Non-Invasive Brain Stimulation for Depression: Complete Clinical Guide

Depression is one of the most prevalent mental health disorders worldwide. According to the World Health Organization (WHO), it affects more than 280 million people globally and is one of the leading causes of disability. Despite advances in pharmacotherapy and psychotherapy, a significant proportion of patients — estimated at between 30% and 40% — do not respond adequately to first-line conventional treatments. This clinical reality has driven research into complementary strategies, among which non-invasive brain stimulation (NIBS) stands out.

This guide reviews the available scientific evidence on two of the main NIBS modalities — transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS) — their safety profile, their role in specific contexts such as post-stroke depression, and how this technology is integrated into clinical practice at GNeuro, in Ourense.

What Is Non-Invasive Brain Stimulation?

Non-invasive brain stimulation encompasses a set of techniques that modulate neuronal activity without the need for surgical procedures. Unlike deep brain stimulation, which requires electrode implantation, non-invasive techniques act from the surface of the scalp and have a considerably more favourable safety profile.

The two modalities with the greatest scientific support in the context of depression are:

• Transcranial direct current stimulation (tDCS): applies a low-intensity electrical current (usually between 1 and 2 mA) through electrodes placed on the scalp. This current modulates cortical excitability in a subthreshold manner — it does not directly generate action potentials, but facilitates or inhibits neuronal activation depending on the polarity of the electrode (anodal or cathodal).
• Repetitive transcranial magnetic stimulation (rTMS): uses pulsed magnetic fields to induce focal electrical currents in specific brain regions. High-frequency rTMS (usually 10 Hz) over the left dorsolateral prefrontal cortex (DLPFC) is the most studied and best-evidenced protocol in depression.

Scientific Evidence: tDCS in Depression

Research on tDCS in depression has grown considerably over the past decade. The most widely used protocol involves placing the anodal electrode over the left dorsolateral prefrontal cortex (DLPFC), a region that shows hypoactivity in many patients with depression, and the cathode at the contralateral supraorbital region or over the right DLPFC.

• The meta-analysis by Brunoni et al. (2016), published in JAMA Psychiatry, analysed individual patient data from six RCTs and concluded that active tDCS was significantly superior to placebo in reducing depression scores, with a moderate effect size. The response rate was 34% versus 19% with sham stimulation ^[1].
• The SELECT-TDCS trial (Brunoni et al., 2017, NEJM) compared tDCS, escitalopram and placebo in 245 patients with unipolar depression. Results showed that tDCS was superior to placebo but did not achieve non-inferiority versus escitalopram. However, the combination of tDCS with the antidepressant showed promising effects ^[2].
• The Cochrane review by Razza et al. (2020) included 23 RCTs and confirmed a significant effect of tDCS on depressive symptoms, while highlighting the need for more studies to determine optimal stimulation parameters and the patient profiles most likely to benefit ^[3].
• A more recent meta-analysis by Moffa et al. (2020) published in the Journal of Affective Disorders included 27 RCTs with 1,204 participants and reported a significant antidepressant effect of active tDCS versus sham ^[4].

Evidence suggests that tDCS can contribute to reducing depressive symptoms as part of an individualised treatment programme. Its efficacy appears to increase when combined with pharmacological or psychotherapeutic interventions.

Scientific Evidence: rTMS in Depression

rTMS has a more extensive evidence base than tDCS and has been approved by the FDA (Food and Drug Administration) for the treatment of treatment-resistant depression since 2008. In Europe, NICE clinical guidelines recognise rTMS as an option for depression that has not responded to conventional treatments ^[5].

• The meta-analysis by Berlim et al. (2014), published in the World Journal of Biological Psychiatry, analysed 29 RCTs and found that high-frequency rTMS over the left DLPFC was significantly superior to sham, with response rates of 29.3% versus 10.4% ^[6].
• The intermittent theta burst (iTBS) protocol, a more recent rTMS modality, demonstrated comparable efficacy to conventional rTMS in the THREE-D trial (Blumberger et al., 2018, The Lancet), with the advantage of reducing session duration from approximately 37 minutes to just 3 minutes ^[7].
• NICE clinical practice guidance (IPG542, updated 2015) states that evidence on the efficacy and safety of rTMS for depression is adequate for clinical use, provided it is implemented within an appropriate clinical governance framework ^[5].

Comparison: tDCS versus rTMS

Safety and Side Effects

Safety of tDCS

The most common side effects of tDCS are mild and transient ^[8]:

• Tingling or itching under the electrodes during the session (reported in approximately 70% of participants in clinical trials).
• Transient skin redness at the electrode contact area.
• Mild headache after the session (infrequent, generally self-limiting).
• Transient fatigue in some patients.

No serious adverse effects have been described in studies following established safety parameters (intensities up to 2 mA, sessions up to 30 minutes). The safety review by Bikson et al. (2016) analysed data from more than 33,000 accumulated sessions without reporting any serious adverse effects ^[8].

Safety of rTMS

The main side effect of rTMS is headache, affecting a variable proportion of patients (20–40% depending on the study) and usually resolving spontaneously or with conventional analgesia. The most relevant risk is the induction of epileptic seizures, although this is extremely rare (less than 0.1% of cases) when the safety protocols of Rossi et al. (2021) are respected ^[9].

Both techniques have contraindications that must be assessed case by case, including intracranial metallic implants, cardiac pacemakers and a history of uncontrolled epilepsy. Prior assessment by a qualified professional is indispensable.

Post-Stroke Depression: The Connection with Neurorehabilitation

Post-stroke depression (PSD) is one of the most common neuropsychiatric complications following a cerebrovascular accident. Epidemiological studies estimate that it affects approximately one third of stroke survivors, with figures ranging from 25% to 41% depending on the series and the time of assessment ^[10].

PSD has significant clinical consequences: it is associated with poorer participation in rehabilitation programmes, slower functional recovery, greater risk of stroke recurrence, and increased mortality. It is, however, frequently underdiagnosed and undertreated, partly because its symptoms may overlap with the cognitive deficits and fatigue inherent to acquired brain injury.

• A meta-analysis by Shen et al. (2017) published in the Journal of Neurology evaluated the effect of rTMS on post-stroke depression and found a significant reduction in depression scores compared with sham treatment ^[11].
• Preliminary studies with tDCS in patients with PSD have shown promising results, although the evidence base is still limited and larger clinical trials are needed ^[12].

In the context of robotic neurorehabilitation, integrating neuromodulation techniques may be especially relevant. A patient participating in a rehabilitation programme with robotic technology (such as a robotic gait training system for gait or an upper limb rehabilitation robot for the upper limb) who presents depressive symptoms may have compromised motivation, capacity for effort and, consequently, functional outcomes. Addressing the emotional dimension in a complementary manner, in coordination with the mental health team, may contribute to optimising the results of the rehabilitation process.

The GNeuro Programme

At GNeuro we have incorporated CE-marked tDCS devices designed specifically for use as a complement in the management of depressive symptoms. This allows us to administer tDCS sessions with the parameters supported by scientific literature (anodal stimulation over the left DLPFC) in an accessible and monitored manner.

Our programme integrates tDCS within a multidisciplinary approach that considers:

• Initial assessment by our team, in coordination with the patient's mental health professional (psychiatrist and/or psychologist).
• Individualised protocol adapted to the clinical characteristics of each person, following the recommendations of available scientific evidence.
• Periodic monitoring of symptomatic evolution using validated scales.
• Coordination with the mental health team managing the patient, ensuring that tDCS is coherently integrated within the overall therapeutic plan.

For Whom May NIBS in Depression Be Indicated?

Based on current scientific literature, non-invasive brain stimulation may be considered as a therapeutic complement in the following clinical profiles, always under professional supervision:

• Patients with unipolar depression who show a partial or insufficient response to first-line pharmacological and/or psychotherapeutic treatment.
• Patients with post-stroke depression who are undergoing neurorehabilitation and whose depressive symptoms may be interfering with participation and outcomes of the rehabilitation programme.
• People who, under the criteria of their mental health professional, may benefit from an augmentation strategy combining neuromodulation with established pharmacological treatment.

Frequently Asked Questions