What is Transcranial Magnetic Stimulation (TMS) and how does it work?

What is Transcranial Magnetic Stimulation (TMS) and How Does It Work?

Transcranial Magnetic Stimulation (TMS) is a non-invasive brain stimulation technique that uses brief, high-intensity electromagnetic pulses to induce neuronal firing in targeted brain regions, modulating cortical excitability through mechanisms of synaptic plasticity similar to long-term potentiation. 1, 2

Basic Physical Principle

TMS operates on the principle of electromagnetic induction discovered by Michael Faraday 3:

• A pulsed magnetic field is generated when current passes through a copper coil positioned superficially over the scalp 4, 3
• The magnetic field penetrates the skull painlessly and reaches the brain, inducing electrical currents that cause axonal depolarization 3, 5
• The magnetic field strength is sufficient to trigger neuronal firing in the targeted cortical region 1
• The stimulation depth from the scalp surface depends on coil geometry and intensity 3

Mechanisms of Action

Neurophysiological Effects

TMS modulates cortical excitability through NMDA receptor-dependent plasticity mechanisms, producing long-term potentiation (LTP) or long-term depression (LTD)-like changes in synaptic coupling 2:

• High-frequency rTMS (>5 Hz) facilitates cortical excitability through rapid calcium influx inducing LTP 1, 2
• Low-frequency rTMS (≤1 Hz) inhibits cortical excitability through sustained calcium flux inducing LTD 1, 2
• The mechanisms increase synaptic activity, alter neurotransmitter secretion, and cause neuronal plasticity 5

Network Effects

Local application of TMS alters activity in distant, functionally connected brain regions, indicating that TMS modulates activity of cortical networks rather than just the stimulated site 6:

• Effects propagate through functional anatomical connections to remote brain areas 7
• This network modulation underlies both the investigational and therapeutic applications of TMS 4

Types of TMS Protocols

Single-Pulse TMS

Single pulses depolarize neurons and evoke measurable effects, used primarily for studying motor thresholds and creating "virtual lesions" to probe brain function 8, 7:

• Can transiently disrupt function in the targeted brain region to establish causal relationships between brain areas and behavior 8
• Provides better temporal resolution than neuroimaging for understanding the timing of neural processing 4

Paired-Pulse TMS

Paired stimuli separated by variable intervals to the same or different brain areas are used to study intracortical inhibitory and facilitatory mechanisms 5, 7

Repetitive TMS (rTMS)

Repetitive TMS delivers continuous trains of pulses at specific frequencies, producing lasting changes in cortical excitability 4, 6:

• Common clinical frequencies include 1 Hz, 5 Hz, 10 Hz, 15 Hz, and 20 Hz 1
• High-frequency (≥5 Hz) typically facilitates cortical excitability 4, 1
• Low-frequency (≤1 Hz) typically inhibits cortical excitability 4, 1
• Treatment sessions typically last 10-20 minutes when applied offline (before task performance) 4

Theta-Burst Stimulation (TBS)

TBS is a patterned form of TMS with shorter stimulation duration compared to conventional rTMS 1:

• Intermittent TBS (iTBS) facilitates cortical excitability 2
• Continuous TBS (cTBS) reduces cortical excitability 2

Timing Paradigms

Offline TMS

Offline TMS involves applying stimulation before task performance, with effects assessed by comparing pre- and post-stimulation behavior 4:

• Induces relatively durable modulation of cortical excitability via plasticity mechanisms 4
• Sensory effects do not interfere directly with task execution 4

Online TMS

Online TMS delivers stimulation at discrete time points while subjects are engaged in a task, allowing assessment of immediate behavioral effects 4:

• Elicits transient stimulation effects and modifies short-term information processing 4
• Provides high temporal resolution for dissecting the chronometry of cognitive processes 4
• Less confounded by compensation or network propagation effects 4

Common Target Regions

The dorsolateral prefrontal cortex (DLPFC) is the most frequently targeted region, with left DLPFC being the most common target 1, 8:

• Left DLPFC is the primary target for depression treatment 6, 8
• Other targets include motor cortex (M1), inferior frontal gyrus (IFG), temporoparietal junction, anterior cingulate cortex, and insula 1

FDA-Approved Clinical Applications

TMS is FDA-approved for major depressive disorder, obsessive-compulsive disorder, and smoking cessation 6, 3:

• For treatment-resistant depression, TMS yields response rates of 40-60% 6
• High-frequency stimulation of left DLPFC is the established protocol for depression 8

Safety Profile

TMS is generally safe and well tolerated, with seizure being the most serious but very rare risk 6:

• The technique is non-invasive and painless 3, 5
• Very few side effects occur with standard protocols 3

Critical Implementation Considerations

Control Conditions

Rigorous design requires stringent control conditions to justify causal claims 4:

• Sham coils can blind TMS-naive participants but may be insufficient for repeated measurements 4
• Active control sites (stimulating different brain regions) provide better blinding and control for somatosensory effects 4
• Combining both sham and active control sites establishes optimal grounds for causal inference 4

Targeting Methods

Targeting can use cost-effective approaches like the 10-20 EEG system or more precise fMRI-guided methods 4:

• fMRI-guided targeting is associated with increased degree of disruption with rTMS 4
• Individual anatomical variability affects stimulation effects 4

Common Pitfalls

Substantial heterogeneity in methods and outcome measures across studies limits reproducibility and evidence synthesis 4, 1:

• The vast parameter space (coil geometry, intensity, frequency, pulse number, timing) creates challenges for standardization 4
• Many studies have small sample sizes without adequate power analyses 9
• Incomplete reporting of stimulation parameters hampers replication 1