Epidemiological studies show that severe childhood adversity explains 32-44% of psychiatric disorders, and is associated with 4.6-fold risk for depression and 6.6-fold risk for substance abuse later in life. Emerging evidence indicates that 20-40% of adults with a history of childhood sexual abuse (CSA) report little to no symptomatology. In spite of these epidemiological data, the neurobiological underpinnings associated with adaptive (resilience) and maladaptive sequelae of CSA remain largely unknown. Preclinical research strongly suggests that early adversity leads to disruptions within mesolimbic and mesocortical dopaminergic pathways critically implicated in reward processing and stress reactivity. These data are consistent with theoretical arguments that a stable and well-functioning reward system and increased prefrontal cortex function might be markers of resilience. The overarching goal of the proposed research is to investigate mesocorticolimbic dopaminergic pathways within young adult females with a history of CSA between the ages of 5-9 years with (CSA/MDD group) and without (CSA/RES group) a current diagnosis of major depressive disorder (MDD). To disentangle CSA- vs. MDD-related effects, these groups will be compared to not only healthy controls but also MDD females without a history of CSA. Moreover, to minimize interpretative issues, participants with a past or current comorbidity of disorders known to affect dopamine and/or striatal pathways (attention deficit hyperactivity disorder, substance dependence/abuse, obsessive compulsive disorder) or disorders that might represent a pathway to depression (post traumatic stress disorder) will be excluded. Finally, to increase study generalizability and recruitment feasibility, co-occurrence of physical abuse with CSA will be allowed in light of prior findings that (1) physical abuse commonly occur with CSA; and (2) co-occurrence of CSA and physical abuse primarily increases the risk of developing MDD. We hypothesize that, relative to healthy control and CSA/RES groups, the CSA/MDD participants will be characterized by (1) reduced reward responsiveness and ventromedial prefrontal cortex activation but cortisol hypersecretion when exposed to an acute psychosocial stress manipulation, (2) reduced dopaminergic transmission, and (3) reduced dopamine transporter binding. These hypotheses will be tested using a novel integration of behavioral, endocrinological, and functional/molecular imaging approaches. Improving our understanding of neurobiological mechanisms associated with different CSA outcomes (specifically MDD and resilience) is of paramount importance in order to (1) identify individuals at risk for psychopathology and maladaptive behavior, (2) prevent revictimization, and (3) develop more targeted therapeutic interventions.

Public Health Relevance

Childhood sexual abuse has been associated with increased risk for psychopathology, revictimization, and health-damaging behavior in adulthood but the neurobiological mechanisms underlying these outcomes remain largely unknown. The goal of the proposed research is to investigate the contributions of mesocorticolimbic dopaminergic mechanisms to adaptive (resilience) and maladaptive (major depression) sequelae of childhood sexual abuse using an innovative integration of behavioral, endocrinological, and functional/molecular imaging approaches. A better understanding of neurobiological underpinnings of abuse-related outcomes will contribute to developing more targeted therapeutic interventions, identifying individuals at risk for psychopathology at a younger age, and preventing revictimization.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
4R01MH095809-04
Application #
9064875
Study Section
Biobehavioral Mechanisms of Emotion, Stress and Health Study Section (MESH)
Program Officer
Borja, Susan
Project Start
2012-09-18
Project End
2017-05-31
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
4
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Mclean Hospital
Department
Type
DUNS #
046514535
City
Belmont
State
MA
Country
United States
Zip Code
Belleau, Emily L; Treadway, Michael T; Pizzagalli, Diego A (2018) The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology. Biol Psychiatry :
Olson, Elizabeth A; Kaiser, Roselinde H; Pizzagalli, Diego A et al. (2018) Anhedonia in Trauma-Exposed Individuals: Functional Connectivity and Decision-Making Correlates. Biol Psychiatry Cogn Neurosci Neuroimaging 3:959-967
Der-Avakian, Andre; Pizzagalli, Diego A (2018) Translational Assessments of Reward and Anhedonia: A Tribute to Athina Markou. Biol Psychiatry 83:932-939
Whitton, Alexis E; Deccy, Stephanie; Ironside, Manon L et al. (2018) Electroencephalography Source Functional Connectivity Reveals Abnormal High-Frequency Communication Among Large-Scale Functional Networks in Depression. Biol Psychiatry Cogn Neurosci Neuroimaging 3:50-58
Ironside, Maria; Kumar, Poornima; Kang, Min-Su et al. (2018) Brain mechanisms mediating effects of stress on reward sensitivity. Curr Opin Behav Sci 22:106-113
Kaiser, Roselinde H; Treadway, Michael T; Wooten, Dustin W et al. (2018) Frontostriatal and Dopamine Markers of Individual Differences in Reinforcement Learning: A Multi-modal Investigation. Cereb Cortex 28:4281-4290
Kaiser, R H; Clegg, R; Goer, F et al. (2018) Childhood stress, grown-up brain networks: corticolimbic correlates of threat-related early life stress and adult stress response. Psychol Med 48:1157-1166
Der-Avakian, Andre; D'Souza, Manoranjan S; Potter, David N et al. (2017) Social defeat disrupts reward learning and potentiates striatal nociceptin/orphanin FQ mRNA in rats. Psychopharmacology (Berl) 234:1603-1614
Whitton, Alexis E; Van't Veer, Ashlee; Kakani, Pragya et al. (2017) Acute stress impairs frontocingulate activation during error monitoring in remitted depression. Psychoneuroendocrinology 75:164-172
Admon, Roee; Treadway, Michael T; Valeri, Linda et al. (2017) Distinct Trajectories of Cortisol Response to Prolonged Acute Stress Are Linked to Affective Responses and Hippocampal Gray Matter Volume in Healthy Females. J Neurosci 37:7994-8002

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