Transcranial magnetic stimulation (TMS) has become one of the most important advances in the treatment of Depression and other mental health conditions, especially for patients who have not found relief with medication. One question patients often ask is simple: how does TMS actually work?
While TMS is FDA-approved and widely used, the science behind it is genuinely complex, and researchers are still working out the full picture. A comprehensive review of TMS mechanisms by Chervyakov and colleagues, published in Frontiers in Human Neuroscience, makes clear that TMS doesn’t rely on a single mechanism. Instead, the evidence suggests it works by influencing the brain on multiple levels, from electrical activity and synaptic connections to neurotransmitters and cellular repair processes. In this article, we break down the key scientific insights into how TMS produces its therapeutic effects, citing the research behind each one.
What Is TMS? A Quick Overview
TMS is a noninvasive brain stimulation treatment that uses magnetic pulses to activate specific areas of the brain. During treatment, a coil is placed gently against the scalp, typically over the left dorsolateral prefrontal cortex (DLPFC), a region involved in mood regulation. These magnetic pulses generate small electrical currents in the brain, helping to shift patterns of activity that may be disrupted in Depression and other conditions. Unlike medication, which circulates throughout the entire body, TMS is highly targeted, focusing on specific brain circuits involved in mood, cognition, and emotional processing.
1. Restoring Healthy Brain Activity
One of the most well-established effects of TMS is its ability to modulate brain activity. In Depression, certain areas of the brain, particularly in the prefrontal cortex, are often underactive, while regions involved in negative emotional processing may be overactive. Research on stimulation frequency supports a fairly consistent principle: high-frequency repetitive TMS (above roughly 5 Hz) increases cortical excitability, while low-frequency stimulation (below 1 Hz) reduces it (Chervyakov et al., 2015). By adjusting frequency, TMS can be used to increase activity in underactive brain regions or calm overactive ones, helping restore a healthier balance that supports improved mood, energy, and cognitive function.
2. Strengthening Brain Connections (Neuroplasticity)
A central concept in understanding TMS is neuroplasticity, the brain’s ability to adapt, reorganize, and form new connections. In Depression, neural circuits can become stuck in maladaptive patterns, and TMS is thought to help shift these circuits by promoting stronger connections between neurons and more effective communication across brain networks. The leading explanation for these lasting effects involves long-term potentiation (LTP) and long-term depression (LTD), processes first identified in the rodent hippocampus that strengthen or weaken synaptic connections depending on the pattern of stimulation, with high-frequency and theta-burst stimulation associated with LTP-like strengthening and low-frequency stimulation associated with LTD-like weakening, largely through NMDA receptor activity (Chervyakov et al., 2015). Repeated TMS has also been shown, primarily in animal studies, to change the expression of genes involved in neuronal plasticity and activity, offering a molecular explanation for how these effects might be sustained over time (Chervyakov et al., 2015). This is one reason TMS can lead to improvement that persists even after a treatment course ends.
3. Rebalancing Brain Chemistry
Many people are familiar with the idea that Depression involves an imbalance in brain chemistry. TMS has been shown to influence several neurotransmitter systems relevant to mood. Imaging research has found that high-frequency stimulation of the left DLPFC increases dopamine release in specific frontal brain regions (Chervyakov et al., 2015), a neurotransmitter linked to motivation and reward. Other studies have found that TMS can alter the density of certain neurotransmitter receptors, including reductions in norepinephrine-related receptors and increases in NMDA receptors, which are involved in the brain’s balance of excitation and inhibition (Chervyakov et al., 2015). Genetic research has also identified variations in serotonin-related genes that appear to predict how strongly some patients respond to TMS treatment (Chervyakov et al., 2015). Unlike medications that act on these systems indirectly and throughout the body, TMS can directly influence the brain regions that produce and regulate these chemicals.
4. Improving Brain Network Function
Modern neuroscience shows that Depression is not just a problem in one part of the brain; it’s a disorder of brain networks. TMS has been studied for its effects on communication between key regions, including the prefrontal cortex, the limbic system, and the default mode network, the network involved in self-reflection and rumination. In Depression, these networks can become dysregulated, contributing to symptoms like persistent negative thinking, low motivation, and emotional distress. By influencing connectivity between these regions, TMS may help the brain function more efficiently as a whole, an effect consistent with research showing that TMS can generate changes in long-distance functional connectivity beyond the site of stimulation itself (Chervyakov et al., 2015).
5. Supporting Brain Growth and Repair
Another important area of TMS research involves its influence on brain-derived neurotrophic factor (BDNF), a protein that plays a key role in neuron growth and survival, the formation of new synaptic connections, and recovery from stress-related damage. Several studies have found that high-frequency TMS increases BDNF levels in blood serum, including a study specifically in patients with Depression (Chervyakov et al., 2015). This BDNF effect is one proposed reason TMS can produce gradual but meaningful improvement over time, similar in principle to the neurotrophic effects associated with antidepressant medication. It is worth noting that not every study has found this effect. Some research in healthy volunteers has found no significant change in BDNF levels following TMS, and low-frequency stimulation has in some cases been associated with reduced BDNF (Chervyakov et al., 2015), so this remains an active and evolving area of research rather than a fully settled finding.
6. Reducing Stress and Hormonal Imbalance
Depression is often associated with dysregulation of the body’s stress response system, known as the hypothalamic-pituitary-adrenal (HPA) axis, which can lead to elevated levels of cortisol, the body’s primary stress hormone. Researchers investigating brain-based Depression treatments have proposed that TMS may help normalize cortisol levels and improve the body’s response to stress, reducing the physiological burden of chronic stress. These effects, if confirmed, would contribute not only to improved mood but also to better overall well-being, though this remains a developing area of TMS research distinct from the plasticity and neurotransmitter mechanisms described above.
7. Decreasing Inflammation in the Brain
An emerging area of research suggests that inflammation plays a role in Depression and other mental health conditions. Some research has associated TMS with reduced levels of inflammatory markers and improved regulation of immune activity in the brain. If this connection holds up in further research, it would suggest TMS may help address inflammation as an underlying contributor to symptoms, particularly for patients who have not responded to more traditional treatments. As with the HPA-axis research above, this is a newer and less thoroughly established line of investigation than the plasticity and neurotransmitter research.
8. Enhancing Blood Flow and Brain Metabolism
Healthy brain function depends on adequate blood flow and energy use. Research, largely from animal models of brain injury and stroke, has found that TMS can increase blood flow to the stimulated region and improve glucose metabolism in affected brain areas (Chervyakov et al., 2015). Related studies have found that TMS increases markers of cellular energy production, such as ATP content, in brain tissue following induced injury (Chervyakov et al., 2015). These changes support the broader idea that TMS affects not just electrical activity but also the metabolic health of brain tissue, which may contribute to improved cognitive clarity, focus, and emotional regulation over a course of treatment.
9. Why TMS Works When Medications Don’t
One of the most important clinical insights is that TMS works differently from antidepressant medication. Medications affect the entire brain and body, depend on digestion and systemic absorption, and often involve a process of trial and error to find an effective option. TMS, by contrast, directly targets specific brain circuits, does not rely on systemic circulation, and can potentially be adjusted based on a patient’s individual brain function. This is part of why TMS is particularly useful for patients with treatment-resistant Depression, when multiple medications have not provided relief.
10. A Multi-Layered Treatment Approach
The most important takeaway is that TMS is not a single-action treatment. Instead, the evidence suggests it works through a combination of mechanisms, including electrical stimulation of brain cells, strengthening of neural connections, effects on neurotransmitter systems, improved brain network function, support for cellular growth and repair, and effects on stress and inflammation. This multi-layered profile is part of what makes TMS a distinctive treatment option among the therapies available for Depression today.
What This Means for Patients
For patients considering TMS, this science translates into several real-world benefits: a noninvasive, medication-free treatment; a targeted approach with minimal side effects; improvement in mood, energy, and cognition; and results that often prove durable well after a treatment course ends. Individual responses vary, and many patients experience meaningful relief, often after other treatments have not worked.
TMS at Mid City TMS
At Mid City TMS, we use evidence-based TMS protocols designed around each patient’s needs, informed by the latest neuroscience research and structured to support both effectiveness and comfort. We also offer esketamine (Spravato) when appropriate, which works through a different mechanism entirely.
Final Thoughts on How TMS Works
TMS represents an important shift in how Depression is treated, moving past a purely chemical model toward a more complete understanding of brain function. By directly targeting the circuits involved in mood regulation and supporting long-term brain health, TMS offers a real option for patients who may have felt stuck after other treatments. As research continues to develop, our understanding of exactly how TMS works will keep deepening, but one thing is already clear from the evidence available today: TMS is not just treating symptoms, it is helping the brain function differently.
If you are considering TMS, learn how Mid City TMS can help and contact us today to schedule a consultation.
Sources
- Chervyakov, A. V., Chernyavsky, A. Y., Sinitsyn, D. O., & Piradov, M. A. (2015). Possible Mechanisms Underlying the Therapeutic Effects of Transcranial Magnetic Stimulation. Frontiers in human neuroscience, 9, 303. https://doi.org/10.3389/fnhum.2015.00303
- Jewett BE, Thapa B. Physiology, NMDA Receptor. [Updated 2022 Dec 11]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2026 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK519495/
- Dunlavey C. J. (2018). Introduction to the Hypothalamic-Pituitary-Adrenal Axis: Healthy and Dysregulated Stress Responses, Developmental Stress and Neurodegeneration. Journal of undergraduate neuroscience education : JUNE : a publication of FUN, Faculty for Undergraduate Neuroscience, 16(2), R59–R60.