title: Fear of the unknown: uncertain anticipation reveals amygdala alterations in childhood anxiety disorders.
abstract: Children with anxiety disorders (ADs) experience persistent fear and worries that are highly debilitating, conferring risk for lifelong psychopathology. Anticipatory anxiety is a core clinical feature of childhood ADs, often leading to avoidance of uncertain and novel situations. Extensive studies in non-human animals implicate amygdala dysfunction as a critical substrate for early life anxiety. To test specific amygdala-focused hypotheses in preadolescent children with ADs, we used fMRI to characterize amygdala activation during uncertain anticipation and in response to unexpected stimuli. Forty preadolescent (age 8-12 years) children, 20 unmedicated AD patients and 20 matched controls completed an anticipation task during an fMRI scan. In the task, symbolic cues preceded fear or neutral faces, such that 'certain' cues always predicted the presentation of fear or neutral faces, whereas 'uncertain' cues were equally likely to be followed by fear or neutral faces. Both AD children and controls showed robust amygdala response to faces. In response to the uncertain cues, AD children had increased amygdala activation relative to controls. Moreover, in the AD children, faces preceded by an 'uncertain' cue elicited increased amygdala activation, as compared with the same faces following a 'certain' cue. Children with ADs experience distress both in anticipation of and during novel and surprising events. Our findings suggest that increased amygdala activation may have an important role in the generation of uncertainty-related anxiety. These findings may guide the development of neuroscientifically informed treatments aimed at relieving the suffering and preventing the lifelong disability associated with pediatric ADs.
authors.affiliation: 1] Department of Psychiatry, Wisconsin Psychiatric Institute and Clinics, University of Wisconsin, Madison, WI, USA [2] HealthEmotions Research Institute, University of Wisconsin, Madison, WI, USA [3] Lane Neuroimaging Laboratory, University of Wisconsin, Madison, WI, USA.
authors.forename: Lisa E
authors.initials: LE
authors.lastname: Williams
authors.affiliation: 1] Department of Psychiatry, Wisconsin Psychiatric Institute and Clinics, University of Wisconsin, Madison, WI, USA [2] HealthEmotions Research Institute, University of Wisconsin, Madison, WI, USA [3] Lane Neuroimaging Laboratory, University of Wisconsin, Madison, WI, USA.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Oler
authors.affiliation: 1] Department of Psychiatry, Wisconsin Psychiatric Institute and Clinics, University of Wisconsin, Madison, WI, USA [2] HealthEmotions Research Institute, University of Wisconsin, Madison, WI, USA [3] Lane Neuroimaging Laboratory, University of Wisconsin, Madison, WI, USA [4] Center for Investigating Healthy Minds, University of Wisconsin, Madison, WI, USA [5] Waisman Laboratory for Brain Imaging and Behavior, University of Wisconsin, Madison, WI, USA.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Fox
authors.affiliation: 1] Department of Psychiatry, Wisconsin Psychiatric Institute and Clinics, University of Wisconsin, Madison, WI, USA [2] HealthEmotions Research Institute, University of Wisconsin, Madison, WI, USA [3] Lane Neuroimaging Laboratory, University of Wisconsin, Madison, WI, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: McFarlin
authors.affiliation: Department of Psychiatry, Wisconsin Psychiatric Institute and Clinics, University of Wisconsin, Madison, WI, USA.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Rogers
authors.affiliation: 1] Department of Psychiatry, Wisconsin Psychiatric Institute and Clinics, University of Wisconsin, Madison, WI, USA [2] HealthEmotions Research Institute, University of Wisconsin, Madison, WI, USA [3] Lane Neuroimaging Laboratory, University of Wisconsin, Madison, WI, USA.
authors.forename: Maria A L
authors.initials: MA
authors.lastname: Jesson
authors.affiliation: 1] Department of Psychiatry, Wisconsin Psychiatric Institute and Clinics, University of Wisconsin, Madison, WI, USA [2] HealthEmotions Research Institute, University of Wisconsin, Madison, WI, USA [3] Center for Investigating Healthy Minds, 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: Richard J
authors.initials: RJ
authors.lastname: Davidson
authors.affiliation: Section on Development and Affective Neuroscience, National Institute of Mental Health, Bethesda, MD, USA.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Pine
authors.affiliation: 1] Department of Psychiatry, Wisconsin Psychiatric Institute and Clinics, University of Wisconsin, Madison, WI, USA [2] HealthEmotions Research Institute, University of Wisconsin, Madison, WI, USA [3] Lane Neuroimaging Laboratory, University of Wisconsin, Madison, WI, USA [4] Center for Investigating Healthy Minds, University of Wisconsin, Madison, WI, USA [5] Waisman Laboratory for Brain Imaging and Behavior, University of Wisconsin, Madison, WI, USA.
authors.forename: Ned H
authors.initials: NH
authors.lastname: Kalin
mesh_terms: D000679:Amygdala / Q000503:physiopathology*; D059031:Anticipation, Psychological / Q000502:physiology*; D001008:Anxiety Disorders / Q000503:physiopathology*; D001931:Brain Mapping; D002648:Child; D003463:Cues; D000066499:Facial Recognition / Q000502:physiology; D005239:Fear / Q000502:physiology; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009483:Neuropsychological Tests; D010775:Photic Stimulation; D035501:Uncertainty