Transcranial magnetic stimulation: applications in neurology

INTRODUCTION: Transcranial magnetic stimulation (TMS) was first applied to assess conduction time along the corticospinal tract, namely by recording motor evoked potentials. STATE OF ART: At present, TMS techniques include cortical excitability and mapping studies using single or paired-pulse paradigms on the one hand, and repetitive TMS to induce cortical plasticity and to modify brain function on the other hand. TMS is a valuable, non-invasive tool in the diagnosis and the pathophysiological assessment of cortical dysfunction involved in various neurological diseases (multiple sclerosis, myelopathy, amyotrophic lateral sclerosis, movement disorders, epilepsy, stroke). PERSPECTIVES AND CONCLUSION: In the near future, repetitive TMS could have therapeutic applications in neurology (epilepsy, stroke rehabilitation program) as is already the case in some psychiatric diseases. However, most of the new indications for treatment with cortical stimulation will be based on surgically-implanted neuromodulation procedures.     

Transcranial magnetic stimulation (TMS)/repetitive TMS in mild cognitive impairment and Alzheimer's disease

Several Transcranial Magnetic Stimulation (TMS) techniques can be applied to noninvasively measure cortical excitability and brain plasticity in humans. TMS has been used to assess neuroplastic changes in Alzheimer's disease (AD), corroborating findings that cortical physiology is altered in AD due to the underlying neurodegenerative process. In fact, many TMS studies have provided physiological evidence of abnormalities in cortical excitability, connectivity, and plasticity in patients with AD. Moreover, the combination of TMS with other neurophysiological techniques, such as high‐density electroencephalography (EEG), makes it possible to study local and network cortical plasticity directly. Interestingly, several TMS studies revealed abnormalities in patients with early AD and even with mild cognitive impairment (MCI), thus enabling early identification of subjects in whom the cholinergic degeneration has occurred. Furthermore, TMS can influence brain function if delivered repetitively; repetitive TMS (rTMS) is capable of modulating cortical excitability and inducing long‐lasting neuroplastic changes. Preliminary findings have suggested that rTMS can enhance performances on several cognitive functions impaired in AD and MCI. However, further well‐controlled studies with appropriate methodology in larger patient cohorts are needed to replicate and extend the initial findings. The purpose of this paper was to provide an updated and comprehensive systematic review of the studies that have employed TMS/rTMS in patients with MCI and AD.     

Assessing cortical network properties using TMS–EEG

The past decade has seen significant developments in the concurrent use of transcranial magnetic stimulation (TMS) and electroencephalography (EEG) to directly assess cortical network properties such as excitability and connectivity in humans. New hardware solutions, improved EEG amplifier technology, and advanced data processing techniques have allowed substantial reduction of the TMS‐induced artifact, which had previously rendered concurrent TMS–EEG impossible. Various physiological artifacts resulting from TMS have also been identified, and methods are being developed to either minimize or remove these sources of artifact. With these developments, TMS–EEG has unlocked regions of the cortex to researchers that were previously inaccessible to TMS. By recording the TMS‐evoked response directly from the cortex, TMS–EEG provides information on the excitability, effective connectivity, and oscillatory tuning of a given cortical area, removing the need to infer such measurements from indirect measures. In the following review, we investigate the different online and offline methods for reducing artifacts in TMS–EEG recordings and the physiological information contained within the TMS‐evoked cortical response. We then address the use of TMS–EEG to assess different cortical mechanisms such as cortical inhibition and neural plasticity, before briefly reviewing studies that have utilized TMS–EEG to explore cortical network properties at rest and during different functional brain states. Hum Brain Mapp, 2013. © 2012 Wiley Periodicals, Inc.     

Magnetic stimulation of the central and peripheral nervous systems

Since 1985, when the technique of transcranial magnetic stimulation (TMS) was first developed, a wide range of applications in healthy and diseased subjects has been described. Comprehension of the physiological basis of motor control and cortical function has been improved. Modifications of the basic technique of measuring central motor conduction time (CMCT) have included measurement of the cortical silent period, paired stimulation in a conditioning test paradigm, repetitive transcranial magnetic stimulation (rTMS), and peristimulus time histograms (PSTH). These methods allow dissection of central motor excitatory versus inhibitory interplay on the cortical motor neuron and its presynaptic connections at the spinal cord, and have proven to be powerful investigational techniques. TMS can be used to assess upper and lower motor neuron dysfunction, monitor the effects of many pharmacological agents, predict stroke outcome, document the plasticity of the motor system, and assess its maturation and the effects of aging, as well as perform intraoperative monitoring. The recent use of rTMS in the treatment of depression and movement disorders is novel, and opens the way for other potential therapeutic applications.     

Transcranial magnetic stimulation and epilepsy.

Epileptic conditions are characterized by an altered balance between excitatory and inhibitory influences at the cortical level. Transcranial magnetic stimulation (TMS) provides a noninvasive evaluation of separate excitatory and inhibitory functions of the cerebral cortex. In addition, repetitive TMS (rTMS) can modulate the excitability of cortical networks. We review the different ways that TMS has been used to investigate pathophysiological mechanisms and effects of antiepileptic drugs in patients with epilepsy and epileptic myoclonus. The safety of different TMS techniques is discussed too. Finally, we discuss the therapeutic prospects of rTMS in this field.     

Diagnostic contribution and therapeutic perspectives of transcranial magnetic stimulation in dementia

Transcranial magnetic stimulation (TMS) is a powerful tool to probe in vivo brain circuits, as it allows to assess several cortical properties such as excitability, plasticity and connectivity in humans. In the last 20 years, TMS has been applied to patients with dementia, enabling the identification of potential markers of the pathophysiology and predictors of cognitive decline; moreover, applied repetitively, TMS holds promise as a potential therapeutic intervention.The objective of this paper is to present a comprehensive review of studies that have employed TMS in dementia and to discuss potential clinical applications, from the diagnosis to the treatment.To provide a technical and theoretical framework, we first present an overview of the basic physiological mechanisms of the application of TMS to assess cortical excitability, excitation and inhibition balance, mechanisms of plasticity and cortico-cortical connectivity in the human brain. We then review the insights gained by TMS techniques into the pathophysiology and predictors of progression and response to treatment in dementias, including Alzheimer’s disease (AD)-related dementias and secondary dementias. We show that while a single TMS measure offers low specificity, the use of a panel of measures and/or neurophysiological index can support the clinical diagnosis and predict progression.In the last part of the article, we discuss the therapeutic uses of TMS. So far, only repetitive TMS (rTMS) over the left dorsolateral prefrontal cortex and multisite rTMS associated with cognitive training have been shown to be, respectively, possibly (Level C of evidence) and probably (Level B of evidence) effective to improve cognition, apathy, memory, and language in AD patients, especially at a mild/early stage of the disease. The clinical use of this type of treatment warrants the combination of brain imaging techniques and/or electrophysiological tools to elucidate neurobiological effects of neurostimulation and to optimally tailor rTMS treatment protocols in individual patients or specific patient subgroups with dementia or mild cognitive impairment.     

Pharmacologic influences on TMS effects.

Transcranial magnetic stimulation (TMS) has been used increasingly to probe the physiology of the human cortex. Besides measuring directly the cortical excitability in motor and visual systems, this noninvasive method can be used to study short- and long-term cortical plasticity. One possible method to examine basic mechanisms underlying cortical excitability and plasticity in humans is the combination of TMS and pharmacologic interventions. In this review the author describes TMS paradigms used to study mechanisms of plasticity in the intact human motor system and its excitability using pharmacologic methods.     

Contribution of transcranial magnetic stimulation in restless legs syndrome: pathophysiological insights and therapeutical approaches

Transcranial magnetic stimulation (TMS) may offer a reliable means to characterize significant pathophysiologic and neurochemical aspects of restless legs syndrome (RLS). Namely, TMS has revealed specific patterns of changes in cortical excitability and plasticity, in particular dysfunctional inhibitory mechanisms and sensorimotor integration, which are thought to be part of the pathophysiological mechanisms of RLS rather than reflect a non-specific consequence of sleep architecture alteration.If delivered repetitively, TMS is able to transiently modulate the neural activity of the stimulated and connected areas. Some studies have begun to therapeutically use repetitive TMS (rTMS) to improve sensory and motor disturbances in RLS. High-frequency rTMS applied over the primary motor cortex or the supplementary motor cortex, as well as low-frequency rTMS over the primary somatosensory cortex, seem to have transient beneficial effects. However, further studies with larger patient samples, repeated sessions, an optimized rTMS setup, and clinical follow-up are needed in order to corroborate preliminary results.Thus, we performed a systematic search of all the studies that have used TMS and rTMS techniques in patients with RLS.     

Toward the establishment of neurophysiological indicators for neuropsychiatric disorders using transcranial magnetic stimulation‐evoked potentials: A systematic review

Transcranial magnetic stimulation (TMS) can depolarize the neurons directly under the coil when applied to the cerebral cortex, and modulate the neural circuit associated with the stimulation site, which makes it possible to measure the neurophysiological index to evaluate excitability and inhibitory functions. Concurrent TMS and electroencephalography (TMS‐EEG) has been developed to assess the neurophysiological characteristics of cortical regions other than the motor cortical region noninvasively. The aim of this review is to comprehensively discuss TMS‐EEG research in the healthy brain focused on excitability, inhibition, and plasticity following neuromodulatory TMS paradigms from a neurophysiological perspective. A search was conducted in PubMed to identify articles that examined humans and that were written in English and published by September 2018. The search terms were as follows: (TMS OR ‘transcranial magnetic stimulation’) AND (EEG OR electroencephalog*) NOT (rTMS OR ‘repetitive transcranial magnetic stimulation’ OR TBS OR ‘theta burst stimulation’) AND (healthy). The study presents an overview of TMS‐EEG methodology and neurophysiological indices and reviews previous findings from TMS‐EEG in healthy individuals. Furthermore, this review discusses the potential application of TMS‐EEG neurophysiology in the clinical setting to study healthy and diseased brain conditions in the future. Combined TMS‐EEG is a powerful tool to probe and map neural circuits in the human brain noninvasively and represents a promising approach for determining the underlying pathophysiology of neuropsychiatric disorders.     

Motor cortex excitability in restless legs syndrome

BACKGROUND AND PURPOSE: A review of the literature shows that the transcranial magnetic stimulation (TMS) is a useful neurophysiological tool to investigate the pathophysiology of the restless legs syndrome (RLS). In this study we used TMS to define motor cortical excitability in RLS subjects. PATIENTS AND METHODS: Six RLS patients and two healthy control subjects underwent TMS (single and paired) examination using two protocols: (1) the evaluation of motor cortical excitability changes occurring at various times after a repetitive finger movement task; (2) the evaluation of the time course of intracortical motor activity tested with pairs of magnetic stimuli applied at inter-stimulus intervals of 1-6 ms. RESULTS: Subjects affected by RLS do not show the normal fluctuations of motor cortical excitability usually found after a bimanual finger movement task. The intracortical inhibition was reduced in RLS subjects. CONCLUSIONS: These results compared with the other studies suggest a modification in the central circuits and suppose a reduction or alteration in the cortical plasticity.     

Neue Einblicke in die Hirnfunktion durch Kombination von transkranieller magnetischer Kortexstimulation und funktioneller zerebraler Bildgebung

The present paper aims to summarize potential applications of transcranial magnetic stimulation (TMS) combined with functional brain imaging. Transcranial magnetic stimulation is a well-established noninvasive tool for stimulating circumscribed areas of the human cortex. Functional imaging techniques such as positron emission tomography, functional magnetic resonance imaging, and electroencephalographic mapping enable assessment of TMS-related functional brain activation. A combination of TMS and functional imaging can be useful in three principal ways. (1) Brain imaging before TMS is helpful in defining the accurate coil position over a distinct cortical area which is targeted by TMS. Since TMS can be used to interfere with regional cortical function during a given task, the effects of focal TMS on task performance can help to clarify the task-specific functional contribution of a given cortical area which has previously shown task-related activation in a functional imaging study. (2) Imaging the brain during TMS is a promising approach for assessing cortical excitability and intracerebral functional connectivity. (3) By evaluating lasting effects of TMS, brain imaging after TMS can be employed to study the plasticity of the human cortex. Moreover, this approach will help to advance our understanding of therapeutical effects related to TMS.     

Transcranial magnetic stimulation in cognitive rehabilitation

Repetitive transcranial magnetic stimulation (rTMS) can generate an increase or a decrease of neuronal excitability, which can modulate cognition and behaviour. Transcranial magnetic stimulation-induced cortical changes have been shown to result in neural plasticity. Thus, TMS provides an important opportunity to gain more insight into the mechanisms responsible for the remarkable flexibility of the central nervous system. The aim of this review was to cover the topics that could be useful when using TMS in the cognitive rehabilitation field after brain damage. The basic TMS principles are introduced, together with the clinical application for diagnosis and prognosis, the biological aspects, and the use in cognitive neuroscience studies. Finally, several hypotheses are discussed to explain the likely mechanisms induced by TMS that favour the recovery of a function after brain damage and cause the adult brain to undergo plasticity. The possibility of non-invasively interacting with the functioning of the brain and its plasticity mechanisms - a possibility that may eventually lead to cognitive and behavioural modifications - opens new and exciting scenarios in the cognitive neurorehabilitation field.     

Cortical excitability in schizophrenia. Studies using transcranial magnetic stimulation

Abnormalities in brain plasticity, including abnormal information processing by disturbed cortical inhibition and facilitation in schizophrenia, have been described several times in the past. Transcranial magnetic stimulation (TMS) provides a neurophysiological technique for the measurement of cortical excitability, especially of the motoneural system. With TMS it is possible to explore important aspects of the pathophysiological mechanisms underlying schizophrenia using recently developed paradigms (paired pulse method, cortical silent period). This review summarizes the results of available diagnostic TMS studies in schizophrenia. Studies investigating the efficacy of therapeutic repetitive magnetic stimulation in patients with treatment resistant hallucinations or predominantly negative symptoms were not considered. The reviewed studies support the assumption of reduced cortical inhibition, probably caused by GABAergic deficit, in schizophrenia. Factors influencing the study results, the limitations of this promising technique in schizophrenia, and further research options are discussed.     

Clinical utility and prospective of TMS–EEG

Concurrent transcranial magnetic stimulation and electroencephalography (TMS–EEG) has emerged as a powerful tool to non-invasively probe brain circuits in humans, allowing for the assessment of several cortical properties such as excitability and connectivity. Over the past decade, this technique has been applied to various clinical populations, enabling the characterization and development of potential TMS–EEG predictors and markers of treatments and of the pathophysiology of brain disorders. The objective of this article is to present a comprehensive review of studies that have used TMS–EEG in clinical populations and to discuss potential clinical applications. To provide a technical and theoretical framework, we first give an overview of TMS–EEG methodology and discuss the current state of knowledge regarding the use of TMS–EEG to assess excitability, inhibition, plasticity and connectivity following neuromodulatory techniques in the healthy brain. We then review the insights afforded by TMS–EEG into the pathophysiology and predictors of treatment response in psychiatric and neurological conditions, before presenting recommendations for how to address some of the salient challenges faced in clinical TMS–EEG research. Finally, we conclude by presenting future directions in line with the tremendous potential of TMS–EEG as a clinical tool.     

Transcranial magnetic stimulation: a new investigational and treatment tool in psychiatry

Transcranial magnetic stimulation (TMS) is a new investigational technique used to explore various neural processes and treat a variety of neuropsychiatric illnesses. The most notable advantage of TMS is its ability to directly stimulate the cortex with little effect on intervening tissue. Single-pulse stimulation techniques can measure cortical inhibition, facilitation, connectivity, reactivity, and cortical plasticity, providing valuable insights into the cortical physiology. Repetitive TMS (rTMS) is currently being used to investigate cognitive processes and as a treatment tool in disorders such as depression and schizophrenia. Both TMS and rTMS are safe and well tolerated. The most serious side effect of high-frequency rTMS is seizures. TMS represents an exciting new frontier in neuroscience research, providing insights into the pathophysiology and treatment of various neuropsychiatric disorders.     

Cortical plasticity is correlated with cognitive improvement in Alzheimer’s disease patients after rTMS treatment

ObjectiveRepetitive transcranial magnetic stimulation (rTMS) has been widely used in non-invasive treatments for different neurological disorders. Few biomarkers are available for treatment response prediction. This study aims to analyze the correlation between changes in long-term potentiation (LTP)-like cortical plasticity and cognitive function in patients with Alzheimer’s disease (AD) that underwent rTMS treatment.MethodsA total of 75 AD patients were randomized into either 20 Hz rTMS treatment at the dorsolateral prefrontal cortex (DLPFC) group (n = 37) or a sham treatment group (n = 38) for 30 sessions over six weeks (five days per week) with a three-month follow-up. Neuropsychological assessments were conducted using the Mini-Mental State Examination (MMSE) and Alzheimer’s Disease Assessment-Cognitive Component (ADAS-Cog). The cortical plasticity reflected by the motor-evoked potential (MEP) before and after high-frequency repetitive TMS to the primary motor cortex (M1) was also examined prior to and after the treatment period.ResultsThe results showed that the cognitive ability of patients who underwent the MMSE and ADAS-Cog assessments showed small but significant improvement after six weeks of rTMS treatment compared with the sham group. The cortical plasticity improvement correlated to the observed cognition change.ConclusionsCortical LTP-like plasticity could predict the treatment responses of cognitive improvements in AD patients receiving rTMS intervention. This warrants future clinical trials using cortical LTP as a predictive marker.     

Brain functional reorganization in children with hemiplegic cerebral palsy: Assessment with TMS and therapeutic perspectives

Transcranial magnetic stimulation (TMS) can be a useful tool for the assessment of the brain functional reorganization in subjects with hemiplegic cerebral palsy (HCP). In this review, we performed a systematic search of all studies using TMS in order to explore the neuroplastic changes that occur in HCP patients. We aimed at investigating the usefulness of TMS to explore cortical excitability, plasticity and connectivity changes in HCP. Children with HCP due to unilateral lesions of the corticospinal system had ipsilateral motor evoked potentials (MEPs) similar to those recorded contralaterally. TMS studies demonstrated that occupational and constraint-induced movement therapy were associated with significant improvements in contralateral and ipsilateral corticomotor projection patterns. In addition, after intensive bimanual therapy, children with HCP showed increased activation and size of the motor areas controlling the affected hand. A TMS mapping study revealed a mediolateral location of the upper and lower extremity map motor cortical representations. Deficits in intracortical and interhemispheric inhibitory mechanisms were observed in HCP. Early hand function impairment correlated with the extension of brain damage, number of involved areas, and radiological signs of corticospinal tract (CST) degeneration. Clinical mirror movements (MMs) correlated with disability and CST organization in subjects with HCP and a positive relationship was found between MMs and MEPs strength. Therefore, TMS studies have shed light on important pathophysiological aspects of motor cortex and CST reorganization in HCP patients. Furthermore, repetitive TMS (rTMS) might have therapeutic effects on CST activities, functional connectivity and clinical status in children with HCP.     

Preferential Activation of Unique Motor Cortical Networks With Transcranial Magnetic Stimulation: A Review of the Physiological,Functional, and Clinical Evidence

ObjectivesThe corticospinal volley produced by application of transcranial magnetic stimulation (TMS) over primary motor cortex consists of a number of waves generated by trans-synaptic input from interneuronal circuits. These indirect (I)-waves mediate the sensitivity of TMS to cortical plasticity and intracortical excitability and can be assessed by altering the direction of cortical current induced by TMS. While this methodological approach has been conventionally viewed as preferentially recruiting early or late I-wave inputs from a given populations of neurons, growing evidence suggests recruitment of different neuronal populations, and this would strongly influence interpretation and application of these measures. The aim of this review is therefore to consider the physiological, functional, and clinical evidence for the independence of the neuronal circuits activated by different current directions.Materials and MethodsTo provide the relevant context, we begin with an overview of TMS methodology, focusing on the different techniques used to quantify I-waves. We then comprehensively review the literature that has used variations in coil orientation to investigate the I-wave circuits, grouping studies based on the neurophysiological, functional, and clinical relevance of their outcomes.ResultsReview of the existing literature reveals significant evidence supporting the idea that varying current direction can recruit different neuronal populations having unique functionally and clinically relevant characteristics.ConclusionsFurther research providing greater characterization of the I-wave circuits activated with different current directions is required. This will facilitate the development of interventions that are able to modulate specific intracortical circuits, which will be an important application of TMS.     

Transcranial magnetic stimulation

Transcranial magnetic stimulation (TMS) allows non-invasive study and modulation of cortical excitability in humans. Changes in cortical excitability in physiological and pathological conditions can be tracked by measurements such as motor threshold, motor evoked potentials, recruitment curves, intracortical facilitation and inhibition. The central motor conduction time can estimate neural transmission in central motor pathways. Changes in areas of representation in sensorimotor cortex can be studied with cortical mapping. Modulation of cortical processing can be used to evaluate different brain functions. Therapeutic use in depression, Parkinson's disease and epilepsy has raised great interest over the past decade. Non-invasive cortical mapping may be achieved by combining TMS to other neurophysiological/ neuroimaging techniques. TMS has great potential both as an investigational and as a therapeutical tool in Neurology and Psychiatry.     

Modifying somatosensory processing with non-invasive brain stimulation

Purposeful manipulation of cortical plasticity and excitability within somatosensory regions may have therapeutic potential. Non-invasive brain stimulation (NBS) techniques such as transcranial magnetic stimulation (TMS) or transcranial direct current stimulation (tDCS) have shown promise towards this end with certain NBS protocols augmenting somatosensory processing and others down-regulating it. Here, we review NBS protocols which, when applied to primary somatosensory cortex, facilitate cortical excitability and tactile acuity (i.e., high-frequency repetitive TMS (rTMS), intermittent theta burst stimulation (TBS), paired associative stimulation (PAS) N20-5 to 0, anodal tDCS), and protocols that inhibit the same (i.e., low-frequency rTMS, continuous TBS, PAS N20-20, cathodal tDCS). Other studies have targeted multisensory regions of the brain to modulate somatosensory processing. These studies in full present a wide array of strategies in which NBS can be utilized to influence somatosensory processing in a behaviorally and clinically relevant capacity.