Predicting Illness Trajectories In Fully Remitted Major Depression Using Concurrent TBS/fNIRS (TBS/fNIRS)

Major depressive disorder (MDD) is the world's leading cause of disability according to the World Health Organization. MDD is highly recurrent, even if clinical remission is reached after successful treatment. In fact, the enormous burden of disability, mortality and financial costs is due to the recurrent and chronic nature of MDD. The reliable prediction of the recurrence of major depressive episodes (MDEs) based on a prognostic model that is informed by biological, neurophysiological or neuroimaging data would be valuable and lifesaving for many. However, such models are still lacking.

Several lines of evidence point to abnormal prefrontal control over limbic emotion processing areas in MDD owing to diminished prefrontal excitability that seems to persist during MDD remission (rMDD). Prefrontal excitability in rMDD may thus be a trait marker of MDD and may potentially be indicative of disease recurrence. Yet, research investigating the potential utility of prefrontal excitability for predicting the recurrence of MDEs is lacking. Cortical excitability can be investigated using transcranial magnetic stimulation (TMS); however, human studies have mostly probed cortical excitability of the motor cortex, a brain region not considered to be central in the neuropathology of MDD. Hence, knowledge of the effect of TMS on prefrontal excitability is limited. Moreover, whether immediate prefrontal modulation by TMS can predict the recurrence of MDEs in fully remitted MDD patients remains to be investigated. Thus, there is a need for research that aims to quantify the direct and immediate aftereffects of TMS on prefrontal function. Most importantly, with regard to precision medicine, there is a need for research that explores the utility of immediate prefrontal reactivity to TMS for predicting MDE recurrence. Here, the investigators propose a research program that will exploit the combination of functional near-infrared spectroscopy (fNIRS) with brain stimulation. Concurrent theta-burst stimulation (TBS)/fNIRS measurements will allow us to systematically investigate stimulation-induced modulation of blood oxygenation as a proxy for induced brain activity changes (TBS is a modern form of patterned TMS). The findings from this study will (1) elucidate the immediate effects of excitatory and inhibitory brain stimulation on prefrontal activity in rMDD and controls and (2) validate the potential utility of stimulation-induced brain modulation for the prediction of MDE recurrence.

Study Overview

• Status: Not yet recruiting
• Conditions: Healthy; Major Depression in Remission
• Intervention / Treatment: Device: Theta-burst stimulation (TBS); Other: telephone interviews

• Study Type: Interventional
• Enrollment (Anticipated): 170
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Georg S Kranz, PhD; Phone Number: 4838 +852 2766; Email: georg.kranz@polyu.edu.hk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• a clinical diagnosis of recurrent depressive disorder by an experienced psychiatrist but currently in full remission (ICD 11, 6A71.7) according to results of the Mini International Neuropsychiatric Interview (MINI) and the Patient Health Questionnaire (PHQ-9), with a score ≤ 4;
• at least two previous MDEs within the last 10 years;
• no or stable (≥4 weeks) psychopharmacological medication.

Exclusion Criteria:

• severe internal diseases;
• neurological disorders or a history of severe head injuries;
• current psychiatric comorbidities, including addiction;
• pregnancy;
• common fNIRS and TMS exclusion criteria, such as a history of brain surgery, head injury, cardiac pacemaker, deep brain stimulation, intracranial metallic particles, history of seizures, and antiepileptics and benzodiazepines corresponding to a dose of >1 mg lorazepam/d. Potential participants taking antidepressants will be included if there has been no recent change to either dosage or medication (within 4 weeks).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: rMDD group; Participants with remitted MDD who will receive concurrent TBS/fNIRS with iTBS and followed by cTBS after one hour. This group will also receive follow-up telephone interviews every 3 months for 2 years to monitor major depressive episode recurrence.	Device: Theta-burst stimulation (TBS); TBS comprises 3-pulse 50-Hz bursts, applied every 200 ms (at 5 Hz), as described previously. iTBS consists of 2-second trains with an inter-train interval of 8 seconds. The investigators will repeat the trains (30 pulses; 10 bursts) 20 times to reach a total number of 600 pulses (3x10x20). cTBS will comprise uninterrupted bursts to reach a total of 600 pulses. Concurrent TBS/fNIRS stimulation will be applied over the left (iTBS) and right (cTBS) DLPFC at an intensity of 90% resting motor threshold (RMT). This corresponds to ~110% of the active motor threshold. Stimulation at 90% RMT will also ensure compliance, reduce sensory discomfort and minimize dropout rates. Still, scalp discomfort will be recorded directly after the stimulation. The stimulation site over the DLPFC will be determined using the international 10-20 system and correspond to the F3 label.; Other Names: Repetitive transcranial magnetic stimulation (rTMS); Other: telephone interviews; Telephone interviews will be conducted at the follow-up stage. RMDD group will receive follow-up telephone interviews every 3 months for 2 years to monitor major depressive episode recurrence
OTHER: Healthy control group; Healthy participants who will receive TBS/fNIRS with iTBS and followed by cTBS after one hour. No follow-up interviews will be conducted for this group.	Device: Theta-burst stimulation (TBS); TBS comprises 3-pulse 50-Hz bursts, applied every 200 ms (at 5 Hz), as described previously. iTBS consists of 2-second trains with an inter-train interval of 8 seconds. The investigators will repeat the trains (30 pulses; 10 bursts) 20 times to reach a total number of 600 pulses (3x10x20). cTBS will comprise uninterrupted bursts to reach a total of 600 pulses. Concurrent TBS/fNIRS stimulation will be applied over the left (iTBS) and right (cTBS) DLPFC at an intensity of 90% resting motor threshold (RMT). This corresponds to ~110% of the active motor threshold. Stimulation at 90% RMT will also ensure compliance, reduce sensory discomfort and minimize dropout rates. Still, scalp discomfort will be recorded directly after the stimulation. The stimulation site over the DLPFC will be determined using the international 10-20 system and correspond to the F3 label.; Other Names: Repetitive transcranial magnetic stimulation (rTMS)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recurrence of a major depressive episode	Primary clinical outcome measure: recurrence of a major depressive episode (based on MINI and PhQ-9 ≥ 5).	Up to 2 years.
Oxyhemoglobin (HbO) change compared to baseline	Primary imaging outcome measure: TBS-induced HbO change in the dorsolateral prefrontal cortex (DLPFC) during and after stimulation.	During and within 3 minutes post TBS-fNIRS measurement.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hemoglobin (Hb) change compared to baseline	Secondary Imaging Outcome Measure: TBS-induced Hemoglobin (Hb) change in the dorsolateral prefrontal cortex (DLPFC) during and after stimulation	During and within 3 minutes post TBS-fNIRS measurement

Collaborators and Investigators

• Sponsor: The Hong Kong Polytechnic University

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): January 1, 2023
• Primary Completion (ANTICIPATED): January 1, 2026
• Study Completion (ANTICIPATED): January 1, 2026

Study Registration Dates

• First Submitted: September 14, 2022
• First Submitted That Met QC Criteria: October 12, 2022
• First Posted (ACTUAL): October 13, 2022

Study Record Updates

• Last Update Posted (ACTUAL): October 13, 2022
• Last Update Submitted That Met QC Criteria: October 12, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: Functional NIRS; Concurrent TBS/fNIRS; Theta-burst stimulation; Remitted depression; Relapse prediction
• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Mood Disorders; Depression; Depressive Disorder; Depressive Disorder, Major
• Other Study ID Numbers: HSEARS20220812002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: IPD may be shared upon request
• IPD Sharing Time Frame: Upon request
• IPD Sharing Access Criteria: Upon request
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No