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 Table of Contents  
REVIEW ARTICLE
Year : 2017  |  Volume : 4  |  Issue : 2  |  Page : 106-114

Transcranial direct current stimulation for mild cognitive impairment


1 Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India
2 Department of Psychiatry, National Institute of Mental Health and Neurosciences; Cognitive Neurobiology Division, Neurobiology Research Centre, Translational Psychiatry Laboratory, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India

Date of Web Publication29-Dec-2017

Correspondence Address:
Palanimuthu T Sivakumar
Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bengaluru - 560 029, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jgmh.jgmh_5_17

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  Abstract 

Mild cognitive impairment (MCI) is recognized as a target for early intervention in elderly with high risk for dementia due to Alzheimer's disease (AD) and other related disorders. Transcranial direct current stimulation (tDCS) is reemerging as a novel method of noninvasive brain stimulation in various neuropsychiatric disorders including MCI and dementia based on the potential clinical applications of its utility in modulating neuroplasticity. In this article, we review the neurobiology of aging, AD, and MCI from the perspective of tDCS and summarize the findings from studies applying tDCS in MCI to improve cognitive function. Studies on therapeutic application of tDCS to improve cognitive function in MCI and other related disorders have shown mixed results. Limited studies available in this topic suggest a potential role for tDCS in MCI. Low risk for adverse effects, lower cost, and the possibility of self-administered home-based intervention are important advantages that encourage further research in this field. There is a need for more evidence from large systematic randomized controlled trials regarding the efficacy of tDCS in MCI. Standardization of stimulation protocols, evaluation of long-term outcome with the possibility of maintenance tDCS, and efficacy of combined intervention of tDCS and cognitive training are important areas for future research in this area.

Keywords: Cognition, mild cognitive impairment, transcranial direct current stimulation


How to cite this article:
Murugaraja V, Shivakumar V, Sinha P, Venkatasubramanian G, Sivakumar PT. Transcranial direct current stimulation for mild cognitive impairment. J Geriatr Ment Health 2017;4:106-14

How to cite this URL:
Murugaraja V, Shivakumar V, Sinha P, Venkatasubramanian G, Sivakumar PT. Transcranial direct current stimulation for mild cognitive impairment. J Geriatr Ment Health [serial online] 2017 [cited 2019 Aug 22];4:106-14. Available from: http://www.jgmh.org/text.asp?2017/4/2/106/221907




  Introduction Top


The ability of noninvasive brain stimulation techniques such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) to modulate cortical excitability and plasticity has resulted in extensive use of these techniques in clinical research and as an adjuvant treatment strategy in various neuropsychiatric disorders.

tDCS is a remerging noninvasive brain stimulation technique, where a minute amount of direct current (0.5–2 mA) is delivered across scalp using bipolar electrodes (anode and cathode) over target regions of interest. Most of the studies so far using conventional tDCS have utilized nonmetallic, conductive rubber electrodes, wrapped in sponge covers soaked in saline. The electrode size ranges from 25 cm to 35 cm. However, recent studies of high-definition tDCS using smaller Ag–AgCl electrodes (1 cm 2) are becoming increasingly popular.[1] In principle, the goal of tDCS is to modulate the neuronal activity of specific brain regions in a polarity-dependent manner.[2] During stimulation, the current flows into the brain between the electrodes modulating the brain such that the region beneath the anode undergoes depolarization resulting in excitation and that beneath the cathode undergoes hyperpolarization resulting in inhibition.[3]

The mechanism of action of tDCS is not completely understood. Preliminary evidences point at alteration in resting membrane potential as the primary mechanism underlying the excitability changes.[4] However, this effect is considered to be of short-term and the long-term effects of tDCS are thought to be due to changes in long-term potentiation and long-term depression brought about by changes in N-methyl-D-aspartate (NMDA) and gamma-aminobutyric acid (GABA) receptor activities, resulting in modulation of neural plasticity.[5],[6]

In the present review, we will focus on the use of tDCS in mild cognitive impairment (MCI). Here, we will first review about MCI and the predominant neurobiological changes reported in the brains of healthy elderly age group, in patients with Alzheimer's disease (AD) and MCI, from the perspectives of tDCS. Following this, we will discuss about the potential application of tDCS to address these changes. We will also review the studies investigating the usage of tDCS in patients with MCI. The review ends with a summary and conclusion regarding the use of tDCS in MCI with possible future directions.


  Cognitive Impairment in Normal Aging, Mild Cognitive Impairment, and Alzheimer's Disease Top


Decline in cognition in any of the domains such as memory, language, visuospatial, and executive function has been noted as a part of normal aging progress as well as due to medical risk factors. Common causes for impaired cognition range from reversible factors such as sleep deprivation, medication side effects, vitamin B12 deficiency, hypothyroidism, and substance abuse to irreversible causes such as dementia due to neurodegenerative disorders and vascular insult.[7]

Dementia is a chronic disorder characterized by progressive deterioration of cognitive function that is severe enough to have an adverse impact on the functional activities of a person. AD is the most common type of dementia associated with significant socioeconomic impact. Disability weight factor for dementia is the second highest, with a factor value of 0.666. Furthermore, as per the WHO report on the leading contributors to the Disability-Adjusted Life Years burden among people aged 60 years and above, dementia was ranked 5th in 2004.[8]

Terms such as benign senescence forgetfulness, age-associated memory impairment, and more recently, the term, “age-associated cognitive decline” were used to describe cognitive complaints which were felt to be a part of normal aging. The term MCI was introduced to describe the transition period from a state of normal cognitive function to dementia and was considered as a prodromal or early stage in the dementia severity. With overall prognosis less favorable than individuals with normal cognitive functions, individuals with MCI are also at higher risk for further progression in to dementia. Several studies have looked into the progression rate of MCI to dementia, and the average rate was around 20%–40% and the average annual dementia conversion rate was around 10%–15% per year.[9] These factors highlight the importance of targeting MCI in tackling dementia.


  Neurobiological Changes in Mild Cognitive Impairment and Alzheimer's Disease Top


A volume loss of more than 0.5% per year is noted in the brain of persons aged 60 years and above.[10] Accelerated global atrophy of the brain with predominant involvement of medial temporal lobe structures, which positively correlated with cognitive decline, when compared to healthy controls has been reported in patients with MCI and AD.[11],[12],[13] MCI patients with medial temporal lobe and hippocampal atrophy were also noted to be at higher risk for conversion to dementia.[14] Although ventricular enlargement along with hippocampal atrophy has been noted in elderly people with normal cognitive functions, these changes are more pronounced in patients with MCI and AD.[15]

Apart from structural deficits, aging and related disorders such as MCI and AD are also associated with several changes in the activation and glucose utilization pattern of specific brain areas. Hypometabolism has also been noted in temporoparietal regions of ApoEε 4 carriers with subjective memory complaints.[16] MCI patients who had converted to dementia were noted to have lower baseline fluorodeoxyglucose uptake in right temporoparietal cortex when compared to nonconverters.[17] Abnormal glucose utilization in MCI and AD is also noted to be correlated to the severity of the disease.[13] Functional magnetic resonance imaging(fMRI) studies have shown increased hippocampal activity during cognitive tasks in patients with MCI. This increased activity has been attributed to the compensatory efforts of the brain to overcome the functional loss due to AD pathology.[18] Altered dorsolateral prefrontal cortex (DLPFC) functional connectivity with various cortical and subcortical regions during resting state has been implicated as one of the possible neural bases responsible for cognitive deficits noted in MCI.[19] MCI patients are also found to have significant abnormalities in resting state activity of default mode network regions, which have been noted to show amyloid deposit in the very early stages of AD.[20],[21]

In addition, it has been reported that electroencephalogram (EEG) oscillations in the alpha and theta frequencies reflect ongoing process in the brain related to cognition and memory.[22],[23] Healthy adult awake EEG is characterized by predominant alpha rhythm and has been positively correlated to cognitive performance.[23] Several studies have demonstrated aging to be characterized by generalized slowing of EEG activity, an increase in power and spatial distribution of low frequency theta and delta rhythms, and decrease in the amplitude of alpha frequency.[24] Further, the slowing down of occipital alpha rhythms in resting state EEG have been noted in patients with early stage of AD.[25] Studies have also demonstrated an association of these electrophysiological changes with impaired global cognitive function and altered regional blood flow in patients with diagnosis of MCI and AD.[26]


  Neurobiological Effects of Transcranial Direct Current Stimulation Top


In tDCS, as mentioned earlier, different cortical areas are stimulated by application of weak electrical currents through saline-soaked sponges of predetermined size, acting as electrode, attached to the scalp. The positions of the electrodes are determined as per the EEG 10–20 classification. It has been demonstrated that, following application of tDCS, cortical excitability can be altered in a polarity-dependent manner with prolonged after-effects.[27] tDCS demonstrated its utility as a tool in cognitive neurorehabilitation as improvements in cognitive function had been noted in patients with AD, depression, and Parkinson's disease (PD).[28],[29],[30] Some of the possible mechanisms of actions and its relevance as a tool to enhance cognitive functions are described below.

Membrane potential changes

tDCS was noted to induce cortical excitability changes in a polarity-dependent manner. Anodal tDCS was noted to modulate cortical excitability by promoting depolarization, and cathodal tDCS was noted to decrease cortical excitability by facilitating neuronal hyperpolarization.[3] The immediate after-effects of the stimulation could be due to local changes in the ionic concentration brought about by the alterations in the transmembrane carrier proteins and changes in the H + ion concentration, secondary to hydrolysis induced by exposure to a field of constant electric current.[31]

N-methyl-D-aspartate receptor and GABAergic interneuron changes

Long-term after-effects induced by tDCS has been noted to be suppressed by NMDA receptor antagonist dextromethorphan.[6] NMDA partial agonist D-cycloserine has been noted to enhance cognitive functions in humans and prolong the after-effects of anodal tDCS suggesting the possible role of NMDA receptors in mediating the same.[32]

Further, studies have also demonstrated the possible role of GABAergic interneurons excessive activity responsible for nitric acid-mediated damage to pyramidal neurons resulting in cognitive deficits.[33] Anodal tDCS was noted to decrease GABA concentration in the stimulated area and cathodal tDCS was noted to inhibit the activity of glutamatergic neurons with a correlated decrease in the concentration of GABA within the stimulated area.[34] Thus, tDCS may be useful to restore the balance between the excitatory and inhibitory neurotransmitter systems in the brain.

Regional cerebral blood flow changes

Neuroimaging studies utilizing arterial spin labeling sequence demonstrated significant changes in cerebral blood flow under the stimulated region possibly by producing microvascular changes, with anodal tDCS increasing and cathodal tDCS decreasing blood flow to the regions underneath the electrodes.[35],[36]

Functional connectivity changes in the brain

Aberrant neural synchronization has been proposed as a mechanism for cognitive decline in dementia.[37] Anodal tDCS has been noted to increase normalized beta and gamma frequency waves over visual cortex in response to a visual stimuli in healthy individuals.[38] Studies in healthy individuals has shown that, by simultaneous stimulation of primary motor cortex with anodal tDCS and inhibition of contralateral prefrontal cortex with cathodal tDCS, the connectivity pattern between various cortical areas can be improved.[39] These studies demonstrate that it is possible to change the neural synchronization pattern between different cortical areas and oscillatory activity to bring about an improvement in cognitive functions with the help of tDCS.


  Effects of Transcranial Direct Current Stimulation on Cognitive Performance in Healthy Individuals Top


DLPFC forms an integral part of the brain circuits involved in working memory, where incoming sensory information are temporarily stored and processed concurrently so that complex tasks such as language comprehension, reasoning, and learning could be carried out. Neurophysiological and neuroimaging studies have implicated altered DLPFC functioning as one of the possible neural bases responsible for the cognitive deficits such as poor episodic memory retrieval and executive function noted in MCI patients.[19],[40] Anode over left DLPFC and cathode over right supraorbital region are the most common electrode montage [Figure 1] used in studies evaluating the utility of tDCS as a cognitive rehabilitative tool due to the above mentioned reasons.
Figure 1: Montage for brain stimulation in mild cognitive impairment. Anode (inside the saline-soaked red color sponge) is placed over left dorsolateral prefrontal cortex with midpoint of electrode (35 cm2) placed between F3 and FP1 (10–20 system); cathodal electrode (inside the saline-soaked yellow color sponge) was placed over the right supraorbital area

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During a working memory task, improved synchronization in the frequency of theta rhythm has been demonstrated between prefrontal and temporoparietal regions.[41] Performance deterioration has been noted in working memory task after a single-pulse TMS [42] and also after a session of repetitive TMS over DLPFC.[43]

In a single-blind, crossover and sham-controlled study involving 15 healthy individuals, online effects of anodal tDCS over left prefrontal cortex were investigated and were noted to improve working memory performance.[44] Time-dependent after-effects that lasted for around 30 min, following anodal tDCS over left DLPFC, have been reported in another study.[45] Improved recognition accuracy with anodal tDCS, when administered over left DLPFC, suggesting enhanced working memory performance has also been demonstrated in first-ever stroke patients with cognitive deficits.[46] Improvement in name recall has been reported in young adults following a session of tDCS with anodal current delivered over right anterior temporal lobe.[47] Anodal tDCS was also noted to enhance implicit memory, verbal episodic memory, declarative memory, and recognition memory in healthy individuals.[48],[49],[50],[51]

In a study by Zaehle et al., amplification in the alpha and theta frequency bands was noted following a session of anodal tDCS over left DLPFC in healthy individuals and has been proposed as one of the possible underlying neural bases for the enhancement in working memory.[52] These improvements were also noted to be dependent on the strength of the stimulation current with 2 mA showing better improvement when compared with 1 mA.[53]

Tremblay et al. in 2014 had done a systematic review of 63 articles investigating the effect of tDCS on healthy individuals with the site of stimulation being DLPFC, irrespective of whether the side of stimulation being right or left and reported that the effects of tDCS are highly variable and depend on the stimulation parameters, given task, and state of activity of the stimulated area and highlighted the need for better standardization procedure to improve the quality of the studies.[54] Some of the studies exploring the utility of tDCS as a tool to improve cognitive performance in healthy individuals are given in [Table 1].
Table 1: Studies investigating the effects of transcranial direct current stimulation on cognitive function in healthy individuals

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  Effects of Transcranial Direct Current Stimulation on Cognitive Performance in Patients With Dementia Top


Multiple studies have investigated the use of tDCS in enhancing the cognitive functions of patients with AD and other dementias. Anodal tDCS over left DLPFC was noted to improve working memory, verbal fluency, and functional connectivity patterns in the related brain networks of patients with PD.[30],[58]

Anodal tDCS was also noted to enhance word recognition memory, visual recognition memory, verbal memory, and improved attention in patients with AD.[28],[59],[60],[61] Studies examining the additive advantage of cognitive training with tDCS in patients with AD reported varied results.[62],[63] Some of the studies are listed in [Table 2].
Table 2: Studies investigating the effects of transcranial direct current stimulation on cognitive function in patients with dementia

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  Effects of Transcranial Direct Current Stimulation on Cognitive Performance in Patients With Mild Cognitive Impairment Top


First study investigating the utility of tDCS as a symptomatic treatment for memory complaints in patients with MCI was done by Meinzer et al. and was published in 2015. It was a double-blind, crossover and sham-controlled study involving 18 patients with a diagnosis of “MCI due to AD.” This was a single session study and current with an intensity of 1 mA for 20 minutes(min) was administered with anode placed over left ventral inferior frontal gyrus and cathode over the right supraorbital region. Following stimulation, semantic word retrieval and functional connectivity patterns in resting state fMRI in patients with MCI improved. The stimulation also decreased the task-related prefrontal hyperactivity noted in patients with MCI.[66]

A randomized sham-controlled study involving 18 PD patients who had MCI, showed improvement in Parkinson's disease cognitive rating scale and verbal fluency with after-effects lasting for 3 months following a combination of physical exercise and anodal tDCS over left DLPFC. The stimulation was delivered with an intensity of 2 mA for 25 min per se ssion and total of 10 sessions were administered over 2 weeks (5 sessions/week).[67]

Another double blind study involving 24 PD patients with MCI, showed that anodal tDCS over left DLPFC along with computer-based cognitive training was noted to produce strong trend towards improved performance in immediate memory skills during follow up (after 4 months). The stimulation was delivered with an intensity of 2 mA for 20 min per se ssion for 4 consecutive weeks (4 sessions/week).[68]

In an another randomized double-blind study involving 16 MCI patients, tDCS with anode over left DLPFC and cathode over the right DLPFC when delivered with an intensity of 2 mA for 30 min for 3 consecutive weeks (3 sessions/week) was noted to produce increased cerebral metabolic activity in dorsolateral, ventrolateral and medial prefrontal cortices, the dorsal anterior cingulate, the anterior and posterior insular regions, and the hippocampal and parahippocampal regions, poststimulation when compared to baseline.[69]

In a recent unpublished open-label study conducted in our laboratory involving ten MCI patients, tDCS with anode over left DLPFC and cathode over the right supraorbital area when delivered with an intensity of 2 mA for 20 min for 5 consecutive days was noted to produce improvements in terms of immediate and delayed recall performance poststimulation with much of the improvements persisting at 1-month follow-up. Some of the studies exploring the utility of tDCS as a tool to improve cognitive performance in patients with MCI are given in [Table 3].
Table 3: Studies investigating the effects of transcranial direct current stimulation on cognitive function in patients with mild cognitive impairment

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  Summary and Conclusions Top


The current review highlights the usefulness of tDCS technique in normal aging and related disorders such as AD and MCI in particular. However, there are several issues that are to be addressed. First, there is a need to devise and standardize the best stimulation protocol comprising the intensity of current, duration of stimulation, electrode placement, and number of sessions of stimulation (single or multiple). Several studies, as summarized earlier, have used current intensity ranging from 1 to 2 mA and the duration of stimulation ranging from 6 to 30 min with varying number of sessions. The second important issue that needs to be addressed is the replication of the efficacy of tDCS in improving cognition by conducting multicentric, double-blind, randomized controlled studies. Such studies will also help in standardizing stimulation parameters. The third issue that needs to be addressed is the need for studies looking into the mechanistic effects of tDCS in improving cognition. Investigational or clinical tDCS studies combined with multimodal brain imaging or mapping techniques are essential to understand the mechanism of action of tDCS as well as the neural basis of cognitive dysfunction. In addition, to understand the variability associated with the response to tDCS, evaluation of genetic factors such as neuroplasticity genes might help in prediction of the outcome of tDCS. Further, most of the studies published till date are largely cross sectional, and the long-term sustenance of the tDCS effects is to be studied systematically. Longitudinal studies evaluating the sustained effects of tDCS, improvement in quality of life, and social autonomy are needed to confirm the promising results. Effects of combined administration of tDCS and cognitive training could further improve the cognitive outcome in MCI. This needs to be evaluated systematically. tDCS, a nascent field, though noninvasive and associated with minimal side effects, the long-term safety is yet to be established. To evaluate the same, future studies must incorporate standard operating procedures and document the side effects using systematic questionnaires.

Although multiple studies have highlighted the utility of tDCS in various psychiatric disorders,[70] the usage of this technique has been largely restricted to research. Familiarizing tDCS among practicing clinicians by conducting suitable training programs in operating the noninvasive brain stimulation devices. Is the need of the hour.

To conclude, tDCS is a safe noninvasive and cost-effective treatment strategy in combating cognitive dysfunction in elderly and the disorders associated with aging. However, there is a serious lack of studies evaluating the utility of tDCS in MCI, the forerunner of AD. More systematic research into this might help in mitigating cognitive dysfunction in aging and related disorders which will help in reducing to some extent, the socioeconomic burden associated with these disorders.

Acknowledgments

This work partly is supported by the Department of Science and Technology (Government of India) Research Grant (DST/SJF/LSA-02/2014-15) to G.V. V.S. is supported by Department of Health Research, Young Scientist in Newer Research Areas: DHR/HRD/Young Scientist/Type-VI(2)/2015.

Financial support and sponsorship

This work partly is supported by the Department of Science and Technology (Government of India) Research Grant (DST/SJF/LSA-02/2014-15) to G.V. V.S. is supported by Department of Health Research, Young Scientist in Newer Research Areas: DHR/HRD/Young Scientist/Type-VI(2)/2015.

Conflicts of interest

There are no conflicts of interest.



 
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