Emotional Cognition: Establishing Constructs and Neural-Behavioral Mechanisms in Older Adults With Depression

Emotional Cognition: Establishing Constructs and Neural-Behavioral Mechanisms in Older Adults With Depression (ENSURE; R21 MH130870)

This is a cross-sectional pilot study designed to establish hot and cold cognitive functions and underlying neurocircuitry in older adults with MDD. The investigators will study 120 participants aged 21-80 years old with MDD. All participants will undergo clinical and neurocognitive assessment, and Magnetoencephalography (MEG)/Magnetic resonance imaging (MRI) procedures at one time point. The investigators will also enroll 120 demographically matched comparable, never-depressed healthy participants (controls) to establish cognitive benchmarks. Healthy controls will complete clinical and neurocognitive measures at one time point. To attain a balanced sample of adults across the lifespan, the investigators will enroll participants such that each age epoch (e.g., 21-30, 31-40, etc.) has a total of ten subjects (n=10) in both the healthy control cohort and depressed cohort.

Major depressive disorder (MDD) is a common, chronic, and disabling disorder that affects individuals across the lifespan. Research has consistently found that a core domain of MDD is cognitive dysfunction, with the majority of clinical research focusing on cold cognitive functions such as attention, memory, and executive function. However, emotional "hot" cognitive impairments are also frequently observed in domains such as emotion processing, impulsivity, reward processing, and social cognition, and as with cold cognitive processes, have been implicated in both disease course and treatment outcomes.

The nomenclature of "cold" and "hot" cognitive function has been used to differentiate between those functions that are less influenced by emotional stimuli and/or processes (i.e., "cold" cognitive function) and those that have an emotional component and/or influence (i.e., "hot" cognitive function). The delineation of cold and hot cognitive function has critical implications for new mechanistic explanations and targeted antidepressant treatment development. Other researchers have proposed a testable cognitive neuropsychological model of MDD that describes the interaction of both cold and hot cognitive functions, underlying neurocircuitry, and proposed associated treatments.

Despite ample evidence of impairments associated with hot cognitive processes, behaviors, and associated neural circuity, there is significantly limited information regarding hot cognitive function in adults across the lifespan with MDD. Prior research has been limited by 1) measurement of only one or two hot cognitive functions, 2) no integration of cold and hot cognitive function assessment, and 3) sparse information on hot cognition and associated neurocircuitry in adults over the age of 60. Given the importance of cognitive dysfunction and aging on disease course and overall functioning in MDD, it is critical to identify mechanisms of action and targeted treatment approaches that will improve cognition to achieve the ultimate goal of improving overall disease course, functioning, and quality of life. Identification of brain network alterations associated with particular hot cognitive functions and treatments that modify these regions will move us closer toward personalized medicine and improved patient outcomes. A first critical step in this endeavor is to better characterize hot cognitive dysfunctions in MDD, their relationship to cold cognitive dysfunctions, potential effects of age on these dysfunctions, and information on the associated underlying neurocircuitry in older adults.

In the proposed preliminary study, 120 adults across the lifespan with MDD will complete clinical and cognitive measures, and MEG at one time-point. The investigators will also enroll 120 demographically matched comparable never-depressed healthy controls to establish cognitive benchmarks. The investigators will use existing healthy control data to establish resting-state and task-based MEG benchmarks. The study aims are:

Aim 1. Establish and integrate hot and cold cognitive dysfunction in adults across the lifespan.

H1.1. Adults with MDD compared to healthy controls will have significantly greater hot and cold cognitive dysfunction as measured by a Neuropsychological Test Battery to Evaluate Emotion, Motivation, Impulsivity, and Social Cognition (EMOTICOM) and the California Verbal Learning Test - Third Edition (CVLT-3)/Delis-Kaplan Executive Function System (D-KEFS), respectively.

H1.2. Age will be associated with greater hot and cold cognitive dysfunction.

Aim 2. Establish and compare specific brain networks underlying hot and cold cognitive tasks.

H2.1. EMOTICOM Emotion Recognition and Categorization task scores will be associated with resting-state and task-based MEG connectivity metrics in the salience network,

Inclusion Criteria:

1. Male and female participants
2. Age between 21-80 years old
3. DSM-5 diagnosis of major depressive disorder (MDD) based on Mini Neuropsychiatric Interview
4. Inventory of Depressive Symptomatology-Clinician Rated version (IDS-C) total score > 14
5. Able to read, write, and comprehend English
6. Provide informed consent; willing to comply with study protocol

Exclusion Criteria:

1. History of bipolar disorder, schizophrenia, or schizoaffective disorder
2. Presence of psychotic features
3. Lifetime central nervous system (CNS) disease (including head injury with loss of consciousness > 5 minutes)
4. History of neurodevelopmental disorder (e.g., Autism spectrum disorder)
5. History of medical conditions that can affect neurocognitive function as well as be confounded with age (e.g., thyroid disease, endocrine illnesses)
6. Women who are pregnant
7. Current use of medications with known impacts on neurocognitive function (e.g., acetylcholinesterase inhibitors, amphetamine, methylphenidate, vortioxetine, sedatives)
8. Alcohol/substance use disorder within past 3 months
9. DSM-5 diagnosis of major cognitive impairment
10. Current sensory or physical impairment that interferes with testing.
11. Contraindication to MRI and MEG (only for depressed participants) (e.g., any electronic / metallic implants near or within the head or body, claustrophobia)