Definition and Overview
Transcranial magnetic stimulation (TMS) is a neuromodulation technique that uses the principle of electromagnetic induction to non-invasively regulate the activity of cortical neurons with magnetic field pulses penetrating the skull. It was first developed in 1985 when Barker et al. at the University of Sheffield, UK, succeeded in inducing contraction of the muscles of the opposite hand by applying a single magnetic pulse to the motor cortex.
Initially, it was used as a neurological diagnostic tool, but as it was discovered that repetitive stimulation induces lasting changes in cortical excitability, it developed into repetitive transcranial magnetic stimulation (repetitive TMS, rTMS) for therapeutic purposes. In 2008, the U.S. Food and Drug Administration (FDA) approved rTMS treatment for drug-resistant major depressive disorder, and later, migraine. (2013), Obsessive Compulsive Disorder (2018), Smoking cessation assistance. The scope of approval was expanded to (2020).
TMS is different from existing invasive brain stimulation procedures (deep brain stimulation, vagus nerve stimulation) in that it can be performed outpatient without surgery or anesthesia. Clinical application is being actively carried out in the fields of neuropsychiatry and neurology around the world, and research on new indications such as autonomic dysfunction, chronic pain, and tinnitus is continuing.
How it works
electromagnetic induction
The physical principle of TMS is based on Faraday's law of electromagnetic induction. When a strong current is momentarily passed through the coil, a rapidly changing magnetic field is formed, and this magnetic field penetrates the skull and generates an induced current in the cerebral cortex. The strength of the magnetic field is approximately 1.5 to 2 Tesla at the coil surface, and the induced current at the surface of the cortex after passing through the skull is strong enough to depolarize nerve cells.
Because the magnetic field penetrates tissues such as the skull, skin, and muscles without resistance, unlike electrical stimulation, there is less scalp pain and less attenuation of energy reaching the cortex. However, the magnetic field strength decreases rapidly with distance from the coil, so the effective stimulation depth of a typical figure-of-eight coil is about 2 to 3 cm from the cortical surface.
Cortical excitability regulation
The current induced by TMS depolarizes the axon in the cortex, causing an action potential. Single stimulation induces transient neural activation, whereas repetitive stimulation (rTMS) causes changes in cortical excitability that persist even after stimulation ends through synaptic plasticity.
The effects of stimulation frequency are as follows.
- High-frequency stimulation (5~20 Hz): Increases cortical excitability. Synaptic transmission efficiency increases through a mechanism similar to long-term potentiation (LTP).
- Low-frequency stimulation (less than 1 Hz): Suppresses cortical excitability. Synaptic transmission is weakened by a mechanism similar to long-term depression (LTD).
This bidirectional regulatory property allows for customized treatment design that suppresses hyperactive regions at low frequencies and activates underactive regions at high frequencies.
Neurotransmitter and neural circuit changes
rTMS not only has local effects at the stimulation site, but also affects remote neural circuits as a whole. Stimulation of the left dorsolateral prefrontal cortex (DLPFC) regulates the activity of the amygdala, hippocampus, and anterior cingulate cortex through the fronto-limbic circuit. During this process, the secretion of neurotransmitters such as serotonin, dopamine, and norepinephrine changes.
Additionally, neuroplastic effects such as increased expression of brain-derived neurotrophic factor (BDNF) and reorganization of cortical-subcortical connectivity have been reported. This multi-layered mechanism explains the effectiveness of treatment in various diseases such as depression, pain, and autonomic dysfunction.
type
Single-pulse transcranial magnetic stimulation (single-pulse TMS, sTMS)
This is a method of applying a single magnetic pulse. It is mainly used for diagnostic purposes, such as measuring the excitability of the motor cortex, testing motor evoked potential (MEP), and measuring central motor conduction time. For treatment purposes, it is applied to block cortical spreading depression by applying a single stimulus to the occipital cortex during an acute attack of migraine, and was approved by the FDA in 2013.
Repetitive transcranial magnetic stimulation (repetitive TMS, rTMS)
This is a method of repeatedly applying magnetic pulses at a certain frequency and intensity. It is the most essential form in the therapeutic application of TMS. Cortical excitability can be modulated bidirectionally depending on stimulation parameters (frequency, intensity, number of stimulations, coil position).
In the standard rTMS protocol, hundreds to thousands of magnetic pulses are applied for 20 to 40 minutes each. In the standard treatment for drug-resistant depression, 10 Hz high-frequency stimulation is performed on the left DLPFC 5 times a week for 4 to 6 weeks.
Theta-burst stimulation (TBS)
It is a patterned stimulation method that repeats three consecutive stimulations (triplets) at 50 Hz in accordance with theta wave (5 Hz) rhythm. It can induce equivalent or superior changes in cortical excitability within a shorter time (3 to 10 minutes) than existing rTMS.
- Intermittent theta burst stimulation (intermittent TBS, iTBS): Repeats 2 seconds of stimulation and 8 seconds of rest, increasing cortical excitability. Total stimulation time is approximately 3 minutes and 10 seconds.
- Continuous theta burst stimulation (continuous TBS, cTBS): Continuous stimulation for 40 seconds and suppresses cortical excitability.
In a large-scale non-inferiority clinical trial by Blumberger et al. in 2018, 3 minutes of iTBS showed equivalent antidepressant effects to 37 minutes of standard 10 Hz rTMS. These results showed the potential to significantly shorten treatment time.
Deep transcranial magnetic stimulation (deep TMS, dTMS)
This is a technology that uses a special coil called an H-coil to stimulate deeper brain areas (approximately 4 to 6 cm from the surface of the cortex) than existing 8-shaped coils. In 2013, the FDA approved it for drug-resistant depression, and in 2018, approval for obsessive-compulsive disorder was added.
Indications
drug-resistant depression
It is the best-established indication for rTMS. In a multisite RCT conducted by O'Reardon et al. in 2007, 10 Hz rTMS was administered to the left DLPFC for 4 to 6 weeks, and the response rate in the active stimulation group was significantly higher than the placebo group in patients with drug-resistant depression. In a subsequent meta-analysis, the response rate for depression treatment with rTMS was reported to be approximately 50-60%, and the remission rate was reported to be approximately 30-35%. Since its FDA approval in 2008, it has become one of the standard treatment options worldwide.
In the 2020 evidence-based guideline by Lefaucheur et al., high-frequency rTMS to the left DLPFC was recommended as Level A (certain effectiveness) for the treatment of drug-resistant depression.
migraine
Single-shot TMS (sTMS) is FDA-approved for the acute treatment of migraine with aura. Lipton et al. (2010) in a randomized, double-blind, controlled trial where sTMS was applied to the occipital cortex when a migraine aura occurred, the pain-free rate after 2 hours showed a significant difference of 39% in the active group versus 22% in the placebo group. rTMS is also indicated for the preventive treatment of chronic migraine, using high-frequency left DLPFC stimulation or low-frequency motor cortex stimulation protocols.
autonomic dysfunction
The prefrontal cortex and insular cortex are the higher centers of autonomic regulation. rTMS to this area can affect sympathetic-parasympathetic balance, and changes in autonomic function can be objectively assessed through heart rate variability (HRV) analysis. There are preliminary studies reporting improvement in HRV indicators after rTMS application in patients with dysautonomia, and research is in progress on alleviating symptoms such as tachycardia, abnormal sweating, and anxiety caused by sympathetic hyperactivity.
chronic pain
High-frequency rTMS over the left primary motor cortex (M1) has Level A evidence for chronic neuropathic pain. It is presumed to activate the descending pain inhibitory pathway through regulation of the thalamo-cortical circuit. It is applied to fibromyalgia, complex regional pain syndrome (CRPS), and trigeminal neuralgia.
Tinnitus
A treatment for chronic subjective tinnitus is being attempted to suppress hyperactivity of the auditory cortex by applying low-frequency rTMS to the temporal cortex. A reduction in tinnitus intensity has been reported in some patients, but further research is needed to determine the consistency of the effect.
Other indications
- Obsessive-compulsive disorder (OCD): dTMS for the medial prefrontal cortex received FDA approval in 2018.
- Smoking cessation aid: dTMS over the bilateral insula and prefrontal cortex received FDA approval in 2020.
- Post-traumatic stress disorder (PTSD): Research is ongoing regarding the effects of low-frequency rTMS on the right DLPFC.
- Motor rehabilitation after stroke: Applies to recovery of motor function through activation of the cortex around the damaged hemisphere or inhibition of the healthy hemisphere.
Procedure
pre-assessment
Before implementing TMS, check the following:
- Medical history: history of epilepsy, head trauma, brain surgery, risk factors for convulsions
- Check for contraindications: intracranial metal implants (cochlear implants, aneurysm clips, deep brain stimulation electrodes), pacemakers, drug implant pumps.
- Check for medications: Drugs that may lower the seizure threshold (tricyclic antidepressants, antipsychotics, theophylline, etc.)
- For depression treatment, measure baseline scores on symptom rating scales (PHQ-9, BDI, etc.)
Exercise threshold measurement
To set the treatment stimulation intensity, motor threshold (MT) is first measured. While a single stimulus is applied to the hand area of the primary motor cortex (M1), the motor-evoked potential of the contralateral hand muscles (mainly the abductor pollicis brevis) is recorded. The minimum stimulation intensity that induces MEPs of 50 μV or more in 5 or more of 10 stimulations is defined as the resting motor threshold (RMT). Treatment stimulation is generally set at an intensity of 80-120% of RMT.
Coil positioning
The stimulation area varies depending on the purpose of treatment.
- Depression: Left dorsolateral prefrontal cortex (DLPFC). The location is determined using the 5-cm rule or neuronavigation in the motor cortex hand area.
- Acute treatment for migraine: occipital cortex.
- Chronic pain: Primary motor cortex (M1) contralateral to pain.
- Tinnitus: Left temporo-parietal junction.
Organizing therapy sessions
A typical session setup for a standard depression rTMS protocol (10 Hz) is as follows:
- Stimulation frequency: 10 Hz
- Stimulus intensity: 120% of RMT
- 1 time stimulation train: 40 stimulations in 4 seconds
- Rest between stimulation heats: 26 seconds
- Total number of stimulations: 3,000 shots/session
- Session time: approximately 37 minutes
- Treatment frequency: 5 times a week
- Total treatment period: 4-6 weeks (total 20-30 sessions)
In the case of the iTBS protocol, a total of 600 stimulations are completed in approximately 3 minutes and 10 seconds, greatly shortening the treatment time.
Care during procedure
The patient sits in a treatment chair and assumes a comfortable posture. Wear earplugs to protect your hearing from the sound of the coil operating. The operator keeps the position and angle of the coil constant and continuously observes the patient's condition. If any adverse reactions such as severe headache, dizziness, or muscle cramps occur during the procedure, stop stimulation immediately.
Effect and evidence
depression
O’Reardon et al. (2007), in a multicenter RCT, performed 10 Hz rTMS on the left DLPFC on 301 patients with drug-resistant depression who had failed two or more antidepressant treatments. As a result, the change in MADRS (Montgomery-Asberg Depression Rating Scale) score in the active group was significantly greater than that in the placebo group at 4 weeks. Afterwards, in real-world clinical data, the treatment response rate of rTMS was reported to be approximately 50 to 60% and the remission rate to be approximately 30 to 35%.
The 2020 guideline by Lefaucheur et al. systematically analyzed more than 60 randomized controlled trials and recommended high-frequency rTMS (10-20 Hz) to the left DLPFC as Level A for the treatment of depression. This means that the clinical trial evidence is at the highest level.
migraine
Lipton et al. (2010), in a double-blind RCT, applied sTMS to the occipital cortex in 164 patients with migraine with aura, and the pain-free rate after 2 hours was 39% in the active group versus 22% in the placebo group (p=0.018). The proportion of patients who remained pain-free after 24 hours was 29% in the active group versus 16% in the placebo group. Based on these results, the FDA approved the sTMS device for the acute treatment of migraine in 2013.
Several clinical trials have also been conducted on the preventive treatment of chronic migraine using rTMS, and significant reductions in migraine attack frequency and intensity have been reported.
chronic pain
High-frequency rTMS over primary motor cortex M1 has Level A evidence in chronic neuropathic pain. A significant reduction in pain intensity (average 15-30% reduction based on VAS) was confirmed in the meta-analysis. The pain suppressive effect is due to complex mechanisms, including activation of descending pain control pathways, increased endogenous opioid secretion, and reorganization of thalamo-cortical connections.
Side effects and safety
TMS is the procedure with the longest safety data among non-invasive brain stimulation technologies. Rossi et al. (2021), the overall safety profile of TMS is good, according to expert safety guidelines.
common side effects
- Scalp discomfort: Mild pain or tingling in the scalp beneath the coils is the most common side effect. In many cases, adaptation is achieved by repeating the procedure.
- Headache after the procedure: A mild headache may occur on the day of the procedure and is controlled with over-the-counter painkillers.
- Temporary hearing change due to coil operating noise: Prevent by wearing earplugs.
Rare side effects
- Convulsions (seizures): The most serious potential side effect, but has an incidence of less than 0.1%. The risk can be minimized by adhering to the range of stimulation parameters suggested by the safety guidelines and screening for convulsive risk factors in advance (history of epilepsy, taking drugs that lower the convulsive threshold, alcohol withdrawal, etc.).
- Syncope (vasovagal): Rarely, vasovagal syncope may occur during the procedure, and is caused by anxiety or tension and is caused by situational factors rather than a direct effect of TMS.
Contraindications
Absolute contraindications are as follows:
- Ferromagnetic metal implants in the vicinity of the stimulation coil: cochlear implants, intracranial metal clips, metal fragments, etc.
- Implantable neurostimulation devices: deep brain stimulation (DBS), vagus nerve stimulation (VNS), spinal cord stimulation (SCS)
- pacemaker or defibrillator
Relative contraindications include a history of epilepsy, brain lesions (brain tumor, stroke, etc.), taking drugs that lower the seizure threshold, and pregnancy. In cases where it is a relative contraindication, the risk-benefit ratio should be carefully evaluated before deciding whether to implement it.
long-term safety
Follow-up studies on the long-term safety of rTMS have found no evidence that repeated rTMS treatments have negative effects on cognitive function, hearing, or brain structure. Rather, some studies reported improvements in cognitive function after rTMS treatment.
life management
Lifestyle management measures to optimize treatment effects during the TMS treatment period are as follows.
- Sleep regularly: Sleep deprivation can lower the seizure threshold and decrease response to treatment. It is recommended to get enough sleep (7 to 8 hours).
- Limit alcohol consumption: Heavy drinking increases the risk of seizures, and alcohol has a negative effect on neuroplasticity. Minimize drinking during treatment.
- Control caffeine: Excessive caffeine consumption can worsen anxiety and insomnia. Adjust to appropriate amount.
- Compliance with medication: Do not stop taking existing medications without consulting your specialist. Be sure to notify your TMS treatment doctor when changing medications.
- Adherence to the treatment schedule: The effects of rTMS build up with regular repeated stimulation. It is important for treatment outcome to attend all scheduled sessions as much as possible.
- Record symptoms: Recording changes in symptoms over treatment can help evaluate treatment response and adjust protocols.