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Original Investigation | Meta-analysis

Meta-analysis of Functional Neuroimaging of Major Depressive Disorder in Youth

Chris H. Miller, BS1; J. Paul Hamilton, PhD2; Matthew D. Sacchet, ScB1; Ian H. Gotlib, PhD1
[+] Author Affiliations
1Stanford Neurosciences Institute, Department of Psychology, Stanford University, Stanford, California
2Laureate Institute for Brain Research, Tulsa, Oklahoma
JAMA Psychiatry. 2015;72(10):1045-1053. doi:10.1001/jamapsychiatry.2015.1376.
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Importance  Despite its high prevalence and morbidity, the underlying neural basis of major depressive disorder (MDD) in youth is not well understood.

Objectives  To identify in youth diagnosed as having MDD the most reliable neural abnormalities reported in existing functional neuroimaging studies and characterize their relations with specific psychological dysfunctions.

Data Sources  Searches were conducted in PubMed and Web of Science to identify relevant studies published from November 2006 through February 2015. The current analysis took place from August 21, 2014, to March 28, 2015.

Study Selection  We retained articles that conducted a comparison of youth aged 4 to 24 years diagnosed as having MDD and age-matched healthy controls using task-based functional magnetic resonance imaging and a voxelwise whole-brain approach.

Data Extraction and Synthesis  We extracted coordinates of brain regions exhibiting differential activity in youth with MDD compared with healthy control participants. Multilevel kernel density analysis was used to examine voxelwise between-group differences throughout the whole brain. Correction for multiple comparisons was performed by computing null hypothesis distributions from 10 000 Monte Carlo simulations and calculating the cluster size necessary to obtain the familywise error rate control at P < .05.

Main Outcomes and Measures  Abnormal levels of activation in youth diagnosed as having MDD compared with control participants during a variety of affective processing and executive functioning tasks.

Results  Compared with age-matched healthy control participants (n = 274), youth with MDD (n = 246) showed reliable patterns of abnormal activation, including the following task-general and task-specific effects: hyperactivation in subgenual anterior cingulate cortex (P < .05) and ventrolateral prefrontal cortex (P < .05) and hypoactivation in caudate (P < .01) across aggregated tasks; hyperactivation in thalamus (P < .03) and parahippocampal gyrus (P < .003) during affective processing tasks; hypoactivation in cuneus (P < .001), dorsal cingulate cortex (P < .05), and dorsal anterior insula (P < .05) during executive functioning tasks; hypoactivity in posterior insula (P < .005) during positive valence tasks; and hyperactivity in dorsolateral prefrontal cortex (P < .001) and superior temporal cortex (P < .003) during negative valence tasks.

Conclusions and Relevance  Altered activations in several distributed brain networks may help explain the following seemingly disparate symptoms of MDD in youth: hypervigilance toward emotional stimuli from the overactivation of central hubs in the subgenual anterior cingulate cortex and thalamus that lead to a cascade of other symptoms; ineffective emotion regulation despite increased activation of the dorsolateral prefrontal cortex and ventrolateral prefrontal cortex during affective processing, which may reverse across development or the clinical course; maladaptive rumination and poor executive control from difficulties shifting from default mode network activity to task-positive network activity during cognitively demanding tasks; and anhedonia from hypoactivation of the cuneus and posterior insula during reward processing.

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Figure 1.
Brain Regions With Significant Differences in Activation Between Youth With Major Depressive Disorder (MDD) and Age-Matched Healthy Control Participants During Different Experimental Conditions

Brain regions reached significance at P = .05 (familywise error rate corrected) for the contrast of youth with MDD minus healthy control participants. Each brain map displays regions of peak difference shown in Talairach standard space according to neurological format. Positive activation values (warm colors) represent areas of hyperactivity (youth with MDD > healthy control participants) whereas negative activation values (cool colors) represent areas of hypoactivity (healthy control participants > youth with MDD).

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Figure 2.
Neural Basis of Major Depressive Disorder (MDD) in Youth

Brain regions with significant (P < .05, familywise error rate corrected) activation differences between youth with MDD and healthy control participants. Red circles indicate hyperactivity (youth with MDD > healthy control participants), and blue circles indicate hypoactivity (healthy control participants > youth with MDD).

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