Medial Forebrain Bundle Stimulation—Speed Access to an Old or Entry into a New Depression Neurocircuit?

Abstract

To the Editor: Arecent study by Schlapfer et al. (1) demonstrated an impressive and rapid antidepressant effect of deep brain stimulation (DBS) of the medial forebrain bundle (MFB) in patients with treatment-resistant depression (TRD), thus adding a new candidate to the current list of DBS targets for TRD, such as the subgenual cingulate, the nucleus accumbens, the lateral habenula (LHb), and the anterior limb of internal capsule. These data raise the question to what degree the various stimulation sites can be conceptualized as being part of, and entry points into, a single dysregulated neurocircuit (2). In favor of such a proposal, posterior MFB stimulation exerts suppressive influence onto lateral parts of the LHb (3). In turn, LHb stimulation induces a functional down-regulation of the monoaminergic pathways (serotonergic via dorsal raphe nucleus, dopaminergic via ventral tegmental area, and noradrenergic via locus coeruleus) (4,5). Since finally, the MFB acts as an integrative extension of these pathways to frontal structures, direct MFB stimulation may thus provide a shorter route to the prefrontal cortex as speed access toward this previously elaborated circuit (Figure 1). However, this notion contrasts with the striking observation in this new study that at least some of the patients reported immediate relief, reminiscent of effects induced by selfstimulation of the MFB (6). This rapid onset, if confirmed in further work, contrasts with the strongly asymmetric time course (DBS-off: fast relapse, DBS-on: slow remission) seen in responders to subgenual cingulate stimulation, nucleus accumbens stimulation, and LHb DBS (7,8). While, therefore, the sustained response to MFB stimulation might be compatible with entry into the same neurocircuit that previous stimulation sites have accessed, the immediate effect should prompt an investigation into nonoverlapping (possibly fast prefrontal) effects of MFB stimulation, especially in conjunction with rapid response pharmacologic approaches such as