title: Association of in vivo κ-opioid receptor availability and the transdiagnostic dimensional expression of trauma-related psychopathology.
abstract: OBJECTIVE
  Exposure to trauma increases the risk for developing threat (ie, fear) symptoms, such as reexperiencing and hyperarousal symptoms, and loss (ie, dysphoria) symptoms, such as emotional numbing and depressive symptoms. While preclinical data have implicated the activated dynorphin/κ-opioid receptor (KOR) system in relation to these symptoms, the role of the KOR system in mediating these phenotypes in humans is unknown. Elucidation of molecular targets implicated in threat and loss symptoms is important because it can help inform the development of novel, mechanism-based treatments for trauma-related psychopathology.
  
  
  OBJECTIVE
  To use the newly developed [11C]LY2795050 radiotracer and high-resolution positron emission tomography to evaluate the relation between in vivo KOR availability in an amygdala-anterior cingulate cortex-ventral striatal neural circuit and the severity of threat and loss symptoms. We additionally evaluated the role of 24-hour urinary cortisol levels in mediating this association.
  
  
  METHODS
  This cross-sectional positron emission tomography study under resting conditions was conducted at an academic medical center. Thirty-five individuals representing a broad transdiagnostic and dimensional spectrum of trauma-related psychopathology, ranging from nontrauma-exposed psychiatrically healthy adults to trauma-exposed adults with severe trauma-related psychopathology (ie, posttraumatic stress disorder, major depressive disorder, and/or generalized anxiety disorder).
  
  
  METHODS
  [11C]LY2795050 volume of distribution values in amygdala-anterior cingulate cortex-ventral striatal neural circuit; composite measures of threat (ie, reexperiencing, avoidance, and hyperarousal symptoms) and loss (ie, emotional numbing, major depressive disorder, and generalized anxiety disorder symptoms) symptoms as assessed using the Clinician-Administered PTSD Scale, Hamilton Depression Rating Scale, and Hamilton Rating Scale for Anxiety; and 24-hour urinary cortisol levels.
  
  
  RESULTS
  [11C]LY2795050 volume of distribution values in an amygdala-anterior cingulate cortex-ventral striatal neural circuit were negatively associated with severity of loss (r = -0.39; 95% CI, -0.08 to -0.66), but not threat (r = -0.03; 95% CI, -0.30 to 0.27), symptoms; this association was most pronounced for dysphoria symptoms (r = -0.45; 95% CI, -0.10 to -0.70). Path analysis revealed that lower [11C]LY2795050 volume of distribution values in this circuit was directly associated with greater severity of loss symptoms and indirectly mediated by 24-hour urinary cortisol levels.
  
  
  CONCLUSIONS
  Results of this study suggest that KOR availability in an amygdala-anterior cingulate cortex-ventral striatal neural circuit mediates the phenotypic expression of trauma-related loss (ie, dysphoria) symptoms. They further suggest that an activated corticotropin-releasing factor/hypothalamic-pituitary-adrenal axis system, as assessed by 24-hour urinary cortisol levels, may indirectly mediate this association. These results may help inform the development of more targeted, mechanism-based transdiagnostic treatments for loss (ie, dysphoric) symptoms.
authors.affiliation: US Department of Veterans Affairs National Center for Posttraumatic Stress Disorder, Clinical Neurosciences Division, VA Connecticut Healthcare System, West Haven.|Department of Psychiatry, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Pietrzak
authors.affiliation: Department of Diagnostic Radiology, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Mika
authors.initials: M
authors.lastname: Naganawa
authors.affiliation: Department of Diagnostic Radiology, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Yiyun
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Psychiatry, New York University School of Medicine, New York.|Department of Radiology, New York University School of Medicine, New York.
authors.forename: Stefani
authors.initials: S
authors.lastname: Corsi-Travali
authors.affiliation: Department of Diagnostic Radiology, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Ming-Qiang
authors.initials: MQ
authors.lastname: Zheng
authors.affiliation: Department of Psychiatry, School of Medicine, University of California, San Diego.|Department of Family and Preventive Medicine, School of Medicine, University of California, San Diego.
authors.forename: Murray B
authors.initials: MB
authors.lastname: Stein
authors.affiliation: Department of Diagnostic Radiology, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Shannan
authors.initials: S
authors.lastname: Henry
authors.affiliation: Department of Diagnostic Radiology, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Keunpoong
authors.initials: K
authors.lastname: Lim
authors.affiliation: Department of Diagnostic Radiology, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Jim
authors.initials: J
authors.lastname: Ropchan
authors.affiliation: Department of Diagnostic Radiology, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Shu-Fei
authors.initials: SF
authors.lastname: Lin
authors.affiliation: Department of Diagnostic Radiology, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Carson
authors.affiliation: Department of Psychiatry, New York University School of Medicine, New York.|Department of Radiology, New York University School of Medicine, New York.|Steven and Alexandra Cohen Veterans Center, New York, New York.
authors.forename: Alexander
authors.initials: A
authors.lastname: Neumeister
mesh_terms: D000328:Adult; D000679:Amygdala / Q000378:metabolism*; D001549:Benzamides; D002250:Carbon Radioisotopes; D016022:Case-Control Studies; D003430:Cross-Sectional Studies; D003863:Depression / Q000150:complications / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000652:urine; D005260:Female; D059907:Functional Neuroimaging; D006179:Gyrus Cinguli / Q000378:metabolism*; D006801:Humans; D006854:Hydrocortisone / Q000652:urine; D008297:Male; D009434:Neural Pathways / Q000378:metabolism; D010698:Phobic Disorders / Q000150:complications / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000652:urine; D049268:Positron-Emission Tomography; D011569:Psychiatric Status Rating Scales; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa / Q000378:metabolism*; D013313:Stress Disorders, Post-Traumatic / Q000150:complications / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000652:urine; D066328:Ventral Striatum / Q000378:metabolism*; D014947:Wounds and Injuries / Q000150:complications / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000652:urine; D055815:Young Adult
chemical_list: C570402:3-chloro-4-(4-((2-(3-pyridyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide; D001549:Benzamides; D002250:Carbon Radioisotopes; D011759:Pyrrolidines; D017473:Receptors, Opioid, kappa; D006854:Hydrocortisone