Introduction

Some text in this chapter is reproduced with permission from Morriss et al.1 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) licence, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: https://creativecommons.org/licenses/by/4.0/. The text below includes minor additions and formatting changes to the original text.

Clinical efficacy

Worldwide, major depressive disorder (MDD) affects 13% of the general population,2 making it the leading cause of disability and suicide.3 Antidepressants and psychotherapies, such as low-intensity psychological interventions and cognitive–behavioural therapy, are found to be effective for MDD. However, a proportion of individuals with MDD will be ‘treatment resistant’, with 33% patients in specialist care4 and 22% in primary care failing to adequately respond to two trials of antidepressants.5 Compared with MDD that is not treatment resistant, treatment-resistant depression (TRD) is associated with higher rates of suicide,6 hospitalisation, poor physical health, and increased costs.7 Therefore, it is essential to find alternative treatments for such TRD.

Therapeutic interventions that can directly modulate the function of targeted brain regions such as electroconvulsive therapy (ECT)8 and repetitive transcranial magnetic stimulation (rTMS)9 can have a significant impact on reducing the burden of TRD symptoms. rTMS employs strong magnetic pulses to alter activity in neural circuits in the brain implicated in the pathophysiology of depression. Compared to ECT, rTMS does not require anaesthesia. While ECT can be associated with a negative impact on cognitive functioning,10 rTMS has shown modest cognitive enhancing effects when compared to sham treatments.11,12 However, it is difficult to ascertain whether these potential modest cognitive enhancing benefits are separate or secondary to overall depression improvement as well as the influence of practice effects.13 Repetitive transcranial magnetic stimulation is also reported to be a more cost-effective first-line treatment than ECT due to better health outcomes and being less expensive.14

Repetitive transcranial magnetic stimulation is either high frequency to generally increase excitability or low frequency to generally induce inhibition, with the left dorsolateral prefrontal cortex (lDLPFC) most targeted for MDD. Meta-analyses of randomised controlled trials (RCTs) have shown that when compared to sham treatments, high-frequency rTMS15 and low-frequency rTMS16 were significantly associated with improvement in clinical symptoms in MDD. These findings also extend to TRD, showing reductions in depression symptoms and increases in response and remission rates after rTMS treatment.9 Hence in 2015, the National Institute for Health and Care Excellence (NICE) recommended the use of rTMS, including theta burst stimulation (TBS), for use of depression and TRD in the NHS.17 Stratified data have also demonstrated that the effectiveness of rTMS may be higher when used as an add-on to antidepressant medication.18 The majority of RCTs have focused on the immediate efficacy of rTMS, with only a few RCTs reporting long-term follow-up efficacy. However, the beneficial effects of rTMS on mood in TRD may be relatively short, lasting only 1–3 months.9,17 Therefore, while rTMS appears to be effective for MDD and TRD in the short term, there is uncertainty about patient selection for TMS, the best TMS treatment regime for use, its use as a maintenance treatment (given the relatively short-lived duration of response after each course of treatment), and long-term outcomes of patients undergoing the treatment. Hence NICE encourages studies addressing these issues.17

Theta burst stimulation is an alternative patterned form of rTMS, which employs high-frequency stimulation, with each treatment administration requiring less time. Unlike standard rTMS, TBS uses bursts of magnetic pulses that mimic endogenous theta rhythms, and it is associated with cortical long-term potentiation that may induce plasticity in more distal brain areas, such as the hippocampus, potentially leading to a higher proportion of responders and a longer duration of effect in TRD.19 This includes intermittent TBS (iTBS), which is expected to enhance cortical excitability, and continuous TBS, which is expected to supress cortical excitability. In addition, rTMS is sometimes used as a generic term for all forms of TMS, including iTBS, but in this report we use it to refer to repetitive transcranial magnetic stimulation only and not as a generic term.

Recent meta-analyses including RCTs, and uncontrolled clinical trials have shown that TBS is superior to sham treatments in MDD.20–22 One meta-analysis also reported that TBS is non-inferior versus left DPLFC high-frequency rTMS,22 albeit this finding was due to one large high-quality non-inferiority RCT of 414 TRD patients.23 Furthermore, a recent meta-analysis reported that TBS applied to the DLPFC has high tolerability, and the optimal parameters of TBS protocols may include ≥ 1800 pulses per session, subthreshold stimulation intensities, and protocols including iTBS.21

It is proposed that more precise identification of DLPFC targets may improve the efficacy of TMS treatments. Neuronavigation technology can co-register a patient’s head with their structural magnetic resonance imaging (MRI) scans, which can enable real-time and on-line feedback for how to adjust the TMS coil to be on target.24 A recent study found that compared to neuronavigated targeting, traditional elastic cap scalp targeting was significantly more off-target in relation to distance, roll/pitch angle and yaw angle deviation, with greater coil drift over time.24 One prospective MDD clinical trial found MRI-guided neuronavigation TMS had significantly greater clinical efficacy compared to scalp-based targeting methods,25 whereas other small studies have found no difference in clinical efficacy when comparing these targeting methods.26,27 However, theoretically, off-target stimulation and coil drift during TMS sessions may suboptimally stimulate neural circuits of interest, which may affect clinical response.24

To our knowledge there are two RCTs that have compared 600 pulse iTBS versus high-frequency rTMS, using structural MRI-guided neuronavigation to target the DLPFC. As previously mentioned, the large high-quality Three-D trial found that iTBS was non-inferior to higher-frequency rTMS at 4 and 12 weeks after treatments.23 There is also the THETA-DEP trial that found similar response and remission rates, between MRI-guided neuronavigated iTBS and rTMS, with both groups having a similar sustained decrease in depression scores up to 6 months after baseline.28 It should be noted that this latter trial was published after recruitment to the BRIGhTMIND trial had completed. In addition, while it is limited by a small sample size of 60 participants and a single centre study with modest treatment resistance and duration of depression episode, it does demonstrate that MRI-neuronavigated treatments may provide longer-lasting durations of depression response.

In addition, non-invasive neuromodulation may affect brain networks rather than just the local stimulation site targeted, and it has further been proposed that modulation of targeted brain networks may yield therapeutic potential.29 Thus, there is increasing recognition of the value of using brain connectivity changes as detected by non-invasive resting state (task-free) functional MRI (rsfMRI) to individualise neurostimulation therapy of MDD.30 Towards these aims, two complementary characteristics of brain network function can be derived from rsfMRI: metrics that quantify the degree of synchronisation of neural activity between regions or networks known as functional connectivity (FC),31 or the influence one brain region’s activity exerts on another known as effective functional connectivity (eFC).32,33 Importantly, FC-guided personalised TMS targets have been found to be reliably and robustly pinpointed, remaining stable over 1 year, with target locations varying widely across individuals.34 This demonstrates that connectivity-guided personalised TMS targets can be reproduced with excellent precision which do not trivially converge to a group-average site.34

A triple network model comprising inter-region brain connectivity between the default mode network (DMN), salience network (SN), and central executive network (CEN) may represent a major abnormality across psychiatric disorders.35 The DMN is involved in internally directed/self-referential mental activity and comprises the ventromedial prefrontal cortex (VMPFC), the posterior cingulate cortex (PCC), bilateral inferior parietal cortex, and the middle temporal lobe.36 The SN is involved in detecting and filtering relevant salient external and internal stimuli and comprises the anterior insula (AI) and the dorsal anterior cingulate cortex.37 The CEN is crucial for maintaining and manipulating decision-making and working memory and primarily comprises the dorsolateral prefrontal cortex (DLPFC) and posterior parietal cortex.38 It is proposed that TMS stimulation of the DLPFC (key node of the CEN) may directly modulate key nodes within the SN and DMN, which in turn rebalances abnormal FC between and within networks.39 A disruption of the reciprocal loop between the DLPFC and insula has been found in depression,33 and given these are key nodes of the CEN and SN respectively, dysfunction of such a loop would have greater effects on these major brain networks. Therefore, the insula is suggested to be a target for neuromodulation.40

One biotype of MDD, characterised by strong FC between the insula and other regions of the brain, has been related to at least 25% improvement in depression symptoms in 82.5% of participants following rTMS delivered to the dorsomedial prefrontal cortex (DMPFC).41 However, these findings were not replicated in a more recent methodological extension of this study when utilising a more heterogeneous sample of individuals with depression and anxiety.42 In addition, in a small pilot study of 27 TRD patients, individualised connectivity-guided IDLPFC targets were determined using Granger causality analysis to provide a measure of eFC seeded from the right anterior insula (rAI).43 They found in the 18 participants who completed all follow-ups that there were a higher proportion of participants with at least 50% reduction in depression symptoms at the 3-month follow-up favouring connectivity-guided iTBS (cgiTBS; 89% of participants) over connectivity-guided rTMS (44% of participants). These findings did not reach statistical significance, but they suggest that iTBS delivered according to connectivity with the insula could lead to longer-lasting efficacy.

It should also be highlighted that alongside the right AI, there is also a significant amount of work to suggest that the subgenual anterior cingulate cortex (sgACC) might be a potential target for TMS treatment. A number of studies have shown that stronger baseline anti-correlations between DLPFC treatment sites and the sgACC are predictive of response to TMS.44–46 Additionally, clinical response to TMS was significantly greater for participants whose actual targets (beam F3) were serendipitously closer to personalised connectivity-guided targets (based on strongest anti-correlation between DLPFC and sgACC).47 It also needs to be acknowledged that since the conceptualisation of the BRIGhTMIND study, the Stanford neuromodulation therapy (SNT) protocol has been developed.48,49 The SNT protocol includes 10 sessions of iTBS per day over 5 consecutive days at an adjusted 90% resting motor threshold (rMT) (1800 pulses per session with 50-minute inter-session intervals) and a personalised individual IDLPFC treatment target based on the strongest FC anti-correlation between the IDLPFC and sgACC. Following the SNT protocol, an open-label study and an RCT with placebo control demonstrated 90.5% and 46.2% reached response and remission, respectively at least once in the 4 weeks after treatment.48,49 The remission rates identified in these studies are commendable; however, they are currently limited by small sample sizes, were not necessarily sustained even at the end of 4 weeks, and equally it is difficult to disentangle whether the efficacy of this protocol may be a consequence of a combination or singular components of its parameters (for example DLPFC targeting method, or greater dose of treatments). Nevertheless, they further emphasise the importance of the continued refinement of TMS protocols and parameters to improve the clinical efficacy of iTBS.

Overall, the research suggests that iTBS may induce widespread and longer-term network change, but that precise anatomical localisation of the target circuitry may be required for maximal efficacy of iTBS to normalise dysfunctional fronto-limbic circuitry. In our view, the clinical importance of cgiTBS is in its potential for a longer duration of response to 16 or even 26 weeks, permitting people with TRD to remain well with 1 or 2 courses of TMS per year. Thus, the study of choice in terms of maximising clinical effectiveness would be a comparison of cgiTBS versus neuronavigated rTMS. Such changes may increase the proportion of people with TRD who reduce their depression symptoms over 26 weeks or obtain a sustained response compared with neuronavigated rTMS.

Primary and secondary clinical efficacy objectives

Therefore, the primary aim of BRIGhTMIND was to examine the efficacy of cgiTBS versus neuronavigated standard rTMS, in treatment-resistant moderate to severe MDD (TRD), originally before the coronavirus disease discovered in 2019 (COVID-19) pandemic by response at 16 weeks, and then by their mean change in depression symptoms over 8, 16 and 26 weeks. We reported on a multicentre RCT in patients with TRD who had a Massachusetts General Hospital Staging Score (MGH-S) of 2 or more, who had not responded to two different antidepressant regimes, antidepressant augmentation strategies, high prolonged dosages of antidepressants, or ECT in their current episode. Study hypotheses are reported in Table 1.

We also reported on other secondary clinical outcomes of importance to patients and clinicians, namely cognition, anxiety symptoms, social function, quality of life and overall clinical improvement. Clinically important change would be supported by improvements across all these outcomes.

Safety, acceptability, facilitators and barriers of transcranial magnetic stimulation

Evidence suggests that TMS in depression is generally well tolerated, and a recent meta-analysis showed common side effects such as headaches, discomfort and pain at the stimulation site are mostly mild and transient after TMS treatment, with the risk of more serious adverse events (SAEs) such as seizure, syncope and mood switches considered rare.50 A further meta-analysis showed no significant difference in combined serious and non-SAEs between TBS and either rTMS or sham treatments.22 However, self-rated intensity of pain was significantly greater for TBS treatment than rTMS, and the comparison of adverse events between TBS and rTMS was limited to two RCTs and combined both SAEs and non-SAEs.22 Therefore, further work is required that provides greater descriptive details of the comparison of side effect profiles for both TBS and rTMS as well as the influence of connectivity-guided personalised targets.

Patient experience is also an important aspect of treatment, and this insight alongside evidence of side effects may help identify important topics for patients both willing and not willing to undergo TMS treatment, which could improve both future research and clinical service implementation.51 Acceptability of TMS for depression has been widely reported in relation to treatment adherence, with no differences in drop-out rates when comparing either rTMS or TBS protocols with sham protocols.20,52 A small number of qualitative and quantitative studies have investigated other facets of acceptability and experience of TMS treatments for depression. A telephone survey study reported that the vast majority of individuals undertaking TMS found it helpful and more acceptable than the prospect of having ECT, and would have TMS again, as well as recommending it to others.53 However, surveys alone provide a small amount of information which limits the exploration of the patients’ experience. A study using open-ended interviews has also explored the acceptability of rTMS for TRD, which highlighted the frustration and helplessness linked to pharmacological treatments, the experience of TMS (including physical response to treatments), mindfulness and awareness experienced during sessions, and the importance of the rapport with the clinician.54 Clinician rapport has further recently been established as a key non-clinical factor of TMS treatments suggested to influence participants response and experience. Notably, clinicians have an important role from delivering TMS treatment, to engaging in constructive therapeutic conversations, providing a relaxing and friendly environment, as well as supportive long-term management.55

This prior research provides significant implications for practice guidance. However, while it focuses predominantly on the patients’ experience of rTMS, patients’ experience of TBS treatment has not been explored, as well as factors impacting decisions to undergo TMS treatment or not, and any concerns individuals may have.

One recent study, which was related to the original pilot study, has examined emails using thematic analysis to explore the reasons why individuals with depression self-referred for TMS treatment. Six themes were identified, namely: treatment resistance; side effects of other treatments; desperation for relief; proactively seeking information; long-term illness; and illness getting worse.56 The authors of this study recommend that future research should include interviews with participants to further explore reasons for seeking TMS treatment, to see whether similar reasons are identified.56 In addition, this study did not identify barriers to participants unwilling to undergo TMS treatment and this too requires further exploration.

Safety, acceptability, facilitators and barriers of transcranial magnetic stimulaton objectives

Therefore, objectives of the BRIGhTMIND study were to: (1) compare AEs and side effect profiles of rTMS versus cgiTBS; (2) explore patients views on the acceptability and experience of rTMS and cgiTBS, as determined by adjustments made to TMS protocols for tolerability, qualitative interviews assessing patient experiences and quantitative measures of patient acceptability; and (3) understand the initial barriers and facilitators to recruitment of participants to the trial.

Economic evaluation objective

To examine whether cgiTBS represents a cost-effective use of resources compared to rTMS in treating moderate to severe TRD in the UK NHS setting.

Economic evaluation

In addition to examining the clinical efficacy of cgiTBS, the BRIGhTMIND study will also examine the cost-effectiveness of cgiTBS relative to rTMS.

Treat resistant depression was estimated to cost the UK economy £3.8M in 2018 with direct health and social costs of £4383 per patient and indirect costs of £22,124.57 High indirect costs were largely driven by absenteeism and costs to families. The direct costs are in line with previous research in specialist mental health services that we have conducted. In direct NHS and social care costs, TRD costs about £4–5000 per patient per year often for many years, while patients seen in a specialist depression service offering both NICE-recommended psychotherapy and pharmacotherapy, the costs are typically £7–8000.58

Treatment-resistant depression is a heterogeneous condition with many different patterns of progression and outcome. This complexity, combined with individual patient circumstances, has led to diverse range of treatment pathways for TRD. In addition to ECT, other invasive neuromodulation approaches such as deep brain stimulation (DBS) or vagus nerve stimulation (VNS) may be employed. These all carry high degrees of risk by their nvasive nature or through serious and sometimes permanent cognitive side effects. They require the expertise of other specialist services such as anaesthetists and neurosurgeons. A major problem is that most patients with TRD are managed within secondary care mental health services that do not have expertise in high-level psychotherapy or pharmacotherapy or around the use of DBS and VNS. An easy to deliver, effective, well tolerated and relatively cheap intervention for TRD, such as TMS, is therefore required. Improvements in therapeutic treatment options for TRD stands to address a variety of unmet needs, alleviate substantial decrements to health, and may achieve health service and societal savings.

Prior studies have shown rTMS to be a dominant/cost-effective alternative when compared with pharmacotherapy and sham treatments with higher quality-adjusted life-years gained (QALYs) for individuals with TRD.59–61 Cost savings from rTMS accrued via reductions in medication courses psychotherapy and ECT sessions compared with usual care. In addition, the shorter session durations and increased treatment capacity associated with iTBS led to significant cost savings per patient and per remission when compared to standard rTMS.62 However, it remains unknown about the cost-effectiveness of iTBS when utilising personalised connectivity-guided targets (known as connectivity-guided iTBS or cgiTBS).

While the current proposed cgiTBS requires structural and functional magnetic resonance imaging (fMRI) to maximise efficacy, such scans are readily available in current NHS facilities and have the additional potential of individual response prediction. Furthermore, given that personalised connectivity-guided targets are suggested to be reliable and stable over time,34 MRI scans may be required only once for a patient even if multiple courses of treatment are needed to maintain their health over the longer term, demonstrating the potential practical utility of the technique. It is likely that if cgiTBS had efficacy over 3–6 months with high patient acceptability and tolerability, there would be widespread benefits to health services and society. These arise not only from reduced use of other types of treatment for depression, reduced self-harm, suicide, and hospitalisation but also from return to work, improved physical health, and improved parental and other family care. Given how highly recurrent MDD can be, especially for patients with TRD, long-term maintenance of health is also critically important. Patients who remain well with cgiTBS over 6 months may only require two courses per year, again further decreasing costs of repeated treatment that is often necessary in practice with rTMS, hence potential long-term saving with cgiTBS.

Mechanism of action

A further objective of the BRIGhTMIND RCT was to analyse the mechanism of action of TMS by studying underlying neurochemical changes using magnetic resonance spectroscopy (MRS) and brain connectivity using rsfMRI.

As previously mentioned, stimulation of the CEN may directly modulate key nodes within the SN and DMN.39 TMS studies in depression have shown baseline FC strength between the lDLPFC and bilateral insula,63 and between the PCC and right AI,64 are positively correlated with treatment response. Importantly the former finding only demonstrated predictive effect when the seed of the lDLPFC was selected as a node in the CEN rather than the traditional BA9 or BA46.63 Following connectivity-guided rTMS or iTBS, baseline eFC of net rAI outflow to lDLPFC was associated with treatment response at participants’ 1 month follow-ups, but not 3-month follow-ups.43 More specifically early response to treatment was superior in those that had greater positive rAI to lDLPFC influence (outflow) than lDLPFC to rAI influence (inflow) at baseline, suggesting more normal inflow/outflow balance between these brain regions could better facilitate fronto-insular modulation, in turn alleviating depressive symptoms.43 Further modulatory evidence of fronto-insular connectivity comes from studies comparing FC before and after TMS treatments. Following iTBS treatments, reduced FC from lDLPFC to the rAI has been found in depressed individuals65 and healthy controls,40 with dampening of DMPFC-bilateral insula connectivity also associated with better treatment response.66 Overall, the findings suggest an important role of the SN CEN/DMN interaction, with stronger baseline connectivity of the lDLPFC-insula and dampening of this connectivity following TMS treatments to be particularly predictive of clinical efficacy.

Preliminary mechanistic evidence further suggests that lDLPFC-targeted TMS may modulate connectivity between the CEN and DMN in depression. While baseline connectivity between the lDLPFC and nodes of the CEN or DMN were not associated with treatment response, there were TMS induced anti-correlated connectivity between the lDLPFC and left medial prefrontal DMN nodes.67 This is further supported by the pilot work, which showed a reduction in FC between the DLPFC and lDMPFC following TMS and change in lDLPFC-lDMPFC FC significantly associated with change in depression symptoms.68 A more recent study also reported a significant relationship between symptom changes and altered bilateral DMPFC-right DLPFC FC following ECT.69

Alongside the rAI, there is also a significant amount of work to suggest that the sgACC should be a potential target for TMS treatment. Several studies have shown that stronger baseline anti-correlations between lDLPFC treatment sites and the sgACC are predictive of response to TMS.44–47 Additionally, reduction in connectivity between the sgACC and nodes in the DMN,64,70 ECN64 and SN70 have been associated with treatment response following TMS. A more recent study also demonstrated a decrease in FC between sgACC and the right DLPFC, fusiform gyrus and middle occipital cortex, both in responders and in non-responders.71 The results overall suggesting that TMS may result in a reduction in connectivity (reduced anti-correlations) between the sgACC and the CEN, which may correlate with treatment response.

In regard to neurochemical changes, brain gamma-aminobutyric acid (GABA) and/or glutamate systems play a key role in inhibitory and excitatory neural processes associated with both changes in long-term potentiation and depression of synaptic transmission.72 It is proposed that the mechanism of action of TMS and other antidepressant treatment modalities involve GABA and or/glutamate systems.73,74

A recent systematic review demonstrated that following lDLPFC rTMS, frontal-lobe increases of GABA, glutamatergic compounds and N-acetylated compounds were commonly associated with clinical improvement in MDD.75 For example, following rTMS an increase in GABA in the MPFC76 and lDLPFC77 has been observed, with changes in lDLPFC GABA found in responders74 and correlating with symptom change.77 A more recent study found no changes in lDLPFC GABA following rTMS, however there was an increase in lDLPFC Glx (glutamate + glutamine) post rTMS, with baseline Glx levels correlating with symptom change.78 Furthermore, Dubin et al.76 found GABA/W and Glx/W were highly correlated in severely depressed patients at baseline but less so after TMS.

In comparison to rTMS, the exploration of GABA and glutamate systems in response to iTBS in MDD is currently sparse. However, it is suggested that iTBS may also affect brain cortical systems through altering inhibitory GABA-related and excitatory glutamate-mediated activity both at the site of stimulation and more distally.79–82 In bipolar depression, MPFC GABA levels, but not Glx levels, have been found to increase significantly following IDLPFC iTBS,82 with a reduction in the lDLPFC and ACC GABA/Glx ratios found following connectivity-guided iTBS in a non-clinical sample.40 Additionally, the pilot work showed a strong significant correlation between baseline prefrontal GABA levels and depression symptoms at 3 months post connectivity-guided iTBS.68 Based on the prior literature, the exact underpinnings of intermittent TBS-induced neurochemical changes and the physiological differences between rTMS and cgiTBS is unclear and requires further exploration.

Mechanism-of-action objectives

Therefore, the overarching objectives of the mechanism-of-action analysis were to explore: (1) baseline EC from rAI to lDLPFC and changes in EC from rAI to lDLPFC with clinical improvement; (2) change in FC between the DLPFC-DMPFC with clinical improvement; (3) baseline FC between lDLPFC and sgACC and changes in FC between the IDLPFC and sgACC with clinical improvement; (4) baseline GABA, change in GABA with clinical improvement; and (5) change in Glx and change in GABA/Glx ratio with clinical improvement.