Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS).
Lefaucheur Jean-Pascal,André-Obadia Nathalie,Antal Andrea,Ayache Samar S,Baeken Chris,Benninger David H,Cantello Roberto M,Cincotta Massimo,de Carvalho Mamede,De Ridder Dirk,Devanne Hervé,Di Lazzaro Vincenzo,Filipović Saša R,Hummel Friedhelm C,Jääskeläinen Satu K,Kimiskidis Vasilios K,Koch Giacomo,Langguth Berthold,Nyffeler Thomas,Oliviero Antonio,Padberg Frank,Poulet Emmanuel,Rossi Simone,Rossini Paolo Maria,Rothwell John C,Schönfeldt-Lecuona Carlos,Siebner Hartwig R,Slotema Christina W,Stagg Charlotte J,Valls-Sole Josep,Ziemann Ulf,Paulus Walter,Garcia-Larrea Luis
Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology
A group of European experts was commissioned to establish guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS) from evidence published up until March 2014, regarding pain, movement disorders, stroke, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy, consciousness disorders, tinnitus, depression, anxiety disorders, obsessive-compulsive disorder, schizophrenia, craving/addiction, and conversion. Despite unavoidable inhomogeneities, there is a sufficient body of evidence to accept with level A (definite efficacy) the analgesic effect of high-frequency (HF) rTMS of the primary motor cortex (M1) contralateral to the pain and the antidepressant effect of HF-rTMS of the left dorsolateral prefrontal cortex (DLPFC). A Level B recommendation (probable efficacy) is proposed for the antidepressant effect of low-frequency (LF) rTMS of the right DLPFC, HF-rTMS of the left DLPFC for the negative symptoms of schizophrenia, and LF-rTMS of contralesional M1 in chronic motor stroke. The effects of rTMS in a number of indications reach level C (possible efficacy), including LF-rTMS of the left temporoparietal cortex in tinnitus and auditory hallucinations. It remains to determine how to optimize rTMS protocols and techniques to give them relevance in routine clinical practice. In addition, professionals carrying out rTMS protocols should undergo rigorous training to ensure the quality of the technical realization, guarantee the proper care of patients, and maximize the chances of success. Under these conditions, the therapeutic use of rTMS should be able to develop in the coming years.
Non-invasive Human Brain Stimulation in Cognitive Neuroscience: A Primer.
Parkin Beth L,Ekhtiari Hamed,Walsh Vincent F
The use of non-invasive brain stimulation is widespread in studies of human cognitive neuroscience. This has led to some genuine advances in understanding perception and cognition, and has raised some hopes of applying the knowledge in clinical contexts. There are now several forms of stimulation, the ability to combine these with other methods, and ethical questions that are special to brain stimulation. In this Primer, we aim to give the users of these methods a starting point and perspective from which to view the key questions and usefulness of the different forms of non-invasive brain stimulation. We have done so by taking a critical view of recent highlights in the literature, selected case studies to illustrate the elements necessary and sufficient for good experiments, and pointed to questions and findings that can only be addressed using interference methods.
Noninvasive human brain stimulation.
Wagner Timothy,Valero-Cabre Antoni,Pascual-Leone Alvaro
Annual review of biomedical engineering
Noninvasive brain stimulation with transcranial magnetic stimulation (TMS) or transcranial direct current stimulation (tDCS) is valuable in research and has potential therapeutic applications in cognitive neuroscience, neurophysiology, psychiatry, and neurology. TMS allows neurostimulation and neuromodulation, while tDCS is a purely neuromodulatory application. TMS and tDCS allow diagnostic and interventional neurophysiology applications, and focal neuropharmacology delivery. However, the physics and basic mechanisms of action remain incompletely explored. Following an overview of the history and current applications of noninvasive brain stimulation, we review stimulation device design principles, the electromagnetic and physical foundations of the techniques, and the current knowledge about the electrophysiologic basis of the effects. Finally, we discuss potential biomedical and electrical engineering developments that could lead to more effective stimulation devices, better suited for the specific applications.
Transcranial direct current stimulation in mild cognitive impairment: Behavioral effects and neural mechanisms.
Meinzer Marcus,Lindenberg Robert,Phan Mai Thy,Ulm Lena,Volk Carina,Flöel Agnes
Alzheimer's & dementia : the journal of the Alzheimer's Association
INTRODUCTION:The long preclinical phase of Alzheimer's disease provides opportunities for potential disease-modifying interventions in prodromal stages such as mild cognitive impairment (MCI). Anodal transcranial direct current stimulation (anodal-tDCS), with its potential to enhance neuroplasticity, may allow improving cognition in MCI. METHODS:In a double-blind, cross-over, sham-controlled study, anodal-tDCS was administered to the left inferior frontal cortex during task-related and resting-state functional magnetic resonance imaging (fMRI) to assess its impact on cognition and brain functions in MCI. RESULTS:During sham stimulation, MCI patients produced fewer correct semantic-word-retrieval responses than matched healthy controls, which was associated with hyperactivity in bilateral prefrontal regions. Anodal-tDCS significantly improved performance to the level of controls, reduced task-related prefrontal hyperactivity and resulted in "normalization" of abnormal network configuration during resting-state fMRI. DISCUSSION:Anodal-tDCS exerts beneficial effects on cognition and brain functions in MCI, thereby providing a framework to test whether repeated stimulation sessions may yield sustained reversal of cognitive deficits.
Applications of transcranial direct current stimulation for understanding brain function.
Filmer Hannah L,Dux Paul E,Mattingley Jason B
Trends in neurosciences
In recent years there has been an exponential rise in the number of studies employing transcranial direct current stimulation (tDCS) as a means of gaining a systems-level understanding of the cortical substrates underlying behaviour. These advances have allowed inferences to be made regarding the neural operations that shape perception, cognition, and action. Here we summarise how tDCS works, and show how research using this technique is expanding our understanding of the neural basis of cognitive and motor training. We also explain how oscillatory tDCS can elucidate the role of fluctuations in neural activity, in both frequency and phase, in perception, learning, and memory. Finally, we highlight some key methodological issues for tDCS and suggest how these can be addressed.
The physiological basis of transcranial magnetic stimulation.
Trends in cognitive sciences
Transcranial magnetic stimulation (TMS) is the noninvasive method of choice for studying the causal relevance of a cortical area in the human brain. The success of TMS, however, is contrasted by limited insight into its mechanism of action. A recent study by Allen and colleagues offers stunning new insight into the physiological underpinnings of TMS. Their findings expand our understanding about a method that is widely used for stimulating research in the cognitive neurosciences.
Mixing Apples and Oranges in Assessing Outcomes of Repetitive Transcranial Stimulation Meta-Analyses.
Brunoni Andre R,Arns Martijn,Baeken Chris,Blumberger Daniel,Brunelin Jerome,Carpenter Linda L,Downar Jonathan,Keeser Daniel,Langguth Berthold,Rachid Fady,Sack Alexander T,Vila-Rodriguez Fidel,Padberg Frank
Psychotherapy and psychosomatics
Transcranial magnetic stimulation: a primer.
Transcranial magnetic stimulation (TMS) is a technique for noninvasive stimulation of the human brain. Stimulation is produced by generating a brief, high-intensity magnetic field by passing a brief electric current through a magnetic coil. The field can excite or inhibit a small area of brain below the coil. All parts of the brain just beneath the skull can be influenced, but most studies have been of the motor cortex where a focal muscle twitch can be produced, called the motor-evoked potential. The technique can be used to map brain function and explore the excitability of different regions. Brief interference has allowed mapping of many sensory, motor, and cognitive functions. TMS has some clinical utility, and, because it can influence brain function if delivered repetitively, it is being developed for various therapeutic purposes.
High Frequency Repetitive Transcranial Magnetic Stimulation Alleviates Cognitive Impairment and Modulates Hippocampal Synaptic Structural Plasticity in Aged Mice.
Ma Qinying,Geng Yuan,Wang Hua-Long,Han Bing,Wang Yan-Yong,Li Xiao-Li,Wang Lin,Wang Ming-Wei
Frontiers in aging neuroscience
Normal aging is accompanied by hippocampus-dependent cognitive impairment, which is a risk factor of Alzheimer's disease. This study aims to investigate the effect of high frequency-repetitive transcranial magnetic stimulation (HF-rTMS) on hippocampus-dependent learning and memory in aged mice and explore its underlying mechanisms. Forty-five male Kunming mice (15 months old) were randomly divided into three groups: aged sham, 5 Hz rTMS, and 25 Hz rTMS. Two sessions of 5 Hz or 25 Hz rTMS comprising 1,000 pulses in 10 trains were delivered once a day for 14 consecutive days. The aged sham group was treated by the reverse side of the coil. In the adult sham group, 15 male Kunming mice (3 months old) were treated the same way as the aged sham group. A Morris water maze (MWM) was conducted following the stimulation, and synaptic ultrastructure was observed through a transmission electron microscope. HF-rTMS improved spatial learning and memory impairment in the aged mice, and 5 Hz was more significant than 25 Hz. Synaptic plasticity-associated gene profiles were modified by HF-rTMS, especially neurotrophin signaling pathways and cyclic adenosine monophosphate response element binding protein (CREB) cofactors. Compared to the aged sham group, synaptic plasticity-associated proteins, i.e., synaptophysin (SYN) and postsynaptic density (PSD)-95 were increased; brain-derived neurotrophic factor (BDNF) and phosphorylated CREB (pCREB) significantly increased after the 5 Hz HF-rTMS treatment. Collectively, our results suggest that HF-rTMS ameliorated cognitive deficits in naturally aged mice. The 5 Hz rTMS treatment significantly enhanced synaptic structural plasticity and activated the BDNF/CREB pathway in the hippocampus.
Brain stimulation improves associative memory in an individual with amnestic mild cognitive impairment.
Cotelli Maria,Calabria Marco,Manenti Rosa,Rosini Sandra,Maioli Claudio,Zanetti Orazio,Miniussi Carlo
In patients with cognitive deficits, brain stimulation has been shown to restore cognition ( Miniussi et al., 2008 , Brain Stimulation, 1, 326). The aim of this study was to assess whether repetitive Transcranial Magnetic Stimulation (rTMS) could improve memory performance in an individual with amnestic Mild Cognitive Impairment (aMCI). Stimulation of the left parietal cortex increased accuracy in an association memory task, and this improvement was still significant 24 weeks after stimulation began. These findings indicate that rTMS to the left parietal cortex improved memory performance in aMCI.
Repetitive Transcranial Magnetic Stimulation Ameliorates Cognitive Impairment by Enhancing Neurogenesis and Suppressing Apoptosis in the Hippocampus in Rats with Ischemic Stroke.
Guo Feng,Lou Jicheng,Han Xiaohua,Deng Yuguo,Huang Xiaolin
Frontiers in physiology
Cognitive impairment is a serious mental deficit caused by stroke that can severely affect the quality of a survivor's life. Repetitive transcranial magnetic stimulation (rTMS) is a well-known rehabilitation modality that has been reported to exert neuroprotective effects after cerebral ischemic injury. In the present study, we evaluated the therapeutic efficacy of rTMS against post-stroke cognitive impairment (PSCI) and investigated the mechanisms underlying its effects in a middle cerebral artery occlusion (MCAO) rat model. The results showed that rTMS ameliorated cognitive deficits and tended to reduce the sizes of cerebral lesions. In addition, rTMS significantly improved cognitive function via a mechanism involving increased neurogenesis and decreased apoptosis in the ipsilateral hippocampus. Moreover, brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related kinase B (TrkB), were clearly upregulated in ischemic hippocampi after treatment with rTMS. Additionally, further studies demonstrated that rTMS markedly enhanced the expression of the apoptosis-related B cell lymphoma/leukemia gene 2 (Bcl-2) and decreased the expression of the Bcl-2-associated protein X (Bax) and the number of TUNEL-positive cells in the ischemic hippocampus. Both protein levels and mRNA levels were investigated. Our findings suggest that after ischemic stroke, treatment with rTMS promoted the functional recovery of cognitive impairments by inhibiting apoptosis and enhancing neurogenesis in the hippocampus and that this mechanism might be mediated by the BDNF signaling pathway.
High-frequency versus theta burst transcranial magnetic stimulation for the treatment of poststroke cognitive impairment in humans
Tsai Po-Yi,Lin Wang-Sheng,Tsai Kun-Ting,Kuo Chia-Yu,Lin Pei-Hsin
Journal of psychiatry & neuroscience : JPN
Background:Because the reliability of repetitive transcranial magnetic stimulation (rTMS) in treating poststroke cognitive impairment has not been convincingly demonstrated, we systematically examined the effectiveness of this regimen with 2 protocols. Methods:We randomly allocated 41 patients with poststroke cognitive impairment to receive 5 Hz rTMS (n = 11), intermittent theta burst stimulation (iTBS; n = 15) or sham stimulation (n = 15). Each group received 10 stimulation sessions over the left dorsolateral prefrontal cortex. We performed the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the Beck Depression Inventory at baseline and after the intervention. Results:The 5 Hz rTMS group showed significantly greater improvement than the sham group in RBANS total score (p = 0.006), attention (p = 0.001) and delayed memory (p < 0.001). The iTBS group showed significantly greater improvement than the sham group in RBANS total score (p = 0.005) and delayed memory (p = 0.007). The 5 Hz rTMS group exhibited a superior modulating effect in attention compared to the iTBS group (p = 0.016). Patients without comorbid hypertension (p = 0.008) were predisposed to favourable therapeutic outcomes. Limitations:Although we included only patients with left hemispheric stroke, heterogeneity associated with cortical and subcortical implications existed. We did not investigate the remote effects of rTMS. Conclusion:Our results demonstrated that both 5 Hz rTMS and iTBS were effective for poststroke cognitive impairment in terms of global cognition, attention and memory function; the domain of attention was susceptible to 5 Hz modulation. Treatment with 5 Hz rTMS may slow cognitive decline, representing both a pivotal process in poststroke cognitive impairment and an aspect of neuroplasticity that contributes to disease-modifying strategies. Clinical trial registration:NCT02006615; clinicaltrials.gov/ct2/show/NCT02006615.
Cerebral Functional Manipulation of Repetitive Transcranial Magnetic Stimulation in Cognitive Impairment Patients After Stroke: An fMRI Study.
Li Yamei,Luo Hong,Yu Qian,Yin Longlin,Li Kuide,Li Yi,Fu Jing
Frontiers in neurology
Recently, the area of repetitive transcranial magnetic stimulation (rTMS) targeting neurological rehabilitation has been advanced as a potential treatment for post-stroke cognitive impairment (PSCI). However, the underlying mechanisms remains to be elusived. This study aims to figure out cerebral functional manipulation of rTMS in patients with PSCI through using the resting-state functional magnetic resonance imaging (rs-fMRI). Thirty patients with PSCI were recruited and randomly allocated into two groups: the rTMS intervention group and control group. The rTMS intervention group was given 20 min of 5 Hz rTMS (or control) over left dorsolateral prefrontal cortex (DLPFC) besides routine cognitive intervention training for 3 consecutive weeks, five times per week, on weekdays. Cognition performance was assessed by the Minimum Mental State Examination (MMSE) and Montreal cognitive assessment (MoCA). Neural activity and functional connectivity (FC) changes were acquired by rs-fMRI with fractional amplitude of low-frequency fluctuation (fALFF) and seed-based correlation analysis. Cognition improvements were observed both in rTMS intervention group and control group ( < 0.01), while the rTMS group got more significant improvent than control group ( < 0.05). To be specified, compared with the control group, the rTMS group got higher fALFF values in these brain regions including superior temporal gyrus, inferior frontal gyrus and parahippocampal gyrus, while lower fALFF values in middle temporal gyrus, middle frontal gyrus and fusiform gyrus. In addition, the rTMS group showed increased FC between LDPFC and toprecuneus, inferior temporal gyrus, middle and inferior frontal gyrus and marginal gyrus, while decreased FC between LDPFC and middle temporal gyrus and thalamus. The increase and decrease of neural activity and FC in cognition-related regions detected by rs-fMRI are good indicators to clarify the underlining mechanisms of rTMS on PSCI.
Neurobiological effects of transcranial direct current stimulation in younger adults, older adults and mild cognitive impairment.
Emonson M R L,Fitzgerald P B,Rogasch N C,Hoy K E
Transcranial direct current stimulation (tDCS) has been investigated as a way to improve motor and cognitive functioning, with largely variable results. Currently, relatively little is known about the neurobiological effects, and possible drivers of variability, in either healthy or clinical populations. Therefore, this study aimed to characterise the neurobiological effects to tDCS in younger adults, older adults and adults with mild cognitive impairment (MCI), and their relationship to cognitive performance. 20 healthy younger adults, 20 healthy older adults and 9 individuals with MCI participated in the study. All completed neuropsychological tasks and TMS-EEG, prior to and following delivery of 20 min of anodal tDCS to the left dorsolateral prefrontal cortex (DLPFC). EEG was also recorded during the 2-Back working memory task. Following tDCS, younger adults demonstrated alterations in early TMS-Evoked Potentials (TEPs), namely P30 and P60. Both younger and older adults exhibited a larger task-related N250 amplitude after stimulation, with contrasting relationships to cognitive performance. The MCI group showed no change in TEPs or ERPs over time. Comparisons between the groups revealed differences in the change in amplitude of early TEP (P60) and ERP (N100) peaks between younger and older adults. Our findings indicate that tDCS was able to modulate cortical activity in younger and older healthy adults, but in varying ways. These findings suggest that varied response to tDCS may be related to factors such as age and the presence/absence of cognitive impairment, and these factors should be considered when assessing the effectiveness of tDCS in healthy and pathological aging.
Neuroimaging mechanisms of high-frequency repetitive transcranial magnetic stimulation for treatment of amnestic mild cognitive impairment: a double-blind randomized sham-controlled trial.
Yuan Li-Qiong,Zeng Qing,Wang Dan,Wen Xiu-Yun,Shi Yu,Zhu Fen,Chen Shang-Jie,Huang Guo-Zhi
Neural regeneration research
Individuals with amnestic mild cognitive impairment (aMCI) have a high risk of developing Alzheimer's disease. Although repetitive transcranial magnetic stimulation (rTMS) is considered a potentially effective treatment for cognitive impairment in patients with aMCI, the neuroimaging mechanisms are poorly understood. Therefore, we performed a double-blind randomized sham-controlled trial in which rTMS was applied to the left dorsolateral prefrontal cortex of aMCI patients recruited from a community near the Third Hospital Affiliated to Sun Yat-sen University, China. Twenty-four patients with aMCI were randomly assigned to receive true rTMS (treatment group, n = 12, 6 men and 6 women; age 65.08 ± 4.89 years) or sham stimulation (sham group, n = 12, 5 men and 7 women; age 64.67 ± 4.77 years). rTMS parameters included a stimulation frequency of 10 Hz, stimulation duration of 2 seconds, stimulation interval of 8 seconds, 20 repetitions at 80% of the motor threshold, and 400 pulses per session. rTMS/sham stimulation was performed five times per week over a period of 4 consecutive weeks. Our results showed that compared with baseline, Montreal Cognitive Assessment scores were significantly increased and the value of the amplitude of low-frequency fluctuation (ALFF) was significantly increased at the end of treatment and 1 month after treatment. Compared with the sham group, the ALFF values in the right inferior frontal gyrus, triangular part of the inferior frontal gyrus, right precuneus, left angular gyrus, and right supramarginal gyrus were significantly increased, and the ALFF values in the right superior frontal gyrus were significantly decreased in the treatment group. These findings suggest that high-frequency rTMS can effectively improve cognitive function in aMCI patients and alter spontaneous brain activity in cognitive-related brain areas. This study was approved by the Ethics Committee of Shenzhen Baoan Hospital of Southern Medical University, China (approval No. BYL20190901) on September 3, 2019, and registered in the Chinese Clinical Trials Registry (registration No. ChiCTR1900028180) on December 14, 2019.
Transcranial Magnetic Stimulation to Address Mild Cognitive Impairment in the Elderly: A Randomized Controlled Study.
Drumond Marra Hellen Livia,Myczkowski Martin Luiz,Maia Memória Cláudia,Arnaut Débora,Leite Ribeiro Philip,Sardinha Mansur Carlos Gustavo,Lancelote Alberto Rodrigo,Boura Bellini Bianca,Alves Fernandes da Silva Adriano,Tortella Gabriel,Ciampi de Andrade Daniel,Teixeira Manoel Jacobsen,Forlenza Orestes Vicente,Marcolin Marco Antonio
Transcranial magnetic stimulation (TMS) is a noninvasive brain stimulation technique with potential to improve memory. Mild cognitive impairment (MCI), which still lacks a specific therapy, is a clinical syndrome associated with increased risk of dementia. This study aims to assess the effects of high-frequency repetitive TMS (HF rTMS) on everyday memory of the elderly with MCI. We conducted a double-blinded randomized sham-controlled trial using rTMS over the left dorsolateral prefrontal cortex (DLPFC). Thirty-four elderly outpatients meeting Petersen's MCI criteria were randomly assigned to receive 10 sessions of either active TMS or sham, 10 Hz rTMS at 110% of motor threshold, 2,000 pulses per session. Neuropsychological assessment at baseline, after the last session (10th) and at one-month follow-up, was applied. ANOVA on the primary efficacy measure, the Rivermead Behavioural Memory Test, revealed a significant group-by-time interaction (p = 0.05), favoring the active group. The improvement was kept after one month. Other neuropsychological tests were heterogeneous. rTMS at 10 Hz enhanced everyday memory in elderly with MCI after 10 sessions. These findings suggest that rTMS might be effective as a therapy for MCI and probably a tool to delay deterioration.
Repetitive Transcranial Magnetic Stimulation Induced Hypoconnectivity Within the Default Mode Network Yields Cognitive Improvements in Amnestic Mild Cognitive Impairment: A Randomized Controlled Study.
Cui Hailun,Ren Rujing,Lin Guozhen,Zou Yang,Jiang Lijuan,Wei Zhengde,Li Chunbo,Wang Gang
Journal of Alzheimer's disease : JAD
BACKGROUND:Repetitive transcranial magnetic stimulation (rTMS) is thought to be effective in alleviating cognitive symptoms in patients with amnestic mild cognitive impairment (aMCI), but the mechanisms related to network modification are poorly understood. OBJECTIVE:Here we tested rTMS efficacy and explored the effect of rTMS-induced changes in the default mode network (DMN) and their predictive value for treatment response. METHODS:Twenty-one subjects clinically diagnosed with aMCI were recruited to complete a 10-session randomized and sham-controlled rTMS treatment targeting the right dorsolateral prefrontal cortex. Resting-state functional magnetic resonance imaging in tandem with neuropsychological assessments were administered before and after the intervention. Changes in functional connectivity of the DMN and relevant brain regions, as well as the correlations between baseline functional connectivity and clinical rating scales were calculated in order to elucidate the mechanism of treatment response to rTMS therapy. RESULTS:Compared to the sham group, the rTMS group achieved improvement of neuropsychological performance and significant functional connectivity changes within the DMN. Group×Time interactions were found between posterior cingulate gyrus and right fusiform gyrus (F (1,19) = 17.154, p = 0.001), and also left anterior cingulate gyrus (F (1,19) = 3.908, p = 0.063), showing an rTMS-induced deactivation of functional connectivity within the DMN. Baseline functional connectivity analysis of seeds within the DMN in the rTMS group revealed negative correlation with AVLT-Recognition score changes. CONCLUSION:rTMS-induced hypoconnectivity within DMN is associated with clinical cognitive improvements in patients with aMCI. Further, pre-rTMS baseline activity of the DMN at rest may be a predictor for favorable rTMS treatment response.
Repetitive transcranial magnetic stimulation for apathy in mild cognitive impairment: A double-blind, randomized, sham-controlled, cross-over pilot study.
Padala Prasad R,Padala Kalpana P,Lensing Shelly Y,Jackson Andrea N,Hunter Cassandra R,Parkes Christopher M,Dennis Richard A,Bopp Melinda M,Caceda Ricardo,Mennemeier Mark S,Roberson Paula K,Sullivan Dennis H
Apathy is a common and disabling behavioral concomitant of many neurodegenerative conditions. The presence of apathy with Mild Cognitive Impairment (MCI) is linked with heightened rates of conversion to Alzheimer's disease. Improving apathy may slow the neurodegenerative process. The objective was to establish the efficacy of repetitive transcranial magnetic stimulation (rTMS) in improving apathy in older adults with MCI. An 8-week, double-blind, randomized, sham-controlled cross-over study was conducted in nine subjects (66 ± 9 years) with apathy and MCI. Subjects were randomized to rTMS or sham treatment (5 days/week) for 2 weeks following which they underwent a 4-week treatment-free period. Subjects then crossed-over to receive the other treatment for 2 weeks. The primary (apathy (AES-C)) and secondary (cognition (3MS & MMSE), executive function (TMT-A & TMT-B), and clinical global impression (CGI)) outcomes were assessed at baseline, 2, 6, and 8 weeks. After adjusting for baseline, there was a significantly greater improvement in the AES-C with rTMS compared to sham treatment at 2 weeks. There was significantly greater improvement in 3MS, MMSE, TMT-A, and CGI-I with rTMS compared to the sham treatment. This study establishes that rTMS is efficacious in improving apathy in subjects with MCI.
The effects of repetitive transcranial magnetic stimulation in older adults with mild cognitive impairment: a protocol for a randomized, controlled three-arm trial.
Taylor Joy L,Hambro Benjamin C,Strossman Nicole D,Bhatt Priyanka,Hernandez Beatriz,Ashford J Wesson,Cheng Jauhtai Joseph,Iv Michael,Adamson Maheen M,Lazzeroni Laura C,McNerney Margaret Windy
BACKGROUND:Mild Cognitive Impairment (MCI) carries a high risk of progression to Alzheimer's disease (AD) dementia. Previous clinical trials testing whether cholinesterase inhibitors can slow the rate of progression from MCI to AD dementia have yielded disappointing results. However, recent studies of the effects of repetitive transcranial magnetic stimulation (rTMS) in AD have demonstrated improvements in cognitive function. Because few rTMS trials have been conducted in MCI, we designed a trial to test the short-term efficacy of rTMS in MCI. Yet, in both MCI and AD, we know little about what site of stimulation would be ideal for improving cognitive function. Therefore, two cortical sites will be investigated in this trial: (1) the dorsolateral prefrontal cortex (DLPFC), which has been well studied for treatment of major depressive disorder; and (2) the lateral parietal cortex (LPC), a novel site with connectivity to AD-relevant limbic regions. METHODS/DESIGN:In this single-site trial, we plan to enroll 99 participants with single or multi-domain amnestic MCI. We will randomize participants to one of three groups: (1) Active DLPFC rTMS; (2) Active LPC rTMS; and (3) Sham rTMS (evenly split between DLPFC and LPC locations). After completing 20 bilateral rTMS treatment sessions, participants will be followed for 6 months to test short-term efficacy and track durability of effects. The primary efficacy measure is the California Verbal Learning Test-II (CVLT-II), assessed 1 week after intervention. Secondary analyses will examine effects of rTMS on other cognitive measures, symptoms of depression, and brain function with respect to the site of stimulation. Finally, selected biomarkers will be analyzed to explore predictors of response and mechanisms of action. DISCUSSION:The primary aim of this trial is to test the short-term efficacy of rTMS in MCI. Additionally, the project will provide information on the durability of cognitive effects and potentially distinct effects of stimulating DLPFC versus LPC regions. Future efforts would be directed toward better understanding therapeutic mechanisms and optimizing rTMS for treatment of MCI. Ultimately, if rTMS can be utilized to slow the rate of progression to AD dementia, this will be a significant advancement in the field. TRIAL REGISTRATION:Clinical Trials NCT03331796. Registered 6 November 2017, https://clinicaltrials.gov/ct2/show/NCT03331796. All items from the World Health Organization Trial Registration Data Set are listed in Appendix A. PROTOCOL VERSION:This report is based on version 1, approved by the DSMB on 30 November, 2017 and amended on 14 August, 2018 and 19 September, 2019.
Early Cognitive Impairment after Minor Stroke: Associated Factors and Functional Outcome.
Suda Satoshi,Nishimura Takuya,Ishiwata Akiko,Muraga Kanako,Aoki Junya,Kanamaru Takuya,Suzuki Kentaro,Sakamoto Yuki,Katano Takehiro,Nishiyama Yasuhiro,Mishina Masahiro,Kimura Kazumi
Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association
OBJECTIVES:Evaluation of cognitive status is not performed routinely in the acute stroke setting. This study aimed to evaluate the frequency of early cognitive impairment in patients with minor ischemic stroke, analyze the factors associated with early cognitive impairment, and assess functional outcomes. METHODS:In this prospective study, 112 consecutive patients with acute minor ischemic stroke were enrolled. Neuroimages were assessed for semiquantitative evaluation of brain atrophy and small vessel disease (SVD) markers. Cognitive performance was measured within 5 days of onset using Montreal Cognitive Assessment (MoCA) scores. Functional outcome analyses were adjusted for demographic variables, premorbid cognitive status, education level, vascular risk factors, neuroimaging characteristics, stroke severity, and MoCA scores. RESULTS:The median MoCA score was 22, and 63% of patients had cognitive impairment. Factors independently associated with cognitive impairment were education (odds ratios [OR], .79; confidence intervals [CI], .63-.99), smoking (OR, .26; 95%CI, .073-.89), and temporal horn atrophy (OR, 4.73; 95% CI, 1.66-13.49). Factors independently associated with poor functional outcome were total MoCA score (OR, .78; 95%CI, .62-.95) and the sum of 4 MoCA subscores (visuospatial/executive, attention, language, and orientation; OR, .72; 95%CI, .53-.92). The cutoff value of the sum of 4 MoCA subscores for predicting poor outcome was 13 points with 76.5% sensitivity and 81.1% specificity. CONCLUSIONS:Early cognitive impairment was common after minor ischemic stroke and was associated with preexisting temporal horn atrophy but not SVD markers. The sum of 4 MoCA subscores was useful in predicting the functional outcome.
Effect of Cognitive Reserve on Risk of Cognitive Impairment and Recovery After Stroke: The KOSCO Study.
Shin Minyoung,Sohn Min Kyun,Lee Jongmin,Kim Deog Young,Lee Sam-Gyu,Shin Yong-Il,Oh Gyung-Jae,Lee Yang-Soo,Joo Min Cheol,Han Eun Young,Han Junhee,Ahn Jeonghoon,Chang Won Hyuk,Shin Min A,Choi Ji Yoo,Kang Sung Hyun,Kim Youngtaek,Kim Yun-Hee
Background and Purpose- The theory of cognitive reserve (CR) was introduced to account for individual differences in the clinical manifestation of neuropathology. This study investigated whether CR has a modulating effect on cognitive impairment and recovery after stroke. Methods- This study is an interim analysis of the Korean Stroke Cohort for Functioning and Rehabilitation. A total of 7459 patients with first-ever stroke were included for analysis. Education, occupation, and composite CR scores derived from those 2 variables were used as CR proxies. Scores from the Korean version of the Mini-Mental State Examination analyzed for 30 months after stroke onset were analyzed. Results- Lower CR increased the risk of cognitive impairment after stroke. The odds ratio was 1.89 (95% CI, 1.64-2.19) in patients with secondary education and 2.42 (95% CI, 2.03-2.90) in patients with primary education compared with patients with higher education. The odds ratio was 1.48 (95% CI, 1.23-1.98) in patients with a skilled manual occupation and 2.01 (95% CI, 1.42-2.83) in patients with a nonskilled manual occupation compared with patients with a managerial or professional occupation. In the multilevel model analysis, the Korean version of the Mini-Mental State Examination total score increased during the first 3 months (1.93 points per month) and then plateaued (0.02 point per month). The slopes were moderated by the level of education, occupation, and composite CR score: the higher the level of education, occupation, or CR score, the faster the recovery. In the older adult group, the Korean version of the Mini-Mental State Examination scores showed a long-term decline that was moderated by education level. Conclusions- Education and occupation can buffer an individual against cognitive impairment caused by stroke and promote rapid cognitive recovery early after stroke. In addition, higher education minimizes long-term cognitive decline after stroke, especially in older patients. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT03402451.