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

Molecular Psychiatry volume 22, pages 724–732 (2017)Cite this article

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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.

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Acknowledgements

Authors acknowledge assistance and critical feedback from A Alexander, A Converse, L Friedman, D Grupe, R Hoks, T Johnson, S Mansavage, K Meyer, L Pessoa, D Pine, P Rudebeck, W Shelledy, M Stockbridge, T Johnstone, E Zao and the staffs of the Harlow Center for Biological Psychology, HealthEmotions Research Institute (HERI), and Wisconsin National Primate Center. We are particularly grateful for the contributions of Helen Van Valkenberg to this work. This work was supported by the National Institutes of Health (DA040717, HD003352, HD008352, MH018931, MH046729, MH069315, MH081884, MH084051, MH091550, MH107444, OD011106 and RR000167), HERI, Meriter Hospital and University of Maryland.

Author contributions

NHK and SES designed the study. RJD provided theoretical guidance. SES collected data. ASF processed data. AJS, ASF, TRO and NHK analyzed data. ASF and TRO developed analytical tools. AJS, ASF, NHK, JAO and RJD contributed to data interpretation. AJS, ASF and NHK wrote the paper. AJS and ASF created figures and tables. NHK supervised the study. All authors reviewed and revised the paper

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  1. A J Shackman and A S Fox: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Psychology, University of Maryland, College Park, MD, USA

    A J Shackman

  2. Neuroscience and Cognitive Science Program, University of Maryland, College Park, MD, USA

    A J Shackman

  3. Maryland Neuroimaging Center, University of Maryland, College Park, MD, USA

    A J Shackman

  4. Department of Psychology and California National Primate Research Center, University of California, Davis, CA, USA

    A S Fox

  5. Department of Psychiatry, University of Wisconsin, Madison, WI, USA

    J A Oler, S E Shelton, R J Davidson & N H Kalin

  6. HealthEmotions Research Institute, University of Wisconsin, Madison, WI, USA

    J A Oler, R J Davidson & N H Kalin

  7. Lane Neuroimaging Laboratory, University of Wisconsin, Madison, WI, USA

    J A Oler & N H Kalin

  8. inseRT MRI, Inc., Middleton, WI, USA

    T R Oakes

  9. Department of Psychology, University of Wisconsin, Madison, WI, USA

    R J Davidson

  10. Center for Investigating Healthy Minds, University of Wisconsin, Madison, WI, USA

    R J Davidson

  11. Waisman Laboratory for Brain Imaging and Behavior, University of Wisconsin, Madison, WI, USA

    R J Davidson & N H Kalin

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  1. A J Shackman
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Shackman, A., Fox, A., Oler, J. et al. Heightened extended amygdala metabolism following threat characterizes the early phenotypic risk to develop anxiety-related psychopathology. Mol Psychiatry 22, 724–732 (2017). https://doi.org/10.1038/mp.2016.132

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