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.
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We acknowledge the assistance of E Ahlers, V Balchen, B Christian, A Converse, L Friedman, M Jesson, E Larson, K Mayer, T Oakes, M Riedel, P Roseboom, J Storey, D Tromp, N Vack, H Van Valkenberg and the staffs of the Harlow Center for Biological Psychology, HealthEmotions Research Institute (HERI), Waisman Center, Waisman Laboratory for Brain Imaging and Behavior and Wisconsin National Primate Center. We thank Julie Fudge, Luiz Pessoa, and several anonymous reviewers for critical feedback. This work was supported by the National Institutes of Health (NIH; Intramural Research Program and extramural grants HD003352, HD008352, MH018931, MH046729, MH081884, MH084051, MH090912, MH091550, OD011106 and RR000167), HERI, Meriter Hospital and the University of Maryland.
The authors declare no conflict of interest.
NHK, JAO, DSP, MJS and SES designed the study. SES collected monkey data. LEW collected human data. ALA optimized imaging methods. DSP, NHK and GMR made childhood psychiatric diagnoses. RMB and ASF developed analytical tools. RMB, JAO, AJS and ASF performed data processing for monkey data. DRM, LEW, JAO, AJS and RMB performed data processing for human data. RMB, AJS, JAO and NHK analyzed monkey data. DRM, LEW, JAO, AJS, RMB and NHK analyzed human data. AJS, NHK, RMB, ASF, JAO, RJD and DSP interpreted data. AJS, ASF, NHK, JAO, LEW and RMB wrote the paper. AJS, ASF and NHK created the figures. AJS, JAO and LEW created the tables. NHK supervised the study. All authors contributed to revising the paper.
Supplementary Information accompanies the paper on the Molecular Psychiatry website
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Birn, R., Shackman, A., Oler, J. et al. Evolutionarily conserved prefrontal-amygdalar dysfunction in early-life anxiety. Mol Psychiatry 19, 915–922 (2014). https://doi.org/10.1038/mp.2014.46
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