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Abstract
Introduction Major depressive disorder (MDD) is a common mental disorder that is characterised by high morbidity, high rates of relapse, high rates of disability and, in severe cases, suicide ideas or even behaviour causing significant distress and burden. Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation technique widely used in the clinical treatment of MDD. Nevertheless, due to the imprecise selection and positioning of stimulation targets, their response rate is not as satisfactory. This trial was designed to treat MDD based on functional connectivity with individual target-TMS (IT-TMS) to stimulate the dorsolateral prefrontal cortex (DLPFC) where it correlates most negatively with the pregenual anterior cingulate cortex (pgACC). We will validate the safety and efficacy of IT-TMS for MDD using pgACC as an effector target, analyse the underlying antidepressant mechanism of the DLPFC-ACC brain network and search for neuroimaging markers that predict the efficacy of TMS.
Methods and analysis This is a single-centre, randomised, double-blind and sham-stimulation-controlled clinical trial. We aim to recruit approximately 68 depressed patients with MDD aged 18–60 years. Eligible participants will be randomised into the DLPFC-pgACC localisation and sham stimulation groups. The IT-TMS treatment will last 10 days and will be combined with antidepressant medication. Assessments will be confirmed at baseline, on day 5 of treatment and at the end of treatment with follow-up at weeks 2, 4 and 8 after the end of treatment. The primary outcome measure is the difference in the Hamilton Depression Scale score between baseline and end of treatment.
Ethics and dissemination The Ethics Committee of the First Affiliated Hospital of the Air Force Medical University has approved this clinical trial (project code: XJLL-KY20222111). The trial’s results will be published in international peer-reviewed journals and presented at academic conferences.
Trial registration number ClinicalTrials.gov PRS (ID: NCT05577481).
- Depression & mood disorders
- Transcranial magnetic stimulation
- Clinical trials
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STRENGTHS AND LIMITATIONS OF THIS STUDY
This is the randomised controlled trial of individual target-transcranial magnetic stimulation (IT-TMS) for major depressive disorder (MDD), first using pregenual anterior cingulate cortex (pgACC) as an effect target.
We will use the internationally recognised sham stimulation control to verify the safety and efficacy of the new TMS protocol.
This clinical trial is conducted at a single centre and has a limited sample size.
The dorsolateral prefrontal cortex-subgenual ACC (sgACC) functional connectivity localisation group was not constructed in this study and the efficacy of IT-TMS for MDD with pgACC and sgACC as effector targets will be compared at a later stage.
Introduction
Major depressive disorder (MDD) is a chronic and recurring mental disorder that is characterised by prolonged periods of low mood. In severe cases, MDD may cause hallucinations, delusions and other psychiatric symptoms and may even lead to suicide. It is estimated that about 350 million people in the world suffer from depression1 and there are about 50 million patients with depressive disorder in China.2 According to the WHO, it is predicted that depression will become the leading cause of disability worldwide by 2030.3
The antidepressants based on monoamine theory are still currently the primary approach in traditional treatment treatments for MDD. However, with limitations including delayed onset to 2–4 weeks, high risk of side effects and approximately 30% of patients may not respond to these medications.4 Additionally, around 60% of patients may relapse even on medication.5 In reducing the symptoms despite the effectiveness of psychotherapy, its application is limited due to higher costs and a longer duration of treatment. Other treatment manoeuvres such as electroconvulsive therapy are widely considered to be the most effective method for treating treatment-resistant depressive disorders.6 However, its implementation requires high physical conditions and affects many adverse reactions affecting its broad clinical usage.7 It is crucial to find and explore a safe, effective and non-invasive treatment method for patients suffering from MDD.
Transcranial magnetic stimulation (TMS) is a safe and non-invasive physiotherapy technique based on Faraday’s law of electromagnetic induction. The brief high-intensity magnetic field generates induced currents that depolarise neurons in the relevant region which alters neuronal excitability, thereby modulating neurophysiological activity in cortically stimulated areas and regions connecting relevant brain regions with functional/structural connections with the cerebral cortex. Neuronal excitability can be modulated by adjusting the stimulating frequency with low-frequency stimulation (≤1 Hz) reducing the cortical activity while high-frequency stimulation (5–20 Hz) increases the cortical activity. TMS can be delivered in an outpatient setting without anaesthesia8 and has been approved by the Food and Drug Administration (FDA) for treating treatment-resistant depression due to its potential efficacy and fewer side effects. Nevertheless, the average response rate of TMS in the treatment of MDD is only about 29%,9 is a reason for the inaccurate selection and localisation of TMS stimulation targets.10 Hence, enhancing the precision of target localisation and identifying the most pertinent stimulation target can potentially increase the efficacy of MDD treatment.
The dorsolateral prefrontal cortex (DLPFC) is the stimulation target for TMS treatment of MDD as approved by the FDA. It comprises various subregions and is an essential brain area impaired in patients with MDD. It plays a role in the processing and regulation of emotions. Previously, the most relevant subregions for MDD may not have been identified causing antidepressant effects to be less than ideal. According to a significant body of literature, MDD is a disorder of neural networks instead of isolated brain regions’ abnormalities. There is evidence that TMS stimulation of the left DLPFC can induce changes in other regions such as the anterior cingulate cortex (ACC), basal ganglia, thalamus and limbic system which have been implicated in the pathophysiology of MDD.11 Past research has demonstrated that the ACC in individuals with MDD presents notable distinctions in functional and structural aspects compared with healthy control subjects.12 The ACC, part of the limbic system, acts as a mediator between attentional and emotional processing and is accountable for consolidating sensory, attentional and affective information from the body. The ACC is functionally divisible into the pregenual ACC (pgACC), subgenual ACC (sgACC) and dorsal ACC (dACC). Fox et al 13 found through a retrospective study that the effect of TMS on MDD was related to the negative functional connectivity strength between the DLPFC and sgACC and creatively proposed that sgACC may be the strong effect target of TMS on MDD. Following this theory, Cole et al from Stanford University used accelerated, high-frequency and high-dose TMS, guided by neuronavigation, to stimulate the most negative correlation in the left DLPFC with the sgACC. This resulted in an 85.7% response rate in treating MDD.14 Simultaneously, it has been demonstrated that there is a functional connectivity between the DLPFC and sgACC allowing for the regulation of deep-related nuclei by activating targets associated with DLPFC.
A meta-analysis conducted in 2017 found that patients suffering from MDD showed a significantly higher amplitude of low-frequency fluctuation (ALFF) in the pgACC region compared with healthy individuals. ALFF is an indicator of the strength of local spontaneous neural activity. This suggests that there is hyperactive spontaneous neural activity in the pgACC of patients with MDD. Furthermore, the difference is primarily concentrated in the pgACC region.15 In 2018, Boes et al 16 conducted a study on the brain structure of MDD and found a correlation between the change in cortical thickness of the left pgACC and the therapeutic effect of TMS in treating MDD. Patients with thicker pgACC cortex were more likely to respond to TMS treatment while those with thinner cortex exhibited weaker efficacy of TMS. Ge et al 17 also demonstrated that the functional connectivity of the pretreatment pgACC can predict the response to TMS for MDD. Additionally, some studies have found that negative functional connectivity between clinically effective DLPFC targets and the pgACC is significantly more potent than that between ineffective DLPFC targets during TMS treatment in patients with MDD suggesting that it may be an effective deep brain target for TMS treatment of MDD.13 18
For safety and ethical considerations, we will combine antidepressant medication from the first day of individual target-TMS (IT-TMS) treatment. The objectives of this randomised, double-blind and sham-stimulation-controlled clinical trial are to validate the efficacy and safety of individualised TMS targeting pgACC in the treatment of MDD to analyse the underlying antidepressant mechanism of the DLPFC-ACC brain network and to find the neuroimaging markers for predicting of TMS efficacy.
Methods and analysis
Study design
In this study, 68 patients with MDD will be recruited from the outpatient department of the psychiatric clinic of Xijing Hospital. Eligible patients will then be randomised into the DLPFC-pgACC localisation group and the sham stimulation group. The duration of IT-TMS treatment is 10 days and the follow-up period is 8 weeks. The primary outcome is the reduction in the 17-item version of Hamilton Depression Scale (HAMD-17) scores before and after treatment (figure 1).
Flow chart. BSI-CV, Beck Scale for Suicide Ideation-Chinese Version; CGI, Clinical Global Impression; DLPFC-pgACC, dorsolateral prefrontal cortex-pregenual anterior cingulate cortex; fMRI, functional MRI; HAMA, Hamilton Anxiety Scale; HAMD-17, the 17-item version of Hamilton Depression Scale; ISI, Insomnia Severity Index; MADRS, Montgomery-Åsberg Depression Rating Scale; MDD, major depressive disorder; PDQ-D, Perceived Deficits Questionnaire-Depression; SAS, Self-Rating Anxiety Scale; SDS, Self-Rating Depression Scale; TESS, Treatment Emergent Symptom Scale; THINC-it, THINC-integrated tool.
Study participants
Inclusion criteria: (1) aged≥18 years, ≤60 years, either sex; (2) According to the Diagnostic and Statistical Manual of Mental Disorders-5th Edition (DSM-5) criteria for MDD, the Mini-International Neuropsychiatric Interview Chinese V.7.0.0 (M.I.N.I.7.0.0) is used to confirm current MDD; (3) HAMD-17 score≥18; (4) subjects who are able and willing to understand and comply strictly with the clinical trial protocol and to sign the informed consent form.
Exclusion Criteria: (1) History of disease or serious physical illness that may affect the central nervous system; (2) Risk of seizures or family history of epilepsy such as abnormal electroencephalogram (EEG), abnormal brain MRI, etc. (3) Bipolar disorder and depression caused by other mental disorders (eg, use of psychoactive substances); (4) Patients with contraindications to MRI scanning or TMS therapy such as metal or electronic instruments in the body, space phobia, etc. (5) Patients with psychotic symptoms requiring combined use of antipsychotic drugs; (6) Patients at high risk of suicide or who have attempted suicide or severe self-harm and require urgent intervention; (7) Any form of antidepressant treatment within 1 month before enrolment; (8) Pregnant, breastfeeding or planning to become pregnant during the study; (9) Other conditions deemed by the investigator to be unsuitable for the study.
Study termination criteria: (1) The subject withdraws informed consent; (2) While the subject is receiving treatment, the investigator believes that the subject should be withdrawn from the study for safety reasons and in the interest of the patient; (3) The subject voluntarily discontinued treatment as prescribed; (4) Female subjects are pregnant; (5) Subjects could not be treated with the investigational device; (6) Subjects with serious protocol violations; (7) In addition to withdrawal of informed consent, participants who completed baseline measurements were included in the final analysis.
Sample size
According to previous studies by our group and previous literature, the efficacy of the functional connectivity localisation group was about 55%19 20 while the efficacy of the sham stimulation group was about 20%.21 The test level was set at α=0.05, β=0.2 and the power was 0.8. The sample size was calculated using the PASS software (V.15) which required a total of 54 people to be included and 68 people were finally included, taking into account the drop-out of subjects (20%).
Recruitment
Recruitment is expected to begin in April 2023 and end in July 2024. Two experienced psychiatrists will diagnose patients with MDD according to DSM-5. The recruitment process will take place in the following stages:
Patients with MDD will be recruited from outpatient clinics using recruitment advertisements and diagnosed according to DSM-5;
Eligible participants will be screened according to the inclusion and exclusion criteria;
The purpose, protocol and content of the study and the possible risks or side effects will be explained in detail to the participants who are informed of their right to withdraw from the study at any time. Subjects will provide written informed consent (see the online supplemental material);
Randomisation.
Supplemental material
Randomisation
Block randomisation with a block size of 4 will be used to ensure a balanced allocation of participants throughout the trial. Randomly generated codes will be sealed in opaque sealed envelopes and stored at the neuromodulation centre. Dedicated research nurses will extract codes. Eligible participants will be selected and assigned 1:1 to the DLPFC-pgACC localisation group and the sham stimulation group.
Blinding
This study will be a double-blind, sham-stimulation control. The operators and research nurses will be aware of the grouping and the patients, clinicians and evaluators will be unaware of the grouping of the patients. Emergency unblinding envelopes are provided in the trial. The principal investigator will be consulted in an emergency and a signed emergency envelope will be opened.
Intervention
TMS treatment parameters: The black dolphin TMS robot (lingtun, SLD-YXRJ-V1.0) from Xi’an Suolide Brain Control Medical Technology is used. Patients’ MRI data are collected before treatment and the individualised three-dimensional facial tracer is created to calibrate the treatment target. The robotic arm can control the TMS probe to move precisely to the stimulation target during treatment. The DLPFC-pgACC localisation group: Patients will be treated with intermittent theta burst stimulation mode, 90% resting motor threshold, 3 pulses per cluster, each pulse interval is 0.2 s, a total of 10 clusters, cluster interval is 8 s, 60 cycles as one treatment, treatment two times a day, each treatment interval is 50 min, 3600 pulses per day and treatment will be continuous for 10 days, 36 000 pulses in total. Sham stimulation group: Using the internationally recognised pseudo-stimulation method, the coil is flipped and placed at 90° to the scalp. The appearance, stimulation frequency, stimulation time and duration of the coil are identical to those of the actual stimulation coil. The magnetic field generated by the coil angle does not pass through the skull to create current resulting in ineffective stimulation.
Combined medicines: Serotonin and norepinephrine reuptake inhibitor (venlafaxine hydrochloride sustained release capsule, Pfizer), 75–225 mg/day, drug specification 75 mg×14 pills, oral, the initial dose of 75 mg/day, after taking 1 week, increase the dose to 150 mg/day, once a day, take in the morning after a meal at a relatively fixed time and then try to keep the drug dose unchanged. During treatment, for patients with more severe insomnia, zolpidem tartrate tablets or dexzopiclone tablets up to the upper limit of the label (maximum recommended dose) may be used at bedtime. Concomitant medication for physical conditions is allowed during the trial and the type and dose of medication will be maintained throughout the trial.
fMRI acquisition and data processing
MRI scans will be performed on a 3.0T uMR780 scanner (Shanghai United Imaging Medical Technology) at the Xi’an Yunying Medical Imaging Diagnostic Centre and the scan sequence has been shared with the China Brain Imaging Alliance. T1-weighted sagittal anatomical images are obtained. The parameters are: Sagittal slices=192, repetition time=7.24 ms, echo time=3.10 ms, slice thickness/gap=0.5/0 mm, in-plane resolution=512 × 512, inversion time=750 ms, field of view=256 × 256 mm, flip angle=10°, voxel size=0.5×0.5×1 mm, average=1. Resting-state functional MRI (fMRI) data are as follows: Sagittal slices=8400, repetition time=2000 ms, echo time=30 ms, slice thickness/gap=4/0 mm, in-plane resolution=64 × 64, inversion time=1100 ms, field of view=224× 224 mm, flip angle=90°, iPAD=2, voxel size=3.5×3.5×4.0 mm3, average=1. All patients are instructed to keep their eyes closed, relax, think of nothing in particular and try not to fall asleep while scanning.
We will conduct data preprocessing as follows: (1) converting of Digital Imaging and Communications in Medicine (DICOM) data into the universal image processing format Neuroimaging Informatics Technology Initiative (NIfTI); (2) discarding the initial 10-time points of data; (3) slice timing correction; (4) correcting head motion; (5) all functional images are co-registered to structural image; (6) normalising functional images to Montreal Neurological Institute space; (7) regressing head motion, white matter, cerebral spinal fluid. Mean global signal was also regressed to remove the spatially coherent confounds and stand out following negative functional connectivity;22 (8) spatial smoothing with a Gaussian kernel with 6 mm full width at half maximum; (9) processing of the delinearisation; (10) filtering with 0.01–0.08 Hz.
TMS individual target generation
After data preprocessing, the pgACC functional connectivity-guided stimulation targets are individually calculated from the imaging data for each subject. Here, the pgACC is defined as a spherical region of interest with a radius of 6 mm centred at (−10, 42, 6).23 First, we calculate the average time series of pgACC and then the functional connectivity between pgACC and each voxel of DLPFC is calculated. Subsequently, the clustering method is used to divide all voxels in the DLPFC into several continuous clusters. We quantify the negative correlation values and the voxel counts for each cluster, ultimately selecting the cluster with the most anticorrelation and the largest voxel count as the stimulation target cluster. Next, the most negatively correlated voxel from this cluster is selected as the target for cerebral cortex stimulation. Finally, a three-dimensional scalp model is reconstructed based on T1 images. The stimulation target corresponding to the scalp will be calculated by combining the scalp normal with the minimum distance.
Positioning of TMS robot
The direction of TMS coil placement is determined by calculating the normal vector based on the stimulation targets on the scalp and the cortical surface of the brain. Subsequently, an individualised and precise treatment will be delivered using the TMS robot. This robotic technology can automatically locate the target area and continuously perform precise positioning during treatment to ensure that the same target area is constantly stimulated which achieves stable and accurate stimulation of the target.
Outcome measures
General clinical data will be documented during the screening visit. Clinical scale outcomes will be assessed at baseline, on day 5 of treatment, at the end of treatment and in weeks 2, 4 and 8 post-treatment. fMRI will be conducted at baseline, end of treatment and 4 weeks after treatment to compare changes in brain function before and after treatment. (table 1)
Study schedule of assessments
General clinical data: A self-reported questionnaire will be used to collect subjects’ gender, age, marital status, education level, height, weight, home address, contact information, childhood experiences, predisposing factors, disease course, use of treatment drugs and other information.
Primary outcome: HAMD-17 scores are reduced before and after treatment (baseline and after 10 days of treatment). The rating scale was developed by Hamilton in 1960 and is commonly used in clinical practice to assess the severity of depressive symptoms. The HAMD-17 will be used in this trial. The higher the total score, the more severe the MDD and≤7 was defined as no depression; scores>7 and ≤17 were classified as mild depression; scores>17 and ≤24 were classified as moderate depression; a score>24 was defined as severe depression.
Secondary Outcomes included changes in HAMD-17, Montgomery-Åsberg Depression Rating Scale (MADRS), Self-Rating Depression Scale (SDS), Beck Scale for Suicide Ideation-Chinese Version (BSI-CV), Hamilton Anxiety Scale (HAMA), Self-Rating Anxiety Scale (SAS), Insomnia Severity Index (ISI), Clinical Global Impression (CGI), Perceived Deficits Questionnaire-Depression (PDQ-D) and THINC-integrated tool (THINC-it) at each follow-up time points. The HAMD-17, MADRS and SDS will be used to assess changes in depressive symptoms; the intensity of suicidal ideation and level of suicide risk will be evaluated using the BSI-CV; the HAMA and SAS will be used to determine subjects’ anxiety symptoms; the ISI will be used to determine the severity of insomnia; the CGI will be used to determine the clinical efficacy of treatment; and subjects’ cognitive function will be evaluated using the PDQ-D and THINC-it software. Their reliability and validity have been validated.24–32
Safety assessments
Potential adverse effects of TMS treatment: The most common adverse effect is transient head or scalp discomfort in and around the treatment site which may affect adjacent areas of the face including the area around the ipsilateral eyes, ears, nose and chin; muscle twitching in these areas may occur during stimulation; headache is also a common adverse effect but it is usually mild and resolved with an increasing number of treatments. A rare adverse effect is the risk of inducing mania or hypomania; the most severe adverse effect is the induction of seizures which occurred in less than 0.1% of patients. Subjects with a history of epilepsy, abnormal head MRI and EEG will be excluded from this study and subjects still have a meagre chance of having a seizure during the study. Before the subjects are formally enrolled in the project, all medical staff will be informed about the clinical manifestations of seizures and related treatment procedures. An emergency seizure rescue team will be established in advance.
Potential adverse effects of antidepressants: The most common adverse reactions are nausea, dry mouth, dizziness, headache, drowsiness, fatigue, constipation, sweating, nervousness and sexual dysfunction; higher doses of venlafaxine are associated with a risk of sustained increase in blood pressure; risk of inducing mania/hypomania.
To monitor and document any adverse events, vital signs (ie, temperature, heart rate, respiration and blood pressure) will be measured at each visit and safety will be assessed for: (1) the overall incidence of adverse events; (2) the incidence of drug-related adverse events; and (3) the dropout rate due to adverse events; (4) general vital signs, EEG and the Treatment Emergent Symptom Scale will be used to assess the side effects of the TMS intervention such as headache, fatigue and tingling.
Data analysis
All data will be analysed using the intention-to-treat principle to preserve the intervention’s actual status as much as possible.
Each group’s baseline data (demographic information and baseline scale scores) will be tabulated. The student’s t-test and analysis of variance will be used to analyse quantitative data. The χ² and Fisher’s exact tests will be used to analyse qualitative data and ordinal categorical variables.
At the end of the study, the scores on each clinical scale and behavioural data will be analysed by repeated-measures analysis of covariance to explore the interaction between pretreatment and post-treatment and between treatment regimens with multiple measurements as the within-group factor, true and false stimulation as the between-group factor and pretreatment scale scores and refractory level as covariates. The paired sample t-test will be used for post hoc analysis. The differences in the scores of each scale and the pretreatment and post-treatment behavioural data of the two treatment regimens will be analysed by a two-sample t-test and χ² test, respectively. The response rate and remission rate of the two treatment regimens will be calculated using a χ² test. All tests are two-tailed with a significance level of p≤0.05.
Survival analysis: The product-limit method will be used to assess the response and remission rates and differences between treatment regimens will be compared. The significance of differences between treatment regimens will be tested using the log-rank test. A two-sided test with a significance level of p≤0.05. The Cox proportional hazards model will be used to analyse the possible factors associated with the clinically effective and ineffective groups.
Statistical analysis of MRI data: The matched samples t-test will be used to investigate changes in MRI parameters (eg, functional connectivity, ALFF, regional homogeneity) before and after treatment with different regimens. The correlation between changes in MRI parameters and clinical scales before and after treatment will also be analysed.
Data monitoring
To ensure the authenticity and scientific rigour of the study, the hospital established the Data Monitoring Committee comprising independent members including ethics experts, statisticians and clinical physicians. Moreover, the Ethics Committee will review the study data regularly.
Patient and public involvement
Patients and/or the public were not involved in this research’s design, conduct, reporting, or dissemination plans.
Ethics and dissemination
The study will be conducted according to the Declaration of Helsinki. The trial has been approved by the Ethics Committee of the First Affiliated Hospital of the Air Force Medical University (project code: XJLL-KY20222111). Ultimately, the results will be published in international peer-reviewed journals and shared at academic conferences.
Discussion
MDD is a disease of neural networks, particularly the reward network, the resting-state networks and the central executive network.33 Reward network dysfunction is the basis of the pathogenesis of MDD involving the prefrontal cortex, nucleus accumbens, amygdala, striatum and cingulate cortex.33 The pgACC is a crucial region within the neural circuitry linked to MDD as demonstrated by its involvement in regulating emotional responses and reward processing.34 35 Studies have found that regional cerebral blood flow increased in the pgACC brain region of patients with MDD and that glucose and lactate levels which are related to the severity of MDD, increased. In contrast, the corresponding levels decreased after antidepressant treatment.35 36 Numerous studies have shown that enhanced pgACC activity (including glucose metabolism, cerebral blood flow and task activation) has been shown to predict the response to antidepressants, sleep deprivation, cognitive behavioural therapy, TMS and ketamine for MDD.37–43 This indicates that the pgACC may play an essential role in MDD.
Fox and colleagues found that the antidepressant efficacy of TMS was related to the strength of the resting state functional connectivity and creatively suggested that the subregions of the DLPFC most negatively correlated with the sgACC might be the best target for individualised stimulation.22 Good remission rates for MDD have been achieved in several clinical trials based on this theory.14 44–46 Our previous study also found a negative correlation between spontaneous blood oxygen level-dependent signals in the ACC and DLPFC at rest. In addition, both sgACC and pgACC showed significant negative functional connectivity with superficial DLPFC. Still, pgACC showed more robust negative functional connectivity with DLPFC than sgACC and the area of negative functional connectivity with pgACC was larger than that of sgACC.18 For this reason, the pgACC is selected as a potential effector target as it could generate a more robust negative connection with the DLPFC than the sgACC.
Consequently, we hypothesised that the pgACC may be an effective deep brain target for TMS in the treatment of MDD and that TMS can be used to stimulate the region of DLPFC most negatively correlated with the pgACC, thereby regulating pgACC function and affecting the DLPFC-ACC network to alleviate depressive symptoms in patients with MDD. The DLPFC-ACC network may be a vital brain network for MDD and may reveal the antidepressant mechanism of TMS.
Strengths and limitations
To the best of our knowledge, this is the first randomised controlled trial of individualised TMS for MDD using pgACC as an effect target which may enrich the selection of TMS therapeutic targets and improve its efficacy in future MDD treatment. In this trial, we will use the internationally recognised sham stimulation control to verify the safety and effectiveness of the new TMS protocol, explore the role of the DLPFC-ACC network in MDD and find the neuroimaging markers for predicting the efficacy of TMS. Nevertheless, this study is a single-centre clinical study and future multicentre and large-sample clinical trials may be needed to verify our results. In addition, the DLPFC-sgACC functional connectivity localisation group is not set up in this study and related studies will be conducted to compare the efficacy of TMS in the treatment of MDD with pgACC and sgACC as the effect targets, respectively. Furthermore, most of our subjects are from central and western China which may affect the applicability of our trial results.
Ethics statements
Patient consent for publication
References
Supplementary materials
Supplementary Data
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Footnotes
NL, NZ and NT are joint first authors.
Contributors NL, NZ and NT contributed equally to the work. NL has written the study protocol. H-NW, YZ and MC have developed the original study design. NL, NT, NZ, TH, YM, RL, Yuyu Zhang, Yaochi Zhang, MC and H-NW have been involved in the revision of the study design and contributed in the review process of the protocol manuscript. TH, RL, Yuyu Zhang and Yaochi Zhang were jointly responsible for data collection and management of study participants. All authors reviewed and approved the final version and agreed to be accountable for all aspects of the work. H-NW is responsible for the overall content (as guarantor).
Funding This study was supported by grants from the National Natural Science Foundation of China (82330043, 81974215).
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.