Beyond Serotonin: How dTMS Can Rebuild The Depressed Brain

Shifting the focus from neurotransmitters to neurogenesis

By Jess Wight | 04 September 2026

“Without the ability to create new neurons, people with depression may not have the resilience to effectively adapt to the environment.”

Maura Dupont, Professor of Psychiatry and Director of the Quantitative Brain Biology Institute, discussing how neurogenesis may be involved in depression

For decades, scientists have worked to understand what changes in the brain when someone develops major depressive disorder (MDD). Depression is far more than a temporary change in mood: it can alter how people think, remember, respond to stress, experience pleasure, and connect with the world around them. Yet translating these symptoms into a precise biological explanation has proven remarkably difficult. MDD is a highly heterogeneous disorder, with substantial variation in both its clinical presentation and its underlying biology. A 2020 review highlighted this variability, emphasizing that depression is unlikely to have a single biological cause.

This complexity is reflected in the long history of attempts to identify biological markers of MDD. A 2024 review examined evidence involving neurotransmitters, inflammation, stress hormones, genetics, brain circuitry, and other biological mechanisms, illustrating the range of processes that have been implicated in depression. Researchers have also investigated potential biomarkers of MDD, including hormonal changes and neuroimaging findings. Although some have shown tentative promise, there is currently no established biological test or biomarker used in the diagnosis of MDD. Diagnosis remains primarily based on clinical assessment and symptoms.

One of the most influential biological explanations emerged from research into monoamine neurotransmitters: these are chemicals such as serotonin, noradrenaline, and dopamine that play important roles in regulating mood, motivation, and emotional processes. The earliest evidence came from observations that some patients treated for hypertension with the monoamine-depleting drug reserpine developed depressive symptoms. In 1954, Edward Freis reported several cases of psychiatric complications associated with reserpine treatment. These observations contributed to the development of the catecholamine hypothesis, which psychiatrist Joseph Schildkraut formally proposed in 1965: this suggested that depression was associated with reduced catecholamines, a subgroup of monoamines including noradrenaline. In 1967, psychiatrist Alec Coppen extended this framework to serotonin, which eventually led to the development of SSRIs for depression treatment.

However, the monoamine hypothesis – particularly the theory that depression can be explained by a simple deficiency of monoamine neurotransmitters – has become increasingly difficult to sustain. Although antidepressants target monoamine systems, this does not demonstrate that depression itself is caused by a deficiency of these neurotransmitters. A large umbrella review from 2023 found no convincing evidence that depression is associated with reduced serotonin activity, with findings across 17 systematic reviews drawing inconsistent conclusions. These findings suggest that while monoaminergic signaling may contribute to depression and to the effects of antidepressant treatment, it is unlikely to provide a complete explanation of the disorder.

This has prompted researchers to look beyond the amount of individual neurotransmitters and towards the way these signaling systems influence the structure and function of the brain more broadly. One increasingly important area of research is neuroplasticity: the brain’s capacity to adapt and change in response to experience. Neuroplasticity encompasses far more than the generation of new neurons. It includes changes in the strength of connections between neurons, the formation and elimination of synapses, changes in dendritic structure, and broader alterations in the organization and activity of neural circuits.

A growing body of research has implicated alterations in these processes in people with depression. For example, a 2022 study investigating the pathogenesis of MDD identifies changes in synaptic connectivity, neuronal structure, and signaling in regions of the hippocampus and prefrontal cortex. This evidence of dysregulated neuroplasticity has helped researchers develop a more comprehensive understanding of MDD and consider how treatments might target the brain’s capacity to adapt and reorganize.

“…they all relate to impairments in neuroplasticity that leave brains in these kind of stuck states that are indicative of depression.”

Dr Chloe Page, psychiatrist and neuroscientist, discussing the symptoms of depression within a neuroplasticity framework reported in new research

One particularly intriguing example of neuroplasticity is adult hippocampal neurogenesis: the generation and maturation of new neurons from neural stem cells in the adult hippocampus. This structure is part of the limbic system, a network of brain regions involved in processes including memory and emotional regulation. In 1998, neuroscientists provided evidence for the generation of new neurons in the adult human hippocampus, challenging the long-held assumption that neurogenesis was restricted to early development. This finding, alongside evidence from animal models, stimulated considerable interest in whether adult hippocampal neurogenesis might contribute to depression. For example, a 2003 paper reported that blocking hippocampal neurogenesis prevented some of the behavioral effects of chronic antidepressant treatment in mice, providing early evidence for a potential relationship between neurogenesis and antidepressant action.

An exciting new publication of human evidence provides further evidence that neuroplastic processes may be altered in MDD. A 2026 study reported evidence of disrupted neurogenesis alongside other changes relating to neuroplasticity in the hippocampus of people with MDD. Their findings suggest that depression may involve changes in the brain’s ability to adapt and reorganize, rather than being explained by an imbalance in a single chemical.

These findings also raise the possibility that treatments capable of repeatedly modifying patterns of brain activity could influence neuroplastic processes in depression.

Deep transcranial magnetic stimulation (dTMS) offers one possible route. dTMS is a non-invasive treatment that uses magnetic pulses to stimulate areas of the brain involved in mood regulation. Unlike medication, which acts primarily through chemical signaling, dTMS applies physical stimulus to neural circuits to modulate patterns of brain activity. When stimulation is delivered repeatedly, it can produce changes in neural activity that extend beyond the immediate stimulation period, engaging mechanisms involved in neuroplasticity.

There is growing evidence that dTMS produces measurable changes in brain function. For example, a 2023 study using EEG reported significant changes in the neurophysiological state of the brain, specifically in the prefrontal regions associated with depression, following a course of dTMS in people with MDD. Another recent study published this year similarly observed changes to the frontal brain regions, with measures moving closer to patterns observed in healthy individuals. These findings do not by themselves demonstrate synaptic plasticity, but they indicate that repeated dTMS can alter neural functioning beyond the immediate delivery of stimulation.

There is also evidence that the clinical effects of dTMS can extend beyond the initial treatment phase. In a 2015 randomized controlled trial, patients receiving dTMS showed significantly higher response and remission rates than those receiving sham treatment, with these improvements maintained during a subsequent 12-week maintenance phase. Similar findings have been reported in subsequent studies.

Research into the broader mechanisms of TMS suggests that neuroplasticity may explain these findings. Preclinical research using intermittent theta-burst stimulation (iTBS), for example, has demonstrated changes in several markers of neuroplasticity: in one animal model of depression, repeated iTBS restored impaired long-term potentiation and normalized abnormal long-term depression – processes that reflect the brain’s ability to strengthen and weaken connections between neurons. Although this study did not use dTMS, it provides preclinical evidence that repeated TMS can engage biological processes involved in synaptic plasticity.

"Turning neurogenesis back on may be a way to treat depression in some people by rewiring their hippocampus circuit."

Maura Dupont, Professor of Psychiatry and Director of the Quantitative Brain Biology Institute, explaining how her new research could change depression treatment

Taken together, these findings provide a potential mechanistic link between neuroplasticity and dTMS. If MDD involves alterations in the brain’s ability to adapt and reorganize, as suggested by new research, then repeatedly stimulating neural circuits could potentially help shift dysfunctional patterns of activity towards more adaptive states. A 2024 review of neuroplasticity in MDD similarly proposes that alterations in synaptic function, structural connectivity, and signaling may contribute to inflexible patterns of activity within cognitive and emotional brain circuits.

Of course, this does not establish that dTMS reverses specific neuroplastic abnormalities observed in MDD. Much of the strongest evidence from synaptic plasticity comes from the broader TMS literature and from preclinical models rather than from studies examining these mechanisms in people receiving dTMS. Nevertheless, this evidence provides a plausible mechanistic explanation for how repeated brain stimulation could produce changes that extend beyond the period of stimulation itself – and why neuroplasticity may be an important part of understanding how dTMS works.

The evidence is increasingly clear that overcoming MDD may rely less on fixing a single chemical imbalance and more on restoring the brain’s ability to adapt. The shift toward a neuroplasticity framework fundamentally changes how we view mental health, reframing depression from an unchangeable biological fate into a state of temporary biological gridlock – one that we are finally learning how to unlock and rewire.