A longitudinal study on deep brain stimulation of the medial forebrain bundle for treatment-resistant depression

Abstract

Deep brain stimulation (DBS) to the superolateral branch of the medial forebrain bundle (MFB) has been reported to lead to rapid antidepressant effects. In this longitudinal study, we expand upon the initial results we reported at 26 weeks (Fenoy et al., 2016), showing sustained antidepressant effects of MFB DBS on six patients with treatment-resistant depression (TRD) over 1 year. The Montgomery-Åsberg Depression Rating Scale (MADRS) was used as the primary assessment tool. Deterministic fiber tracking was used to individually map the target area; analysis was performed to compare modulated fiber tracts between patients. Intraoperatively, upon stimulation at target, responders reported immediate increases in energy and motivation. An insertional effect was seen during the 4-week sham stimulation phase from baseline (28% mean MADRS reduction, p = 0.02). However, after 1 week of initiating stimulation, three of six patients had a > 50% decrease in MADRS scores relative to baseline (43% mean MADRS reduction, p = 0.005). One patient withdrew from study participation. At 52 weeks, four of remaining five patients have > 70% decrease in MADRS scores relative to baseline (73% mean MADRS reduction, p = 0.007). Evaluation of modulated fiber tracts reveals significant common orbitofrontal connectivity to the target region in all responders. Neuropsychological testing and 18F-fluoro-deoxyglucose-positron emission tomography cerebral metabolism evaluations performed at baseline and at 52 weeks showed minimal changes and verified safety. This longitudinal evaluation of MFB DBS demonstrated rapid antidepressant effects, as initially reported by Schlaepfer et al. (2013), and supports the use of DBS for TRD.

Conflict of interest statement

Dr. Soares receives grant/research support from Bristol-Meyers Squibb, Forest Laboratories, Merck and Elan Pharmaceuticals, and is a consultant for Pfizer, Abbot, and Astellas Pharma, Inc. Dr. Zanotti-Fregonara has received fees as a speaker for Eli Lilly. The remaining authors declare no conflict of interest.

Figures

Fig. 1. Study protocol.

DBS, deep brain stimulation; SE, side effects; PET, positron emission tomography; Hz, Hertz; us, microseconds; V, volts; MADRS, Montgomery-Åsburg Depression Rating Scale, HAM-A, Hamilton Anxiety Scale; YMRS, Young Mania Rating Scale; CGI, Clinical Global Impressions

Fig. 2. MADRS scores recorded over time.

Initiation = bilateral DBS ON at t = 4w OFF following MADRS assessment. End-sham = 4w OFF. DBS initiation begun after End-Sham assessment. Mean % change MADRS baseline–12 w ON = 64%; mean % change MADRS baseline–52 w = 73%. MADRS, Montgomery-Åsburg Depression Rating Scale. Insert: Chronology of > 50% treatment response by month ( ±) for each patient for 12 months

Fig. 3. Representation of active cathodal contacts in two planes for each of the six patients presented in this series, superimposed upon the deterministic tractography-defined target of the medial forebrain bundle for Patient 1; this is presented on adaptations of stereotactic atlas slices from Schaltenbrand and Wahren.

a H.v. 4.5, axial view b F.p. 3.0, Coronal view. STN = subthalamic nucleus; RN = red nucleus; SNr = substantia nigra; Mmt = mammillothalamic tract; Fx = fornix; V3 = 3rd ventricle

Fig. 4. Depiction of modulated fiber tracts (assuming an isotropic model) from active cathodal contacts in patients #1–#6.

Chronological order of implantation. Significant orbitofrontal connectivity to the MFB target region seen in all responder patients but minimally seen in the non-responder Patient no. 3