Effect of Amygdala Neurofeedback on Depressive Symptoms and Processing Biases

Major depressive disorder (MDD) is the leading cause of years lived with disability worldwide. Traditional pharmacological and/or psychological interventions are ineffective in up to one-half of patients, and treatments (such as electroconvulsive therapy, vagus nerve stimulation, and deep brain stimulation) available for severely ill patients who do not respond to standard interventions are invasive, and associated with potentially significant side effects. Therefore, there is a need to explore and develop novel non-invasive treatments.

One such non-invasive method is real-time functional magnetic resonance imaging neurofeedback (rtfMRI-nf), which allows a person to see and regulate the fMRI signal from his or her own brain. Emerging evidence suggests rtfMRI-nf has clinical utility in reducing symptoms of chronic pain, tinnitus, and Parkinson's disease. The goal of the current study is to leverage recent advances in rtfMRI-nf to determine whether this procedure can be adapted as treatment for MDD. While amygdala activity is exaggerated in response to negative stimuli in MDD, evidence further suggests that the amygdala response to positive stimuli is attenuated in MDD and normalizes with remission. Therefore, the target for our rtfMRI-nf procedure is the left amygdala. Participants will be randomly assigned to receive rtfMRI-nf from either the left amygdala or the left horizontal segment of the intraparietal sulcus (HIPS; a region not involved in emotional processing) and to increase the activity within that region to a target level by thinking of positive autobiographical memories. This neurofeedback condition will alternate with periods of rest and counting backwards in order to allow participants to disengage from memory contemplation. A final run without neurofeedback information will be included to determine whether participants can maintain the learned amygdala elevation during positive memory recall in the absence of neurofeedback. Participants will complete two sessions within a one-week period. Clinical ratings will be taken at the time of each scan to determine whether the amygdala rtfMRI-nf procedure results in improvement of depression symptoms, and changes within the emotional regulation network that occur with successful amygdala regulation will be examined. Furthermore, the investigators aim to determine whether the rtfMRI-nf procedure will alter assessments of emotional processing conducted within three days prior to, and following completion of, the rtfMRI-nf procedure.

Specific Aim 1: In individuals with MDD, determine the degree to which rtfMRI-nf enhances voluntary control over neural activity in the amygdala, co-modulates other brain regions within the emotion regulation circuitry, and alters depressive symptom severity ratings.

• Hypothesis 1.1: MDD participants receiving rtfMRI-nf regarding blood oxygen-level dependent (BOLD) activity within their amygdala can learn to voluntarily regulate this activity in response to positive stimuli. MDD participants receiving rtfMRI-nf regarding left amygdala activity will demonstrate greater activity in this region while contemplating positive autobiographical memories (AMs) than MDD participants receiving rtfMRI-nf regarding BOLD activity in the left HIPS, a region not involved in emotion.
• Hypothesis 1.2: The investigators hypothesize enhancing control over the amygdala via rtfMRI-nf will increase connectivity strengths between the amygdala and prefrontal regions involved in modulating emotional behavior including the pregenual anterior cingulate cortex and ventromedial prefrontal cortex.
• Hypothesis 1.3: The investigators hypothesize participants showing the greatest enhancement of amygdala activity in response to rtfMRI-nf also will show the greatest improvement in depressive symptom severity ratings at the end of the study.

Specific Aim 2: In MDD patients, determine the degree to which rtfMRI-nf from the amygdala restores a normative mood-congruent processing bias during the processing of emotionally valenced stimuli.