Depression is one of the most common mental health disorders affecting approximately 332 million people worldwide, according to the World Health Organization (WHO). It can significantly impact a person's emotional well-being, relationships, work performance, and overall quality of life. While everyone experiences periods of sadness or low mood, major depressive disorder is a medical condition characterised by persistent feelings of sadness, hopelessness, loss of interest in daily activities, changes in sleep and appetite, difficulty concentrating, fatigue, and, in some cases, thoughts of self-harm or suicide (World Health Organization, 2025).
The exact cause of depression is complex and multifactorial. Genetics, life experiences, chronic stress, physical health conditions, and environmental factors all contribute to its development. Earlier explanations of depression often placed greater emphasis on changes in neurotransmitter systems such as serotonin and noradrenaline. However, research now supports a much more complex picture. Depression involves interactions between brain circuits, neurotransmitters, genetics, stress responses, psychological processes, physical health and environmental factors. No single biological mechanism fully explains depression in every person.
In the UK, treatment for depression may include psychological therapies, antidepressant medication, lifestyle interventions and other treatments, depending on the severity of symptoms, individual circumstances and previous treatment response. NICE guidance recommends a range of treatment options and emphasises shared decision-making based on an individual's needs and preferences.
However, some people continue to experience significant symptoms despite appropriate treatment. NICE describes depression as treatment-resistant when symptoms have not improved after at least two standard treatments. In clinical research, treatment-resistant depression (TRD) is commonly defined using treatment history, although exact definitions vary between studies and clinical settings (NICE, 2026).
This continuing need for effective treatments has contributed to interest in neuromodulation approaches such as transcranial magnetic stimulation (TMS).
Depression does not appear to result from dysfunction in a single "depression centre" in the brain. Instead, research has identified changes involving multiple interconnected regions and large-scale networks involved in mood, motivation, cognitive control, emotional processing and self-focused thought (Hamilton et al., 2015).
The dorsolateral prefrontal cortex (DLPFC) is one of the most extensively studied brain regions in depression and is an important target for TMS. Located near the surface of the frontal lobe, the DLPFC is involved in cognitive control, working memory, planning, decision-making and aspects of emotional regulation (Lefaucheur et al., 2020).
Research has identified altered activity and connectivity within prefrontal regions in people with depression. However, these changes are not identical in every individual, and depression cannot be reduced to a simple model in which one side of the prefrontal cortex is always "underactive" while the other is always "overactive."
This is important because modern approaches to TMS increasingly view the DLPFC not simply as an isolated treatment target, but as an accessible entry point into wider brain networks (Fox et al., 2012).
Another network that has received considerable attention in depression is the Default Mode Network (DMN). The DMN is involved in internally focused processes such as self-referential thinking, autobiographical memory and reflection. Its activity normally changes depending on whether attention is directed towards internal thoughts or an external task.
Research has identified alterations in DMN activity and connectivity in depression, although findings vary between studies and individuals. The DMN has also been associated with rumination – repetitive, difficult-to-disengage negative thinking that is common in depression (Hamilton et al., 2015). This provides one possible explanation for why difficulties with attention and disengaging from repetitive negative thoughts can occur alongside changes in brain-network activity.
The subgenual anterior cingulate cortex (sgACC), sometimes referred to as the subgenual prefrontal cortex, is another region of interest in depression. Research has implicated this area in emotional processing and identified differences in its activity and connectivity in people with depression. Its interactions with other brain networks have also been associated with depressive symptoms and rumination.
Transcranial magnetic stimulation (TMS) is a non-invasive form of brain stimulation that uses rapidly changing magnetic fields to generate electrical currents in targeted areas of the cerebral cortex. For depression, TMS is most commonly delivered to regions of the prefrontal cortex, particularly the DLPFC.
During treatment, a magnetic coil is positioned against the scalp. The coil produces brief magnetic pulses that pass through the skull and induce small electrical currents in the underlying cortex. By adjusting factors such as stimulation location, frequency, intensity and pattern, clinicians can deliver different TMS protocols.
TMS is used clinically for major depressive disorder, particularly for people who have not achieved sufficient improvement with previous treatments. Evidence-based guidelines support high-frequency rTMS applied to the left DLPFC as an effective treatment approach, while other protocols, including low-frequency right-sided stimulation and bilateral approaches, have also been studied (Lefaucheur et al., 2020).
TMS encompasses several stimulation approaches, including repetitive transcranial magnetic stimulation (rTMS) and theta-burst stimulation (TBS).
Repetitive TMS (rTMS) delivers a series of magnetic pulses according to a predetermined stimulation protocol. Different frequencies, intensities, treatment locations and session structures can be used depending on the clinical approach.
Theta-burst stimulation (TBS) delivers magnetic pulses in short, patterned bursts. Some TBS protocols can deliver stimulation in substantially shorter periods than conventional rTMS (NICE, 2026).
The choice of protocol depends on the individual's clinical circumstances, the treatment system being used and the clinician's assessment.
One of the most important things to understand about TMS is that it does not need to directly stimulate every brain region involved in depression.
The DLPFC is located close enough to the surface of the brain to be directly influenced by a TMS coil. However, the DLPFC does not operate in isolation – it communicates with numerous other cortical and subcortical regions involved in cognitive control, motivation, emotional processing and mood regulation.
This means that stimulating the DLPFC may produce effects beyond the area directly exposed to the magnetic field. Through its functional connections with other brain regions, TMS may influence wider networks involved in depression (Lefaucheur et al., 2020; Fox et al., 2012).
The relationship between the DLPFC and sgACC is an important example. The sgACC is too deep to be directly stimulated by conventional TMS in the same way as the cortical surface. However, neuroimaging research has demonstrated that DLPFC regions used as TMS treatment targets are functionally connected with the subgenual cingulate (Fox et al., 2012).
Importantly, the strength and pattern of this connectivity have been associated with differences in the antidepressant effectiveness of TMS targets. This has contributed to growing interest in connectivity-guided TMS. Rather than selecting a treatment location based solely on its anatomical position, researchers are investigating whether individualised brain-connectivity patterns can help identify the cortical targets most strongly connected to relevant mood-related circuits.
Research also suggests that TMS can influence activity and connectivity within the DMN and its interaction with cognitive control networks (Hamilton et al., 2015; Lefaucheur et al., 2020). These network-level changes may help explain how TMS can support improvements in attention, cognitive control and the ability to disengage from repetitive negative thinking. This is particularly relevant to depression because symptoms such as rumination, impaired concentration and difficulty regulating emotions are unlikely to result from dysfunction in a single brain region.
TMS treatment involves repeated stimulation across multiple sessions rather than a single treatment. Repeated stimulation can produce changes in cortical excitability and functional connectivity that may extend beyond an individual treatment session.
Neuroplasticity – the brain's ability to modify and adapt patterns of neural activity and communication – is thought to be one of the mechanisms that may contribute to the longer-lasting effects of repeated TMS. Experimental research has identified plasticity-related changes following patterned brain stimulation, while clinical and neuroimaging studies have investigated changes in connectivity between networks involved in depression (Lefaucheur et al., 2020).
However, the precise biological mechanisms responsible for the antidepressant effects of TMS are not fully understood. It is therefore more accurate to describe neuroplasticity as one proposed mechanism rather than suggesting that it completely explains how TMS works. The broader concept is that repeated stimulation may gradually alter the way interconnected brain networks communicate. These changes may contribute to improvements in depressive symptoms, including mood, cognitive control and emotional regulation.
TMS is generally well tolerated and does not require anaesthesia. During treatment, patients may feel tapping or pressure on the scalp and may experience temporary discomfort, headache or facial muscle twitching. The magnetic coil also produces a clicking sound during stimulation, so hearing protection is typically provided if necessary.
A seizure is a recognised but uncommon potential adverse effect of TMS. International safety guidelines describe seizure induction as the most serious potential risk but report that the risk is low when established stimulation parameters are used appropriately. Screening before treatment is therefore important to identify factors that may affect safety or suitability (Rossi et al., 2021).
As with any medical treatment, TMS is not suitable for everyone. A qualified clinician should assess an individual's medical history, current treatment and potential risk factors before treatment begins.
TMS is supported by a substantial body of evidence, including randomised controlled trials, systematic reviews and meta-analyses.
A meta-analysis of 65 randomised sham-controlled trials involving 2,982 participants found that active rTMS produced greater reductions in depressive symptoms than sham treatment. It also found higher response and remission rates with active treatment, although the authors noted variation between studies (Dalhuisen et al., 2022).
TMS has also been studied specifically in people whose depression has not responded adequately to previous antidepressant treatments. A 2023 meta-analysis of randomised sham-controlled studies involving people with major depressive disorder after two antidepressant treatment failures found that adjunctive rTMS was associated with higher response and remission rates than sham treatment alongside standard pharmacotherapy (Vida et al., 2023).
Neuroimaging research provides another important part of the evidence base. Studies have identified changes in brain activity and functional connectivity following TMS, supporting the view that its effects may extend beyond the area directly stimulated. Research linking DLPFC treatment targets with connectivity to the sgACC has also helped drive interest in more personalised and connectivity-guided approaches (Fox et al., 2012).
However, it is important to note that TMS does not work for everyone. Treatment response can vary according to individual clinical characteristics, treatment parameters and the brain circuits being targeted. This variability is one reason why researchers continue to investigate personalised approaches to brain stimulation.
One of the most useful ways to understand TMS is to think of it as network modulation rather than simply stimulation of one brain region.
The DLPFC is an accessible treatment target, but its connections with other brain regions mean that stimulation may influence wider networks involved in mood, motivation, cognitive control and emotional processing.
TMS is delivered as a course of treatment rather than a single session because repeated stimulation may produce cumulative changes in brain activity and connectivity. However, the precise relationship between these biological changes and clinical improvement remains an active area of research.
Depression is a complex condition involving interactions between brain circuits, neurotransmitter systems, genetics, psychological processes and environmental factors. Rather than affecting a single area of the brain, depression can involve changes in communication between networks responsible for mood, motivation, cognition and emotional processing.
TMS provides a non-invasive way of influencing some of these networks by targeting accessible regions of the cerebral cortex, particularly the DLPFC. Although deeper regions such as the sgACC cannot be directly stimulated by conventional TMS in the same way, their functional connections with cortical targets provide one possible route through which TMS can produce wider network effects.
The precise mechanisms underlying TMS remain an active area of research. Nevertheless, clinical evidence supports rTMS as an effective treatment option for many people with depression, including people whose symptoms have not improved sufficiently with previous treatments (Dalhuisen et al., 2022; Vida et al., 2023).
Ongoing research is now focusing increasingly on treatment optimisation, brain connectivity, stimulation protocols and personalised approaches to help determine which treatments are most likely to benefit individual patients.
Written by Rogelio, Smart TMS Manchester Practitioner
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