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.

- Hypothesis 2.1: During the performance of a backward masking task in which emotional
faces are presented below conscious awareness, the investigators hypothesize MDD
participants will initially show a processing bias toward negative stimuli in the
amygdala that will reverse to a processing bias toward positive stimuli in participants
receiving active vs HIPS rtfMRI-nf

- Hypothesis 2.2: The investigators hypothesize that MDD patients will initially show a
mood-congruent processing bias toward negative stimuli on the P1Vital Emotional Test
Battery that will reverse to a bias toward positive stimuli following amygdala (vs HIPS)
rtfMRI-nf.

Results from this project will lead to new insights into the plastic neurobiological
mechanisms that govern recovery from MDD and promote novel, non-invasive approaches to MDD
treatment.

Inclusion Criteria:

- clinical diagnosis of major depressive disorder

- right handed

- adult aged 18-55

- currently depressed

Exclusion Criteria:

- clinically significant or unstable cardiovascular, pulmonary, endocrine, neurological,
gastrointestinal illness or unstable medical disorder

- met Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria for
alcohol and/or substance abuse or substance dependence (other than nicotine) within 12
months prior to screening

- endorse suicidal intent or have made a suicide attempt within the preceding three
months

- history of traumatic brain injury

- inability to complete MRI scan due to claustrophobia or general MRI exclusions (e.g.,
shrapnel inside body)

- current pregnancy or breast feeding

- a primary language other than English

- received psychotropic drugs for at least 3 weeks (8 weeks for fluoxetine) prior to
scanning (Effective medications will not be discontinued for the purposes of the
study)