This proposal seeks to conduct a pragmatic single arm, open label pilot implementation to validate our individualized functional Magnetic Resonance Imaging (fMRI) connectome-guided localization approach for accelerated TMS among Asian patients with depression.

Participants will be patients with Major Depressive Disorder not responding to standard treatment, with no exclusions to fMRI or transcranial magnetic stimulation (TMS) (essentially metal implants in the head) and willing to participate in the pilot.

All participants will undergo MRI scans before and after the accelerated TMS treatment. The multi-session hierarchical Bayesian model (MS-HBM) approach will be used to estimate individualized connectome-guided target locations.

Patients will undergo accelerated TMS applied to individualized connectome-guided target locations (based on the MS-HBM approach).

Patients will undergo 10 sessions (each session lasting 10 min) spread out over 10 hours each day for 5 consecutive working days.

All clinical outcome data will be collected for each patient by a pre-defined questionnaire at four time points: at baseline, post-treatment, 1 month and 3 months during follow-up.

The clinical outcome data will be analyzed using linear regression or repeated analysis of variance (ANOVA) after adjusting for baseline clinical characteristics and socio-demographics. Trajectories of the clinical outcome data at baseline, post-treatment and all follow-up time points will be plotted and compared with time series statistical analysis models with the other clinical and socio-demographic characteristics included as confounders.

Inclusion Criteria:

1. Age ≥ 21 years.
2. DSM-5 diagnosis of current Major Depressive Episode.
3. Montgomery-Asberg Depression Rating Scale score of 20 or more.
4. Inadequate response to an adequate trial (4 weeks) of at least one antidepressant medication.
5. Able to give informed consent.

Exclusion Criteria:

1. DSM-5 psychotic disorder
2. Drug or alcohol abuse or dependence (preceding 3 months).
3. Rapid clinical response required, e.g., high suicide risk.
4. Significant neurological disorder, which may pose increased risks with TMS, e.g., epilepsy.
5. Metal in the cranium, skull defects, pacemaker, cochlear implant, medication pump or other electronic device.
6. Pregnancy.
7. Unsuitable for MRI.