Transdiagnostic Brain-Behavior Profiling to Enhance Cognitive Behavioral Therapy Response

Major Depressive Disorder (MDD) and generalized Social Anxiety Disorder (gSAD) are pervasive
major public health problems. These disorders are characterized by emotion dysregulation, an
inability or inefficiency to regulate negative and positive affect as reflected in common and
disorder-specific symptoms (e.g., attentional bias to negative stimuli,
excessive/inappropriate negative thoughts, hyperarousal, anhedonia, emotional blunting). Such
dysregulation is believed to result from an imbalance between top-down 'emotion regulating'
(ER) frontal nodes central in inhibitory control of bottom-up subcortical
'emotion-generating' (EG) nodes in a Fronto-Limbic Affect Regulation and Emotional Salience
(FLARES) network. Therefore, successful treatment would be expected to 'normalize'
neurofunctional disturbances in the FLARES network, which can be measured with fMRI and more
distal units of brain function -- event-related potentials (ERPs) from
electroencephalography, startle potentiation from electromyography (EMG), neurocognitive
performance, and use of regulation strategies in daily life via self-report. The overarching
objective of the proposed study is to understand how, when, and where CBT works and for whom
to tailor treatment to improve clinical outcome.

Without precisely identified "targets" and "predictors" of change, CBT response will continue
to be unpredictably varied with few achieving meaningful clinical improvement placing them at
risk for relapse and recurrence. Our proposal builds on published data from our lab and
others and Preliminary Data which shows FLARES function, as assayed with fMRI, ERPs, EMG, and
behaviors, is sensitive to change following CBT.

Importantly, both baseline fMRI and non-fMRI units of brain-behavioral measures predict CBT
response better than baseline clinical measures. Such knowledge can lead to more precise
interventions aimed at capitalizing on 'strengths' or improving 'deficits' that may each
exist before CBT and/or explain why CBT does not work for some patients. The dual development
of fMRI ('mechanistic') and non-fMRI ('pragmatic') predictors and indices of therapeutic
change is aimed at advancing precision medicine while increasing the clinical utility of
'biomarkers' in the outpatient setting. With this objective, we propose to employ
well-validated paradigms to test ER and EG in the context of negative stimuli, reward
processes, and fear systems in MDD and gSAD to delineate common and disorder-specific
mechanisms of change and predictors of CBT outcome. We will enroll 200 patients: 100 MDD
(without comorbid gSAD), 100 gSAD (without comorbid MDD) and randomize them to 12 weeks of
manualized CBT or 12 weeks of 'placebo' psychotherapy (supportive therapy) (1:1 ratio).
Multiple units of FLARES function will be collected in all patients before (Week 0), during
(midway/Week 6) and after treatment (Week 12) to ascertain CBT 'dose' effects, and in 40
healthy controls for comparison. Pre-CBT predictors based on binary (responder/non-responder
status) and continuous (extent of change) outcomes will be examined midway (Week 6),
immediately after treatment (Week 12), and at 6-month follow-up.

Inclusion Criteria:

1. generally medically and neurologically healthy, including no evidence of mental
retardation or serious cognitive impairment that would interfere with protocol
adherence and/or task performance

2. between the ages of 18 - 65 years old, inclusive

3. right-handed

4. primary diagnosis of MDD or gSAD based on the SCID DSM-5. Patients will be permitted
to have limited comorbid and/or history of internalizing psychopathologies (e.g.,
generalized anxiety disorder, specific phobia, adjustment disorder)

Exclusion Criteria:

1. personal current or past manic/hypomanic episode or psychotic symptoms

2. active suicidal ideation as determined by the Columbia Suicide Severity Rating Scale
(C-SSRS)

3. prior history of standard CBT (failure or success)

4. any current or recent (past 4 weeks) use of medication (prescription or
non-prescription) with psychotropic effects

5. psychotherapy other than CBT or psychotropic medication use during study

6. cognitive dysfunction (traumatic brain injury, mental retardation, dementia)

7. active moderate or severe alcohol and/or substance use disorders

For healthy controls: history or current Axis I disorder.

Additional exclusion criteria for all participants pertaining to the fMRI scan include:

1. presence of ferrous-containing metals within the body (e.g., aneurysm clips,
shrapnel/retained particles)

2. inability to tolerate small, enclosed spaces without anxiety (e.g., claustrophobia)