Evolutionarily conserved prefrontal-amygdalar dysfunction in early-life anxiety

R M Birn¹, A J Shackman², J A Oler³, L E Williams³, D R McFarlin⁴, G M Rogers⁵, S E Shelton⁵, A L Alexander⁶, D S Pine⁷, M J Slattery⁵, R J Davidson⁸, A S Fox⁹, N H Kalin¹⁰

Affiliations

¹ 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.
² 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.
³ 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 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 Psychiatry, University of Wisconsin, Madison, WI, USA.
⁶ 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.
⁷ Section on Development and Affective Neuroscience, National Institute of Mental Health, Bethesda, MD, USA.
⁸ 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.
⁹ 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.
¹⁰ 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.

PMID: 24863147
PMCID: PMC4111803
DOI: 10.1038/mp.2014.46

Evolutionarily conserved prefrontal-amygdalar dysfunction in early-life anxiety

R M Birn et al. Mol Psychiatry. 2014 Aug.

. 2014 Aug;19(8):915-22.

doi: 10.1038/mp.2014.46. Epub 2014 May 27.

Authors

R M Birn¹, A J Shackman², J A Oler³, L E Williams³, D R McFarlin⁴, G M Rogers⁵, S E Shelton⁵, A L Alexander⁶, D S Pine⁷, M J Slattery⁵, R J Davidson⁸, A S Fox⁹, N H Kalin¹⁰

Affiliations

¹ 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.
² 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.
³ 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 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 Psychiatry, University of Wisconsin, Madison, WI, USA.
⁶ 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.
⁷ Section on Development and Affective Neuroscience, National Institute of Mental Health, Bethesda, MD, USA.
⁸ 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.
⁹ 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.
¹⁰ 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.

PMID: 24863147
PMCID: PMC4111803
DOI: 10.1038/mp.2014.46

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.

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Conflict of interest statement

Authors declare no conflicts of interest.

Figures

**Fig. 1. Intrinsic functional connectivity of the central nucleus (Ce) of the amygdala in young monkeys**
**A. Method overview.** The seed for functional connectivity analyses (depicted in turquoise) was functionally defined as the 95% spatial confidence interval (CI) surrounding the Ce voxel where FDG metabolism best predicted individual differences in anxious temperament (AT) in a superset of 238 individuals (detailed in Ref. ). Using the mean de-noised echoplanar imaging (EPI) time-series from the seed (see the Method and SI), we computed voxelwise estimates of the strength of functional connectivity for each of the 89 individuals. **B. Regions with significant functional connectivity with the Ce.** Significant (p<.05, corrected) clusters included the dorsolateral prefrontal cortex (dlPFC), pregenual anterior cingulate cortex (pgACC), subgenual ACC (sgACC), bed nucleus of the stria terminalis (BNST), and contralateral Ce. Red lines indicate the locations of the two coronal slices. **Abbreviations—L:** left hemisphere; R: right hemisphere.

**Fig. 2. Prefrontal cortex (PFC)-Ce intrinsic functional connectivity predicts Ce metabolism in young monkeys**
**A. Method overview.** For each monkey, a Ce functional connectivity map was computed and the mean level of FDG metabolism was extracted from the Ce seed (turquoise region). Individual differences in Ce metabolism were used to predict voxelwise functional connectivity with the Ce throughout the brain. B. Decreased functional connectivity with the medial PFC (mPFC) predicts increased Ce metabolism. C. Decreased functional connectivity with the right dorsolateral PFC (dlPFC) predicts increased Ce metabolism. For illustrative purposes, scatter plots depict the partial correlations between connectivity and metabolism for the cluster averages. Axis labels indicate the minimum, maximum, and interquartile range. Partial correlation coefficients computed using robust regression techniques are shown to the right of each scatter plot.

**Fig. 3. Intrinsic functional connectivity between the PFC and Ce predicts individual differences in the AT phenotype in young rhesus monkeys**
**A. Decreased connectivity between the PFC and Ce predicts higher levels of AT.** Upper panel depicts the regions within the mPFC and dlPFC clusters where the strength of functional connectivity significantly predicted variation in both Ce metabolism and AT (displayed in green; p<.05, corrected). Lower panel shows the partial correlation between dlPFC-Ce connectivity and AT (controlling for age and sex). **B. Increased Ce metabolism predicts higher levels of AT. C. Relations between PFC-Ce connectivity and AT are significantly mediated by Ce metabolism.** Summary of the four tests (a-d) incorporated in the multivariate mediation framework (see the SI). For scatter plot conventions, see Fig. 3. Panel depicts results for the dlPFC. Similar results were obtained for the mPFC (see Table S4).

**Fig. 4. Homologous dlPFC subdivisions show decreased intrinsic connectivity with the Ce in anxious children and monkeys**
**A. Children with anxiety disorders at rest.** Bottom-left panel shows the Ce seed (cyan in red ring). Upper-left panel depicts a coronal slice through the human dlPFC cluster (dark orange; p<.05, corrected for the combined volume of the mPFC and right dlPFC; n.s. when corrected for the volume of the whole brain). The intermediate frontal sulcus (IFS) is shown in dark red. Upper-right panel shows the IFS with the location of the coronal slice indicated by the blue vertical line. Bottom-right panel shows the location of the dlPFC cluster relative to the architectonic subdivisions of the human dlPFC. **B. Young monkeys with high levels of AT under anesthesia.** Conventions are similar to A; dark red indicates the location of the sulcus principalis. The bottom-right panels of this figure were adapted with permission from Ref. .

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Evolutionarily conserved prefrontal-amygdalar dysfunction in early-life anxiety

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Evolutionarily conserved prefrontal-amygdalar dysfunction in early-life anxiety

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