Neurobiology of Depression in Children and Adolescents

Since the 1900s it has been theorized that aggression and suicidality are associated with each other. Research has provided empirical support for such theories, including the specific mechanisms which may explain the association between the two variables. While some researchers have begun examining the specific features of aggression and suicidality that are related to each other, this meta-analysis sought to provide an overall estimate of the association between the two variables among adolescents in order to understand the relationship as a whole. Research reports were retrieved by searching databases (e.g., PsycINFO) and reviewing subsequent reference lists. After reviewing potential research reports, 122 (N = 182,623) were selected, and 142 correlations were included in the random-effects meta-analytic model. The average correlation between aggression and suicidality was found to be 0.20, z = 14.53, p < 0.001, 95% CI [0.17, 0.23], I² = 95.0%, and three moderators were found to significantly influence effect sizes. This meta-analysis demonstrates that there can be a moderate correlation between aggression and suicidality among adolescents, however the average effect size might be smaller or larger depending on methodological features of individual research reports. The observed average correlation may also be a conservative estimate due to the analytic choices for this study. Nonetheless, the results from this study could provide a general sense of the relationship between aggression and suicidality in adolescents.

Child maltreatment and abuse represent the most adverse and stressful challenges that confront children in all societies that have been studied. These stressful events probably serve as pathogenic processes for the developing brain. Genetic polymorphisms have been found to interact with environmental adverse factors and result in psychopathology. New data show that the timing of the insult to the developing brain is crucial for the outcome. This effect has biological correlates in the structure of the brain in rodents and probably humans. Future studies will attempt to evaluate this in human subjects using imaging and molecular imaging techniques. Personalized treatments will follow.

Neurophysiologic correlates of depression severity potentially have great utility in diagnosis and treatment planning. Transcranial magnetic stimulation (TMS) measures of cortical inhibition and excitability have shown promise as biomarkers in psychiatry, but no prior work has examined correlates of illness severity in pediatric mood disorders. This study sought to examine the relationship between depression severity and TMS measures of cortical inhibition and excitability in children and adolescents.

Twenty-four depressed and 22 healthy control youth underwent TMS testing (cortical silent period [CSP], short-interval intracortical inhibition at 2-ms and 4-ms interstimulus intervals (ISIs) [SICI-2,-4], resting motor threshold [RMT] and intracortical facilitation at 10-, 15-, and 20-ms ISIs [ICF-10,-15,-20]). Symptom severity was assessed with the Quick Inventory of Depressive Symptomatology (QIDS-A₁₇-SR) and the Children's Depression Rating Scale-Revised (CDRS-R).

In the overall sample, the following significant negative correlations were observed: CDRS-R and CSP (right hemisphere, ρ=−0.35, p=0.021); QIDS-A₁₇-SR and CSP (left, ρ=−0.33, p=0.031; right, ρ=−0.42, p=0.004); and CDRS-R and SICI-4 (right, ρ=−0.30, p=0.042). Among healthy control participants, additional significant negative correlations were observed between QIDS-A₁₇-SR and right ICF-10; QIDS-A₁₇-SR and right ICF-15; and QIDS-A₁₇-SR and left ICF-20. Among depressed participants, significant negative correlations were observed between QIDS-A₁₇-SR and bilateral CSP; CDRS-R and bilateral ICF-10; CDRS-R and bilateral ICF-15; QIDS-A₁₇-SR and left ICF-10; and QIDS-A₁₇-SR and bilateral ICF-15.

Small sample, potential developmental/age- and sex-related effects.

These preliminary results provide evidence for a relationship between depression severity and dysfunction in GABAergic and glutamatergic cortical processes in a pediatric population.

Early stressful life events predict depression and anxiety in carriers of specific polymorphisms and alter brain responses but brain structural phenotypes are largely unknown. We studied the interaction between short-term stress during specific time-windows and emotion-regulation using a genetic animal model of depression, the Wistar–Kyoto (WKY) rat. Brain structural alterations were analyzed using Diffusion Tensor Imaging (DTI). WKY (n=49) and Wistar (n=55) rats were divided into experimental groups: Early stress (ES): From postnatal day (PND) 27 rats were exposed to three consecutive days of stressors; Late stress (LS): From PND 44 rats were exposed to the same protocol; Control: No stressors. From PND 50, all animals were behaviorally tested for levels of anxiety and despair-like behaviors and then scanned. Gene×Environment×Timing (G×E×T) interactions (p=0.00022 after Hochberg correction) were found in ventral orbital cortex, cingulate cortex, external capsule, amygdala and dentate gyrus and in the emotion regulation measures. WKY showed longer immobility in forced swim test, but no effect of ES was detected. ES increased open-field anxiety-like behaviors in Wistar rats but not in WKY, possibly indicating a ceiling effect in WKY. Stress in pre-pubertal or adolescent phases in development may influence structural integrity of specific brain regions and emotion regulation behaviors depending on genetic vulnerability, consistent with a G×E×T interaction in mood dysregulation.

Previous research has indicated that symptom severity and amygdala reactivity during the viewing of facial expressions of emotion are related in depression. However, it remains unclear how early in development this can be detected.

A sample of 11 depressed preschoolers (4.5 ± 0.8; 6 males) participated in an fMRI experiment where they viewed facial expressions of emotion. A region of interest approach was used in order to examine the relationship between amygdala activation and depression severity. Additional whole-brain analyses were conducted and the results of these analyses were examined for potential relationships with depression severity.

Findings indicated that depressed preschoolers exhibited a significant positive relationship between depression severity and right amygdala activity when viewing facial expressions of negative affect. In addition, we found a significant positive relationship between degree of functional activation in the occipital cortex while viewing faces and level of depression severity.

Additional research including a larger sample of depressed preschoolers, as well as a healthy comparison group, is needed to replicate the current findings and examine their specificity at this age.

This is the first study directly examining brain function in depressed preschoolers. The results suggest that, similar to older children and adults with depression, amygdala responsivity and degree of depression severity are related as early as age 3.