A distinct biomarker of continuous transcutaneous vagus nerve stimulation treatment in major depressive disorder

Abstract

Background: Major depression is the fourth leading cause of disability worldwide and poses a socioeconomic burden worldwide. Transcutaneous vagus nerve stimulation (tVNS) is a promising noninvasive clinical device that may reduce the severity of major depression. However, the neural mechanism underlying continuous tVNS has not yet been elucidated.

Objective: We aimed to explore the effect of hypothalamic subregion functional connectivity (FC) changes during continuous tVNS treatment on major depressive disorder (MDD) patients and to identify the potential biomarkers for treatment outcomes.

Methods: Forty-one mild to moderate MDD patients were recruited and received either real or sham tVNS treatment for 4 weeks. We used a seed-to-whole brain approach to estimate the FC changes of hypothalamic subregions and their surrounding control areas during continuous tVNS treatment and explored their association with clinical outcome changes after 4 weeks of treatment.

Results: Of the thirty-six patients that completed the study, those in the tVNS group had significantly lower scores on the 24-item Hamilton Depression (HAM-D) Rating Scale compared to the sham tVNS group after 4 weeks of treatment. The FC between the bilateral medial hypothalamus (MH) and rostral anterior cingulate cortex (rACC) was significantly decreased during tVNS but not during sham tVNS. The strength of this FC was significantly correlated with HAM-D improvements after 4 weeks of tVNS.

Conclusion: The FC between the bilateral MH and rACC may serve as a potential biomarker for the tVNS state and predict treatment responses. Our results provide insights into the neural modulation mechanisms of continuous tVNS and reveal a potential therapeutic target for MDD patients.

Keywords: Biomarker; Functional connectivity; Hypothalamus; Major depressive disorder; Rostral anterior cingulate cortex; Transcutaneous vagus nerve stimulation.

Conflict of interest statement

Conflict of Interest

J.K has a disclosure to report (holding equity in a startup company (MNT)), but declares no conflict of interest.

Copyright © 2018 Elsevier Inc. All rights reserved.

Figures

Figure 1

The study protocols. (A) Procedures and data used for the study. In baseline, a resting-state fMRI, a continuous tVNS fMRI and clinical scores were collected and used for the patient in the real tVNS group. All subsequent 4-week treatments were self-administered by the patients at home, except for the 6-mintue tVNS during the MRI scan. The investigators collected the patient’s clinical scores at the end of the 4-week treatment. All procedures performed in the sham tVNS treatment group were identical to the procedures for the real tVNS group, except for the location of stimulation. (B) Locations for real tVNS and sham tVNS stimulation. (C) Selected medial hypothalamus (MH) and lateral hypothalamus (LH) for seed-base whole-brain connectivity analyses (seeds marked in blue). Red dots represent the positions of controlled null seeds.

Figure 2

Identified significantly different MH FCs and their relationships with HAM-D improvements. First column: Compared to sham group, tVNS group had significantly lower FCs in rACC and MFG, while higher FCs in CB. Second column: real but not sham tVNS significantly modulated the strength of MH-rACC, MH-MFG and MH-CB. Third column: All connections in sham and real groups during resting-state were not significantly correlated with HAM-D improvements. Fourth column: Only the strength of MH-rACC in real tVNS group during treatment was significantly correlated with HAM-D improvements. ns: no significance; *: p < 0.05.

Figure 3

Identified significantly different LH FCs and their relationships with HAM-D improvements. First column: Compared to sham group, tVNS group had significantly lower FCs in MCC and Putamen. Second column: Both real and sham tVNS significantly modulated the strength of LH-MCC and LH-MFG. Third column: All connections in sham and real groups during resting-state were not significantly correlated with HAM-D improvements. Fourth column: All connections in sham and real groups during treatment were not significantly correlated with HAM-D improvements. *: p < 0.05.