title: Evolutionarily conserved prefrontal-amygdalar dysfunction in early-life anxiety.
abstract: Some individuals are endowed with a biology that renders them more reactive to novelty and potential threat. When extreme, this anxious temperament (AT) confers elevated risk for the development of anxiety, depression and substance abuse. These disorders are highly prevalent, debilitating and can be challenging to treat. The high-risk AT phenotype is expressed similarly in children and young monkeys and mechanistic work demonstrates that the central (Ce) nucleus of the amygdala is an important substrate. Although it is widely believed that the flow of information across the structural network connecting the Ce nucleus to other brain regions underlies primates' capacity for flexibly regulating anxiety, the functional architecture of this network has remained poorly understood. Here we used functional magnetic resonance imaging (fMRI) in anesthetized young monkeys and quietly resting children with anxiety disorders to identify an evolutionarily conserved pattern of functional connectivity relevant to early-life anxiety. Across primate species and levels of awareness, reduced functional connectivity between the dorsolateral prefrontal cortex, a region thought to play a central role in the control of cognition and emotion, and the Ce nucleus was associated with increased anxiety assessed outside the scanner. Importantly, high-resolution 18-fluorodeoxyglucose positron emission tomography imaging provided evidence that elevated Ce nucleus metabolism statistically mediates the association between prefrontal-amygdalar connectivity and elevated anxiety. These results provide new clues about the brain network underlying extreme early-life anxiety and set the stage for mechanistic work aimed at developing improved interventions for pediatric anxiety.
authors.affiliation: 1] Department of Medical Physics, University of Wisconsin, Madison, WI, USA [2] Department of Psychiatry, University of Wisconsin, Madison, WI, USA [3] HealthEmotions Research Institute, Wisconsin Psychiatric Institute and Clinics, University of Wisconsin, Madison, WI, USA [4] Lane Neuroimaging Laboratory, University of Wisconsin, Madison, WI, USA [5] Waisman Laboratory for Brain Imaging and Behavior, University of Wisconsin, Madison, WI, USA.
authors.forename: R M
authors.initials: RM
authors.lastname: Birn
authors.affiliation: 1] Department of Psychology, University of Maryland, College Park, MD, USA [2] Neuroscience and Cognitive Science Program, University of Maryland, College Park, MD, USA [3] Maryland Neuroimaging Center, University of Maryland, College Park, MD, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Shackman
authors.affiliation: 1] Department of Psychiatry, University of Wisconsin, Madison, WI, USA [2] HealthEmotions Research Institute, Wisconsin Psychiatric Institute and Clinics, University of Wisconsin, Madison, WI, USA [3] Lane Neuroimaging Laboratory, University of Wisconsin, Madison, WI, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Oler
authors.affiliation: 1] Department of Psychiatry, University of Wisconsin, Madison, WI, USA [2] HealthEmotions Research Institute, Wisconsin Psychiatric Institute and Clinics, University of Wisconsin, Madison, WI, USA [3] Lane Neuroimaging Laboratory, University of Wisconsin, Madison, WI, USA.
authors.forename: L E
authors.initials: LE
authors.lastname: Williams
authors.affiliation: 1] Department of Psychiatry, University of Wisconsin, Madison, WI, USA [2] HealthEmotions Research Institute, Wisconsin Psychiatric Institute and Clinics, University of Wisconsin, Madison, WI, USA [3] Lane Neuroimaging Laboratory, University of Wisconsin, Madison, WI, USA [4] Waisman Laboratory for Brain Imaging and Behavior, University of Wisconsin, Madison, WI, USA.
authors.forename: D R
authors.initials: DR
authors.lastname: McFarlin
authors.affiliation: Department of Psychiatry, University of Wisconsin, Madison, WI, USA.
authors.forename: G M
authors.initials: GM
authors.lastname: Rogers
authors.affiliation: Department of Psychiatry, University of Wisconsin, Madison, WI, USA.
authors.forename: S E
authors.initials: SE
authors.lastname: Shelton
authors.affiliation: 1] Department of Medical Physics, University of Wisconsin, Madison, WI, USA [2] Waisman Laboratory for Brain Imaging and Behavior, University of Wisconsin, Madison, WI, USA.
authors.forename: A L
authors.initials: AL
authors.lastname: Alexander
authors.affiliation: Section on Development and Affective Neuroscience, National Institute of Mental Health, Bethesda, MD, USA.
authors.forename: D S
authors.initials: DS
authors.lastname: Pine
authors.affiliation: Department of Psychiatry, University of Wisconsin, Madison, WI, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Slattery
authors.affiliation: 1] Department of Psychiatry, University of Wisconsin, Madison, WI, USA [2] HealthEmotions Research Institute, Wisconsin Psychiatric Institute and Clinics, University of Wisconsin, Madison, WI, USA [3] Waisman Laboratory for Brain Imaging and Behavior, University of Wisconsin, Madison, WI, USA [4] Department of Psychology, University of Wisconsin, Madison, WI, USA [5] Center for Investigating Healthy Minds, University of Wisconsin, Madison, WI, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Davidson
authors.affiliation: 1] Department of Psychiatry, University of Wisconsin, Madison, WI, USA [2] HealthEmotions Research Institute, Wisconsin Psychiatric Institute and Clinics, University of Wisconsin, Madison, WI, USA [3] Lane Neuroimaging Laboratory, University of Wisconsin, Madison, WI, USA [4] Waisman Laboratory for Brain Imaging and Behavior, University of Wisconsin, Madison, WI, USA [5] Department of Psychology, University of Wisconsin, Madison, WI, USA [6] Center for Investigating Healthy Minds, University of Wisconsin, Madison, WI, USA.
authors.forename: A S
authors.initials: AS
authors.lastname: Fox
authors.affiliation: 1] Department of Psychiatry, University of Wisconsin, Madison, WI, USA [2] HealthEmotions Research Institute, Wisconsin Psychiatric Institute and Clinics, University of Wisconsin, Madison, WI, USA [3] Lane Neuroimaging Laboratory, University of Wisconsin, Madison, WI, USA [4] Waisman Laboratory for Brain Imaging and Behavior, University of Wisconsin, Madison, WI, USA [5] Department of Psychology, University of Wisconsin, Madison, WI, USA.
authors.forename: N H
authors.initials: NH
authors.lastname: Kalin
mesh_terms: D000818:Animals; D001007:Anxiety / Q000503:physiopathology*; D001008:Anxiety Disorders / Q000503:physiopathology*; D005075:Biological Evolution; D001931:Brain Mapping; D066274:Central Amygdaloid Nucleus / Q000503:physiopathology*; D002648:Child; D005260:Female; D019788:Fluorodeoxyglucose F18; D006801:Humans; D008253:Macaca mulatta; D008279:Magnetic Resonance Imaging; D008297:Male; D009434:Neural Pathways / Q000503:physiopathology; D049268:Positron-Emission Tomography; D017397:Prefrontal Cortex / Q000503:physiopathology*
chemical_list: D019788:Fluorodeoxyglucose F18