TMS & Neuromodulation · Part 2

Overview

Transcranial magnetic stimulation (TMS) uses a rapidly changing magnetic field to induce a brief electric field in the cerebral cortex. That induced electric field—not magnetism by itself—can activate neural elements beneath the treatment coil. Repeated pulses delivered with a defined target, intensity, pattern, and schedule can then influence connected brain networks beyond the small region directly exposed to the strongest field.¹²

The physics of TMS is well established. The biological chain from a pulse to lasting clinical improvement is more complicated: it involves local neural activation, network-level effects, and plasticity-like changes that differ across people, targets, and protocols. Good explanations of TMS should separate what is measured directly from what remains a plausible but incomplete model.¹³

The most important points are:

• A changing magnetic field induces an electric field. The electric field in brain tissue is what stimulates neural elements.¹²
• TMS is regional rather than pinpoint. Figure-of-eight coils can be relatively focal, but the stimulated volume depends on coil design, intensity, orientation, scalp-to-cortex distance, and individual anatomy.¹²
• Motor threshold individualizes intensity. It is a practical calibration measured in motor cortex, not a direct assay of the optimal biological dose in prefrontal cortex.
• Pulse pattern matters, but simple rules have limits. “High frequency excites and low frequency inhibits” is a useful motor-cortex teaching heuristic—not a universal law of human brain networks.⁴⁵⁶⁷
• Therapeutic TMS acts on circuits. The cortical site under the coil is an entry point into a distributed network, which is why target selection increasingly incorporates network connectivity.⁸⁹
• MRI navigation improves localization and reproducibility. It does not create a razor-thin focus or guarantee that treatment will work.⁹¹⁰

Evidence cutoff: This article reflects publicly available evidence and U.S. regulatory information through July 10, 2026. Device capabilities and treatment claims are specific to the coil, software, indication, age group, target, and protocol studied or authorized.

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Step 1: A Pulse of Current Flows Through the Coil

A TMS system briefly sends a very large, precisely controlled current through an insulated treatment coil. Because the current rises and falls quickly, it creates a rapidly changing magnetic field around the coil. The pulse lasts only a fraction of a millisecond, but it is strong enough to induce an electric field in nearby conductive tissue.¹²

The scalp and skull attenuate ordinary electrical current, which is one reason direct transcranial electrical stimulation at high intensity can be uncomfortable. Magnetic fields are affected far less by these tissues. It is still more accurate to say that the TMS magnetic field passes through the scalp and skull with relatively little attenuation than to say it passes “unimpeded.” Coil-to-cortex distance and head anatomy continue to matter substantially.¹²

Step 2: The Magnetic Field Induces an Electric Field in the Cortex

Faraday’s law of electromagnetic induction explains the next step: a time-varying magnetic field produces an electric field in nearby conductive material. In TMS, brain tissue is the conductor. The resulting electric field can depolarize excitable neural elements when its magnitude and orientation are sufficient.¹²

This distinction is clinically important. TMS is not “magnetizing” the brain. The magnetic pulse is the delivery mechanism; the induced electric field is the immediate stimulus. FDA device descriptions likewise characterize TMS as producing an electric field that activates neural pathways in cerebral cortex.³

What Actually Gets Activated?

TMS does not simply turn an entire brain region on or off. The first neural elements activated are thought to include axons and bends or branches of axons whose orientation aligns favorably with the induced electric field. The response depends on:

• electric-field strength and direction;
• coil position and angle;
• the folds of the cortex and the direction of local nerve fibers;
• scalp-to-cortex distance;
• pulse waveform and pattern;
• the ongoing physiological state of the network.

A familiar demonstration is stimulation of the hand area of motor cortex. A single pulse can produce a measurable muscle response called a motor-evoked potential. This shows that an external magnetic pulse can activate a cortical pathway in a person who is awake and not sedated. It does not mean that every therapeutic target has an equally visible output.

How Focal Is TMS?

“Focused” is a relative term. A figure-of-eight coil concentrates the strongest electric field beneath the point where its two windings meet, but stimulation still covers a region of cortex rather than a single neuron or a perfectly bounded spot. As intensity rises, the volume of tissue exposed above a given electric-field threshold generally expands.¹²

The depth–focality tradeoff is fundamental: a coil designed to expose a deeper or larger volume usually stimulates a broader superficial region as well. Marketing language should not obscure that physical constraint.¹²

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How the Dose Is Individualized: Motor Threshold

Clinicians commonly calibrate TMS intensity using a patient’s motor threshold. The coil is positioned over motor cortex, and the system determines the lowest output that reliably produces a hand-muscle response, observed either as a movement or recorded with electromyography (EMG). Treatment is then prescribed as a percentage of that threshold.

Motor threshold helps account for some person-to-person differences in excitability and coil-to-cortex geometry. It is practical, reproducible when measured carefully, and embedded in many studied protocols. It also has limits:

• it is measured in motor cortex, while depression treatment is usually delivered to prefrontal cortex;
• it does not directly measure electric-field strength at the treatment target;
• it does not predict with certainty who will respond clinically;
• it can change with health status, medications, sleep, substances, and measurement technique.

For these reasons, motor threshold is best understood as a validated calibration reference, not a complete biological definition of dose.¹⁰¹¹

How the Target Is Chosen

Scalp-Based Targeting

Established depression protocols may locate the left dorsolateral prefrontal cortex with scalp measurements, the Beam F3 method, or a fixed distance from the motor hotspot. These approaches are practical and have substantial clinical evidence. Their limitation is that the same scalp rule can correspond to somewhat different cortical locations in different people.

Structural-MRI Neuronavigation

Neuronavigation registers the patient’s head to a structural MRI and tracks the coil in three dimensions. It can help clinicians select an anatomical target and return to the same location and orientation across sessions. The Nexstim NBS 6 system, for example, combines MRI-based localization, TMS, and EMG for motor mapping and for locating treatment targets for adult major depression and adjunctive adult OCD.¹⁰

Structural-MRI navigation improves spatial reproducibility. It does not by itself identify the most effective functional network target, and it should not be presented as proof of superior outcomes in every patient.

Functional-Connectivity Targeting

Depression research increasingly treats the prefrontal target as an access point to a distributed mood circuit. Earlier work found that depression targets with stronger negative functional connectivity to the subgenual cingulate tended to be associated with better outcomes.⁸ In a 2026 randomized trial of 40 adults receiving the same high-dose accelerated treatment, connectivity-based targeting produced a larger median improvement than Beam F3 scalp targeting at one month.⁹

That study provides direct support for individualized connectivity targeting in a specialized accelerated protocol. It does not establish that every MRI-guided course is better than every well-delivered standard protocol, or that functional MRI is required for all TMS.

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Pulse Patterns: Frequency, Trains, and Theta Burst

A TMS protocol is more than a frequency. It includes the target, coil, pulse waveform, intensity, pulses per train, train duration, pauses between trains, total pulses per session, sessions per day, and spacing between sessions. Changing one component can change both effectiveness and safety.

The familiar frequency rule came largely from motor-cortex experiments. A 2026 reassessment found that the binary “higher is excitatory, lower is inhibitory” model does not consistently predict neurophysiological effects across the broader literature.⁷ Terms such as LTP-like and LTD-like are therefore more defensible than claiming that TMS reproduces cellular long-term potentiation or depression exactly.

Why Repeated Sessions Can Outlast the Pulse

A single pulse produces a brief response. A therapeutic course aims for changes that outlast each session. Proposed mechanisms include altered synaptic efficacy, shifts in excitation and inhibition, changes in network connectivity, and state-dependent learning or plasticity. These mechanisms are biologically plausible and supported by experimental work, but no single mechanism fully explains clinical response.⁴¹¹

Repeated sessions are important because plasticity is cumulative and context-sensitive. The total dose, timing between sessions, medications, sleep, stress, and what a patient is doing or thinking during stimulation may influence response. This is one reason a protocol validated as a complete package should not be reduced to one headline number such as “10 Hz” or “90,000 pulses.”

Why Two People Can Respond Differently

Even when the same nominal protocol is used, the electric field and physiological response can differ. Sources of variability include:

• brain anatomy and scalp-to-cortex distance;
• coil placement and orientation;
• baseline network activity and disease subtype;
• age, medications, sleep, and substance exposure;
• prior treatment history;
• measurement noise and day-to-day biological variability.

Large studies of theta-burst stimulation have shown substantial interindividual variability, and repeated testing can produce different physiological aftereffects in the same person.⁵⁶ This does not make TMS arbitrary; it means that population-average effects do not permit perfect individual prediction.

Where the Science Is Going

Several research directions aim to make TMS more precise:

• individual electric-field dosing based on each patient’s anatomy;
• functional-connectivity targeting based on disease-relevant circuits;
• TMS combined with EEG to measure cortical reactivity and network propagation;
• state-dependent or closed-loop stimulation timed to ongoing brain activity;
• biomarkers of early response that could guide continuation, extension, or retargeting.

TMS-EEG is a particularly promising research tool because it can record brain responses directly after a pulse. A 2026 integrative review, however, emphasized that differences in hardware, artifact removal, analysis, and reporting still limit routine clinical translation.¹² “Closed loop” and biomarker-guided TMS should therefore be described as emerging approaches unless a specific device and indication have FDA authorization.

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What This Means for Patients

A high-quality TMS program should be able to explain the complete treatment prescription: the diagnosis, target, coil, intensity, pulse pattern, number of pulses, session schedule, targeting method, safety screening, and how outcomes will be measured. Terms such as “deep,” “precision,” “MRI-guided,” or “personalized” are not substitutes for those details.

Bottom line: TMS uses well-understood electromagnetic physics to induce an electric field in cortex. Its clinical effects arise from a more complex interaction among local neural activation, distributed brain circuits, repeated dosing, and plasticity. The technology is precise enough to target a defined cortical region and reproducible enough for clinical treatment, but it is neither a pinpoint switch nor a fully solved biological system.

Previous: What Is TMS? An Introduction to Transcranial Magnetic Stimulation & Neuromodulation
Next: A Brief History of TMS and Brain Stimulation

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References

1. Peterchev AV, Wagner TA, Miranda PC, et al. Fundamentals of transcranial electric and magnetic stimulation dose: definition, selection, and reporting practices. Brain Stimul. 2012;5(4):435-453. doi:10.1016/j.brs.2011.10.001.
2. Wagner T, Rushmore J, Eden U, Valero-Cabré A. Biophysical foundations underlying TMS: setting the stage for an effective use of neurostimulation in the cognitive neurosciences. Cortex. 2009;45(9):1025-1034. doi:10.1016/j.cortex.2008.10.002.
3. U.S. Food and Drug Administration. De Novo Classification Request: BrainsWay Deep Transcranial Magnetic Stimulation System (DEN170078). Decision August 17, 2018.
4. Huang YZ, Edwards MJ, Rounis E, Bhatia KP, Rothwell JC. Theta burst stimulation of the human motor cortex. Neuron. 2005;45(2):201-206. doi:10.1016/j.neuron.2004.12.033.
5. Corp DT, Bereznicki HGK, Clark GM, et al. Large-scale analysis of interindividual variability in the effects of theta-burst stimulation of the motor cortex. Brain Stimul. 2020;13(5):1476-1488. doi:10.1016/j.brs.2020.07.018.
6. Ozdemir RA, Boucher P, Fried PJ, et al. Reproducibility of cortical response modulation induced by intermittent and continuous theta-burst stimulation. Brain Stimul. 2021;14(4):949-964. doi:10.1016/j.brs.2021.05.013.
7. Yassi IE, Bagci Das D, Fried PJ, Pascual-Leone A, Shafi MM, Ozdemir RA. Reassessing the neurophysiological effects of repetitive transcranial magnetic stimulation: a systematic review and comparative meta-analysis across protocols, outcome measures, and cortical sites. Neurosci Biobehav Rev. 2026;185:106648. doi:10.1016/j.neubiorev.2026.106648.
8. Fox MD, Buckner RL, White MP, Greicius MD, Pascual-Leone A. Efficacy of transcranial magnetic stimulation targets for depression is related to intrinsic functional connectivity with the subgenual cingulate. Biol Psychiatry. 2012;72(7):595-603. doi:10.1016/j.biopsych.2012.04.028.
9. Taylor JJ, Kare MR, Haj-Darwish D, et al. Connectivity- vs scalp-based targeting of accelerated transcranial magnetic stimulation for depression: a randomized clinical trial. JAMA Psychiatry. Published online June 24, 2026. doi:10.1001/jamapsychiatry.2026.1100.
10. U.S. Food and Drug Administration. Nexstim Navigated Brain Stimulation (NBS) 6 System: 510(k) Summary (K253098). March 20, 2026.
11. Soleimani G, et al. Dose-response relationships in transcranial brain stimulation: physics, physiology and mechanism. Brain Stimul. 2026;19(3):103067. doi:10.1016/j.brs.2026.103067.
12. Wang W, He Y, Xing H, Zhang H. Toward clinical translation of TMS-EEG: an integrative review of multidimensional neurophysiological measures. Front Hum Neurosci. 2026;20:1804482. doi:10.3389/fnhum.2026.1804482.

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