How does Transcranial Magnetic Stimulation (TMS) work for treating major depressive disorder?

How Transcranial Magnetic Stimulation (TMS) Works

Fundamental Mechanism

TMS delivers brief, focal electromagnetic pulses through the skull that induce electrical currents strong enough to cause neurons beneath the coil to fire, modulating cortical excitability through mechanisms similar to long-term potentiation (LTP) and long-term depression (LTD). 1, 2

Core Biophysical Principles

• Electromagnetic induction is the foundational principle: a magnetic coil positioned over the scalp generates a rapidly changing magnetic field that penetrates the skull and induces electrical currents in underlying brain tissue 1

• The induced electrical field is strong enough to directly trigger action potentials in cortical neurons located beneath the coil, unlike transcranial direct current stimulation (tDCS) which only modulates membrane potential without directly causing neuronal firing 1

• Frequency determines the direction of effect: high-frequency stimulation (5-25 Hz) induces LTP-like excitatory effects, while low-frequency stimulation (≤1 Hz) produces LTD-like inhibitory effects 1, 2

Neuroplastic Changes and Mechanisms

TMS produces lasting changes in brain activity through synaptic plasticity mechanisms that persist beyond the stimulation period. 3, 4

Cellular and Molecular Level

• The neuroplastic effects are strictly dependent on NMDA and AMPA receptor signaling within glutamatergic synapses in addiction-related and mood-regulating brain regions 1

• Human studies demonstrate that NMDA-receptor blockade suppresses TMS-induced effects, confirming the glutamatergic dependence of the mechanism 1

• Dopaminergic transmission also plays a significant role in shaping TMS-induced effects, particularly in reward and motivation circuits 1

• TMS modulates expression of brain-derived neurotrophic factor (BDNF), an active regulator of synaptic plasticity, within cortical and subcortical areas 1

• Non-synaptic mechanisms include plasticity-related gene expression and neurogenesis, though their specific role in therapeutic effects requires further exploration 1

Network-Level Effects

• Local TMS application alters activity in distant, functionally connected brain regions, indicating that TMS modulates entire cortical networks rather than just the stimulation site 3

• TMS corrects generalized and local functional connectivity abnormalities that characterize major depressive disorder, which likely contributes substantially to its antidepressant effects 4

• Neuroimaging studies show that TMS induces neuronal activation in both cortical and subcortical areas, extending its influence beyond the direct stimulation target 1

Clinical Application Parameters

Critical Stimulation Variables

The therapeutic effect depends on precise manipulation of several parameters 1:

• Stimulation frequency: Determines excitatory versus inhibitory effects
• Pattern of stimulation: Single pulses, paired pulses, repetitive trains (rTMS), or theta-burst patterns (iTBS/cTBS)
• Intensity of stimulation: Must account for individual coil-to-cortex distance
• Duration and number of sessions: Longer treatment duration and higher session numbers contribute to faster clinical improvement 1

Common Treatment Protocols

• Standard rTMS for depression: Daily sessions for 4-6 weeks targeting the dorsolateral prefrontal cortex (DLPFC), with 77 out of 84 published studies in substance use disorders targeting this region 2, 5

• Accelerated protocols: Multiple sessions per day over several days to intensify efficacy and shorten treatment duration 6

• Deep rTMS: FDA-approved for OCD, targeting the medial prefrontal cortex and anterior cingulate cortex, often using tailored symptom provocation to personalize treatment 1, 2

Clinical Efficacy Evidence

For major depressive disorder after failure of two or more medication trials, TMS achieves response rates of 29-48% with a number needed to treat of 3.4-9 for response and 5-7 for remission. 2, 7

• Response rates reach 40-60% in treatment-resistant depression when TMS becomes part of standard care 3

• For stroke rehabilitation, low-frequency rTMS has Level A evidence for hand function recovery 2

• TMS demonstrates large treatment effects for substance use disorders, with high-frequency protocols reducing spontaneous and cue-induced craving 2

Safety Profile

• Most common adverse events are transient headaches and scalp discomfort, which are mild to moderate in intensity 8

• Seizure is the most serious risk but occurs very rarely 3

• TMS has significantly fewer systemic side effects compared to antidepressants 2

• Auditory threshold and cognitive function do not change with treatment 8

• Discontinuation rate due to adverse events during acute treatment is low at 4.5% 8

Important Clinical Caveats

• Excessive stimulation can paradoxically reduce efficacy through homeostatic plasticity mechanisms 2

• Anti-craving effects do not necessarily translate to behavioral change or abstinence in substance use disorders, highlighting the need for combination approaches 1, 7

• TMS should be combined with cognitive behavioral therapy for optimal results, as behavioral interventions provide the framework for sustained recovery 1, 2, 7

• Electric field modeling based on individualized cortical anatomy may help normalize TMS dosage and account for individual differences in response, though this is not yet standard practice 1