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Year : 2018  |  Volume : 27  |  Issue : 2  |  Page : 172-180  Table of Contents     

Transcranial magnetic stimulation: A review of its evolution and current applications

1 Department of Psychiatry, Armed Forces Medical College, Pune, Maharashtra, India
2 Associate Professor, Armed Forces Medical College, Pune, Maharashtra, India

Date of Web Publication14-Jun-2019

Correspondence Address:
Dr. Rajiv Kumar Saini
Department of Psychiatry, Armed Forces Medical College, Pune - 411 040, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ipj.ipj_88_18

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Repetitive transcranial magnetic stimulation (rTMS) is a recently developed noninvasive brain stimulation method for the treatment of psychiatric and neurological disorders. Although, its exact mechanism of action is still not clear, current evidence points toward its role in causing long-term inhibition and excitation of neurons in certain brain areas. As evidence steadily grows in favor of rTMS as a therapeutic tool; there is a need to develop standardized protocols for its administration. There have been no reports of any serious side effects with rTMS, though its use is restricted in those having magnetic implants or recent adverse neurological or cardiac event. Of all the psychiatric indications of rTMS, the evidence is most robust for treatment of refractory unipolar depression. This paper reviews contemporary literature highlighting the evolution of rTMS as a diagnostic and therapeutic tool, especially in the management of treatment-resistant depression.

Keywords: Long-term potentiation, repetitive transcranial magnetic stimulation, treatment-resistant depression

How to cite this article:
Chail A, Saini RK, Bhat P S, Srivastava K, Chauhan V. Transcranial magnetic stimulation: A review of its evolution and current applications. Ind Psychiatry J 2018;27:172-80

How to cite this URL:
Chail A, Saini RK, Bhat P S, Srivastava K, Chauhan V. Transcranial magnetic stimulation: A review of its evolution and current applications. Ind Psychiatry J [serial online] 2018 [cited 2022 May 29];27:172-80. Available from: https://www.industrialpsychiatry.org/text.asp?2018/27/2/172/260424

Energy is dynamic, has a frequency, can change its form and is electromagnetic (EM) in nature. All atoms, chemicals and cells produce EM fields (EMFs) of their own and all 70 trillion cells in the body communicate via EM exchanges.[1] Disruption of EM flow of energy in cells can causes impaired cell metabolism and its role and that may be the underlying cause of any disease process. These principles have led to an explosion of information pertaining to understanding of normal and abnormal brain in the past few decades. Barker et al. discovered the induction of finger and foot movements through the use of magnetic coil placed on the motor cortex.[2] Transcranial magnetic stimulation (TMS) is a neurophysiological procedure for noninvasive stimulation of the nervous system. It involves the application of rapidly changing magnetic field to the superficial layers of the cerebral cortex, which locally induces small electric currents, known as “Eddy or Foucault currents.” Cerebral cortex acts as a secondary coil in this situation.[3] TMS has an advantage over electroconvulsive therapy (ECT) as it is focused and bypasses the impedance of skull and superficial tissues. Therefore, it needs lesser stimulus strength and need for a true seizure or any form of anesthesia is completely obviated. However, despite the plethora of evidence supporting its usefulness in selected cases, skeptics continue to question its efficacy and the usage of repetitive TMS (rTMS) is still less. Therefore, a need was felt to systematically review the data on evolution and use of TMS in the treatment of refractory depression. We searched the PubMed/MEDLINE, EMBASE, PsycInfo, and Web of Science from inception up until July 2018. Two authors (AC and RKS) independently performed the search. Disagreements were discussed with other authors (PSB and KS) and resolved by consensus.

   The Development of Modern Transcranial Magnetic Stimulation Top

Experiments on electrical stimulation of cerebral cortex started somewhere in 1874 in which contralateral motor response was elicited. The laws of electro-magnetic induction were given by Faraday in 1881.[4] d'Arsonval (1896) pioneered the use of magnetic fields to induce cortical stimulation.[5] In 1959, Kolin et al.[6] achieved nerve stimulation by using magnetic energy in frogs which laid the foundation for EM stimulation of neural tissue for diagnostic and therapeutic purposes. In the past few years, there have been rapid advances in the development of shape of coils to ensure concentrated magnetic field to achieve better control over the spatial extent of excitation. While the old form of treatment took up to 37 min per session, with high-frequency (HF) theta-burst stimulation the session may last for few minutes only.[7] It is likely that treatment protocols will undergo further refinements in the years to come making it more comfortable for patients.

Mechanism of action

TMS uses principles of EM induction. According to the principle of EM induction when an electric current is passed through a coil (primary coil), a magnetic field is generated. When the magnetic flux flows to the secondary coil (neural tissue), a secondary electrical field is induced, and this causes stimulation of the same.[5] Neurons have bent or curved axonal processes, passing at right angles to the lines of force of the magnetic field. They act like secondary coils and thus experience electrical effects.[8],[9] Therefore, by changing the direction of current flow at HFs, rapidly alternating magnetic fields can be generated which in turn stimulate the underlying neurons and their fibers. The phenomenon of applying such stimulation in pulses is known as pulsed EMF stimulation which causes persistent depolarization. These pulsed stimulations are known to correct impaired functioning of cells and aid healing. Repetitive TMS works on similar principles and thus leads to observable clinical effects.[10]

   Effects of Transcranial Magnetic Stimulation Top

The effect of rTMS stimulation on the cortical surface depends on the frequency of pulses of stimulation. At low frequency (LF), i.e., <1 Hz, rTMS is inhibitory to the underlying cortex while stimulation at HF, i.e., >5 Hz, it is excitatory.[11],[12] In TMS studies, cortical excitability (CSE) can be assessed by either calculation of resting motor threshold (RMT) or by calculation of Motor evoked potential (MEP). RMT is the minimal stimulation intensity required to produce a reliable motor response (twitch) in a peripheral muscle. The strength of the stimulus is then calculated based on RMT and normally, it is 120% of the RMT. In the other method to calculate CSE, the test stimulus is adjusted to produce MEP responses up to 0.5 mV. MEP size is the averaged response to a series of pulses applied at consistent stimulator intensity. HF rTMS (i.e., >5 Hz) appears to produce a persistent increase in MEP size and a reduction in cortical inhibition.[13]

The effects of TMS can be acute or prolonged depending on the mode of stimulation.

Acute effects

Acute effects of TMS will depend on the area of the cortex being stimulated. In the primary motor cortex, it produces a muscle activity referred to as motor evoked potential (MEP). In the occipital cortex, it generates flashes of light or visual distortions also known as phosphenes. In other areas, it may lead to slowed cognition or speech arrest.[14]

Prolonged effects

rTMS can increase or decrease the excitability of the cortical neurons depending on the frequency of stimulation. The mechanism of these effects is believed to reflect changes in synaptic efficacy akin to long-term potentiation or long-term depression. Other proposed mechanisms include alteration in levels of neurotrophic factors such as BDNF, modulation of CSE, and functional connectivity among brain circuits.[8] In a systematic review of patients treated with ECT, Fidalgo et al. reported a correlation of clinical outcome with changes in BDNF levels.[15] Although the study was conducted on patients undergoing ECT, the underlying biological mechanisms are akin to rTMS.

Depth of stimulation

Depending on the type of coil and intensity of stimulus used, depth of stimulation can vary from 2 to 4 cm below the cortical surface. This means that only superficial brain structures can be stimulated.[13] Therefore, achieving equilibrium in depth-focality trade-off is a matter of intense research. Figure-8 type coils exhibit superior depth-focality than other coils.[16],[17]

Administration of transcranial magnetic stimulation

Informed consent – All patients are to be informed about the procedure, role in treatment, and expected adverse effects.

Transcranial magnetic stimulation safety screen – It is a standard set of 13 questions proposed by Rossi et al.[18] on behalf of the International Federation of Clinical Neurophysiology.

Food and Drug Administration (FDA) recommends at least 20 sessions spread over 4–6 weeks at a frequency of at least 5 times a week for treatment-resistant depression (TRD). It is also important to measure the symptoms with the help of a standardized questionnaire to monitor weekly progress or lack of it. A self-rated questionnaire in local vernacular (like Beck's Depression Inventory) is a useful instrument as it eliminates observer bias.[19],[20]

Scalp position of coil

While administering TMS, it is important to determine the position of the scalp and coil orientation for optimal therapeutic effects. In experimental models, the growing cells respond differently to moving electric fields. They tend to align preferentially either parallel or antiparallel to the field vector, a process known as galvanotaxis.[21] Forces in the direction perpendicular and parallel to the electric field are in competition with one another in a voltage-dependent manner, which ultimately govern the trajectories of the cells in the presence of an electric field.[22] Since hypofunctioning of the left dorsolateral prefrontal cortex (DLPFC) has been implicated in the pathophysiology of several psychiatric illnesses including depressive disorder; it remains the preferred area for stimulation in most of the studies.[23] There are two ways of determining surface landmark of DLPFC:

5 cm technique About 05 cm toward the left of the vertex a point is marked and about 02 cm ahead of that lies the motor cortex. The motor cortex is functionally localized as a scalp position where TMS evokes a motor movement and a measurable motor-evoked potential (MEP) in the contralateral hand. The prefrontal cortex stimulation site is determined as 5 cm anterior further ahead of the motor strip in the parasagittal line. It corresponds to an area between F3 and F5 position of 10–20 system of EEG recording.[24]

Neuro-navigational method – This method is theoretically more precise and employs MRI scan to pinpoint DLFPC with live video navigation. Fitzgerald et al.[25] studied 51 patients with treatment-resistant depression using this method and compared matched controlled subjects with standard 5 cm technique and found the superior response at the end of 3 weeks. However, the method is yet to gain popularity probably owing to the high costs of equipment involved.[26]

According to existing literature, 5 cm method remains fairly reliable and popular method as far as daily rTMS sessions are concerned.

Coil orientation in repetitive transcranial magnetic stimulation

In routine clinical and experimental models with rTMS, the amplitude of muscle evoked potential (MEP) is an indicator of the maximum effect of a particular orientation with reference to head position. Optimal stimulation has been reported if coil current was at an angle of 45° with respect to the sagittal plain.[27],[28]

Terminologies and dosing considerations associated with transcranial magnetic stimulation

These are the terms frequently encountered while using rTMS in either experimental or treatment models. A detailed description of these terms is given in [Table 1]. It is to be noted that modern rTMS machines have inbuilt software which automatically do most of these calculations though RMT has to be determined by one of the above-mentioned methods and pre-selected protocol has to be mentioned to the machine.[8],[9]
Table 1: Various terms used in transcranial magnetic stimulation[5],[8]

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Treatment protocols and their efficacy

A brief summary of these protocols and the results are given in a tabular form as per [Table 2]. In the past two decades, research has focused on establishing sound protocols which could be replicated across various studies. However, the field is still wide open and newer protocols are being proposed.
Table 2: Various protocols used for treatment resistant depression

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Indications/applications of transcranial magnetic stimulation

What initially started as a purely noninvasive diagnostic tool is slowly emerging as an effective tool in the hands of a harried clinician dealing with intractable and chronic psychiatric and neurological conditions. The discussion below is restricted to the psychiatric applications, especially for TRD.

Investigational/diagnostic applications

Initially, the role of TMS was restricted to experimental brain research to localize motor and sensory areas. When combined with functional magnetic resonance imaging, positron-emission tomography or single-photon emission computed tomography, TMS indicates the functional integrity of intracortical neuronal structures and gives information about the conduction along various fibers, the function of nerve roots and peripheral motor pathways. It can also help in localizing level of the lesion within the nervous system in conditions such as stroke, injury, or demyelination/sclerosis.[39]

Therapeutic uses

TMS is slowly gaining popularity as a useful therapeutic tool in many psychiatric disorders though FDA has cleared its role in Major unipolar depression and obsessive-compulsive disorder only. This paper focuses primarily on current evidence supporting its role in the treatment of unipolar depression. The findings are summarized in [Table 3]. George and Wassermann [40] first reported the benefits of daily rTMS to left PFC in resistant depression which were further corroborated by Pascual-Leone et al.[41] in 1996 and Liu et al.[42] In their meta-analysis, the pooled rates for rTMS group were 46.6% and 22.1% for response and remission, respectively. The pooled odds ratio was 5.12 (95% confidence interval; 2.11–12.45, P = 0.0003). The number needed to treat in their analysis was 3.4. However, there was marked variability in terms of number of treatments and the stimulus intensity. Padberg et al.[43] provided evidence of relation between antidepressant efficacy and stimulation intensity. They found clinical improvement at 100% RMT as compared to sub-threshold at 90% RMT. Avery et al.[44] reported results of their double-blind sham-controlled RCT done on 68 TRD patients (35 in rTMS and 33 in the sham arm). Patients with medication-resistant depression were randomized to receive 15 sessions of active or sham rTMS delivered to the left DLPFC at 110% RMT. Each session consisted of 32 trains of 10 Hz rTMS delivered in 5-s trains. They concluded that by adjusting the protocol to therapeutic levels in terms of stimulation intensity, pulse frequency and number of treatments, rTMS is an effective strategy to treat-resistant depression. The probability of adverse effects besides clinical improvement was the focus of research by O'Reardon et al.[45] They found a significant reduction in HAMD score after 4 weeks of treatment with rTMS and reported minimal side effects such as scalp pain (35%) and local discomfort (10%). These effects were transient and resolved spontaneously within a few minutes or hours. Long-term efficacy of rTMS in the prevention of recurrence and relapse has been topic of intense debate. Dunner et al.[46] studied long-term effectiveness of TMS across many sites and concluded that TMS demonstrates a statistically and clinically meaningful durability of acute benefit over 12 months of follow-up. Cost-benefit ratio was another area of research, which warranted systematic analysis. Nguyen and Gordon [47] concluded that rTMS was statistically superior and cost-effective antidepressant for patients with TRD. However, web results in this area did not reveal many references. In brief, research about long-term efficacy and cost-benefit ratio is sparse and continues to be hotly debated, especially in third world countries where resources are limited. Regarding who may benefit more from rTMS therapy, Fregni et al.[48] concluded that rTMS may be most suited for younger and less treatment-resistant patients. Head-to-head comparison of rTMS with ECT was done by Slotema et al.,[49] who reported that ECT was superior to rTMS in the treatment of depression (mean weighted effect size −0.47, P < 0.004). However, comparative acceptability and side effect profile were superior for rTMS. Chen et al.,[50] conducted head-to-head comparison of ECT and rTMS as augmentation strategy for TRD. They included 25 studies with 1288 individuals with MDD. They reported that ECT was more efficacious than bilateral-PFC rTMS, however, differences were not statistically significantly. Razza et al.[51] reported that though there may be placebo response to rTMS in depression trials, pooled data reveal that current protocols achieve 29%–49% response and 19%–34% remission in TRD, indicating intermediate efficacy between medication and ECT. In 2014, the International Federation of Clinical Neurophysiology gave guidelines for therapeutic use of rTMS.[13] They gave three levels of evidence for the efficacy of rTMS in various neuro-psychiatric disorders, i.e., level A (definite efficacy) was for antidepressant effect of HF-rTMS of left DLPFC, level B (probable efficacy) for antidepressant effect of LF rTMS of the right DLPFC and HF-rTMS of the left DLPFC for the negative symptoms of schizophrenia; whereas level C (possible efficacy) was for LF-rTMS of the left temporoparietal cortex for auditory hallucinations in Schizophrenia. The most recent approval by US FDA for rTMS has been for obsessive-compulsive disorders in Aug 2018.[52]
Table 3: Summary of evidence for therapeutic uses of repetitive transcranial magnetic stimulation

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Use of repetitive transcranial magnetic stimulation in special population

Although a lot of data and best practice recommendations for TMS usage in adults are largely available, there is a dearth of similar data for the pediatric population. However, its practice in children continues to grow. Its minimal risk, excellent tolerability and increasingly sophisticated ability to interrogate neurophysiology and plasticity make it an easy technology for use in pediatric research, with future extension into therapeutic trials. While adult trials show promise in using TMS as a novel, noninvasive, nonpharmacologic diagnostic and therapeutic tool in a variety of neurological disorders, its use in children is only just emerging.[53],[54] Its use in pregnancy is safe and effective and pregnancy per se is not a contraindication.[55] rTMS was well tolerated and found to be statistically and clinically effective in pregnant patients with TRD. It may be preferred choice of treatment in the elderly population owing to the lack of cognitive side effects and very little chance of drug interactions. Cognitive impairment has been researched the most in this population and evidence so far suggests that TMS may, in fact, have therapeutic benefits.[56] However, additional research that specifically includes older subjects is needed to replicate findings and to optimize treatment protocols for this population.

Other psychiatric indications of transcranial magnetic stimulation

There are reports of the role of rTMS in chronic schizophrenia in controlling intractable hallucinations and negative symptoms. The US FDA and NICE guidelines (UK) have included rTMS a therapy for treating migraine.[57],[58] There are also reports of its role in treatment of anxiety disorder like PTSD and substance use disorders. However, detailed description of these indications is beyond the purview of this article and reader is advised to refer to other sources of information.[59],[60]

   Conclusion Top

The field of diagnostics and therapeutics in psychiatry is still in a state of flux. As research in neurosciences moves at a rapid pace, there is a need to translate the findings into treatment methods. rTMS is a big step in this direction and offers a therapeutic approach without serious and long-lasting side effects. It is slowly emerging as an effective tool in managing TRD, though evidence in favor of its role in other psychiatric conditions is still sparse. It is safe and well tolerated by most patients. There is a need to develop well-standardized protocols for its application and to establish it as an affordable therapeutic tool.

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Conflicts of interest

There are no conflicts of interest.

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  [Table 1], [Table 2], [Table 3]

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