Depression and anxiety disorders together account for the majority of mental health disorders in childhood and adolescence, and are often comorbid.
The frequent co-occurrence of these disorders has ...motivated clinicians and researchers to consider dimensional taxonomy models that focus on neurobiological substrates that explain transdiagnostic constructs of functioning (eg, reward processing abnormalities). Such an approach would redefine not only depression and anxiety disorders but could also revolutionize clinical care, as such biobehavioral targets, rather than a traditional primary diagnosis, could serve as the basis for treatment planning. In this issue of the Journal, Auerbach et al.
examined whether and how a key structure involved in reward processing, the nucleus accumbens (NAcc), is altered in adolescents aged 14 to 17 years with depression and/or anxiety (including generalized anxiety, separation anxiety, social anxiety, specific phobia, agoraphobia, and panic) disorders, and whether NAcc morphometry and function would improve prediction of 6-month symptomatology. As part of the Boston Adolescent Neuroimaging of Depression and Anxiety (BANDA) initiative,
the researchers compared 129 adolescents with primary diagnoses of depression and/or anxiety and 64 psychiatrically healthy controls on gray matter volumes of the NAcc and on functional activation of the NAcc during a monetary incentive delay task using magnetic resonance imaging (MRI) protocols harmonized with the Human Connectome project (http://www.humanconnectomeproject.com/). Compared to healthy adolescents, depressed/anxious adolescents exhibited significantly smaller volumes of the NAcc and blunted NAcc responses to reward receipt. Among the 88 depressed/anxious adolescents and 57 healthy controls who provided symptom data 6 months later, the researchers also found that inclusion of NAcc volumes, but not reward-related responses of the NAcc on the task, significantly improved statistical prediction of subsequent depression symptoms.
Abstract
Early exposure to psychosocial adversity is among the most potent predictors of depression. Because depression commonly emerges prior to adulthood, we must consider the fundamental ...principles of developmental neuroscience when examining how experiences of childhood adversity, including abuse and neglect, can lead to depression. Considering that both the environment and the brain are highly dynamic across the period spanning gestation through adolescence, the purpose of this review is to discuss and integrate stress-based models of depression that center developmental processes. We offer a general framework for understanding how psychosocial adversity in early life disrupts or calibrates the biobehavioral systems implicated in depression. Specifically, we propose that the sources and nature of the environmental input shaping the brain, and the mechanisms of neuroplasticity involved, change across development. We contend that the effects of adversity largely depend on the developmental stage of the organism. First, we summarize leading neurobiological models that focus on the effects of adversity on risk for mental disorders, including depression. In particular, we highlight models of
allostatic load, acceleration maturation, dimensions of adversity, and sensitive or critical period
s. Second, we expound on and review evidence for the formulation that distinct mechanisms of neuroplasticity are implicated depending on the timing of adverse experiences, and that inherent within certain windows of development are constraints on the sources and nature of these experiences. Finally, we consider other important facets of adverse experiences (e.g., environmental unpredictability, perceptions of one’s experiences) before discussing promising research directions for the future of the field.
Suicide is the second leading cause of death among adolescents. While clinicians and researchers have begun to recognize the importance of considering multidimensional factors in understanding risk ...for suicidal thoughts and behaviors (STBs) during this developmental period, the role of puberty has been largely ignored. In this review, we contend that the hormonal events that occur during puberty have significant effects on the organization and development of brain systems implicated in the regulation of social stressors, including amygdala, hippocampus, striatum, medial prefrontal cortex, orbitofrontal cortex, and anterior cingulate cortex. Guided by previous experimental work in adults, we also propose that the influence of pubertal hormones and social stressors on neural systems related to risk for STBs is especially critical to consider in adolescents with a neurobiological sensitivity to hormonal changes. Furthermore, facets of the pubertal transition, such as pubertal timing, warrant deeper investigation and may help us gain a more comprehensive understanding of sex differences in the neurobiological and psychosocial mechanisms underlying adolescent STBs. Ultimately, advancing our understanding of the pubertal processes that contribute to suicide risk will improve early detection and facilitate the development of more effective, sex-specific, psychiatric interventions for adolescents.
Despite the significant prevalence of adolescent depression, little is known about the neuroanatomical basis of this disorder. Functional dysregulation in frontolimbic circuitry has been suggested as ...a key neural correlate of adult and adolescent depression impeding emotional regulation. However, less is known about whether this dysregulation is overlaid on impaired white matter microstructure. Guided by neuroimaging findings, we test the a priori hypotheses that adolescent depression is associated with alterations in white matter microstructure in the uncinate fasciculus (UF) and cingulum bundles.
Diffusion tensor magnetic resonance imaging (DTI) data were obtained on 52 unmedicated adolescents with major depressive disorder (MDD) and 42 matched controls. We calculated fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD) for bilateral UF and cingulum. We also completed a voxelwise comparison of participants with depression and control participants using tract-based spatial statistics (TBSS).
Adolescents with depression had significantly lower FA and higher RD in bilateral UF; no significant differences were observed in cingulum. TBSS results additionally revealed lower FA values in the white matter associated with the limbic-cortical-striatal-thalamic circuit, corpus callosum, and anterior and superior corona radiata.
Unmedicated adolescent depression is associated with reduced fractional anisotropy in emotion regulatory networks, which may underlie the functional differences in frontolimbic circuitry characterizing depressive disorder. Given the relatively recent onset of depression in our sample, our findings in the context of the current literature provide preliminary evidence that reduced fractional anisotropy in the UF could be a predisposing risk factor for depression.
Background Very few studies have been performed to understand the underlying neural substrates of adolescent major depressive disorder (MDD). Studies in depressed adults have demonstrated that the ...subgenual anterior cingulate cortex (sgACC) plays a pivotal role in depression and have revealed aberrant patterns of resting-state functional connectivity (RSFC). Here, we examine the RSFC of the sgACC in medication-naïve first-episode adolescents with MDD. Methods Twenty-three adolescents with MDD and 36 well-matched control subjects underwent functional magnetic resonance imaging to assess the RSFC of the sgACC. Results We observed elevated connectivity between the sgACC and the insula and between the sgACC and the amygdala in the MDD group compared with the control subjects. Decreased connectivity between the sgACC and the precuneus was also found in the MDD group relative to the control subjects. Within the MDD group, higher levels of depression significantly correlated with decreased connectivity between the sgACC and left precuneus. Increased rumination was significantly associated with reduced connectivity between sgACC and the middle and inferior frontal gyri in the MDD group. Conclusions Our study is the first to examine sgACC connectivity in medication-naïve first-episode adolescents with MDD compared with well-matched control participants. Our results suggest aberrant functional connectivity among the brain networks responsible for salience attribution, executive control, and the resting-state in the MDD group compared with the control participants. Our findings raise the possibility that therapeutic interventions that can restore the functional connectivity among these networks to that typical of healthy adolescents might be a fruitful avenue for future research.
Abstract Background The incidence of major depressive disorder (MDD) rises during adolescence, yet the neural mechanisms of MDD during this key developmental period are unclear. Altered amygdala ...resting-state functional connectivity (RSFC) has been associated with both adolescent and adult MDD, as well as symptom improvement in response to treatment in adults. However, no study to date has examined whether amygdala RSFC is associated with changes in depressive symptom severity in adolescents. Method We examined group differences in amygdala RSFC between medication-naïve depressed adolescents (N=48) and well-matched healthy controls (N=53) cross-sectionally. We then longitudinally examined whether baseline amygdala RSFC was associated with change in depression symptoms three months later in a subset of the MDD group (N=24). Results Compared to healthy controls, depressed adolescents showed reduced amygdala-based RSFC with the dorsolateral prefrontal cortex (DLPFC)and the ventromedial prefrontal cortex (VMPFC). Within the depressed group, more positive baseline RSFC between the amygdala and insulae was associated with greater reduction in depression symptoms three months later. Limitations Only a subset of depressed participants was assessed at follow-up and treatment type and delivery were not standardized. Conclusions Adolescent depression may be characterized by dysfunction of frontolimbic circuits (amygdala-DLPFC, amygdala-VMPFC) underpinning emotional regulation, whereas those circuits (amygdala-insula) subserving affective integration may index changes in depression symptom severity and may therefore potentially serve as a candidate biomarker for treatment response. Furthermore, these results suggest that the biomarkers of MDD presence are distinct from those associated with change in depression symptoms over time.
IMPORTANCE: Adolescence is a neurodevelopmental period during which experience-dependent plasticity in brain circuitry may confer vulnerability to depression as well as resilience to disorder. Little ...is known, however, about the neural mechanisms that underlie resilience during this critical period of brain development. OBJECTIVE: To examine neural functional connectivity correlates of resilience in adolescent females at high and low familial risk for depression who did and did not develop the disorder. DESIGN, SETTING, AND PARTICIPANTS: A longitudinal study was conducted at Stanford University from October 1, 2003, to January 31, 2017. Sixty-five female adolescents participated in the study: 20 at high risk in whom depression did not develop (resilient), 20 at high risk in whom depression developed (converted), and 25 at low risk with no history of psychopathology (control). MAIN OUTCOMES AND MEASURES: We compared functional connectivity between resilient and converted, and between resilient and control, adolescent females using voxelwise 2-sided t tests to examine neural markers of resilience to depression as the main outcomes of interest. Specifically, we assessed differences in connectivity of the limbic (amygdala seed), salience (anterior insula seed), and executive control (dorsolateral prefrontal cortex seed) networks, implicated in emotion regulation. We also examined the association between functional connectivity and life events. RESULTS: Of the 65 participants (mean SD age, 18.9 2.5 years), adolescent females in the resilient group had greater connectivity between the amygdala and orbitofrontal cortex (z score = 0.23; P < .001) and between the dorsolateral prefrontal cortex and frontotemporal regions (z score = 0.24; P < .001) than did converted adolescent females. In adolescent females in the resilient group only, strength of amygdala-orbitofrontal cortex connectivity was correlated with positive life events (r18 = 0.48; P = .03). Resilient adolescent females had greater connectivity within frontal (z score = 0.07; P < .001) and limbic (z score = 0.21; P < .001) networks than did control individuals. Both high-risk groups had greater salience network connectivity: the converted group had greater intranetwork connectivity than did the resilient (z score = 0.13; P < .001) and control (z score = 0.10; P < .001) groups, and the adolescent females in the resilient group had greater salience network connectivity with the superior frontal gyrus than did the converted (z score = 0.24; P < .001) adolescent females. CONCLUSIONS AND RELEVANCE: Resilient adolescent females have compensatory functional connectivity patterns in emotion regulatory networks that correlate with positive life events, suggesting that experience-dependent plasticity within these networks may confer resilience to depression. Further studies are warranted concerning connectivity-associated targets for promoting resilience in high-risk individuals.
Exposure to early life stress (ELS) is alarmingly prevalent and has been linked to the high rates of depression documented in adolescence. Researchers have theorized that ELS may increase ...adolescents' vulnerability or reactivity to the effects of subsequent stressors, placing them at higher risk for developing symptoms of depression.
We tested this formulation in a longitudinal study by assessing levels of stress and depression during the COVID-19 pandemic in a sample of adolescents from the San Francisco Bay Area (
= 109; 43 male; ages 13-20 years) who had been characterized 3-7 years earlier (
= 5.06,
= 0.86 years) with respect to exposure to ELS and symptoms of depression.
As expected, severity of ELS predicted levels of depressive symptoms during the pandemic
(107) = 0.26,
= 0.006, which were higher in females than in males
(107) = -3.56,
< 0.001. Importantly, the association between ELS and depression was mediated by adolescents' reported levels of stress, even after controlling for demographic variables.
These findings underscore the importance of monitoring the mental health of vulnerable children and adolescents during this pandemic and targeting perceived stress in high-risk youth.
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