Abnormal Amygdala Resting-State Functional Connectivity in Adolescent Depression
Open accessAbstract
IMPORTANCE: Major depressive disorder (MDD) frequently emerges during adolescence and can lead to persistent illness, disability, and suicide. The maturational changes that take place in the brain during adolescence underscore the importance of examining neurobiological mechanisms during this time of early illness. However, neural mechanisms of depression in adolescents have been understudied. Research has implicated the amygdala in emotion processing in mood disorders, and adult depression studies have suggested amygdala-frontal connectivity deficits. Resting-state functional magnetic resonance imaging is an advanced tool that can be used to probe neural networks and identify brain-behavior relationships. OBJECTIVE: To examine amygdala resting-state functional connectivity (RSFC) in adolescents with and without MDD using resting-state functional magnetic resonance imaging as well as how amygdala RSFC relates to a broad range of symptom dimensions. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional resting-state functional magnetic resonance imaging study was conducted within a depression research program at an academic medical center. Participants included 41 adolescents and young adults aged 12 to 19 years with MDD and 29 healthy adolescents (frequency matched on age and sex) with no psychiatric diagnoses. MAIN OUTCOMES AND MEASURES: Using a whole-brain functional connectivity approach, we examined the correlation of spontaneous fluctuation of the blood oxygen level-dependent signal of each voxel in the whole brain with that of the amygdala. RESULTS: Adolescents with MDD showed lower positive RSFC between the amygdala and hippocampus, parahippocampus, and brainstem (z >2.3, corrected P < .05); this connectivity was inversely correlated with general depression (R = -.523, P = .01), dysphoria (R = -.455, P = .05), and lassitude (R = -.449, P = .05) and was positively correlated with well-being (R = .470, P = .03). Patients also demonstrated greater (positive) amygdala-precuneus RSFC (z >2.3, corrected P < .05) in contrast to negative amygdala-precuneus RSFC in the adolescents serving as controls. CONCLUSIONS AND RELEVANCE: Impaired amygdala-hippocampal/brainstem and amygdala-precuneus RSFC have not previously been highlighted in depression and may be unique to adolescent MDD. These circuits are important for different aspects of memory and self-processing and for modulation of physiologic responses to emotion. The findings suggest potential mechanisms underlying both mood and vegetative symptoms, potentially via impaired processing of memories and visceral signals that spontaneously arise during rest, contributing to the persistent symptoms experienced by adolescents with depression.
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Decreased intrinsic connectivity within limbic regions is linked to increased lassitude.
“↓ intrinsic connectivity within limbic regions linked to ↑ lassitude 153”
From Neuroplasticity in cognitive and psychological mechanisms of depression: an integrative model (2020) · cites this paper as [153]
Depressed adolescents demonstrate increased hyperactivation of the amygdala and aberrant functional connectivity between the amygdala and other emotional regulation areas.
“Previous and current fMRI studies from our group and others consistently show that depressed adolescents demonstrate increased hyperactivation of the amygdala, a key limbic structure involved in emotion generative processing (18) and aberrant functional connectivity between the amygdala and other emotional regulation areas (19, 23, 24).”
Unmedicated adolescents with major depressive disorder show less resting-state fMRI connectivity between hippocampus and amygdala than healthy controls, and this lack of connectivity correlates with depression severity.
“Interestingly, unmedicated adolescents with MDD showed less resting state fMRI (rsfMRI) connectivity between hippocampus and amygdala compared with healthy controls52. This lack of connectivity between hippocampus and amygdala correlated with severity of depression52.”
From Dysregulation of adult hippocampal neuroplasticity in major depression: Pathogenesis and therapeutic implications (2022) · cites this paper as [52]
Altered limbic and intra-hippocampal connectivity has been observed in major depressive disorder.
“In addition to dysfunctional top-down regulation, altered limbic and intra-hippocampal connectivity has been observed in MDD.”
From Dysregulation of adult hippocampal neuroplasticity in major depression: Pathogenesis and therapeutic implications (2022) · cites this paper as [52]
Studies of children and adolescents with major depressive disorder found increased connectivity between the amygdala and parietal and occipital cortices.
“Notably, studies that have examined amygdalar RSFC in children and adolescents with major depressive disorder have found increased connectivity of the amygdala with parietal and occipital cortices (Cullen et al., 2014, Jacobs et al., 2014, Pannekoek et al., 2014);”
From Developmental sex differences in resting state functional connectivity of amygdala sub-regions (2015) · cites this paper as Cullen et al., 2014
Cullen and colleagues found depression-related differences in amygdala seed-based resting-state functional connectivity, but this was not related to suicide severity.
“Cullen and colleagues identify depression-related differences in amygdala seed-based resting state functional connectivity (RSFC), but this is not related to suicide severity (100).”
From Neural correlates associated with suicide and nonsuicidal self-injury in youth (2021) · cites this paper as [100]
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References 74 · Cited by 324
Research works printed but not linked: 1
- [28]Poznanski EO Freman LN Mokros HB Children’s depression rating scale-revised Psychopharmacology Bulletin 1985 21 979 989
- Authors
- Cullen, K. R., Westlund, M. K., Klimes-Dougan, B., Mueller, B. A., Houri, A., Eberly, L. E., & Lim, K. O.
- Affiliations
- University of Minnesota (US)
- Department of Psychology, College of Liberal Arts, University of Minnesota, Minneapolis
- Corresponding author
- Cullen, Kathryn R.
- Venue
- JAMA Psychiatry
- Publisher
- American Medical Association (AMA)
- Published
- 2014-10-01
- Volume
- 71
- Issue
- 10
- Pages
- 1138
- ISSN
- 2168-622X (ISSN-L)
- PMC
- PMC4378862
- OpenAlex
- W2017303933
- Cited by
- 324
- References
- 74
- Citations by year
- 2026: 18 · 2025: 23 · 2024: 30 · 2023: 25 · 2022: 36 · 2021: 47 · 2020: 23 · 2019: 28 · 2018: 29 · 2017: 21 · 2016: 22 · 2015: 20 · 2014: 2
- FWCI
- 12.09
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- JAMA Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (UL1TR000114)
- National Institute of Mental Health (K23MH090421)
- National Institute of Biomedical Imaging and Bioengineering (P41EB015894)
- National Center for Research Resources (P41RR008079)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Functional Brain Connectivity Studies
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- adolescent depression, major depressive disorder, amygdala, resting-state functional connectivity, brainstem, dysphoria, lassitude, well-being, emotional processing, brain maturation, neurobiology of depression, adolescents and young adults, symptom dimensions, brain-behavior relationship
- MeSH terms
- Adolescent, Amygdala, Brain Stem, Child, Cross-Sectional Studies, Major Depressive Disorder, Female, Hippocampus, Humans, Magnetic Resonance Imaging, Male, Neural Pathways, Case-Control Studies, Parahippocampal Gyrus, Young Adult, Functional Neuroimaging
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