The Utility of Concurrent TBS/fNIRS for Antidepressant Treatment Optimization

Repetitive transcranial magnetic stimulation (rTMS) with theta bursts (i.e. TBS) of the dorsolateral prefrontal cortex (DLPFC) is an innovative treatment for major depressive disorder (MDD). Indeed, the U. S. Food and Drug Administration (FDA) has only recently approved TBS (in August 2018). However, fewer than 50% of patients show sufficient response to this treatment; markers for response prediction are urgently needed. Moreover, there is a lack of knowledge of the mechanism of action of TBS of the DLPFC. This is due to difficulties of directly measuring prefrontal stimulation effects, as compared to the stimulation of motor cortex and utilizing motor evoked potentials as direct readout. However, knowledge of immediate DLPFC modulation by TBS is necessary to extrapolate downstream effects on the neural and symptoms level.

Thus, there is a need for research that aims to quantify the direct and immediate after-effects of TBS on DLPFC function. Most importantly, with regard to precision medicine, there is a need for research that explores the utility of immediate DLPFC reactivity to TBS for the prediction of antidepressant treatment response. There is common agreement that certain forms of rTMS inhibit or excite brain activity, respectively. However, evidence indicates that there is considerable individual variability in the brain responses to rTMS. Whether differences in individual DLPFC modulation by rTMS can be utilized as a predictive marker for treatment response remains to be investigated.

This research program will exploit the combination of functional near-infrared spectroscopy (fNIRS) with brain stimulation. Concurrent TBS/fNIRS measurements will allow us to systematically investigate TBS-induced modulation of blood oxygenation as a proxy for induced brain activity changes. The findings from this study will (1) elucidate the immediate effects of excitatory and inhibitory TBS on prefrontal activity in TBS treatment-naïve patients with MDD and (2) validate the potential utility of TBS-induced brain modulation at baseline for the prediction of antidepressant response to four weeks of daily TBS treatment.

Major depression is a severe mental disorder and is associated with considerable economic costs but adequate treatments are poorly explored. This research program will pave the way towards an affordable and easy-to-implement method for response prediction before treatment commencement. Thus, our research proposal has high potential to inform tailored treatment strategies, as envisaged in precision medicine.

Study Overview

• Status: Recruiting
• Conditions: Major Depressive Disorder
• Intervention / Treatment: Device: Theta-burst stimulation (TBS)

Detailed Description

Please refer to the full proposal

• Study Type: Interventional
• Enrollment (Estimated): 90
• Phase: Not Applicable

Contacts and Locations

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

Study Locations

• Hong Kong
  • Hong Kong, Hong Kong
    • Recruiting
    • The Hong Kong Polytechnic University
    • Contact: Georg S Kranz, PhD; Phone Number: 4838 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

Description

MDD group:

Inclusion Criteria:

• MDD (DSM-5), HAMD17 ≥18, approval for TBS treatment by the physician in charge, stable antidepressive medication 4 weeks before treatment (the sample will include at least 20 drug-naïve patients in order to avoid confounding effects of medication for testing hypothesis 4).

Exclusion Criteria:

• a history of brain surgery, head injury, stroke or neurodegenerative disorder, diagnosis of personality disorder, psychotic features, active suicidal intent, severe somatic comorbidities, cardiac pacemakers, deep brain stimulation, intracranial metallic particles, history of seizures, antiepileptics and benzodiazepines corresponding to a dose of >1 mg lorazepam/d, substance dependence or abuse, if it is the primary clinical problem.

HC group:

Inclusion Criteria:

• age between 18 and 60, right-handedness.

Exclusion Criteria:

• a current or previous diagnosis of a psychiatric, neurological disorder or severe internal illness, common contraindications to rTMS,26 and a psychiatric disorder in their first-degree relatives.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Concurrent TBS/fNIRS with iTBS and followed by cTBS after 1h; self-explanatory, see Arm Title

Device: Theta-burst stimulation (TBS); TBS comprises 3-pulse 50-Hz bursts, applied every 200 ms (at 5 Hz) as described previously (Huang, Edwards et al. 2005). iTBS consists of 2-second trains with an inter-train-interval of 8 seconds. We will repeat trains (30 pulses; 10 bursts) for 20 times to reach a total number of 600 pulses (3x10x20). cTBS will comprise uninterrupted bursts to reach a total number of 600 pulses, as done routinely by others. Concurrent TBS/fNIRS stimulation will be applied over the left (iTBS) and right (cTBS) DLPFC at an intensity of 70-120%* resting motor threshold (RMT) (The ideal %RMT will be determined first in a pilot study). In part two, stimulation intensity for patients will be 120% RMT (titration to full therapeutic dose over the first three days), as approved by the FDA in the U.S. (Blumbeger et al. 2018). The stimulation site will be the same as in the concurrent TBS/fNIRS stimulation (see above).; Other Names: Transcranial Magnetic Stimulation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response rate after treatment (Montgomery-Asberg depression rating scale, MADRS reduction ≥50% of baseline)	We will use the MADRS as the primary outcome measure because this symptom rating scale is more sensitive to changes over time. The score of MADRS is ranging from 0 to 60, with higher scores indicative of greater depressive symptomology.	post treatment, up to 22 months
Oxygenated hemoglobin (HbO) change compared to baseline	TBS-induced HbO change in the DLPFC during and after stimulation	during and post TBS-fNIRS measurement, an average of 2 months. As well as at follow-up, up to 30 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Remission rate after treatment (MADRS≤10)	See above	post treatment, up to 22 months
Absolute change of mean Hamilton depression rating scale (HAMD17) after 2 and 4 weeks of treatment, as well as at 1 month follow-up	The score of HAMD is ranging from 0 to 53, on which increasing scores represent increasing severity of symptoms	at follow-up, up to 30 months
Absolute change of mean Inventory of depression symptomatology-clinician (IDS-C30) after 2 and 4 weeks of treatment, as well as at 1 month follow-up	The score of IDS-C30 ranges from 0 to 84, on which increasing scores represent increasing severity of symptoms	at follow-up, up to 30 months
Hb change compared to baseline	TBS-induced Hb change in the DLPFC during and after stimulation	during and post TBS-fNIRS measurement, an average of 2 months. As well as at follow-up, up to 30 months
the area under curve of HbO and Hb value during stimulation	TBS-induced HbO and Hb change in the DLPFC during stimulation	during TBS-fNIRS measurement, an average of 2 months. As well as at follow-up, up to 30 months
the steepness of the Hb and HbO values change	TBS-induced HbO and Hb change in the DLPFC during stimulation	during TBS-fNIRS measurement, an average of 2 months. As well as at follow-up, up to 30 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of Patient Health Questionnaire (PHQ-9, Chinese version) at each treatment day	The score of PHQ-9 ranges from 0 to 27, on which increasing scores represent increasing severity of symptoms	till to end of treatment, up to 18 months

Collaborators and Investigators

• Sponsor: Dr Georg Kranz
• Collaborators: Chinese University of Hong Kong; Prince of Wales Hospital, Shatin, Hong Kong; Kowloon Hospital, Hong Kong
• Investigators: Principal Investigator: Georg S Kranz, PhD, The Hong Kong Polytechnic University

Publications and helpful links

General Publications

• Kan RLD, Mak ADP, Chan SKW, Zhang BBB, Fong KNK, Kranz GS. Protocol for a prospective open-label clinical trial to investigate the utility of concurrent TBS/fNIRS for antidepressant treatment optimisation. BMJ Open. 2022 Feb 10;12(2):e053896. doi: 10.1136/bmjopen-2021-053896.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2023
• Primary Completion (Estimated): June 1, 2024
• Study Completion (Estimated): June 1, 2024

Study Registration Dates

• First Submitted: August 19, 2020
• First Submitted That Met QC Criteria: August 21, 2020
• First Posted (Actual): August 25, 2020

Study Record Updates

• Last Update Posted (Estimated): March 5, 2024
• Last Update Submitted That Met QC Criteria: March 4, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Major depression; Theta-Burst Stimulation; Treatment prediction; Functional NIRS; Concurrent TBS/fNIRS
• Additional Relevant MeSH Terms: Mental Disorders; Mood Disorders; Depressive Disorder; Depressive Disorder, Major
• Other Study ID Numbers: 15100120

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes