now finding its place in the management of AD. This review highlights the potential uses, techniques, and side effects of rTMS in AD.


  Methods Top


The review presented is a narrative review. The databases that were searched for the present review were primarily Google Scholar and PubMed. We used the following search terms: rTMS and Alzheimer's disease; rTMS and cognition; rTMS and dementia; and brain stimulation and Alzheimer's disease. Studies where rTMS was used therapeutically were only included. The types of papers included for the review were original research, case reports and case series, narrative reviews, systematic reviews, and meta-analyses. Research articles pertaining to other types of dementia or mixed type of dementia were excluded. Studies where only abstracts were available were also excluded. The focus of the present review was to highlight the mechanism of action of rTMS in AD, the site and nature of stimulation, and the procedures in conducting research, including outcome measures and side effects.


  Mechanism of Action of Repetitive Transcranial Magnetic Stimulation in Alzheimer's Disease Top


It was seen that stimulation of various parts of the brain led to an improvement in cognition and memory.[9],[10] Wang et al. demonstrated improvement in associative memory by showing that multiple session magnetic stimulation of the hippocampus increased functional connectivity among distributed cortical–hippocampal networks.[9] It was based on these findings that rTMS was tried in AD.[11] The use of rTMS typically involves the induction of local electric currents, called eddy currents by means of rapidly changing magnetic fields. This process then leads to trans-synaptic depolarizations of pools of neurons located in the superficial cortical layers.[12],[13] This modification of cortical activity leads to readjustment in pathological patterns of brain activity, thereby providing an opportunity for developing novel, healthier activity patterns within the affected functional networks.[14] rTMS can produce enhancement or suppression of cortical excitability in specific cortical regions depending on its various stimulation parameters such as frequency, duration of stimulation, and stimulus intensity.[15],[16] In general, it has been observed that high-frequency rTMS facilitates cortical excitability, whereas low-frequency rTMS suppresses cortical excitability.[17],[18] rTMS, however, has to be given typically for much longer periods, applying several hundred or thousand stimuli to incite a therapeutic response.[19] Only with such repetitive stimulations can long-lasting effects on cortical excitability be seen that will persist even after termination of stimulation.[19] rTMS is also known to facilitate neuroplasticity, as do other brain stimulation modalities and effects are demonstrated usually in large-scale neurocircuitry, particularly the hippocampal–parietal and central-executive networks, which have been shown to be dysfunctional in AD.[10],[11] Long-term potentiation in the synaptic neuronal activities is frequently linked to memory and learning processes, and co-activation of these neural circuits is facilitated by rTMS.[20] This could potentially enhance learning and memory and this explains why rTMS finds a place in the management of AD. The other added advantages of developing rTMS as a potential treatment strategy in AD also include safety, its noninvasive quality, and the ease of applying various combinations of stimuli.[19],[21]


  Stimulation – Site, Stage, and Method Top


The region of application of rTMS is one of the most important factors in deciding its clinical efficacy. Lefaucheur et al.[22] have demonstrated that the area of stimulation can vary based on the diagnosis of the patient and the outcome desired. Pertaining to research in AD, recent literature on neuroimaging highlights increased activation in the right dorsolateral prefrontal cortex (DLPFC) and has attributed this area to the functional brain abnormalities associated with memory deficits in AD.[23] This has made DLPFC a common target for rTMS in various experiments and therapeutic protocols.[12] Furthermore, DLPFC forms an important part of the executive network, justifying its use in AD.[11] In patients with AD, disrupted DLPFC plasticity is linked to worsened working memory and language comprehension in AD as well, and targeting the DLPFC could potentially alleviate these deficits.[24] Stimulation of this region has shown benefits in both short-term and long-term stimulation therapies.[25],[26] DLPFC additionally serves the advantage of alleviating other symptoms of BPSD as well, such as depression and apathy.[19],[27]

Targeting the right inferior frontal gyrus and superior temporal gyrus in a study has led to an improvement in attention and cognitive speed in AD.[28] Other studies involving stimulation of the parietal cortex[29] and the dorsal precuneus[30] also demonstrated improvement in overall cognition. In a study involving multisite stimulation in rTMS, Rabey and Dobronevsky[7] targeted six potential sites: Wernicke's area (left superior temporal gyrus), Broca's area (left inferior frontal gyrus), left and right DLPFCs; and left and right parietal somatosensory association cortices. Their sessions alternated between these sites, and they documented significant improvement in overall cognition. Thus, it appears that choosing the right area is crucial to demonstrate significant improvement in AD. Future research can perhaps target case sensitive areas of the brain, which show dysfunction for rTMS. One such technique is magnetic resonance imaging (MRI) navigated rTMS, which initially confirms the site as efficacious and then directs the machine to take a reliable position.[28],[30]

There has also been variation in delivering the stimulus. A few studies have applied rTMS while the patient was performing a certain cognitive task.[10],[31] Many used multiple session trials,[32],[33] while some combined it with cognitive stimulation therapy.[7] Each of these factors can affect the improvement seen. The stage of AD in which rTMS is applied also determines the improvement. While good clinical improvement is seen in normal aging, mild cognitive impairment (MCI), and mild AD, improvement is minimal in severe AD.[19],[25],[29] Choosing the wrong area and widespread brain atrophy have been given as the two most important reasons for the failure of rTMS in severe AD.[11],[28]


  Procedures in Research of Repetitive Transcranial Magnetic Stimulation in Alzheimer's Disease Top


Studies involving rTMS in AD have shown a variety of enrollment criteria. Majority of the studies use the National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer's Disease and Related Disorders Association criteria to diagnose AD.[32],[33] One study has used Diagnostic and Statistical Manual of Mental Disorders, 4th edition, to include probable AD in their study.[20] There have been studies performed on MCI and AD with varying degrees of severity (mild to severe).[33] This can thus lead to difference in their outcomes. Exclusion criteria applied by many researchers have ruled out patients with strokes, epilepsy, metabolic side effects, etc., which can hamper cognition.[19],[33] A few have also excluded comorbid depression.[34] This might lead to significant bias as these conditions are frequently comorbid with AD. Since many studies are randomized control trials, sham groups have to be included. Lee et al. have described how they created a sham group in their study. They achieved it by replicating the noise induced by the rTMS machine.[20]

No study has shown uniformity in measuring outcomes of rTMS in AD. While some studies have focused on specific cognitive domains such as memory, language, picture naming, sentence comprehension, and executive functions, majority have used standard cognitive batteries.[33] Tests have also been added to measure the change in functioning, activities of daily living (ADLs), behavioral issues, depression, etc. The most common tests include Alzheimer Disease Assessment Scale (ADAS)-Cognitive, the ADAS-ADLs, Mini-Mental State Examination, Montreal Cognitive Assessment, Battery for Analysis of Aphasic Deficits, the Revised Memory and Behavior Checklist, World Health Organization–University of California–Los Angeles–Auditory Verbal Learning Test, Instrumental Daily Living Activity scale, the Geriatric Depression Scale, Clinical Global Impression of Change, and Neuropsychiatric Inventory.[7],[19],[20],[33] Needless to say, that using different assessment tools and using them at different intervals can affect the outcomes being measured. This has also generated varied results. Apart from cognition, few studies assessed mood, global impression, and functional performance.[7],[19],[20] Often, it is such behavioral disturbances, quality of life, and functionality that is a source of distress or burden in AD. It is imperative that such factors be considered in outcome measures in studies pertaining to AD and further trials should incorporate them.

Several studies used rTMS as an adjunct and patients receiving rTMS were also on medications. A study done by Cotelli et al.[32] had enrolled patients already on a stable dose of donepezil or rivastigmine for 6 months and subsequently used rTMS as an adjunctive treatment, and they excluded AD patients on other medications, whereas Lee et al.[20] asked the patients to continue the same treatment that they were on throughout the trial. Zhao et al.[29] had patients on donepezil but did not define the levels at the beginning. They have mentioned this as their limitation. Some studies have also used cognitive training exercises in adjunct to rTMS.[7] Lee et al.[20] delivered rTMS while the patients were performing cognitive tasks. Such methods of using adjunctive rTMS with other techniques might bias the outcomes and as such caution should be exercised when interpreting such findings. A recent meta-analysis, which evaluated noninvasive brain stimulation in healthy older people and AD, showed that multiple session rTMS had long-lasting outcomes than single sessions.[33] Ahmed et al.[19] have shown that high-frequency rTMS had significantly more improvement in cognition over low-frequency rTMS. A particular study compared single-site versus multisite rTMS (stimulating six different sites with three sites at a time) in terms of cognition and showed that improvement was similar in both.[35]

Considering the endpoint at which to measure cognitive improvement is also crucial. The range of endpoints has varied from as little as 1 week to 10 months.[7],[19],[32],[33] Hardly any literature is available where long-term follow-ups of patients were available. Rutherford et al. kept a follow-up for every 3 months for a few patients and found that cognitive improvement lasts only a few weeks after the last rTMS session.[34] They recommended repeating sessions every 3 months. Not to mention, many studies had patients on medications, and it is difficult to say if these doses were maintained or changed after discontinuation of rTMS.[20],[29],[32] This might again impact their cognitive changes. Surprisingly, majority of the studies had little to no side effects. Most common side effects reported have been headache, fatigue, and dizziness.[7],[29],[33] It is interesting to note that one study has shown similar side-effects in the sham group as well.[29] This implies that rTMS may be a safe and cost-effective option in AD.


  Conclusions and Future Implications Top


There appears to be a fair amount of data that highlight the beneficial role of rTMS in the treatment of AD. Modification of cortical activity and neuroplasticity appears to be responsible for its effect. There is considerable variation in its use, site of application, quantifying outcomes, and follow-up of patients. Having uniform enrollment criteria is also equally crucial as patients at various stages respond differently. Locating and stimulating the right region of the brain is probably the most important deciding factor in cognitive improvement and modalities such as MRI-navigated rTMS could pave the way in this aspect. Concurrent treatment with pharmacological agents and cognitive exercises confound few of the available literature. Outcome measures should include other factors such as psychopathology, quality of life, functioning, and disability which are crucial in determining the management and prognosis of the patient. Majority of the clinical studies on rTMS in AD do not correlate changes in cognition with neoplastic changes/changes in regional blood flow or with levels of neurotransmitters. It would be interesting to analyze the interplay between these factors and such studies should be undertaken in future. Studies with a longer duration of follow-up can shed better light on the exact success of rTMS in AD.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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