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Neuromodulation

Transcranial Magnetic Stimulation

Transcranial Magnetic Stimulation

TMS explained: mechanism of action, rTMS protocols, clinical applications in depression, pain, and autonomic disorders, FDA-approved indications, and safety considerations.

2026-03-27

At a Glance

TMS explained: mechanism of action, rTMS protocols, clinical applications in depression, pain, and autonomic disorders, FDA-approved indications, and safety considerations.

Definition and Overview

Transcranial magnetic stimulation (TMS) is a neuromodulation technology that non-invasively modulates cortical neuronal activity using magnetic field pulses that penetrate the skull, based on the principle of electromagnetic induction. It was first developed in 1985 when Barker et al. at the University of Sheffield successfully induced contralateral hand muscle contractions by applying a single magnetic pulse to the motor cortex [1].

Initially utilized as a neurological diagnostic tool, it evolved into repetitive TMS (rTMS) for therapeutic purposes when repeated stimulation was found to induce sustained changes in cortical excitability. In 2008, the U.S. Food and Drug Administration (FDA) approved rTMS treatment for treatment-resistant major depressive disorder [2], with subsequent approval expansions to migraine (2013), obsessive-compulsive disorder (2018), and smoking cessation aid (2020).

TMS is distinguished from existing invasive brain stimulation techniques (deep brain stimulation, vagus nerve stimulation) by its ability to be performed on an outpatient basis without surgery or anesthesia. Clinical applications in neuropsychiatry and neurology are actively expanding worldwide, with ongoing research into new indications such as dysautonomia, chronic pain, and tinnitus [4].

Mechanism of Action

Electromagnetic Induction

The physical principle of TMS is based on Faraday's law of electromagnetic induction. When a brief, strong current passes through the coil, a rapidly changing magnetic field is generated, which penetrates the skull and induces an electrical current in the cerebral cortex [1]. The magnetic field strength is approximately 1.5-2 Tesla at the coil surface, and the induced current at the cortical surface after passing through the skull is of sufficient intensity to depolarize neurons.

Because the magnetic field penetrates tissue such as skull, skin, and muscle without resistance, there is less scalp pain compared to electrical stimulation and less attenuation of energy reaching the cortex. However, magnetic field strength decreases rapidly with distance from the coil, and the effective stimulation depth of a standard figure-of-eight coil is approximately 2-3 cm from the cortical surface [5].

Cortical Excitability Modulation

The induced current from TMS depolarizes cortical axons, eliciting action potentials. While single pulses induce transient neural activation, repetitive stimulation (rTMS) produces sustained changes in cortical excitability through synaptic plasticity that persist beyond the stimulation period [4].

The effects based on stimulation frequency are as follows.

  • High-frequency stimulation (5-20 Hz): Increases cortical excitability. Synaptic transmission efficiency is enhanced through a mechanism resembling long-term potentiation (LTP).
  • Low-frequency stimulation (1 Hz or below): Suppresses cortical excitability. Synaptic transmission is weakened through a mechanism resembling long-term depression (LTD).

This bidirectional modulatory property enables customized treatment design, where overactive regions can be inhibited with low-frequency stimulation and underactive regions can be activated with high-frequency stimulation [4].

Neurotransmitter and Neural Circuit Changes

rTMS exerts not only local effects at the stimulation site but also influences remote neural circuits throughout the brain. Stimulation of the left dorsolateral prefrontal cortex (DLPFC) modulates activity in the amygdala, hippocampus, and anterior cingulate cortex through the fronto-limbic circuit. This process alters the release of neurotransmitters including serotonin, dopamine, and norepinephrine [4].

Additionally, neuroplasticity effects have been reported, including increased expression of brain-derived neurotrophic factor (BDNF) and reorganization of cortico-subcortical connectivity. These multilayered mechanisms explain the therapeutic effects across various conditions including depression, pain, and dysautonomia.

Types

Single-Pulse TMS (sTMS)

This method delivers a single magnetic pulse. It is primarily used for diagnostic purposes, including measurement of motor cortex excitability, motor evoked potential (MEP) testing, and central motor conduction time assessment [1]. For therapeutic purposes, it is applied to block cortical spreading depression by delivering a single pulse to the occipital cortex during acute migraine attacks and received FDA approval in 2013 [3].

Repetitive TMS (rTMS)

This method delivers repeated magnetic pulses at a consistent frequency and intensity. It is the most fundamental form of therapeutic TMS application. Cortical excitability can be bidirectionally modulated by adjusting stimulation parameters (frequency, intensity, number of pulses, coil position) [4].

Standard rTMS protocols deliver hundreds to thousands of magnetic pulses over 20-40 minutes per session. For standard treatment of treatment-resistant depression, high-frequency 10 Hz stimulation is applied to the left DLPFC five times per week for 4-6 weeks [2].

Theta-Burst Stimulation (TBS)

This is a patterned stimulation method that delivers 50 Hz triplet bursts at theta rhythm (5 Hz) intervals. It can induce equivalent or superior cortical excitability changes in a shorter time (3-10 minutes) compared to conventional rTMS [4].

  • Intermittent TBS (iTBS): Alternates between 2 seconds of stimulation and 8 seconds of rest, increasing cortical excitability. Total stimulation time is approximately 3 minutes and 10 seconds.
  • Continuous TBS (cTBS): Delivers continuous stimulation for 40 seconds, suppressing cortical excitability.

In a large-scale non-inferiority trial by Blumberger et al. in 2018, 3 minutes of iTBS demonstrated antidepressant efficacy equivalent to 37 minutes of standard 10 Hz rTMS. This result showed the potential for dramatically reducing treatment time.

Deep TMS (dTMS)

This technology uses a specialized H-coil to stimulate deeper brain regions (approximately 4-6 cm from the cortical surface) than conventional figure-of-eight coils. The FDA approved it for treatment-resistant depression in 2013 and added approval for obsessive-compulsive disorder in 2018.

Indications

Treatment-Resistant Depression

This is the most well-established indication for rTMS. In the 2007 multisite randomized controlled trial (RCT) by O'Reardon et al., 10 Hz rTMS was applied to the left DLPFC for 4-6 weeks in patients with treatment-resistant depression who had failed two or more antidepressant trials, resulting in significantly higher response rates in the active stimulation group compared to sham [2]. Subsequent meta-analyses reported rTMS treatment response rates of approximately 50-60% and remission rates of approximately 30-35% [4]. Since FDA approval in 2008, it has become established as a standard treatment option worldwide.

The 2020 evidence-based guidelines by Lefaucheur et al. recommended high-frequency rTMS to the left DLPFC for treatment-resistant depression at Level A (definite efficacy) [4].

Migraine

Single-pulse TMS (sTMS) has received FDA approval for acute treatment of migraine with aura. In a randomized, double-blind controlled trial by Lipton et al. (2010), application of sTMS to the occipital cortex during migraine aura resulted in pain-free rates at 2 hours of 39% in the active group versus 22% in the sham group, a significant difference [3]. rTMS is also applied for preventive treatment of chronic migraine, using high-frequency left DLPFC stimulation or low-frequency motor cortex stimulation protocols.

Dysautonomia

The prefrontal cortex and insular cortex are higher-order autonomic regulatory centers. rTMS targeting these regions can influence sympathetic-parasympathetic balance, and changes in autonomic function can be objectively assessed through heart rate variability (HRV) analysis. Preliminary studies have reported improvements in HRV parameters following rTMS application in patients with dysautonomia, and research is ongoing regarding symptom relief for tachycardia, sweating abnormalities, and anxiety caused by sympathetic hyperactivity.

Chronic Pain

High-frequency rTMS to the primary motor cortex (M1) has Level A evidence for chronic neuropathic pain [4]. It is presumed to activate descending pain inhibitory pathways through modulation of the thalamo-cortical circuit. It is applied to fibromyalgia, complex regional pain syndrome (CRPS), trigeminal neuralgia, and other conditions.

Tinnitus

Low-frequency rTMS to the temporal cortex is being investigated to suppress auditory cortex hyperactivity in chronic subjective tinnitus. Reduction in tinnitus intensity has been reported in some patients, but additional research is needed regarding the consistency of effects [4].

Other Indications

  • Obsessive-compulsive disorder (OCD): dTMS to the medial prefrontal cortex received FDA approval in 2018.
  • Smoking cessation aid: dTMS to bilateral insular and prefrontal cortices received FDA approval in 2020.
  • Post-traumatic stress disorder (PTSD): Research on the effects of low-frequency rTMS to the right DLPFC is ongoing.
  • Post-stroke motor rehabilitation: Applied for motor function recovery through activation of perilesional cortex or inhibition of the contralesional hemisphere.

Procedure Process

Pre-Treatment Assessment

The following items are confirmed prior to TMS administration.

  • Medical history: History of epilepsy, head trauma, brain surgery, and seizure risk factors
  • Contraindication screening: Intracranial metallic implants (cochlear implants, aneurysm clips, DBS electrodes), cardiac pacemakers, implanted medication pumps
  • Medication review: Medications that may lower the seizure threshold (tricyclic antidepressants, antipsychotics, theophylline, etc.)
  • For depression treatment, baseline symptom assessment scale scores (PHQ-9, BDI, etc.)

Motor Threshold Determination

The motor threshold (MT) is first measured to set the therapeutic stimulation intensity. Single pulses are delivered to the hand area of the primary motor cortex (M1) while recording motor evoked potentials from the contralateral hand muscles (typically the abductor pollicis brevis). The resting motor threshold (RMT) is defined as the minimum stimulation intensity that elicits MEPs of 50 microV or greater in at least 5 out of 10 stimulations [5]. Therapeutic stimulation is typically set at 80-120% of RMT.

Coil Positioning

The stimulation target varies according to the therapeutic objective.

  • Depression: Left dorsolateral prefrontal cortex (DLPFC). Position is determined using the 5-cm anterior displacement method from the motor cortex hand area or neuronavigation.
  • Acute migraine treatment: Occipital cortex.
  • Chronic pain: Contralateral primary motor cortex (M1).
  • Tinnitus: Left temporo-parietal junction.

Treatment Session Configuration

A typical session configuration for the standard depression rTMS protocol (10 Hz) is as follows.

  • Stimulation frequency: 10 Hz
  • Stimulation intensity: 120% of RMT
  • Per stimulation train: 40 pulses over 4 seconds
  • Intertrain interval: 26 seconds
  • Total pulses: 3,000 per session
  • Session duration: Approximately 37 minutes
  • Treatment frequency: 5 times per week
  • Total treatment duration: 4-6 weeks (20-30 sessions total)

The iTBS protocol delivers a total of 600 pulses in approximately 3 minutes and 10 seconds, significantly reducing treatment time.

Intraprocedural Management

The patient sits comfortably in a treatment chair. Earplugs are worn to protect hearing from coil operating sounds. The operator maintains consistent coil position and angle while continuously monitoring the patient's condition [5]. If adverse reactions such as severe headache, dizziness, or muscle spasms occur during the procedure, stimulation is immediately discontinued.

Efficacy and Evidence

Depression

In the multisite RCT by O'Reardon et al. (2007), 10 Hz rTMS was applied to the left DLPFC in 301 patients with treatment-resistant depression who had failed two or more antidepressant trials, resulting in significantly greater MADRS (Montgomery-Asberg Depression Rating Scale) score changes in the active group compared to sham at 4 weeks [2]. Subsequent real-world data reported rTMS treatment response rates of approximately 50-60% and remission rates of approximately 30-35% [4].

The 2020 guidelines by Lefaucheur et al. systematically analyzed more than 60 randomized controlled trials and recommended high-frequency rTMS (10-20 Hz) to the left DLPFC for depression treatment at Level A [4]. This represents the highest level of clinical trial evidence.

Migraine

In the double-blind RCT by Lipton et al. (2010), sTMS was applied to the occipital cortex in 164 patients with migraine with aura, resulting in pain-free rates at 2 hours of 39% in the active group versus 22% in the sham group (p=0.018) [3]. The proportion maintaining pain-free status at 24 hours was 29% in the active group versus 16% in the sham group. Based on these results, the FDA approved the sTMS device for acute migraine treatment in 2013.

Multiple clinical trials have also been conducted on preventive treatment of chronic migraine using rTMS, reporting significant reductions in migraine attack frequency and intensity.

Chronic Pain

High-frequency rTMS to the primary motor cortex M1 has Level A evidence for chronic neuropathic pain [4]. Meta-analyses confirmed significant reductions in pain intensity (mean 15-30% reduction on VAS). The analgesic effect is attributed to multiple mechanisms including activation of descending pain modulatory pathways, increased endogenous opioid release, and reorganization of thalamo-cortical connectivity.

Side Effects and Safety

TMS is the non-invasive brain stimulation technique with the longest safety data record. According to the expert safety guidelines by Rossi et al. (2021), the overall safety profile of TMS is favorable [5].

Common Side Effects

  • Scalp discomfort: Mild pain or tingling at the scalp beneath the coil is the most common side effect. Many patients adapt with repeated sessions.
  • Post-procedure headache: Mild headache may occur on the day of treatment and is managed with standard analgesics.
  • Transient hearing changes from coil operating sounds: Prevented by wearing earplugs.

Rare Side Effects

  • Seizure: The most serious potential side effect, but the incidence is less than 0.1% [5]. Risk can be minimized by adhering to the stimulation parameter ranges specified in safety guidelines and pre-screening for seizure risk factors (history of epilepsy, medications that lower the seizure threshold, alcohol withdrawal, etc.).
  • Syncope (vasovagal): Vasovagal syncope may rarely occur during the procedure and is attributable to situational factors such as anxiety or tension rather than a direct effect of TMS.

Contraindications

Absolute contraindications are as follows [5].

  • Ferromagnetic metallic implants near the stimulation coil: Cochlear implants, intracranial metallic clips, metallic fragments, etc.
  • Implanted neurostimulators: Deep brain stimulators (DBS), vagus nerve stimulators (VNS), spinal cord stimulators (SCS)
  • Cardiac pacemakers or defibrillators

Relative contraindications include history of epilepsy, brain lesions (brain tumors, stroke, etc.), medications that lower the seizure threshold, and pregnancy. In cases with relative contraindications, the risk-benefit ratio is carefully evaluated before proceeding.

Long-Term Safety

Follow-up studies on the long-term safety of rTMS have found no evidence that repeated rTMS treatment adversely affects cognitive function, hearing, or brain structure [5]. In fact, some studies have reported improvements in cognitive function following rTMS treatment.

Lifestyle Management

The following lifestyle management recommendations help optimize treatment outcomes during the TMS treatment period.

  • Regular sleep: Sleep deprivation can lower the seizure threshold and reduce treatment response. Adequate sleep (7-8 hours) is recommended.
  • Alcohol restriction: Excessive drinking increases seizure risk and negatively affects neuroplasticity. Minimize alcohol consumption during the treatment period.
  • Caffeine moderation: Excessive caffeine intake can worsen anxiety and insomnia. Maintain appropriate intake levels.
  • Medication compliance: Do not discontinue prescribed medications without consulting your physician. Always inform the TMS treating physician of any medication changes.
  • Treatment schedule adherence: The effects of rTMS are cumulative with regular repeated stimulation. Attending all scheduled sessions is important for optimal treatment outcomes.
  • Symptom tracking: Recording symptom changes throughout the treatment course aids in evaluating treatment response and adjusting protocols.

Frequently Asked Questions

TMS is a non-invasive treatment that stimulates specific brain regions by placing an electromagnetic coil on the scalp and delivering magnetic field pulses. No craniotomy or anesthesia is required, and it can be comfortably received while seated in a chair on an outpatient basis. It has demonstrated efficacy for conditions such as depression, migraine, and chronic pain that do not respond adequately to medication.

You may feel a light tapping sensation or tingling on the scalp during stimulation, but it is generally well tolerated by most patients. No anesthesia or injections are needed, and you can converse during the procedure. Even if you experience scalp discomfort during the first 1-2 sessions, most patients gradually adapt with repeated treatments.

Many patients begin to notice symptom changes from the 2nd to 3rd week. For depression, improvement occurs gradually over a 4-6 week treatment course, while for migraine, single-pulse TMS has been reported to achieve relatively rapid pain reduction during acute attacks. Individual responses vary, so we recommend monitoring your progress in consultation with your specialist.

It varies depending on the condition and protocol. The standard protocol for treatment-resistant depression involves 5 sessions per week for 4-6 weeks, totaling 20-30 sessions. Maintenance treatments may be added at 1-2 week intervals depending on the patient's status. For migraine or dysautonomia, treatment plans are individually tailored to the patient's condition.

The most common side effects are scalp discomfort at the treatment site and mild headache, which resolve spontaneously after the procedure. The incidence of seizure, the most concerning potential side effect, is very low at less than 0.1%. The procedure is safely administered by setting stimulation intensity and frequency according to safety guidelines and pre-screening for seizure risk factors. Thorough explanations are provided before the procedure.

TMS can be safely administered in most patients, but there are several contraindications. It cannot be performed in patients with intracranial metallic implants (cochlear implants, deep brain stimulators, etc.) or cardiac pacemakers. Careful evaluation is required for patients with a history of epilepsy. Eligibility is determined through detailed medical history review during the consultation.

Yes, TMS can be administered concurrently with existing medication therapy. In fact, some studies suggest that combining TMS with medication produces better treatment outcomes. However, since certain medications can lower the seizure threshold, please inform us of all current medications so that stimulation parameters can be safely configured.

TMS requires no anesthesia and no special recovery time after the procedure. You can immediately return to driving, work, and daily activities right after the session. Occasionally, mild headache may occur on the day of treatment, which is adequately managed with standard analgesics.

References

  1. [1] Barker AT, Jalinous R, Freeston IL (1985). "Non-invasive magnetic stimulation of human motor cortex." The Lancet, 325: 1106-1107. DOI PubMed
  2. [2] O'Reardon JP, Solvason HB, Janicak PG, Sampson S, Isenberg KE, Nahas Z, McDonald WM, Avery D, Fitzgerald PB, Loo C, Demitrack MA, George MS, Sackeim HA (2007). "Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: a multisite randomized controlled trial." Biological Psychiatry, 62: 1208-1216. DOI PubMed
  3. [3] Lipton RB, Dodick DW, Silberstein SD, Saper JR, Aurora SK, Pearlman SH, Fischell RE, Ruppel PL, Goadsby PJ (2010). "Single-pulse transcranial magnetic stimulation for acute treatment of migraine with aura: a randomised, double-blind, parallel-group, sham-controlled trial." The Lancet Neurology, 9: 373-380. DOI PubMed
  4. [4] Lefaucheur JP, Aleman A, Baeken C, Benninger DH, Brunelin J, Di Lazzaro V, Filipovic SR, Grefkes C, Hasan A, Hummel FC, Jääskeläinen SK, Langguth B, Leocani L, Londero A, Nardone R, Nguyen JP, Nyffeler T, Oliveira-Maia AJ, Oliviero A, Padberg F, Palm U, Paulus W, Poulet E, Quartarone A, Rachid F, Rumi DO, Sadnicka A, Siebner HR, Slotema CW, Stagg CJ, Valls-Sole J, Vecsei L, Ziemann U, Hallett M, Rossini PM (2020). "Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS): an update (2014-2018)." Clinical Neurophysiology, 131: 474-528. DOI PubMed
  5. [5] Rossi S, Antal A, Bestmann S, Bikson M, Brewer C, Brockmöller J, Carpenter LL, Cincotta M, Chen R, Daskalakis JD, Di Lazzaro V, Fox MD, George MS, Gilbert D, Kimiskidis VK, Koch G, Ilmoniemi RJ, Lefaucheur JP, Leocani L, Lisanby SH, Miniussi C, Padberg F, Pascual-Leone A, Paulus W, Peterchev AV, Quartarone A, Rotenberg A, Rothwell J, Rossini PM, Santarnecchi E, Shafi MM, Siebner HR, Ugawa Y, Wassermann EM, Zangen A, Ziemann U, Hallett M (2021). "Safety and recommendations for TMS use in healthy subjects and patient populations, with updates on training, ethical and regulatory issues: expert guidelines." Clinical Neurophysiology, 132: 269-306. DOI PubMed

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