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Mol Psychiatry. 2017 May;22(5):724-732. doi: 10.1038/mp.2016.132. Epub 2016 Aug 30.

Heightened extended amygdala metabolism following threat characterizes the early phenotypic risk to develop anxiety-related psychopathology.

Shackman AJ1,2,3, Fox AS4, Oler JA5,6,7, Shelton SE5, Oakes TR8, Davidson RJ5,6,9,10,11, Kalin NH5,6,7,11.

Author information

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.
4
Department of Psychology and California National Primate Research Center, University of California, Davis, CA, USA.
5
Department of Psychiatry, University of Wisconsin, Madison, WI, USA.
6
HealthEmotions Research Institute, University of Wisconsin, Madison, WI, USA.
7
Lane Neuroimaging Laboratory, University of Wisconsin, Madison, WI, USA.
8
inseRT MRI, Inc., Middleton, WI, USA.
9
Department of Psychology, University of Wisconsin, Madison, WI, USA.
10
Center for Investigating Healthy Minds, University of Wisconsin, Madison, WI, USA.
11
Waisman Laboratory for Brain Imaging and Behavior, University of Wisconsin, Madison, WI, USA.

Abstract

Children with an anxious temperament are prone to heightened shyness and behavioral inhibition (BI). When chronic and extreme, this anxious, inhibited phenotype is an important early-life risk factor for the development of anxiety disorders, depression and co-morbid substance abuse. Individuals with extreme anxious temperament often show persistent distress in the absence of immediate threat and this contextually inappropriate anxiety predicts future symptom development. Despite its clear clinical relevance, the neural circuitry governing the maladaptive persistence of anxiety remains unclear. Here, we used a well-established nonhuman primate model of childhood temperament and high-resolution 18fluorodeoxyglucose positron emission tomography (FDG-PET) imaging to understand the neural systems governing persistent anxiety and to clarify their relevance to early-life phenotypic risk. We focused on BI, a core component of anxious temperament, because it affords the moment-by-moment temporal resolution needed to assess contextually appropriate and inappropriate anxiety. From a pool of 109 peri-adolescent rhesus monkeys, we formed groups characterized by high or low levels of BI, as indexed by freezing in response to an unfamiliar human intruder's profile. The high-BI group showed consistently elevated signs of anxiety and wariness across >2 years of assessments. At the time of brain imaging, 1.5 years after initial phenotyping, the high-BI group showed persistently elevated freezing during a 30-min 'recovery' period following an encounter with the intruder-more than an order of magnitude greater than the low-BI group-and this was associated with increased metabolism in the bed nucleus of the stria terminalis, a key component of the central extended amygdala. These observations provide a neurobiological framework for understanding the early phenotypic risk to develop anxiety-related psychopathology, for accelerating the development of improved interventions, and for understanding the origins of childhood temperament.

PMID:
27573879
PMCID:
PMC5332536
DOI:
10.1038/mp.2016.132
[Indexed for MEDLINE]
Free PMC Article

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