Clinical aspects

Description

	• A handheld wire coil magnetic stimulator consists of a power supply, a capacitor, and controlling electronics.
	• When placed against the skull, a secondary current is induced in the underlying cortical neurons at a depth of about 2 cm below the brain’s surface; this current triggers action potentials.
	• Transcranial magnetic stimulation can be used for brain mapping and has several diagnostic applications.
	• There are several therapeutic applications of repetitive transcranial magnetic stimulation, eg, management of pain and post-stroke rehabilitation.
	• Low-frequency repetitive transcranial magnetic stimulation (rTMS) has been used for inhibition of seizure activity, but high-frequency rTMS, used for the treatment of depression, may provoke seizures.

Technology. A typical magnetic stimulator consists of a power supply, a capacitor, and controlling electronics. The capacitor can discharge 3000 to 8000 amperes through a handheld wire coil. When the current is rapidly turned on and off in the coil, through the discharge of capacitors, a magnetic field lasting for about 100 to 200 microseconds is produced. The magnetic field created around the coil has a strength of 2- to 3-tesla. When the coil is held against the skull, a secondary current is induced in the underlying cortical neurons, which serves to trigger action potentials. With current technology, the area of depolarization is limited to a depth of about 2 cm below the brain’s surface.

Cortical mapping by stimulation. Transcranial magnetic stimulation can influence all parts of the brain beneath the skull, but most studies have been of the motor cortex where the motor-evoked potential can be produced. A single transcranial magnetic stimulation pulse of adequate intensity over the motor cortex can cause involuntary movement. Known as the motor threshold, the magnetic field intensity needed to produce motor movement varies considerably among individuals. Placing the coil over different areas of the motor cortex causes contralateral movement in different muscles, corresponding to the well-known homunculus. Transcranial magnetic stimulation can then be used to map the representation of body parts in the motor cortex on an individual basis. Applied over the primary visual cortex, transcranial magnetic stimulation can produce the perception of flashes of light. Beside the extensive use of transcranial magnetic stimulation, no reports of the elicitation of memories, smells, or other complex psychological phenomena like those reported during direct cortical stimulation in epilepsy surgery are advanced. Possible explanations include the lack of transcranial magnetic stimulation usage as an adjunct of epilepsy surgery and the spread of electric current beyond the point of direct cortical stimulation.

Investigation of cortical plasticity. Transcranial magnetic stimulation measurements of motor cortex function are reliable enough to be potentially useful in investigation of motor system plasticity.

Brain mapping. The transcranial magnetic stimulation-compatible multichannel (60-channel) EEG system enables location of transcranial magnetic stimulation-evoked electric activity in the brain. A brain map is then generated by measuring responses of different motor and sensory functions in response to this stimulation. Frameless stereotaxy has been used for planning, monitoring, and documenting the location of the transcranial magnetic stimulation coil relative to the subject’s brain. Association of the 3-dimensional positions of the transcranial magnetic stimulation probe on the scalp enables a 3-dimensional brain reconstruction. Single-pulse transcranial magnetic stimulation maps the motor cortex; the motor output maps may be used as an estimation of the represented muscle location in the motor cortex. Combination of transcranial magnetic stimulation with EEG enables the study of interhemispheric connections with high spatiotemporal specificity and the assessment of cortical reactivity with excellent sensitivity. EEG analysis following transcranial magnetic stimulation is called transcranial magnetic stimulation-evoked potentials (20). Basal ganglia-cortical relationships can be assessed using electrodes placed in the process of deep brain stimulation therapy. Cerebellar-cortical relationships can be determined using transcranial magnetic stimulation over the cerebellum.

Beside EEG, neuroimaging techniques (eg, PET and MRI) can be combined with repetitive transcranial magnetic stimulation for the assessment of connectivity and excitability in the human cerebral cortex. Besides the combination of repetitive transcranial magnetic stimulation with EEG and neuroimaging, application of neuroactive drugs can provide a powerful tool for studying the human cortex that will advance our understanding of how repetitive transcranial magnetic stimulation interacts with neuronal networks in the human brain (55).

Although diffusion tensor imaging tractography provides 3-dimensional reconstruction of principal white matter tracts of the brain, its spatial accuracy is questionable. In comparison to this method of fiber tracking, navigated transcranial magnetic stimulation enables a more accurate somatotopic mapping of the motor cortex as well as the motor pathway and is less operator-dependent. A clinical trial has shown that combination of tractography based on navigated transcranial magnetic stimulation increases the accuracy of fiber tracking with diffusion tensor imaging and has the potential to become a supplemental tool for guiding electrode implantation (16).

Investigation of central motor conduction. Transcranial magnetic stimulation has been used for investigating the integrity and speed of central motor conduction. Abnormal central motor conduction time is asymmetric and related to clinical score. The following are some examples of applications in various disorders:

	• Transcranial magnetic stimulation can provide evidence for motor cortex dysfunction in movement disorders such as Parkinson disease.
	• Transcranial magnetic stimulation-induced motor-evoked potentials can be used to detect spinal cord ischemia during surgery for thoracoabdominal aneurysms.
	• Transcranial magnetic stimulation is of value as a rapid, inexpensive, and noninvasive technique for screening patients before MRI studies in spinal cord compression due to cervical spondylosis.
	• Transcranial magnetic stimulation has been used as a prognostic tool in stroke patients. Presence of motor-evoked potentials following a stroke is usually considered a sign of good outcome. Absence of response to transcranial magnetic stimulation during the first hours following stroke indicates a poor outcome for motor recovery.

Study of movement disorders. Transcranial magnetic stimulation has been used to study the pathophysiology of movement disorders such as Parkinson disease, chronic tic disorders, and essential tremor. These studies have provided useful information but there is disagreement that questions the validity of some of the findings as reliable diagnostic biomarkers because of interindividual variability (30).

Study of brain-behavior relations. Transcranial magnetic stimulation can create virtual lesions, thereby enabling determination of the contribution of a given cortical region to a specific behavior. Positron emission tomography studies done during transcranial magnetic stimulation might identify the area of the brain activated. When combined with functional neuroimaging, transcranial magnetic stimulation can be used to study the neural networks involved in behavior. Thus, transcranial magnetic stimulation is a tool for cognitive neuroscience and can be used to map the functional connectivity between brain regions.

Investigation of human memory. Transcranial magnetic stimulation of the brain can provide insight into human memory as a basis for therapy of its dysfunction. Unlike long-term memory, which is preserved in synaptic connections, the neurons involved in short-term or working memory decouple easily. Working memory is temporary, becomes latent, and is erasable. A study has shown that transcranial magnetic stimulation can be used to reactivate latent memories, ie, recovering information that seems to be lost forever (45). The results support a synaptic theory of working memory.

Transcranial magnetic stimulation of the posterior inferior parietal cortex, targeted to the hippocampus, can specifically modulate the encoding of new associations into memory without directly influencing retrieval processes and supports the idea that it may be a potential tool for manipulating hippocampal function in healthy participants (50). However, studies combining hippocampal-targeted continuous theta-burst transcranial magnetic stimulation with neuroimaging are required for a better understanding of the neural basis of memory changes induced by transcranial magnetic stimulation.

Combination of transcranial magnetic stimulation with fMRI. A reflective tag, which can be tracked by an optical sensor, is attached to the coil, allowing the coil's position to be displayed on the MRI scan. This and similar methods should allow the neural connections within the brain to be mapped out. This can enable the investigation of how tasks such as learning change neural connections.

Investigation of pathomechanism of cerebellar tremor. Tremor can be induced by repetitive transcranial magnetic stimulation at 10 to 30 Hz and intensities above motor threshold when applied over the motor cortex. This is like cerebellar tremor, suggesting that cerebellar tremor is caused by interference with adaptive cerebellar afferent inflow to motor cortex. Resting tremor in Parkinson disease can be reset by stimulation of primary motor cortex, but not by cerebellar stimulation, whereas postural tremor can be reset by both types of stimulation. Assessment of the cerebellothalamocortical pathway by transcranial magnetic stimulation of the cerebellum has shown that it is involved in the generation or transmission of postural tremor (41).

Investigation of pathomechanism of myoclonus. Several transcranial magnetic stimulation studies have shed some light on sensorimotor plasticity and cortical excitability in different forms of myoclonus, as well as on the pathophysiology of this movement disorder. Characteristic motor cortical excitability patterns have identified various disorders characterized by myoclonus, even though they need to be confirmed in studies on larger cohorts of patients (38). Repetitive transcranial magnetic stimulation has a therapeutic potential in some patients with myoclonus, like that reported in other neurologic disorders.

Peripheral nerve conduction studies. Transcranial magnetic stimulation can be used for stimulating the peripheral nerves. Yet, it is not suitable for routine nerve conduction studies because the site of stimulation is uncertain. It is useful in situations where location of the exact site of stimulation is not important and electrical stimulation is painful. One example of a useful application in the peripheral nervous system is the evaluation of the conduction in the cauda equina.

The goal is to obtain information about the function of the nervous system and to improve abnormal function as an alternative or supplement to pharmacotherapy.

Indications

These are both diagnostic and therapeutic as shown in Table 1:

Table 1. Indications for Transcranial Magnetic Stimulation

Diagnostic: Single-pulse or paired-pulse transcranial magnetic stimulation
	• Measuring speed of conduction in the central motor pathways (eg, multiple sclerosis). • Measuring nerve conduction in cauda equina. • Mapping cerebral cortical function. • Evaluating the efficacy of drug action on the brain. • Determining location of the motor cortex during neurosurgical procedures. • Determining prognosis in poststroke hand palsy. • Distinguishing Alzheimer disease from frontotemporal dementia
Therapeutic: Repetitive transcranial magnetic stimulation
	• Depression and other psychiatric disorders • Drug addiction • Posttraumatic stress disorder • Parkinson disease • Huntington disease • Alzheimer disease • Multiple sclerosis • Stroke • Chronic pain • Phantom limb pain • Migraine • Sleep disorders

Contraindications

High-intensity repetitive transcranial magnetic stimulation should not be used for the treatment of depression in epileptic patients due to the risk of inducing seizures.

Results

Diagnostic applications. Navigated transcranial magnetic stimulation is a reliable alternative for localizing cortical functions and may be a useful adjunct to other functional neuroimaging methods.

The latency of motor responses evoked by single-pulse transcranial magnetic stimulation conveys information about conduction velocity. The difference in latency for responses evoked with cortical and cervical spinal transcranial magnetic stimulation assesses the central motor conduction time. This method is useful in the following conditions:

Alzheimer disease versus frontotemporal dementia. Paired-pulse transcranial magnetic stimulation is used to investigate intracortical inhibition as well as facilitation and short-latency afferent inhibition to measure the activity of different intracortical circuits in patients with Alzheimer disease and distinguish them from patients with frontotemporal dementia and healthy controls (03).

Amyotrophic lateral sclerosis. A high rate of central motor conduction abnormalities has been found in patients with amyotrophic lateral sclerosis who do not have definite upper motor neuron signs. Transcranial magnetic stimulation can contribute to a more reliable diagnosis in these patients.

Multiple sclerosis. Central motor conduction time is frequently abnormal in patients with multiple sclerosis and is also delayed in other disorders associated with demyelination. Transcranial magnetic stimulation is an established neurophysiological tool to examine the integrity of the fast-conducting corticomotor pathways in a wide range of diseases associated with motor dysfunction, including multiple sclerosis (18).

Phantom limb pain. A systematic review indicates the potential of transcranial magnetic stimulation to gain insights into pathophysiological aspects of phantom limb pain, help in the selection of patients for various therapies, and possibly have therapeutic value, but the evidence is still very preliminary and well-designed studies on patients are required (39).

Evaluation of pharmaceutical prophylaxis of migraine. Transcranial magnetic stimulation has been used to measure occipital cortex excitability as a noninvasive adjunct to assessment of migraine prophylaxis with various drugs.

Therapeutic applications. Although many successes have been reported concerning treatment of neurologic disorders by transcranial magnetic stimulation, the results of blinded, sham-controlled trials do not provide clear evidence of beneficial effects that replace or even match the effectiveness of conventional treatments in any disorder. The use of repetitive transcranial magnetic stimulation has been explored in the following conditions:

Epilepsy. Low-frequency repetitive transcranial magnetic stimulation may have a significant antiepileptic effect in patients with refractory partial epilepsy (49). Additionally, the treatment was reported to improve the psychological condition of these patients.

Paired-pulse inhibition is reduced in focal epilepsy and enhanced by gamma-aminobutyric-acid agents. Pharmacological manipulations suggest that intracortical paired-pulse inhibition reflects the activation of inhibitory gamma-aminobutyric-acid-ergic and dopaminergic interneurons, whereas paired-pulse facilitation reflects excitatory N-methyl-D-aspartate-mediated interneurons, and ion channel conductivity modulates motor threshold. These profiles provide novel methods for investigating local alterations in neurochemical systems in epilepsy.

Transcranial magnetic stimulation can be used for assessing the efficacy of a drug in an epileptic patient and for monitoring antiepileptic drugs levels. Changes in threshold intensity of transcranial magnetic stimulation in response to anticonvulsant treatment may prove useful in guiding therapy. Paired-pulse transcranial magnetic stimulation can be used as an in vivo method for the assessment of the of drug effects on cortical facilitatory as well as inhibitory phenomena. Repetitive transcranial magnetic stimulation reduces seizure frequency in patients with refractory epilepsy and may be an alternative treatment for pharmaco-resistant patients with clearly identifiable seizure foci in the cortical convexity, such as arteriovenous malformations, and who are not eligible for surgical treatment. A systematic review of randomized clinical trials has concluded that the evidence for efficacy of repetitive transcranial magnetic stimulation for seizure reduction is still lacking despite reasonable evidence that it is effective at reducing epileptiform discharges (08). A meta-analysis of real-world evidence suggests that low-frequency repetitive transcranial magnetic stimulation using a figure-8 coil may be an effective therapy for the treatment of drug-resistant epilepsy in pediatric patients and can be tested in a randomized clinical trial (10).

Navigated transcranial magnetic stimulation for language mapping is clinically useful and safe in epilepsy surgery. In a study of comparison with direct cranial stimulation, the sensitivity of navigated transcranial magnetic stimulation was 68%, specificity was 76%, positive predictive value was 27%, and negative predictive value was 95% (32).

Anxiety disorder. Transcranial magnetic stimulation is not yet approved for the clinical treatment of any anxiety disorder. Some clinical trials suggest that transcranial magnetic stimulation has a significant effect, but in other studies, the effect is small and short-lived (43). Controlled trials are needed.

Posttraumatic stress disorder. A meta-analysis of clinical trials shows that active repetitive transcranial magnetic stimulation applied to the dorsolateral prefrontal cortex is an effective treatment for posttraumatic stress disorder (05).

Functional (conversion) neurologic disorders. Preliminary evidence suggests that transcranial magnetic stimulation may be an effective treatment for functional neurologic disorders (42).

Depression. Repetitive transcranial magnetic stimulation is approved by the U.S. Food and Drug Administration for the care of treatment-resistant depression. Several open as well as controlled clinical trials have been conducted. The mechanism of improvement in refractory depression is postulated to be an increase in the level of brain-derived neurotrophic factors. A systematic review of randomized clinical trials has shown that repetitive transcranial magnetic stimulation appears to provide significant benefits in short-term treatment of patients with treatment-resistant depression, but further studies are needed before it can be considered as a first-line monotherapy. Repetitive transcranial magnetic stimulation can be useful in the treatment of depression associated with Parkinson disease, epilepsy, stroke, multiple sclerosis, and Alzheimer disease.

In contrast to electroconvulsive therapy, repetitive transcranial magnetic stimulation does not require the generation of a major motor seizure to achieve therapeutic efficacy. Therefore, it obviates the need for general anesthesia and avoids side effects such as transient memory loss, which is seen following electroconvulsive therapy.

There is no uniform pattern of response to transcranial magnetic stimulation in patients with depression. Variations in the responses are due to factors that are specific to patients, concomitant illnesses, as well as modality of treatment. Because of the individual variability in mood states and symptoms of depression, one protocol may work for some whereas different protocols work for others. This indicates the need for personalized approaches that take into consideration the individual variations in patients with depression. A review of various studies indicates that response to transcranial magnetic stimulation in depression can be predicted, and this can help clinicians in the appropriate selection of patients for transcranial magnetic stimulation treatment to improve the outcome (25).

Drug addiction. Repetitive transcranial magnetic stimulation influences neural activity by mechanisms that involve neuroplasticity both locally and at the network level throughout the brain (12). Long-term neurophysiological changes induced by repetitive transcranial magnetic stimulation can affect drug craving, intake, and relapses. Transcranial magnetic stimulation is safe and cost-effective potential treatment for some substance use disorders. Results of a randomized study suggest that 10Hz repetitive transcranial magnetic stimulation of the left dorsolateral prefrontal cortex may reduce craving with no negative effects on cognitive function in patients addicted to methamphetamine (48). A meta-analysis of studies of transcranial magnetic stimulation on substance use disorder identified a beneficial effect of high-frequency repetitive transcranial magnetic stimulation on craving associated with nicotine use but not alcohol use (34). Other studies have shown that repetitive transcranial magnetic stimulation is an innovative, safe, and cost-effective treatment for alcohol use disorder (11).

Mild cognitive impairment. The risk of progression of mild cognitive impairment to Alzheimer disease is high and cholinesterase inhibitors have not proven effective in slowing the rate of progression. Previous studies suggest that repetitive transcranial magnetic stimulation can enhance memory and cognition in mild cognitive impairment. A clinical trial of repetitive transcranial magnetic stimulation in mild cognitive impairment (NCT03331796) will evaluate the short-term efficacy as well as provide information on the durability of cognitive improvement and potentially distinct effects of stimulating dorsolateral prefrontal cortex versus the lateral parietal cortex regions for improving understanding of the therapeutic mechanisms and optimizing repetitive transcranial magnetic stimulation for slowing the rate of progression of mild cognitive impairment to dementia of Alzheimer disease (51).

Development of motor memory in rehabilitation. Pairing motor training with repetitive transcranial magnetic stimulation of primary motor cortex enhances the formation of a motor memory. The enhancing effect of repetitive transcranial magnetic stimulation on the formation of motor memories depends on the frequency and time of the stimulus in relationship to the onset of the training movements and this should be considered in the design of rehabilitation treatment strategies using repetitive transcranial magnetic stimulation (07).

Schizophrenia. A systematic review of meta-analyses has concluded that repetitive transcranial magnetic stimulation is an effective and promising therapeutic treatment for both major depression and schizophrenia (22).

Obsessive-compulsive disorder. Various clinical trials of repetitive transcranial magnetic stimulation for treating obsessive-compulsive disorder have yielded conflicting results. There is some evidence that repetitive transcranial magnetic stimulation targeting the orbitofrontal cortex or the supplementary motor area may be effective for treating obsessive-compulsive disorder. Future controlled trials of repetitive transcranial magnetic stimulation for this indication need to include more clinical variables as well as stimulation parameters and brain targets (04).

Parkinson disease. Dose dependency between the applied electromagnetic field in repetitive transcranial magnetic stimulation and the parkinsonian symptoms has been demonstrated with long-term maintenance of the improvement. Therapeutic efficacy by application of pulsed electromagnetic fields in the picotesla flux density in Parkinson disease involves the activation of dopamine D2 receptor sites, which are the main sites of action in dopaminergic pharmacotherapy.

A randomized double-blind, placebo-controlled trial on patients with Parkinson disease has shown that priming with 1 and 25 Hz rTMS can augment the benefits of treadmill training and lead to long-term motor improvement up to 3 months postintervention (09). In these cases, rebalancing cortical excitability by rTMS is critical for induction of plasticity.

Restless legs syndrome. A pilot randomized prospective study compared high-frequency repetitive transcranial magnetic stimulation over supplementary motor area with sham stimulation in restless legs syndrome and showed statistically significant improvement with real stimulation (01). This should be verified in larger studies.

Huntington disease. Repetitive transcranial magnetic stimulation can improve choreic movements in Huntington disease patients.

Alzheimer disease. An open-label study has shown that Alzheimer disease patients can benefit from repetitive transcranial magnetic stimulation combined with cognitive training in terms of cognitive performances, apathy, and dependence (40). There is a need for controlled studies on a larger number of patients and identification of prognostic factors associated with good outcome.

Amyotrophic lateral sclerosis. A systematic review of 3 randomized clinical trials did not provide adequate evidence to draw any conclusions about the efficacy and safety of repetitive transcranial magnetic stimulation in the treatment of amyotrophic lateral sclerosis (19). Nevertheless, single- and paired-pulse TMS techniques help in differentiating amyotrophic lateral sclerosis from disorders that mimic it, thereby suggesting a potential diagnostic use. Combining TMS with MR spectroscopy may enable an earlier diagnosis of amyotrophic lateral sclerosis (52).

Multiple sclerosis. Transcranial magnetic stimulation, with pulsed electromagnetic fields in the picotesla flux density, has been useful in the symptomatic treatment of multiple sclerosis. No controlled studies of transcranial magnetic stimulation have been done in such patients.

Essential tremor. Continuous transcranial magnetic stimulation with theta-burst stimulation of the primary motor cortex has shown consistent but subclinical reduction in tremor amplitude in patients with essential tremor as compared to normal controls (21).

Tic disorders. A systematic search of clinical trials and review of evidence-based studies did not reveal any evidence to support the use of repetitive transcranial magnetic stimulation for the treatment of tics (47). Because the procedure is associated with a low rate of known complications, it may continue to be further evaluated in research studies.

Benign essential blepharospasm. A randomized, prospective study has shown that repetitive transcranial magnetic stimulation is safe and improves clinical symptoms of benign essential blepharospasm immediately and 1 hour after stimulation (26).

Neurologic rehabilitation. Repetitive transcranial magnetic stimulation can be used to modulate neuroplasticity for facilitating neurologic rehabilitation. Mapping the central representation of muscles provides a method for investigating the cortical reorganization that follows training, amputation, and injury to the central nervous system. Such studies of human plasticity may have important implications for neurologic rehabilitation.

Modulation of plasticity by repetitive transcranial magnetic stimulation may favor the recovery of a function after brain damage. Use of repetitive transcranial magnetic stimulation, by inducing cognitive and behavioral modifications, has potential usefulness for cognitive neurorehabilitation (36).

Stroke management. By increasing the activation threshold of the cortical neurons, repetitive transcranial magnetic stimulation may increase the speed at which the cortex acquires a new function and may facilitate poststroke rehabilitation. Several studies suggest that transcranial magnetic stimulation might be a suitable method to combine with physiotherapy and improve recovery of useful limb function in stroke patients, but further investigations are required to determine the best stimulation parameters and selection of patients who are likely to respond to this treatment. A randomized study has shown that repetitive transcranial magnetic stimulation might be an effective, safe, and feasible complementary therapy for poststroke aphasia (54).

However, a meta-analysis of studies of the efficacy of transcranial magnetic stimulation for rehabilitation of post-stroke nonmotor deficits such as aphasia, dysphagia, and neglect reported statistically significant functional improvements (13). There are still some issues that need to be addressed, the most important of which is the definition of parameters of stimulation that bring out the best results. Further clinical trials are needed to determine the optimal parameters. A 2-week randomized, sham-controlled, single-blind trial on patients with ischemic or hemorrhagic stroke in the middle cerebral artery territory showed that high-frequency rTMS over the contralesional cortex was superior to low-frequency rTMS and sham stimulation in promoting motor recovery acting on contralesional cortex plasticity (53). There was a positive correlation between cortical conductivity of the uninjured hemisphere and recovery of motor impairment.

Chronic pain. Use of transcranial magnetic stimulation for management of chronic pain has been suggested based on the success of electrical stimulation of the cerebral cortex in relieving pain. The mechanism of this analgesic effect is unknown. Transcranial magnetic stimulation might influence the affective-emotional component of chronic pain by means of cingulate and orbitofrontal activation, which leads to descending inhibition of pain impulses by activation of the upper brainstem. Analgesic effects have been produced by repetitive transcranial magnetic stimulation in patients with neuropathic pain, fibromyalgia, or visceral pain. Although the clinical usefulness of repetitive transcranial magnetic stimulation in pain remains to be proven, it offers insights into the pathophysiologic processes involved in the maintenance and exacerbation of chronic neuropathic pain. Initial response to transcranial magnetic stimulation can be used to select patients who are likely to respond favorably to repetitive transcranial magnetic stimulation for the management of intractable neuropathic pain.

Low-frequency repetitive transcranial magnetic stimulation of the right dorsolateral prefrontal cortex or the left motor cortex has a pain-modulating effect in and is useful for the long-term treatment of fibromyalgia (31).

Migraine. A randomized, double-blind, parallel-group, 2-phase, sham-controlled study showed that relief of pain was sustained from 24 to 48 hours with single-pulse transcranial magnetic stimulation (sTMS) as compared to relief for 2 hours with sham treatments (33). A review of patient responses in the setting of routine clinical practice has shown that sTMS is a valuable addition to options for the treatment of both episodic and chronic migraine (06). A randomized study has shown that 3 sessions of 10 Hz repetitive transcranial magnetic stimulation are more effective than a single session in relief from chronic migraine (24). A meta-analysis of randomized clinical trials has shown that single-pulse transcranial magnetic stimulation is effective for the acute treatment of migraine with aura after the first attack, but the efficacy for management of chronic migraine was not significant (28).

Sleep disorders. Low-frequency transcranial magnetic stimulation acting on the right dorsolateral prefrontal cortex or the posterior parietal cortex reduces cortical hyperexcitability and improves quality of sleep in subjects with chronic primary insomnia (37). Transcranial magnetic stimulation has beneficial effects in patients with restless legs syndrome (29). Stimulation of upper airway muscles during sleep by transcranial magnetic stimulation can improve airflow dynamics in obstructive sleep apnea syndrome patients without arousal. Repetitive transcranial magnetic stimulation may contribute to the development of new nonpharmacological neuromodulation of several other sleep disorders.

Tinnitus. A randomized, blinded, placebo-controlled clinical trial of repetitive transcranial magnetic stimulation on persons who experience chronic tinnitus showed that application of 1-Hz repetitive transcranial magnetic stimulation daily for 10 consecutive workdays resulted in a significantly greater percentage of responders to treatment in the active repetitive transcranial magnetic stimulation group compared with the placebo (14).

Potential applications in child neurology. Most of the reported clinical experience with applications of transcranial magnetic stimulation has been in adult patients, with limited use in children. However, because of its excellent safety and possible therapeutic effect, this technique is recommended for further use in pediatric neurology (17).

Adjunct to planning of surgery for brain tumors. Navigated transcranial magnetic stimulation is comparable to direct cortical stimulation for motor cortex mapping and is an adjunct to preoperative planning for resection of central region brain tumors (15). In preoperative planning of high-grade gliomas navigated transcranial magnetic stimulation improves outcomes by increasing the rate of gross total resection and by reducing the surgery-related neurologic deficits (27). A systematic review and meta-analysis provides data that favor the use of navigated transcranial magnetic stimulation motor mapping as an adjunct to brain tumor surgery as it reduces postoperative motor deficits, increases the gross tumor resection rate, and enables a personalized surgical approach compared to standard surgery without the use of preoperative navigated transcranial magnetic stimulation mapping (44).

Adverse effects

Single-pulse transcranial magnetic stimulation is safe and creates no adverse effects. Although tissue damage is unlikely following transcranial magnetic stimulation, adverse effects have been observed following repeated stimulations, and the possibility of unintended long-term changes in brain function are theoretically possible. An updated review of guidelines for the risk and safety of conventional transcranial magnetic stimulation protocols addresses the adverse effects and risks of transcranial magnetic stimulation interventions, eg, the applications of transcranial magnetic stimulation in patients with implanted electrodes in the central nervous system (46). The following are examples of events that may occur following repetitive transcranial magnetic stimulation:

Tension headache. Low-intensity transcranial magnetic stimulation is usually painless, but stimulation at higher intensities and frequencies is generally more painful. The pain is most likely due to the repetitive stimulation of peripheral facial and scalp muscles. As a result, muscle tension headaches are reported in 5% to 20% of patients in various studies. These headaches respond to treatment with acetaminophen or aspirin.

Seizures. Low-frequency repetitive transcranial magnetic stimulation has been used for inhibition of seizure activity. Alternatively, high-frequency repetitive transcranial magnetic stimulation, used for the treatment of depression, may provoke seizure activity. This is rare because only a few patients with repetitive transcranial magnetic stimulation-induced seizures have been reported to date. The transcranial magnetic stimulation-induced seizures are usually self-limiting and do not seem to leave permanent sequelae. The risk of seizure induction is related to the parameters of stimulation. No seizures have been reported with single-pulse transcranial magnetic stimulation or repetitive transcranial magnetic stimulation delivered at a low frequency. Status epilepticus or life-threatening seizures have not been reported in patients undergoing repetitive transcranial magnetic stimulation, which appears to be nearly as safe in patients with epilepsy as in nonepileptic individuals.

Special considerations

No contraindication of transcranial magnetic stimulation during pregnancy exists. Pregnant patients with depression can be treated safely with transcranial magnetic stimulation, whereas all the currently available antidepressant medications have the potential for harm to the fetus.

Clinical trials. As of 1 April 2021, 1706 studies mentioning the term “transcranial magnetic stimulation” are listed on the US Government web site for clinical trials, clinicaltrials.gov. Results of 47 clinical trials were published during the past year; a selected few are described briefly in the clinical applications section of this article.

Scientific basis

	• Transcranial magnetic stimulation is “electrodeless” electrical stimulation as the magnetic field acts as the medium between electricity in the coil and induced electrical currents in the brain.
	• Changes may be induced in the electrochemical properties of the neurons by repetitive transcranial magnetic stimulation (rTMS), and these persist for some time after the termination of the stimulation.
	• Experimental studies show that rTMS can induce genes and produces changes in cerebral blood flow and neurochemistry.
	• Changes produced in the brain by rTMS can be exploited for therapeutic purposes, eg, reduction of oxidative stress in neurons may have a neuroprotective effect.

The interdependent relationship between electricity and magnetism is well recognized. Passage of an electric current through a coil of wire generates a magnetic field perpendicular to the current flow in the coil. If a conducting medium, such as the brain, is adjacent to the magnetic field, the current will be induced in the conducting medium. The flow of the induced current will be parallel but opposite in direction to the current in the coil. Thus, transcranial magnetic stimulation has been referred to as “electrodeless” electrical stimulation to emphasize that the magnetic field acts as the medium between electricity in the coil and induced electrical currents in the brain.

The effects of magnetic energy on the nervous system have been investigated extensively and the physiological effects of transcranial magnetic stimulation have been well documented. Transcranial magnetic stimulation may be applied as single-pulse transcranial magnetic stimulation or paired-pulse transcranial magnetic stimulation. Single pulses affect brain function for just a few milliseconds. Repeated rhythmic application of transcranial magnetic stimulation is called repetitive transcranial magnetic stimulation. If the stimulation occurs faster than once per second (1 Hz), it is referred to as fast-repetitive transcranial magnetic stimulation.

Changes may be induced in the electrochemical properties of the neurons by repetitive transcranial magnetic stimulation, and these persist for some time after the termination of the stimulation. A rapid method of conditioning the human motor cortex using low intensity repetitive transcranial magnetic stimulation at 50 Hz produces a long-lasting effect on motor cortex in healthy people after an application period of only 20 to 190 seconds (23). This is a version of the classic theta burst stimulation protocol and has implications for the development of clinical applications of repetitive transcranial magnetic stimulation. Cortical excitability increases with higher frequency pulses and decreases with lower frequency pulses. With the ability to increase or decrease cerebral activity, repetitive transcranial magnetic stimulation can partially correct overactivity or underactivity and has the potential to “tune” the cortex.

Mechanisms of action of transcranial magnetic stimulation. Studies with intracranial electrodes in rhesus monkeys have provided information about the nature and spatial extent of the repetitive transcranial magnetic stimulation-induced electric field. Corticospinal tract development, aspects of motor control, and medication effects on corticospinal excitability have been studied extensively in nonhuman primates using single-pulse transcranial magnetic stimulation. Experimental studies reveal that transcranial magnetic stimulation-evoked motor responses result from direct excitation of corticospinal neurons at or close to the axon hillock. Repetitive transcranial magnetic stimulation can induce the following changes that can be exploited for therapeutic purposes:

• Changes in brain monoamines. • Reduction of the detrimental effects of oxidative stress in neurons that may have a neuroprotective effect. • Changes in beta-adrenergic receptor binding. • Gene induction. • Changes in cerebral blood flow.

Transcranial magnetic stimulation preferentially activates different structures than transcranial electrical stimulation. These differences occur because different structures in the motor cortex have a differential threshold to the different techniques of stimulation.