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Original Investigation |

Abnormal Amygdala Resting-State Functional Connectivity in Adolescent Depression ONLINE FIRST

Kathryn R. Cullen, MD1; Melinda K. Westlund, BA2; Bonnie Klimes-Dougan, PhD2; Bryon A. Mueller, PhD1; Alaa Houri, BS1; Lynn E. Eberly, PhD3; Kelvin O. Lim, MD1
[+] Author Affiliations
1Department of Psychiatry, School of Medicine, University of Minnesota, Minneapolis
2Department of Psychology, College of Liberal Arts, University of Minnesota, Minneapolis
3Department of Biostatistics, School of Public Health, University of Minnesota, Minneapolis
JAMA Psychiatry. Published online August 13, 2014. doi:10.1001/jamapsychiatry.2014.1087
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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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Figure 1.
Lower Amygdala Functional Connectivity in Adolescents With Major Depressive Disorder (MDD)

A, The cluster resulting from group analysis of amygdala functional connectivity in the controls > MDD contrast, which includes the left hippocampus, parahippocampus, brainstem, orbitofrontal cortex, and temporal pole. The coordinates represent the position of the voxel with the highest intensity in Montreal Neurological Institute standard space (z = 5.00). B, The means (bars within the boxes) and ranges (limit lines) of functional connectivity z scores in this cluster for the 2 groups. The analyses were repeated with the MDD outlier removed and the results remained significant: t67 = 5.77; P < .001. z Values are represented by the color bars. HCs indicates healthy controls.

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Figure 2.
Greater Amygdala Functional Connectivity in Adolescents With Major Depressive Disorder (MDD)

A, The cluster resulting from group analysis of amygdala functional connectivity in the MDD > controls contrast, which includes the bilateral precuneus. The coordinates represent the position of the voxel with the highest intensity in Montreal Neurological Institute standard space (z = 4.3). B, The means (bars within the boxes) and ranges (limit lines) of functional connectivity z scores in this cluster for the 2 groups. z Values are represented by the color bars. HCs indicates healthy controls.

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