Sarah J. Ordaz

Predicting first onset of depression in young girls: Interaction of diurnal cortisol and negative life events.

Interactions between biological vulnerability and environmental adversity are central to the pathophysiology of depression. Given evidence that the hypothalamic-pituitary-adrenal (HPA) axis influences biological responses to environmental events, in the current longitudinal study the authors examined HPA-axis functioning, negative life events, and their interaction as predictors of the first onset of depression. At baseline, girls ages 9 to 14 years provided saliva samples to assess levels of diurnal cortisol production, quantified by total cortisol production (area under the curve with respect to ground; AUCg) and the cortisol awakening response (CAR). The authors then followed these participants until they reached age 18 in order to assess their subsequent experience of negative life events and the onset of a depressive episode. They found that the influence of negative life events on the subsequent onset of depression depended on HPA-axis functioning at baseline. Specifically, negative life events predicted the onset of depression in girls with higher levels of AUCg, but not in girls with lower levels of AUCg. In contrast, CAR did not predict the onset of depression either alone or in interaction with negative life events. These findings suggest that elevated total cortisol production in daily life potentiates susceptibility to environmental adversity and signals the need for early intervention.

The impact of the severity of early life stress on diurnal cortisol: The role of puberty

Researchers have documented dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in children and adolescents who experienced early life stress (ELS). The precise nature of this dysregulation, however, has been difficult to discern. In fact, both elevated and blunted patterns of diurnal cortisol regulation have been reported in children and adolescents exposed to greater ELS, including both reduced and heightened cortisol levels and change in cortisol across the day. These divergent findings may be due to developmental changes in the relation between ELS and HPA-axis functioning. The present study was designed to examine the role of puberty in the impact of the severity of ELS on the regulation of diurnal cortisol. Boys and girls (N=145) ages 9-13 years recruited from lower-risk communities completed an interview about their ELS experiences and at-home collection of diurnal cortisol. ELS experiences were objectively coded for severity, and childrens level of pubertal development was measured using Tanner Staging. Multi-level piecewise mixed-effects models tested the effects of ELS severity and pubertal stage on cortisol levels at waking, the cortisol awakening response (CAR), and the daytime cortisol slope. While we found no significant interactive effects of pubertal stage and ELS severity on cortisol levels at waking or the daytime cortisol slope, findings indicated that pubertal stage interacted with ELS severity to predict the cortisol awakening response (CAR). Specifically, in earlier puberty, higher ELS was associated with a blunted CAR compared to lower ELS; in contrast, in later puberty, higher ELS was associated with a heightened CAR compared to lower ELS. Differences in the relation between ELS severity and the CAR were uniquely determined by puberty, and not by age. By considering and examining the role of puberty, the current study provides a developmental explanation for previous divergent findings of both blunted and heightened patterns of diurnal cortisol following ELS. These results indicate that careful attention should be given to childrens pubertal status before drawing conclusions concerning the nature of diurnal cortisol dysregulation.

Ruminative brooding is associated with salience network coherence in early pubertal youth.

Abstract Rumination, and particularly ruminative brooding, perpetuates dysphoric mood states and contributes to the emergence of depression. Studies of adults and older adolescents have characterized the association between rumination and intrinsic functional connectivity within default mode (DMN), salience (SN) and executive control (ECN) networks; we know little, however, about the brain network basis of rumination during early puberty, a sensitive period for network reorganization. 112 early puberty boys and girls completed resting-state scans, the Ruminative Response Scale, and the Youth Self-Report questionnaire. Using independent components analysis and dual regression, we quantified coherence for each individual in networks of interest (SN, ECN, DMN) and in non-relevant networks (motor, visual) in which we predicted no correlations with behavioral measures. Boys and girls did not differ in levels of rumination or internalizing symptoms, or in coherence for any network. The relation between SN network coherence and rumination; however, and specifically ruminative brooding, was moderated by sex: greater SN coherence was associated with higher levels of brooding in girls but not in boys. Further, in girls, brooding mediated the relation between SN coherence and internalizing symptoms. These results point to coherence within the SN as a potential neurodevelopmental marker of risk for depression in early pubertal girls.

Network basis of suicidal ideation in depressed adolescents.

BACKGROUND Suicidal ideation rates rise precipitously in adolescence, contributing to risk for attempts. Although researchers are beginning to explore the brain basis of attempts in depressed adolescents, none have focused on the basis of ideation, which has implications for prevention. This study examined the association between intrinsic neural network coherence and the severity of suicidal ideation in depressed adolescents. METHODS Forty adolescents diagnosed with Major Depressive Disorder were administered the Columbia-Suicide Severity Rating Scale and underwent resting-state fMRI. We quantified within-network coherence in the executive control (ECN), default mode (DMN), and salience (SN) networks, and in a non-relevant network consisting of noise signal. We associated coherence in each of these networks with the greatest lifetime severity of suicidal ideation experienced, covarying for motion, age of depression onset, and severity of current depressive and anxious symptoms. RESULTS Lower coherence in the left ECN, anterior DMN, and SN were independently associated with greater lifetime severity of suicidal ideation. When including all three significant networks and covariates in a single model, only the left ECN significantly predicted suicidal ideation. LIMITATION Studies with a larger sample size are needed to verify our findings. CONCLUSIONS Our finding of hypoconnectivity in multiple networks extends emerging evidence for hypoconnectivity in adolescent suicidality and is consistent with theoretical conceptualizations of suicidal ideation as a complex set of cognitions associated with cognitive control, self-referential thinking, and processing salient information. While multiple networks could be targets for effective early interventions, those targeting ECN functionality (cognitive control) may be particularly beneficial.

Hyperactivation in Cognitive Control and Visual Attention Brain Regions During Emotional Interference in Adolescent Depression

BACKGROUND Individuals with Major Depressive Disorder (MDD) are characterized by biases in attention to negative emotional material. While there is evidence that anomalous functioning in frontocingulate regions may underlie these biases, we know little about the neural correlates of negative emotional biases in depressed adolescents. METHODS Eighteen adolescents diagnosed with MDD and 21 matched healthy control (CTL) adolescents underwent fMRI while performing an emotional distractor task. On each trial participants were presented with task-relevant house pairs and task-irrelevant face pairs. Participants indicated whether the house pairs were identical while ignoring the face pairs, which were either fearful, sad, or neutral. RESULTS Despite equivalent behavioral performance (response time and accuracy) between groups, adolescents with MDD exhibited greater activation in frontocingulate regions, including dorsal anterior cingulate cortex (dACC) and inferior frontal gyrus/middle frontal gyrus (IFG/MFG), and occipitoparietal regions, including lateral occipital cortex and superior parietal lobule when ignoring fearful versus neutral faces. Response times to these trial conditions also correlated negatively with activation in IFG/MFG and lateral occipital cortex suggesting these regions are recruited in order to effectively ignore emotional distractors. Groups did not differ when ignoring sad versus neutral faces or fearful versus sad faces. CONCLUSIONS Adolescents with MDD recruit both cognitive control and visual attention regions to a greater degree than do CTL adolescents, reflecting greater cognitive demand when downregulating threat-related stimuli.

The Importance of Assessing Neural Trajectories in Pediatric Depression

In this issue of JAMA Psychiatry, Luby et al1 report neuroimagingfindings fromalongitudinal studyof193youthswhowere carefully assessed for clinical depression since preschool and underwent neuroimagingmultiple timesduring early adolescence. Using growth curve modeling, Luby and colleagues characterized trajectories of cortical structure as a functionofdepression.They foundthatglobalvolumeofgray matter, indexed by cortical thickness, declined more steeply inadolescentswithmore severedepression.Given that theage rangemodeled here is characterized by a decrease in volume of graymatter that is posited to reflect synaptic pruning, this finding suggests that synaptic pruning is particularly aggressive in individuals who have experienced symptoms of depression. The research presented by Luby et al highlights the types of clinical questions that can be addressed through longitudinal neuroimaging research. We describe 3 specific ways in which such research can informourunderstanding of psychiatric disorders: by revealing variability in etiologic pathways to disorder, by elucidating how external influences can alter neural trajectories and thereby either contribute to psychiatric disorders or counteract maladaptive developmental processes, and by clarifying critical changes during specific sensitive developmental periods.

Effects of sensitivity to life stress on uncinate fasciculus segments in early adolescence

Abstract Previous research suggests that exposure to early life stress (ELS) affects the structural integrity of the uncinate fasciculus (UF), a frontolimbic white matter tract that undergoes protracted development throughout adolescence. Adolescence is an important transitional period characterized by the emergence of internalizing psychopathology such as anxiety, particularly in individuals with high levels of stress sensitivity. We examined the relations among sensitivity to ELS, structural integrity of the UF, and anxiety symptoms in 104 early adolescents. We conducted structured interviews to assess exposure to ELS and obtained subjective and objective ratings of stress severity, from which we derived an index of ELS sensitivity. We also acquired diffusion MRI and conducted deterministic tractography to visualize UF trajectories and to compute measures of structural integrity from three distinct segments of the UF: frontal, insular, temporal. We found that higher sensitivity to ELS predicted both reduced fractional anisotropy in right frontal UF and higher levels of anxiety symptoms. These findings suggest that fibers in frontal UF, which are still developing throughout adolescence, are most vulnerable to the effects of heightened sensitivity to ELS, and that reduced structural integrity of frontal UF may underlie the relation between early stress and subsequent internalizing psychopathology.

The association between early life stress and prefrontal cortex activation during implicit emotion regulation is moderated by sex in early adolescence

Early life stress (ELS) is a significant risk factor for the emergence of internalizing problems in adolescence. Beginning in adolescence, females are twice as likely as males to experience internalizing disorders. The present study was designed to examine sex differences in the association between ELS and internalizing problems in early pubertal adolescents, and whether and how corticolimbic function and connectivity may underlie these associations. Fifty-nine early pubertal males and 78 early pubertal females, ages 9-13 years (all Tanner Stage 3 or below) underwent functional magnetic resonance imaging as they performed an emotion label task that robustly interrogates corticolimbic function. Participants were also interviewed about their experience of ELS. Females exhibited a positive association between ELS and internalizing problems, whereas males exhibited no such association. Whole-brain and amygdala region of interest analyses indicated that whereas females exhibited a positive association between ELS and the ventrolateral prefrontal cortex during implicit emotion regulation, males showed no such association. Activation in these regions was positively associated with internalizing problems in females but not males; however, activation in these regions did not mediate the association between ELS and internalizing problems. Finally, both boys and girls exhibited an association between ELS and increased negative connectivity between the right ventrolateral prefrontal cortex and bilateral amygdala. Using a carefully characterized sample of early pubertal adolescents, the current study highlights important sex differences in the development of corticolimbic circuitry during a critical period of brain development. These sex differences may play a significant role in subsequent risk for internalizing problems.

Reduced dorsal striatal gray matter volume predicts implicit suicidal ideation in adolescents

Abstract Suicidal ideation (SI), a potent risk factor for suicide attempts, increases in adolescence. While alterations in dopaminergic functioning have been implicated in suicidal acts—particularly in adults—we do not know whether morphological alterations in dopamine‐rich regions of the brain, such as the striatum, are vulnerability factors for the emergence of SI in adolescents. At baseline, a community sample of 152 adolescents (89 female; mean age: 11.41 ± 1.01 years) completed a magnetic resonance imaging (MRI) scan that was used to estimate gray matter volumes (GMVs) of three striatal structures: caudate, nucleus accumbens and putamen. At a 24 month follow‐up session, participants completed a self‐report measure of SI frequency [Suicidal Ideation Questionnaire (SIQ)] and the death version of the Implicit Association Test (IAT). Robust linear regression models were conducted to predict SIQ and IAT scores from striatal GMV. Bilateral putamen and left caudate GMV significantly predicted IAT scores (all Ps < 0.03). No other associations were significant (all Ps > 0.05). Our finding of reduced dorsal striatal GMV predicting implicit SI may indicate that downstream dopaminergic dysfunction is implicated in the development of overt suicidal behaviors. Self‐reported SI was not associated with striatal GMV, suggesting that biological correlates of suicide risk may correlate specifically with objective measurements of SI in adolescents.

Time-varying effects of income on hippocampal volume trajectories in adolescent girls

Children from lower-SES families exhibit smaller hippocampal volume than do their higher-SES peers. Few studies, however, have compared hippocampal developmental trajectories as a function of SES. Thus, it is unclear whether initial rank-order stability is preserved, or whether volumes diverge/converge over the course of adolescence. In a sample of 101 girls ages 10–24 years, we examined the longitudinal association between family income and parental education, proxies for SES, and changes in hippocampal volume. Hippocampal volume was obtained using MRI; using mixed modeling, we examined the effects of income and education on hippocampal volume across age. As expected, changes in volume were non-linear across development. Further, trajectories diverged in mid-adolescence, with lower-income girls exhibiting reductions in hippocampal volume. Maximal income-related differences were observed at 18 years, and trajectories converged thereafter. This interaction remained significant when accounting for maternal hippocampal volume, suggesting a unique contribution of environment over potential heritable differences. In contrast, the association between parental education and offspring hippocampal volume appeared to be stable across adolescence, with higher levels of parental education predicting consistently larger hippocampal volume. These findings constitute preliminary evidence that girls from lower-income homes exhibit unique trajectories of hippocampal growth, with differences most evident in late adolescence.