This research aims to elucidate mechanisms through which change occurs during cognitive behavior therapy (CBT) for depression. Assessing meta-cognitive processes of self-knowledge (top-down), electrophysiological and behavioral correlates of emotion processing (bottom-up), and their relation to treatment outcome will provide new insights into the mechanisms of emotion regulation deficits in depression. It will also contribute toward the clinical goal of identifying patients who may benefit most from CBT for unipolar depression.

This R21 application aims to clarify the neurobiological mechanisms by which change occurs during cognitive behavior therapy (CBT) for major depressive disorder (MDD). This hypothesis-driven study will explore the association between the psychological constructs of psychological mindedness (PM) and mindfulness (M) during the time course of CBT for MDD, and its relationship to electrophysiological and behavioral measures of automatic (i.e. stimulus-driven or bottom-up) emotion processing. This objective is motivated by the following rationale: PM and M represent different meta-cognitive processes of self-knowledge deemed critical for emotion regulation (ER) and CBT success. Event-related potentials (ERPs) to salient affective pictures reflect different stages of motivated attention. Using advanced analytic EEG techniques, we have linked these stages to the hierarchical activation of 'emotional' brain regions along the occipitotemporal ventral stream, ranging from preconscious stimulus categorization (right secondary visual cortex, right temporoparietal junction) to conscious appraisal (posterior cingulate cortex, ventromedial cortex). Importantly, blunted ERP responses to emotionally-arousing stimuli have been observed in clinical depression, and hypoactivation of right temporoparietal and dorsolateral prefrontal regions normalize after successful antidepressant or electroconvulsive treatment. A dichotic emotion recognition test, which provides an auditory measure of bottom-up emotion processing in form of a left ear (right hemisphere) advantage for recognizing the emotional intonation of speech patterns, has revealed behavioral deficits in MDD patients. Moreover, an increased right ear advantage for verbal stimuli (left hemisphere) is seen in CBT responders. Employing a sample of 60 MDD patients randomly assigned to CBT or nonspecific supportive therapy (placebo), we will obtain psychological, electrophysiological, behavioral and clinical outcome measures of response to 12 weeks of CBT in a pre-post treatment design to determine: (1) when and where in the brain automatic emotion processing is altered by CBT; (2) if changes in emotional responding are moderated or mediated by meta-cognitive processes of self-knowledge; and, (3) if these measures, alone or in combination, have promise as markers of CBT treatment response. Existing ERP and behavioral data for healthy adults (HC) obtained using the same experimental protocols will provide normative (yardstick) data. This study brings together experienced clinical psychologists and psychiatrists doing treatment and research in depression with investigators having expertise in affective neuroscience and electrophysiological studies in MDD. It will provide a critical new step for outlining the affective-cognitive and neurophysiological mechanisms of ER by which change through CBT occurs. Apart from their theoretical relevance, the findings of this project will also aid in developing novel and more targeted interventions and in identifying patients who may benefit most from CBT for unipolar depression.

Inclusion Criteria:

• aged 18-65

• right-handed

• be able to speak English well enough to comprehend and comply with protocol requirements

• recruited to achieve equal gender representation (i.e. about half male) in both treatment arms

• medically healthy individuals will be included as MDD patients if they:

  1. meet DSM-5 criteria for a current MDD episode based on a structured clinical interview (SCID);
  2. score greater or equal to 13 on the Beck Depression Inventory (BDI-II)
  3. score greater or equal to 14 on the Hamilton Rating Scale for Depression (HRSD)

Exclusion Criteria:

• Participants are excluded for any of the following reasons or DSM-5 criteria:

  1. substance abuse or dependence (including alcohol) in last 6 months;
  2. positive toxicology screen as determined by blood/urine testing (e.g. thyroid dysfunction, street drug use);
  3. history of schizophrenia or other current psychotic disorder;
  4. MDD with psychotic or catatonic features;
  5. Bipolar I, II Affective Disorder;
  6. Organic Mental Disease;
  7. significant suicidal ideation with a plan and intent, also assessed using the Columbia-Suicide Severity Rating Scale (C-SSRS), that cannot be managed safely as an outpatient, or homicidal ideation (suicidality monitored throughout study);
  8. a primary diagnosis of panic disorder, obsessive-compulsive disorder, psychogenic pain disorder, anorexia/bulimia, or any unstable medical condition;
  9. any recent (less than or equal to 12 mos) history of CBT (as determined during an in-person interview);
  10. prior seizure disorder, significant head trauma or other neurological disorders;
  11. lack of capacity to give informed consent;
  12. received psychotropic medication, over-the-counter antidepressant, or any non-CBT intervention (e.g. deep breathing, meditation/mindfulness, psychotherapy - except for minimal supportive nonspecific therapy PBO) for at least 1 month prior to recruitment (3 months for fluexetine);
  13. hearing loss (>30 dB in either ear) or hearing asymmetry (>10 dB across ears) assessed via standard audiogram

Right-handed MDD patients (N = 60; Beck Depression Inventory [BDI] > 12, Hamilton Rating Scale for Depression [HRSD] > 13), aged 18 to 65 (~half male), recruited through the Depression Evaluation Service at NY State Psychiatric Institute (NYSPI)

The institution and PIs will adhere to the NIH Data Sharing Policy (Notice of Data Sharing Policy for the National Institute of Mental Health NOT-MH-19-033). Accordingly, we will deposit de-identified individual raw and analyzed data (primary and secondary outcome measures) from experiments involving human subjects into the NIMH Data Archive (NDA) infrastructure (i.e., for all data for which we will obtain informed consent). Raw data will be submitted to NDA every 6 months and include demographic, self-report, clinical, and EEG, following NDA Harmonization Standards (i.e., for clinical/phenotypic data and neuro-signal recordings) and using NDA GUIDs. These submissions will undergo validations and other quality control checks as the data are deposited.

Data will be available 12 months after end of NIMH funding (06/30/2023).

Data will be available through the NIMH Data Archive (NDA depositiory).