Up to two-thirds of patients diagnosed with major depressive disorder (MDD) will not respond to standard pharmacological and psychological interventions and will be considered treatment resistant (TR-MDD). Decreased reactivity to positive stimuli, indexed by low amygdala reactivity to positive autobiographical memory recall, may be a causal mechanism interfering with recovery from TR-MDD. Previous work in our lab suggests that individuals who do respond to antidepressant medications show increased amygdala activity that is indistinguishable from controls relative to baseline, while TR-MDD individuals fail to show this increase in amygdala activity. Furthermore, we have found that MDD participants (more generally, not specifically TR- MDD) are indeed able to increase their amygdala response during positive memory recall via real-time fMRI neurofeedback (rtfMRI-nf) training, and that this increase is associated with large and rapid reductions in depressive symptoms. Here, we propose to evaluate whether rtfMRI-nf training to increase the amygdala response to positive memories may serve as an intervention for TR-MDD. The R61 period will involve intervention refinement and evaluation of mechanism; N=40 TR-MDD individuals will undergo five amygdala rtfMRI-nf training sessions and we will assess changes in amygdala activity with the goal of confirming that patients with TR-MDD are able to increase the amygdala response to positive memories, and to determine the minimal number of training sessions required for sufficient target engagement/amygdala asymptote to be reached. The R33 phase will involve a mechanistic comparison to a control intervention and evaluation of clinical change (including duration of effects). N=60 TR-MDD individuals will be randomly assigned under double-blind conditions to the amygdala rtfMRI-nf intervention or to a control rtfMRI-nf intervention where they are trained to regulate a parietal region putatively not involved in emotional processing or MDD. Success will suggest a new non-pharmacological, non-invasive intervention for a traditionally treatment-resistant population of MDD individuals.
We propose to investigate the ability of individuals with treatment-resistant major depressive disorder (TR- MDD) to increase and sustain activity of the amygdala during positive memory recall, and relate this ability to outcomes that are clinically relevant for those with the disorder. We expect these studies to guide the development of non-pharmacological, non-invasive treatments to increase the processing of positive stimuli in patients with TR-MDD.
