Multimodal Biomarkers and Precision TMS for Postpartum Depression

NCT07757815 | Not Yet Recruiting

• 1 other identifier: BSE-1885-2026
• Study Type: interventional
• Target: 290
• Locations: 1 country
• Sites: 2

Brief Summary

The purpose of this study is to identify multimodal biological markers associated with postpartum depression (PPD) and to evaluate the effectiveness of precision brain stimulation treatment. PPD is a common mental health condition after childbirth that can affect maternal well-being and early child development. Current identification of PPD relies largely on clinical assessments and screening questionnaires, which may not fully capture underlying biological changes. This study uses brain activity, cardiac signals, blood-based biomarkers, interoceptive assessments, and clinical measures to characterize multimodal biological profiles associated with PPD and treatment response. The main questions it aims to answer are:

• What multimodal biological differences exist between women with diagnosed PPD and healthy comparison groups, including postpartum and non-postpartum controls?
• Which biological or psychological markers can predict whether a patient will respond well to repetitive transcranial magnetic stimulation (rTMS) treatment?
• Can a clinical model be created to help doctors choose the best treatment based on these markers? The study focuses on characterizing multimodal biological differences in women with diagnosed PPD and examining clinical response profiles following rTMS treatment, rather than predicting the onset of PPD in the general population. Participants will:
• Undergo electroencephalography (EEG) using a 128-channel cap to measure neural activity.
• Have electrocardiography (ECG) recorded to analyze heart rate variability and autonomic function.
• Provide blood samples to measure inflammatory cytokines, endocrine levels, and metabolic markers.
• Complete Interoceptive Assessments (tasks to measure awareness of internal body signals) and clinical psychological surveys.
• Complete follow-up assessments via online surveys and scheduled visits at 2 weeks, 1 month, and 3 months postpartum. Participants in the PPD group will:
• Receive 4 weeks of high-precision, robot-guided rTMS treatment (20 sessions total).
• Undergo pre-intervention multimodal assessments, including EEG, ECG, blood biomarkers, and interoceptive tasks, to identify potential predictors of clinical response to rTMS treatment.

Conditions

Depression, Postpartum

Keywords

Repetitive Transcranial Magnetic Stimulation; Electroencephalography; Postpartum Depression; Biomarkers; Electrocardiography; Interoception; Machine Learning; Blood biomarkers; Hormonal Measures; Interleukin-6 (IL-6); Multidimensional Assessment of Interoceptive Awareness-2 (MAIA-2); Body Perception Questionnaire-Short Form (BPQ-SF); WHO Quality of Life Instrument-Short Form (WHOQOL-BREF); Hamilton Depression Rating Scale (HAMD-17); Beck Depression Inventory-II (BDI-II)

Outcome Measures

Primary Outcomes (14)

• Postpartum depressive symptom severity measured by the Edinburgh Postnatal Depression Scale (EPDS)

  The EPDS total score ranges from 0 to 30, with higher scores indicating greater postpartum depressive symptom severity. Scores of 10 or above indicate elevated depressive symptoms, while scores of 13 or above are commonly used as a threshold for probable postpartum depression. The EPDS will serve as the primary measure of postpartum depressive symptom severity and risk identification. EPDS scores will be tracked longitudinally from late pregnancy through 3 months postpartum to characterize symptom development and identify high-risk individuals.

  T0 (Baseline, third trimester of pregnancy); T1 (2 weeks postpartum remote follow-up); T2 (1 month postpartum remote follow-up); T3 (3 months postpartum remote follow-up); Pre-rTMS treatment

• Self-reported depressive symptom severity measured by the Beck Depression Inventory-II (BDI-II)

  The BDI-II will be used to assess self-reported depressive symptom severity. The BDI-II total score ranges from 0 to 63, with higher scores indicating more severe depressive symptoms. Scores of 0-13 indicate minimal depression, 14-19 mild depression, 20-28 moderate depression, and 29-63 severe depression.

  T0 (Baseline, third trimester of pregnancy); T1 (2 weeks postpartum remote follow-up); T2 (1 month postpartum remote follow-up); T3 (3 months postpartum remote follow-up); Pre-rTMS treatment

• Depression severity measured by the 17-item Hamilton Depression Rating Scale (HAMD-17)

  The HAMD-17 total score ranges from 0 to 52, with higher scores indicating greater depression severity. Scores of 0-7 are generally considered normal, 8-16 mild depression, 17-23 moderate depression, and ≥24 severe depression.

  T0 (Baseline, third trimester of pregnancy); T1 (2 weeks postpartum remote follow-up); T2 (1 month postpartum remote follow-up); T3 (3 months postpartum remote follow-up); Pre-rTMS treatment

• Quality of life measured by the WHO Quality of Life Instrument-Short Form (WHOQOL-BREF)

  The WHOQOL-BREF is a 26-item self-report questionnaire used to assess quality of life across four distinct domains: Physical Health (7 items), Psychological Health (6 items), Social Relationships (3 items), and Environment (8 items). Each item is rated on a 5-point Likert scale. Raw domain scores are mathematically transformed to a linear 0 to 100 scale for each domain according to the official WHO guidelines. Scores range from 0 to 100, where higher scores represent a better perceived quality of life in that specific domain.

  T0 (Baseline, third trimester of pregnancy); T1 (2 weeks postpartum remote follow-up); T2 (1 month postpartum remote follow-up); T3 (3 months postpartum remote follow-up); Pre-rTMS treatment

• Body perception and autonomic awareness measured by the Body Perception Questionnaire-Short Form (BPQ-SF)

  The BPQ-SF is a 46-item self-report instrument used to evaluate subjective interoceptive awareness and bodily perception via two primary subscales rated on a 5-point Likert scale: the Body Awareness subscale (26 items, score range 26 to 130), where higher scores indicate greater awareness of visceral and physical states, and the Autonomic Reactivity subscale (20 items, score range 20 to 100), where higher scores reflect higher perceived autonomic nervous system reactivity to stress, with higher total scores across both domains indicating elevated somatic hyper-vigilance or reactivity.

  T0 (Baseline, third trimester of pregnancy); T1 (2 weeks postpartum remote follow-up); T2 (1 month postpartum remote follow-up); T3 (3 months postpartum remote follow-up); Pre-rTMS treatment

• Interoceptive sensibility measured by the Multidimensional Assessment of Interoceptive Awareness-2 (MAIA-2)

  The MAIA-2 is a 37-item self-report questionnaire used to measure multi-dimensional subjective interoceptive awareness across 8 subscales (Noticing, Not-Distracting, Not-Worrying, Attention Regulation, Emotional Awareness, Self-Regulation, Body Listening, and Trust) rated on a 6-point Likert scale. Scores for each subscale are calculated as the average of its item responses, resulting in an independent score range of 0 to 5 per domain, where higher scores across all dimensions indicate more functional, adaptive, and highly developed subjective interoceptive capacities.

  T0 (Baseline, third trimester of pregnancy); T1 (2 weeks postpartum remote follow-up); T2 (1 month postpartum remote follow-up); T3 (3 months postpartum remote follow-up); Pre-rTMS treatment

• Heartbeat Discrimination Task

  The Heartbeat Discrimination Task is an objective measure of interoceptive accuracy, where participants judge whether a series of auditory or visual triggers are presented in sync or out of sync with their own heartbeats. Performance is quantified using the standard cross-correlation or psychophysical sensitivity index, where higher scores represent greater objective interoceptive accuracy.

  T0 (Baseline, third trimester of pregnancy); Pre-rTMS treatment

• Resting-state EEG functional connectivity biomarkers

  Resting-state EEG functional connectivity biomarkers will be calculated from 128-channel EEG recordings to characterize alterations in large-scale neural network organization associated with postpartum depression and treatment response. Functional connectivity analyses will evaluate inter-regional communication patterns and network-level synchronization across cortical regions. Connectivity measures may include phase-based synchronization and other validated connectivity metrics to quantify altered functional integration and segregation within brain networks. These EEG functional connectivity biomarkers will be examined as candidate neurophysiological markers associated with depressive symptom severity and potential predictors of clinical response to robot-guided repetitive transcranial magnetic stimulation (rTMS) treatment.

  T0 (Baseline, third trimester of pregnancy); Pre-rTMS treatment

• EEG Vigilance Regulation

  Vigilance regulation patterns will be evaluated using a validated vigilance algorithm that classifies sequential 1-second resting-state EEG segments into distinct alertness levels: Stage 0 (highest alertness), Stages A1/A2/A3 (sustained wakefulness), Stages B1/B2/B3 (lowered vigilance), and Stage C (sleep onset). The study quantifies the temporal evolution and spatial distribution of these stages. Key metrics include the presence of "hyperstability" (prolonged adherence to high-alertness stages) or "instability" (rapid, premature decline to low-vigilance stages), indicating central autonomic and alertness dysregulation associated with postpartum depression.

  T0 (Baseline, third trimester of pregnancy); Pre-rTMS treatment

• Quantitative EEG (qEEG) Biomarkers

  Quantitative EEG (qEEG) biomarkers will be derived from 10-minute eyes-closed resting-state EEG recordings acquired using a 128-channel EEG system. qEEG analyses will characterize neural oscillatory activity and cortical dynamics associated with postpartum depression and treatment response. qEEG features will include: (1) Power spectral features, including spectral power across canonical frequency bands (delta, theta, alpha, beta, and gamma), to characterize alterations in neural oscillatory activity; (2) Frontal alpha asymmetry (FAA), calculated from predefined frontal electrode regions using log-transformed alpha power differences between hemispheres, as a marker of affective regulation and depressive symptomatology; and (3) Aperiodic spectral parameters and EEG complexity features, including 1/f characteristics, to characterize background neural dynamics and cortical information processing. These qEEG biomarkers will be examined as candidate neurophysiological markers associated wi

  T0 (Baseline, third trimester of pregnancy); Pre-rTMS treatment

• Heart Rate Variability (HRV) Metrics

  Short-term heart rate variability (HRV) will be quantified from resting-state electrocardiography (ECG) recording to assess autonomic nervous system regulation. Lower HRV values reflect diminished vagal tone, autonomic dysregulation, and heightened emotional vulnerability associated with postpartum depression risk.

  T0 (Baseline, third trimester of pregnancy); Pre-rTMS treatment

• Respiratory Sinus Arrhythmia (RSA)

  Respiratory Sinus Arrhythmia (RSA) will be derived from synchronized resting-state ECG and respiration tracking to evaluate cardiorespiratory coupling and parasympathetic nervous system activity. Lower RSA scores represent compromised vagal regulation and reduced stress resilience.

  T0 (Baseline, third trimester of pregnancy); Pre-rTMS treatment

• Serum Interleukin-6 (IL-6) Concentration

  Serum IL-6 concentrations will be quantified using standardized laboratory assays to characterize peripheral inflammatory profiles.

  T0 (Baseline, third trimester of pregnancy); Pre-rTMS treatment

• Serum endocrine hormone concentrations

  Serum endocrine markers, including cortisol and thyroid-related hormones, will be quantified to characterize neuroendocrine regulation.

  T0 (Baseline, third trimester of pregnancy); Pre-rTMS treatment

Secondary Outcomes (4)

• Area Under the Receiver Operating Characteristic Curve for Prediction of rTMS Treatment Response

  After completion of 20 rTMS sessions (4 weeks)

• F1-Score of the Multimodal Model for Prediction of rTMS Treatment Response

  After completion of 20 rTMS sessions (4 weeks)

• Clinical Response to Robot-Guided rTMS Treatment

  Before initiation of rTMS treatment and after completion of 20 rTMS sessions (4 weeks)

• Association Between Baseline Multimodal Biomarkers and rTMS Treatment Response

  Before initiation of rTMS treatment and after completion of 20 rTMS sessions (4 weeks)

Other Outcomes (2)

• Fertility Intentions

  T1 (2 weeks postpartum remote follow-up); T2 (1 month postpartum remote follow-up)

• Subjective Experiences and Perceptions of the Traditional Postpartum Ritual ("Sitting-the-Month")

  T1 (2 weeks postpartum remote follow-up); T2 (1 month postpartum remote follow-up)

Study Arms (3)

Patients with PPD

EXPERIMENTAL

Participants diagnosed with postpartum depression ((n=40) will receive standardized repetitive transcranial magnetic stimulation (rTMS) treatment targeting the left dorsolateral prefrontal cortex. Multimodal biomarkers will be evaluated as predictors of treatment response.

Device: Repetitive Transcranial Magnetic Stimulation (rTMS)

Woman in late pregnancy

NO INTERVENTION

Pregnant women in the third trimester of pregnancy (n=200) will be recruited from the obstetrics outpatient clinics and inpatient wards of Mirror Lake Hospital. Participants will undergo comprehensive multimodal assessments during late pregnancy, including psychological questionnaires, electroencephalography (EEG), autonomic measures, inflammatory markers, and hormonal measures. Follow-up assessments will be conducted at 2 weeks, 1 month, and 3 months postpartum to investigate longitudinal changes associated with postpartum depression risk and progression.

Healthy Non-Parturient Control (HC)

NO INTERVENTION

Healthy non-pregnant and non-postpartum women (n=50) recruited from the University of Macau and the local community. This group consists of age-matched individuals with no history of psychiatric disorders, serving as a baseline control.

Interventions

Repetitive Transcranial Magnetic Stimulation (rTMS) DEVICE

Participants diagnosed with postpartum depression will receive a standardized repetitive transcranial magnetic stimulation (rTMS) intervention targeting the left dorsolateral prefrontal cortex (DLPFC). Treatment will be administered by trained clinicians using a neuronavigation-assisted rTMS system. Resting motor threshold (RMT) will be determined prior to treatment, and coil positioning will be guided by a robotic navigation system with a localization error of less than 1 mm. Stimulation will be delivered at 10 Hz and 120% of the individual resting motor threshold. Each train will last 4 seconds with an inter-train interval of 26 seconds, for a total of 3,000 pulses per session. Participants will receive 20 treatment sessions over 4 weeks (5 sessions per week).

Patients with PPD

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Biological female, aged 18-45 years.
• For HR-PPD and LR-PPD groups: Pregnant women in the third trimester (≥ 32 weeks gestation) with a singleton pregnancy.
• For HR-PPD group: Beck Depression Inventory (BDI) score ≥ 14 during the third trimester.
• For LR-PPD group: BDI score \< 14 during the third trimester, with no history of depression.
• For HC group: Healthy women with no pregnancy in the past 12 months.
• No history of central nervous system diseases or major medical/surgical conditions.
• No history of medication use that may interfere with EEG or ECG measurements.
• Willing and able to complete baseline and follow-up assessments and provide written informed consent.

You may not qualify if:

• Multiple pregnancies, preterm labor, or severe pregnancy complications (e.g., pre-eclampsia, gestational diabetes with complications).
• Life-threatening emergencies during delivery (e.g., amniotic fluid embolism, major hemorrhage).
• Cognitive impairment or language barriers that hinder cooperation with assessments.
• History of major psychiatric disorders (e.g., schizophrenia, bipolar disorder).
• Other conditions that, in the opinion of the investigator, make the participant unsuitable for the study.

Sponsors & Collaborators

• University of Macau: lead
• Kiang Wu Hospital: collaborator

Study Sites (2)

Kiang Wu Hospital

Macao, 999078, Macau

Location

the Center for Cognitive and Brain Sciences, Research Building N21

Macao, 999078, Macau

Location

Related Publications (19)

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• Ganho-Avila A, Poleszczyk A, Mohamed MMA, Osorio A. Efficacy of rTMS in decreasing postnatal depression symptoms: A systematic review. Psychiatry Res. 2019 Sep;279:315-322. doi: 10.1016/j.psychres.2019.05.042. Epub 2019 Jun 10.

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• Cox EQ, Killenberg S, Frische R, McClure R, Hill M, Jenson J, Pearson B, Meltzer-Brody SE. Repetitive transcranial magnetic stimulation for the treatment of postpartum depression. J Affect Disord. 2020 Mar 1;264:193-200. doi: 10.1016/j.jad.2019.11.069. Epub 2019 Nov 13.

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• Hartmann R, Schmidt FM, Sander C, Hegerl U. Heart Rate Variability as Indicator of Clinical State in Depression. Front Psychiatry. 2019 Jan 17;9:735. doi: 10.3389/fpsyt.2018.00735. eCollection 2018.

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• Ip CT, Ganz M, Dam VH, Ozenne B, Ruesch A, Kohler-Forsberg K, Jorgensen MB, Frokjaer VG, Sogaard B, Christensen SR, Knudsen GM, Olbrich S. NeuroPharm study: EEG wakefulness regulation as a biomarker in MDD. J Psychiatr Res. 2021 Sep;141:57-65. doi: 10.1016/j.jpsychires.2021.06.021. Epub 2021 Jun 18.

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MeSH Terms

Conditions

Depression, Postpartum

Interventions

Transcranial Magnetic Stimulation

Condition Hierarchy (Ancestors)

Puerperal Disorders; Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Depressive Disorder; Mood Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Magnetic Field Therapy; Therapeutics

Study Officials

• Cheng Teng Ip, PhD

  Institute of Collaborative Innovation, University of Macau

  STUDY CHAIR

Central Study Contacts

Cheng Teng Ip, PhD

CONTACT

(853) 8822-9378; chengtengip@um.edu.mo

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor

Study Record Dates

• First Submitted: July 28, 2026
• First Posted: August 11, 2026
• Study Start (Estimated): September 1, 2026
• Primary Completion (Estimated): September 1, 2030
• Study Completion (Estimated): August 31, 2031
• Last Updated: August 11, 2026

Record last verified: 2026-08

Data Sharing

• IPD Sharing: Will not share

Locations

MA (2)