A Developmental Shift from Positive to Negative Connectivity in Human Amygdala–Prefrontal Circuitry
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Recent human imaging and animal studies highlight the importance of frontoamygdala circuitry in the regulation of emotional behavior and its disruption in anxiety-related disorders. Although tracing studies have suggested changes in amygdala–cortical connectivity through the adolescent period in rodents, less is known about the reciprocal connections within this circuitry across human development, when these circuits are being fine-tuned and substantial changes in emotional control are observed. The present study examined developmental changes in amygdala–prefrontal circuitry across the ages of 4–22 years using task-based functional magnetic resonance imaging. Results suggest positive amygdala–prefrontal connectivity in early childhood that switches to negative functional connectivity during the transition to adolescence. Amygdala–medial prefrontal cortex functional connectivity was significantly positive (greater than zero) among participants younger than 10 years, whereas functional connectivity was significantly negative (less than zero) among participants 10 years and older, over and above the effect of amygdala reactivity. The developmental switch in functional connectivity was paralleled by a steady decline in amygdala reactivity. Moreover, the valence switch might explain age-related improvement in task performance and a developmentally normative decline in anxiety. Initial positive connectivity followed by a valence shift to negative connectivity provides a neurobiological basis for regulatory development and may present novel insight into a more general process of developing regulatory connections.
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In TD youth, amygdala reactivity to negative faces and images decreases with age, accompanied by greater structural and functional connectivity between amygdala and mPFC/rACC.
“amygdala reactivity to negative faces and images decreases with age [21,33–36], and is accompanied by greater structural and functional connectivity between the amygdala and mPFC/rACC [25,33,34,36].”
From Trauma, PTSD, and the Developing Brain (2017) · cites this paper as [33]
The Results sections report that amygdala reactivity to fearful faces decreased with age and that amygdala–mPFC functional connectivity shifted from positive to more negative across development. The Discussion says the reactivity and connectivity changes were independent. The paper does not establish the broader claim about negative images, greater structural connectivity, or rACC connectivity. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAmygdala-mPFC connectivity partly mediates age-related decreases in normative anxiety.
“amygdala-mPFC connectivity appears to partly mediate age-related decreases in normative anxiety [33].”
From Trauma, PTSD, and the Developing Brain (2017) · cites this paper as [33]
This change in connectivity is associated with reduced subcortical activity in response to emotional cues.
“This shift in connectivity has been associated with decreasing subcortical activity to emotional cues (e.g., [35,41])”
From Development of the emotional brain (2019) · cites this paper as [35]
Human imaging shows that functional coupling between prefrontal and limbic subcortical regions such as the amygdala changes from positive to negative between childhood and adulthood.
“Human imaging studies show that functional coupling between prefrontal and limbic subcortical regions (e.g., amygdala) shifts from positive to negative from childhood to adulthood [35].”
From Development of the emotional brain (2019) · cites this paper as [35]
Compared with subcortical changes, activity in ventromedial prefrontal cortex and its connectivity change more slowly with age.
“In contrast to subcortical changes, activity in ventromedial prefrontal cortex and its connectivity, show more protracted changes with age [18,35].”
From Development of the emotional brain (2019) · cites this paper as [35]
Most studies observe linear decreases in amygdala reactivity to affective stimuli with age.
“Most studies observe linear decreases in amygdala reactivity to affective stimuli with age [30,31,32]”
From Positive and Negative Emotion Regulation in Adolescence: Links to Anxiety and Depression (2019) · cites this paper as [30]
By mid-adolescence, most youth display inverse amygdala-PFC connectivity, with stronger inverse connectivity corresponding to lower symptoms of anxiety in a non-clinical sample.
“By mid-adolescence, most youth display inverse amygdala–PFC connectivity, with stronger inverse connectivity corresponding to lower symptoms of anxiety in a non-clinical sample [30,94].”
From Positive and Negative Emotion Regulation in Adolescence: Links to Anxiety and Depression (2019) · cites this paper as [30]
A shift from positive to inverse amygdala-PFC connectivity occurs from childhood to adolescence.
“A shift from positive to inverse amygdala–PFC connectivity occurs from childhood to adolescence [30].”
From Positive and Negative Emotion Regulation in Adolescence: Links to Anxiety and Depression (2019) · cites this paper as [30]
Structural connections between prefrontal and limbic regions continue to mature during adolescence, resulting in greater top-down control and strengthening routinely used pathways.
“Structural connections between these regions continue to mature during adolescence, resulting in greater top-down control, and strengthening pathways that are called upon routinely (Gee et al., 2013).”
From Neurocognitive bases of emotion regulation development in adolescence (2015) · cites this paper as Gee et al., 2013
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Gabard-Durnam, L. J., Flannery, J., Goff, B., Gee, D. G., Humphreys, K. L., Telzer, E., Hare, T., & Tottenham, N. (2014) · NeuroImage · doi:10.1016/j.neuroimage.2014.03.038 · Cited by 372 · see citing works
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Self-citationStress and adolescence: vulnerability and opportunity during a sensitive window of development
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Self-citationMechanisms contributing to prefrontal cortex maturation during adolescence
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Navigating the Social Environment in Adolescence: The Role of Social Brain Development
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Early-life stress has persistent effects on amygdala function and development in mice and humans
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Self-citationStress and the adolescent brain
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Callaghan, B. L., & Tottenham, N. (2016) · Neuropsychopharmacology · doi:10.1038/npp.2015.204 · Cited by 268 · see citing works
Self-citationThe impact of developmental timing for stress and recovery
Gee, D. G., & Casey, B. J. (2015) · Neurobiology of Stress · doi:10.1016/j.ynstr.2015.02.001 · Cited by 245 · see citing works
“In contrast to the immature positive functional connectivity displayed in comparison children, the children who experienced early-life stress showed the adult-like pattern of inverse amygdala-mPFC functional connectivity (Gee et al., 2013a,b) (Fig.”
BackgroundResultSelf-citationAdolescent neurobiological susceptibility to social context
Schriber, R. A., & Guyer, A. E. (2016) · Developmental Cognitive Neuroscience · doi:10.1016/j.dcn.2015.12.009 · Cited by 246 · see citing works
Trauma, PTSD, and the Developing Brain
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Gunnar, M. R., Hostinar, C. E., Sanchez, M. M., Tottenham, N., & Sullivan, R. M. (2015) · Social Neuroscience · doi:10.1080/17470919.2015.1070198 · Cited by 158 · see citing works
Self-citationFunctional differences in emotion processing during adolescence and early adulthood
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Elevated amygdala response to faces and gaze aversion in autism spectrum disorder
Tottenham, N., Hertzig, M. E., Gillespie-Lynch, K., Gilhooly, T., Millner, A. J., & Casey, B. J. (2014) · Social Cognitive and Affective Neuroscience · doi:10.1093/scan/nst050 · Cited by 144 · see citing works
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“While the present study is the first to examine developmental effects associated with prefrontal–amygdala connectivity during reappraisal, these results are consistent with a growing literature suggesting that differences in prefrontal–subcortical connectivity underlie a host of emotional changes that occur during ado…”
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Prenatal stress alters amygdala functional connectivity in preterm neonates
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Implications of newborn amygdala connectivity for fear and cognitive development at 6-months-of-age
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Altered amygdala connectivity in urban youth exposed to trauma
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“Research in humans and animals consistently demonstrates altered frontoamygdala connectivity is another consequence of early life stress (Gee et al., 2013a; Malter Cohen et al., 2013a; Philip et al., 2013; Grant et al., 2014).”
BackgroundResultInfluentialPrefrontal–Amygdala Dysregulation to Threat in Pediatric Posttraumatic Stress Disorder
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Adolescent nicotine induces persisting changes in development of neural connectivity.
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Social scaffolding of human amygdala-mPFCcircuit development
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Self-citationDevelopmental sex differences in resting state functional connectivity of amygdala sub-regions
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Sensitive periods in affective development: nonlinear maturation of fear learning
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Sex-dependent neural effect of oxytocin during subliminal processing of negative emotion faces.
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- Authors
- Gee, D. G., Humphreys, K. L., Flannery, J., Goff, B., Telzer, E. H., Shapiro, M., Hare, T. A., Bookheimer, S. Y., & Tottenham, N.
- Affiliations
- University of California, Los Angeles (US)
- University of Zurich (CH)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2013-03-06
- Volume
- 33
- Issue
- 10
- Pages
- 4584-4593
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3670947
- OpenAlex
- W2003598308
- Cited by
- 731
- References
- 78
- Citations by year
- 2026: 50 · 2025: 41 · 2024: 41 · 2023: 52 · 2022: 55 · 2021: 68 · 2020: 90 · 2019: 65 · 2018: 66 · 2017: 48 · 2016: 54 · 2015: 52 · 2014: 27 · 2013: 19
- FWCI
- 27.68
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
- Europe PMC (PubMed Central) (acceptedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- National Science Foundation
- National Institute of Mental Health (BRAINS R01, R01MH091864)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Life Sciences › Neuroscience › Cognitive Neuroscience › Functional Brain Connectivity Studies
- Social Sciences › Psychology › Clinical Psychology › Child and Adolescent Psychosocial and Emotional Development
- Keywords
- amygdala, medial prefrontal cortex, functional connectivity, developmental changes, adolescence, childhood, amygdala reactivity, emotion regulation, anxiety
- MeSH terms
- Adolescent, Age Factors, Amygdala, Anxiety, Brain Mapping, Child, Child Development, Child, Preschool, Emotions, Facial Expression, Fear, Female, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Neural Pathways, Oxygen, Regression Analysis, Prefrontal Cortex, Young Adult
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