title: Elevated Amygdala Perfusion Mediates Developmental Sex Differences in Trait Anxiety.
abstract: Adolescence is a critical period for emotional maturation and is a time when clinically significant symptoms of anxiety and depression increase, particularly in females. However, few studies relate developmental differences in symptoms of anxiety and depression to brain development. Cerebral blood flow is one brain phenotype that is known to have marked developmental sex differences.
  
  
  
  We investigated whether developmental sex differences in cerebral blood flow mediated sex differences in anxiety and depression symptoms by capitalizing on a large sample of 875 youths who completed cross-sectional imaging as part of the Philadelphia Neurodevelopmental Cohort. Perfusion was quantified on a voxelwise basis using arterial spin-labeled magnetic resonance imaging at 3T. Perfusion images were related to trait and state anxiety using general additive models with penalized splines, while controlling for gray matter density on a voxelwise basis. Clusters found to be related to anxiety were evaluated for interactions with age, sex, and puberty.
  
  
  
  Trait anxiety was associated with elevated perfusion in a network of regions including the amygdala, anterior insula, and fusiform cortex, even after accounting for prescan state anxiety. Notably, these relationships strengthened with age and the transition through puberty. Moreover, higher trait anxiety in postpubertal females was mediated by elevated perfusion of the left amygdala.
  
  
  
  Taken together, these results demonstrate that differences in the evolution of cerebral perfusion during adolescence may be a critical element of the affective neurobiological characteristics underlying sex differences in anxiety and mood symptoms.
authors.affiliation: Departments of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Antonia N
authors.initials: AN
authors.lastname: Kaczkurkin
authors.affiliation: Departments of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Tyler M
authors.initials: TM
authors.lastname: Moore
authors.affiliation: Departments of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Kosha
authors.initials: K
authors.lastname: Ruparel
authors.affiliation: Departments of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Rastko
authors.initials: R
authors.lastname: Ciric
authors.affiliation: Departments of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Monica E
authors.initials: ME
authors.lastname: Calkins
authors.affiliation: Biostatistics and Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Russell T
authors.initials: RT
authors.lastname: Shinohara
authors.affiliation: Radiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Elliott
authors.affiliation: Departments of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Ryan
authors.initials: R
authors.lastname: Hopson
authors.affiliation: Departments of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: David R
authors.initials: DR
authors.lastname: Roalf
authors.affiliation: Biostatistics and Epidemiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Simon N
authors.initials: SN
authors.lastname: Vandekar
authors.affiliation: Departments of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Efstathios D
authors.initials: ED
authors.lastname: Gennatas
authors.affiliation: Departments of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Wolf
authors.affiliation: Departments of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; Philadelphia Veterans Administration Medical Center, Philadelphia, Pennsylvania.
authors.forename: J Cobb
authors.initials: JC
authors.lastname: Scott
authors.affiliation: Emotion and Development Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, Maryland.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Pine
authors.affiliation: Emotion and Development Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, Maryland.
authors.forename: Ellen
authors.initials: E
authors.lastname: Leibenluft
authors.affiliation: Radiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; Neurology,University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: John A
authors.initials: JA
authors.lastname: Detre
authors.affiliation: Departments of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Edna B
authors.initials: EB
authors.lastname: Foa
authors.affiliation: Departments of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; Radiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Raquel E
authors.initials: RE
authors.lastname: Gur
authors.affiliation: Departments of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; Radiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; Emotion and Development Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, Maryland.
authors.forename: Ruben C
authors.initials: RC
authors.lastname: Gur
authors.affiliation: Departments of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. Electronic address: sattertt@upenn.edu.
authors.forename: Theodore D
authors.initials: TD
authors.lastname: Satterthwaite
mesh_terms: D000293:Adolescent; D041923:Adolescent Development / Q000502:physiology*; D000328:Adult; D000679:Amygdala / Q000502:physiology* / Q000503:physiopathology; D001007:Anxiety / Q000503:physiopathology; D002540:Cerebral Cortex / Q000502:physiology* / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000502:physiology*; D002648:Child; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D010551:Personality / Q000502:physiology*; D012727:Sex Characteristics; D013113:Spin Labels; D055815:Young Adult
chemical_list: D013113:Spin Labels
keywords: Adolescence; Amygdala; Anxiety; Cerebral blood flow; Depression; Insula; Perfusion