What is Transcranial Magnetic Stimulation (TMS)?
TMS is a non-invasive brain stimulation technique that uses electromagnetic induction to deliver brief, focal magnetic pulses through the skull to stimulate targeted brain regions, inducing neuronal firing and modulating cortical excitability through mechanisms of synaptic plasticity. 1, 2
Core Mechanism and Technical Principles
TMS operates on the electromagnetic induction principle discovered by Michael Faraday, where a pulsed current passes through a copper coil positioned over the scalp, generating a magnetic field that penetrates the skull painlessly to reach the brain. 3, 4 The magnetic field is strong enough to induce axonal depolarization and neuronal firing beneath the area where the coil is positioned. 5, 2
The technique modulates brain activity through long-term potentiation (LTP) and long-term depression (LTD)-like changes in synaptic coupling of neurons, critically dependent on NMDA and AMPA receptor signaling within glutamatergic synapses. 6, 2 Dopaminergic transmission also plays a significant role, and TMS modulates expression of neurotrophic factors like BDNF, a key regulator of synaptic plasticity. 2
Types of TMS Stimulation
Single-Pulse TMS (spTMS)
Single pulses are used to measure cortical excitability, motor threshold, and phosphene threshold. 5, 4
Paired-Pulse TMS (PP-TMS)
Two paired pulses separated by variable intervals are used to study intracortical inhibitory and facilitatory mechanisms. 5, 4
Repetitive TMS (rTMS)
Continuous trains of stimulation at specific frequencies produce lasting changes in cortical excitability, with high-frequency rTMS (>5 Hz) facilitating cortical excitability through rapid calcium influx inducing LTP, while low-frequency rTMS (<1 Hz) inhibits it through sustained calcium flux inducing LTD. 1, 6, 2 Common clinical frequencies include 1 Hz, 5 Hz, 10 Hz, 15 Hz, and 20 Hz. 1
Theta-Burst Stimulation (TBS)
Patterned stimulation with specific inter-train intervals, available as intermittent TBS (iTBS) or continuous TBS (cTBS), offers shorter stimulation duration compared to conventional rTMS. 1, 2 iTBS enhances cortical excitability while cTBS reduces it. 6
Primary Clinical Applications
FDA-Approved Indications
TMS has received FDA approval for major depressive disorder, obsessive-compulsive disorder, and smoking cessation. 7, 8
Treatment-Resistant Depression
TMS is rapidly becoming standard of care for treatment-resistant depression, yielding response rates of 40-60% when targeting the left dorsolateral prefrontal cortex (DLPFC) with high-frequency protocols (10-25 Hz). 2, 7 At least 4-6 weeks of daily treatment (up to 30 sessions) is required for significant clinical improvement compared to sham. 2 For responders, transition to maintenance TMS over 6 months is recommended. 2
Emerging Neurological Applications
Significant data supports consideration of TMS approval for stroke rehabilitation, spasticity, migraine, dementia, and Parkinson's disease. 3, 4 However, most of these indications remain off-label pending FDA clearance. 8
Target Brain Regions
The dorsolateral prefrontal cortex (DLPFC) is the most frequently targeted region, with the left DLPFC being the most common target followed by right DLPFC. 1, 2 Other targets include frontal pole, temporoparietal junction, inferior frontal gyrus, superior frontal gyrus, motor cortex, anterior cingulate cortex, and insula. 1
Safety Profile
TMS is generally safe and well tolerated, with significantly fewer systemic side effects compared to antidepressants. 2, 7 Common side effects include clicking sounds, scalp sensations, and mild muscle contractions during stimulation. 2 The most serious risk is seizure, which occurs very rarely. 7 TMS is considered a safe, non-invasive technique with very few side effects. 3, 9
Critical Implementation Parameters
The effects of TMS depend critically on three parameters: stimulation frequency, pattern of stimulation, and intensity. 5 High-frequency stimulation (10 Hz) induces LTP-like effects, while low-frequency (1 Hz) produces LTD-like effects. 2 Stimulation at 5 Hz is particularly effective for disrupting reaction time in cognitive tasks. 2 Doubling the number of pulses enhances clinical effects in depressed patients. 2
Important Caveats and Limitations
Systematic studies comparing different repetition intervals, frequencies, and intensities are lacking, and the relationship between stimulation parameters and outcomes remains incompletely understood. 2 Homeostatic plasticity principles mean that excessive stimulation can paradoxically reduce efficacy. 2 Many online TMS studies are underpowered, with median sample sizes of only 5 when adjusted for multiple conditions. 2
The tremendous variability in methods and outcome measures across TMS trials makes reproducibility and interpretation difficult. 5 Many studies have small sample sizes, do not contain rigorous control conditions, and are not sufficiently blinded. 5
Clinical Utility Beyond Treatment
TMS provides novel insights into pathophysiology of neural circuitry underlying neurological and psychiatric disorders, can be developed into clinically useful diagnostic and prognostic tests, and has therapeutic uses in various diseases. 9 By inducing "virtual lesions"—transient disruption of function in targeted brain regions—TMS yields important insights into functional organization of the prefrontal cortex with respect to working memory, language, and other core cognitive functions. 8 Unlike neuroimaging, which is limited to observing correlations, TMS can lead to causal inferences by directly interacting with neural circuits. 8