LHB and major depressive disorder: Based on earlier studies, LHb is a key brain region in the pathophysiology of depression, and its hyperactivity,58,61 as observed in TRD patients in the current study, is associated with depressive symptoms, such as helplessness, anhedonia and excessive focus on the negative.57,58,62 When a reward is deemed inadequate and unsatisfactory by TRD patients, the firing rate of the LHb may increase, leading to dopamine release inhibition from midbrain dopaminergic neurons that project onto NAc and inhibit its activity.62,63