*3.5. Lateral Habenula*

The activity of the lateral habenula (LHb) is negatively associated with reward, meaning its neurons increase their firing rate in a non-reward situation or in the omission of a reward. LHb hyperactivity could therefore explain the lower reward-seeking behavior in TRD [75] (Table 2). Speculation that DBS of the LHb could lead to the inhibition of hyperactivity prompted the first case study of LHb-DBS in TRD, which notably led to full remission of the patients' depressive symptoms [44]. A clinical non-randomized study in six patients suffering from TRD is currently being held, investigating the safety, tolerability, and benefit of LHb DBS in TRD. Patients that respond at 12 months of stimulation will enter a randomized, staggered withdrawal phase. During this phase, a double-blind discontinuation will be attempted at month 12 or 13, decreasing the stimulation by 50% and then completely discontinuing it during the following two weeks. Evaluation will take place at 15 months, where, in the meantime, escape criteria are included, and if met, will stop the blinded phase in continuing with an open treatment [76].
