Sex differences, hormones, and fMRI stress response circuitry deficits in psychoses.
Response to stress is dysregulated in psychosis (PSY). fMRI studies showed hyperactivity in hypothalamus (HYPO), hippocampus (HIPP), amygdala (AMYG), anterior cingulate (ACC), orbital and medial prefrontal (OFC; mPFC) cortices, with some studies reporting sex differences. We predicted abnormal steroid hormone levels in PSY would be associated with sex differences in hyperactivity in HYPO, AMYG, and HIPP, and hypoactivity in PFC and ACC, with more severe deficits in men. We studied 32 PSY cases (50.0% women) and 39 controls (43.6% women) using a novel visual stress challenge while collecting blood. PSY males showed BOLD hyperactivity across all hypothesized regions, including HYPO and ACC by FWE-correction. Females showed hyperactivity in HIPP and AMYG and hypoactivity in OFC and mPFC, the latter FWE-corrected. Interaction of group by sex was significant in mPFC (F = 7.00, p = 0.01), with PSY females exhibiting the lowest activity. Male hyperactivity in HYPO and ACC was significantly associated with hypercortisolemia post-stress challenge, and mPFC with low androgens. Steroid hormones and neural activity were dissociated in PSY women. Findings suggest disruptions in neural circuitry-hormone associations in response to stress are sex-dependent in psychosis, particularly in prefrontal cortex.
Connors Center for Women׳s Health and Gender Biology, Division of Women׳s Health, Brigham and Women׳s Hospital, Boston, MA, USA; Departments of Psychiatry and Medicine, Harvard Medical School, Boston, MA, USA; Division of Psychiatric Neuroscience, Athinoula A. Martinos Center, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA. Electronic address: jill_goldstein@hms.harvard.edu.
Jill M
JM
Goldstein
Connors Center for Women׳s Health and Gender Biology, Division of Women׳s Health, Brigham and Women׳s Hospital, Boston, MA, USA. Electronic address: katie.lancaster@virginia.edu.
Katie
K
Lancaster
Connors Center for Women׳s Health and Gender Biology, Division of Women׳s Health, Brigham and Women׳s Hospital, Boston, MA, USA. Electronic address: longenecker.julia@gmail.com.
Julia M
JM
Longenecker
Connors Center for Women׳s Health and Gender Biology, Division of Women׳s Health, Brigham and Women׳s Hospital, Boston, MA, USA. Electronic address: brandon.abbs@gmail.com.
Brandon
B
Abbs
Connors Center for Women׳s Health and Gender Biology, Division of Women׳s Health, Brigham and Women׳s Hospital, Boston, MA, USA; Departments of Psychiatry and Medicine, Harvard Medical School, Boston, MA, USA; Division of Psychiatric Neuroscience, Athinoula A. Martinos Center, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA. Electronic address: lholsen@partners.org.
Laura M
LM
Holsen
Connors Center for Women׳s Health and Gender Biology, Division of Women׳s Health, Brigham and Women׳s Hospital, Boston, MA, USA. Electronic address: scherkerzian@partners.org.
Sara
S
Cherkerzian
Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA. Electronic address: swg@mit.edu.
Susan
S
Whitfield-Gabrieli
Departments of Psychiatry and Medicine, Harvard Medical School, Boston, MA, USA; Division of Psychiatric Neuroscience, Athinoula A. Martinos Center, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA. Electronic address: nmakris@partners.org.
Nicolas
N
Makris
Center for Behavior Genomics, Department of Psychiatry, University of California at San Diego, San Diego, CA, USA. Electronic address: mtsuang@ucsd.edu.
Ming T
MT
Tsuang
Department of Community Health, Brown University, Providence, RI, USA. Electronic address: stephen_buka@brown.edu.
Stephen L
SL
Buka
Division of Psychiatric Neuroscience, Athinoula A. Martinos Center, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA; Department of Psychiatry, Harvard Medical School, Boston, MA, USA; Beth Israel Deaconess Medical Center, Division of Public Psychiatry, Massachusetts Mental Health Center and Harvard Medical School, Boston, MA, USA. Electronic address: lseidman@bidmc.harvard.edu.
Larry J
LJ
Seidman
Department of Medicine, Harvard Medical School, Boston, MA, USA; Neuroendocrine Unit, Massachusetts General Hospital, Boston, MA, USA. Electronic address: aklibanski@partners.org.
Anne
A
Klibanski
D000328:Adult; D000679:Amygdala / Q000503:physiopathology*; D001931:Brain Mapping; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000097:blood*; D007031:Hypothalamus / Q000503:physiopathology*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D017397:Prefrontal Cortex / Q000503:physiopathology*; D011618:Psychotic Disorders / Q000097:blood / Q000503:physiopathology*; D012727:Sex Characteristics; D013315:Stress, Psychological / Q000097:blood / Q000503:physiopathology*
D006854:Hydrocortisone
HPA axis; HPG axis; Negative valence affect; Schizophrenia; Sex differences; Stress response