Nearly half of all HIV patients eventually develop neuropsychiatric difficulties, despite advances in combined antiretroviral therapy (cART) permitting greater control of viral migration into the brain post-infection. Increased importance has thus been placed on understanding the role that comorbid conditions play in the etiology of HIV-related neurocognitive and psychological disorders in the cART era. This K23 proposal takes the novel approach of investigating early-life stress (ELS), as a comorbid risk factor for increased neuropsychiatric impairments in HIV patients. Such an investigation is critical given that high ELS, which is known to cause significant brain abnormalities, is common among HIV+ individuals. Preliminary structural MRI findings indicate that HIV and high ELS have combined effects on brain volume, specifically in the amygdala, which correlate with cognitive impairments in HIV patients. The proposed K23 study will investigate the independent and combined effects of HIV and high ELS on amygdala function using functional magnetic resonance imaging (fMRI), which offers a more direct method of examining brain dysfunction than structural MRI. The study employs a cross sectional 2x2 design that will include 50 HIV+ and 50 HIV-seronegative control participants, with and without high ELS (4 groups of 25 participants). The primary dependent variables will be measures of fMRI blood oxygen level dependent (BOLD) response during cognitive and emotional tasks, and performances on cognitive and psychological measures assessed outside of the MRI scanner. The study will test whether HIV and high-ELS interact to: 1) increase abnormalities in amygdala fMRI BOLD response, and 2) reduce the functional connectivity between amygdala and frontal lobe regions. It will also test whether these two fMRI measures are associated with cognitive and psychological dysfunction in HIV patients. Exploratory analyses will test the relation of fMRI measures to plasma biomarkers of inflammation (e.g., cytokines). It is hypothesized that HIV+ high-ELS patients will display increased amygdala BOLD response and reduced amygdala-frontal lobe connectivity, which will correlate with cognitive and psychological dysfunction and biomarker abnormalities. The long-term objective of this research program is to better understand the mechanisms through which high ELS increases neural dysfunction in HIV patients, in order to improve our ability to prevent, assess, and treat HIV-related neuropsychiatric disorders. This 5-year award aims to foster the PI's transition into becoming an independent fMRI investigator whose research examines the etiology of neuropsychiatric disorders in HIV patients. The PI is trained in clinical neuropsychology and structural MRI investigations of HIV-related neural abnormalities. The proposed training plan will provide coursework and mentorship at Brown University to build the PI's expertise in 3 vital areas: fMRI methodology, the cognitive sequelae of neuroAIDS, and the biological correlates of ELS. This K23 addresses key issues in the etiology of neuroAIDS, and will fully prepare the PI to conduct independent patient-oriented research in this field.

Public Health Relevance

This study will provide valuable information about the lasting effects of high levels of childhood adversity ('early-life stress') on brain functions in adults wih and without HIV. We will obtain a novel understanding of the biological mechanisms associated with high levels of early-life stress that lead to increased risk for cognitive and emotional dysfunction in HIV+ patients and otherwise healthy adults. This research will build the necessary groundwork for future studies that aim to reduce and prevent brain abnormalities that result from high levels of early-life adversity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23MH096628-04
Application #
8843745
Study Section
Behavioral and Social Consequences of HIV/AIDS Study Section (BSCH)
Program Officer
Stoff, David M
Project Start
2012-05-23
Project End
2018-04-30
Budget Start
2015-05-01
Budget End
2016-04-30
Support Year
4
Fiscal Year
2015
Total Cost
$176,916
Indirect Cost
$13,105
Name
Icahn School of Medicine at Mount Sinai
Department
Neurology
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
M Elicer, Isabel; Byrd, Desiree; Clark, Uraina S et al. (2018) Motor function declines over time in human immunodeficiency virus and is associated with cerebrovascular disease, while HIV-associated neurocognitive disorder remains stable. J Neurovirol 24:514-522
Clark, Uraina S; Miller, Evan R; Hegde, Rachal R (2018) Experiences of Discrimination Are Associated With Greater Resting Amygdala Activity and Functional Connectivity. Biol Psychiatry Cogn Neurosci Neuroimaging 3:367-378
Clark, Uraina S; Arce RenterĂ­a, Miguel; Hegde, Rachal R et al. (2018) Early Life Stress-Related Elevations in Reaction Time Variability Are Associated with Brain Volume Reductions in HIV+ Adults. Front Behav Neurosci 12:6
Robinson-Papp, Jessica; Navis, Allison; Dhamoon, Mandip S et al. (2018) The Use of Visual Rating Scales to Quantify Brain MRI Lesions in Patients with HIV Infection. J Neuroimaging 28:217-224
Holmes, Christopher; Owens, Max; Beach, Steven R H et al. (2018) Peer influence, Frontostriatal connectivity, and delay discounting in African American emerging adults. Brain Imaging Behav :
Windle, Michael; Gray, Joshua C; Lei, Karlo Mankit et al. (2018) Age sensitive associations of adolescent substance use with amygdalar, ventral striatum, and frontal volumes in young adulthood. Drug Alcohol Depend 186:94-101
Clark, Uraina S; Sweet, Lawrence H; Morgello, Susan et al. (2017) High early life stress and aberrant amygdala activity: risk factors for elevated neuropsychiatric symptoms in HIV+ adults. Brain Imaging Behav 11:649-665
Day, Anne M; Kahler, Christopher W; Ahern, David C et al. (2015) Executive Functioning in Alcohol Use Studies: A Brief Review of Findings and Challenges in Assessment. Curr Drug Abuse Rev 8:26-40
Alosco, Michael L; Gunstad, John; Beard, Courtney et al. (2015) The synergistic effects of anxiety and cerebral hypoperfusion on cognitive dysfunction in older adults with cardiovascular disease. J Geriatr Psychiatry Neurol 28:57-66
Clark, Uraina S; Walker, Keenan A; Cohen, Ronald A et al. (2015) Facial emotion recognition impairments are associated with brain volume abnormalities in individuals with HIV. Neuropsychologia 70:263-71

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