Early Life Adversity and Psychiatric Symptomatology in Late Adolescence: Neural, Cognitive and Inflammatory Processes

Early life adversity is associated with increased risk for a range of psychiatric disorders, including depression and anxiety disorders. A better understanding of the biological and cognitive processes associated with early life adversity may lead to improved prevention and intervention efforts. Nusslock and Miller’s neuroimmune network hypothesis proposes that early life adversity accentuates cortico-amygdala threat sensitivity and attenuates cortico-basal ganglia reward sensitivity both directly and via inflammatory processes, contributing to emotional and physical health problems. To test the neuroimmune network hypothesis, the current studies examined the associations of fear acquisition, reward anticipation and consumption, and working memory with early life adversity, peripheral inflammation and depression and anxiety symptoms in a sample of 18- to 19-year-olds. Rather than taking a cumulative risk approach, the current studies modeled instances of adversity according to the dimensions of threat and deprivation as proposed by McLaughlin and Sheridan’s dimensional model of adversity and psychopathology. Study 1 found that a deprivation adversity composite was significantly associated with neural activation in regions of interest during the acquisition phase of a differential fear conditioning paradigm, but that this neural activation did not predict subsequent anxiety symptoms. Study 2 found that the deprivation adversity composite was significantly associated with neural activation in the ventral striatum during reward consumption, but that neural activation during reward processing did not predict subsequent depressive symptoms. Study 3 found that the threat adversity composite was significantly associated with working memory task performance for both neutral and negative verbal stimuli, and that slower mean reaction time for a block of mixed neutral and negative words predicted lesser subsequent anxiety symptoms. Peripheral inflammation was not significantly associated with early adversity, neural activation during fear conditioning or reward processing, or working memory. The current studies tested recent theoretical models in early life adversity research, providing insight into the neural, cognitive and inflammatory processes thought to underlie the association between early adversity and psychiatric symptomatology

Early Life Adversity and Psychiatric Symptomatology in Late Adolescence: Neural, Cognitive and Inflammatory Processes

Early life adversity is associated with increased risk for a range of psychiatric disorders, including depression and anxiety disorders. A better understanding of the biological and cognitive processes associated with early life adversity may lead to improved prevention and intervention efforts. Nusslock and Miller’s neuroimmune network hypothesis proposes that early life adversity accentuates cortico-amygdala threat sensitivity and attenuates cortico-basal ganglia reward sensitivity both directly and via inflammatory processes, contributing to emotional and physical health problems. To test the neuroimmune network hypothesis, the current studies examined the associations of fear acquisition, reward anticipation and consumption, and working memory with early life adversity, peripheral inflammation and depression and anxiety symptoms in a sample of 18- to 19-year-olds. Rather than taking a cumulative risk approach, the current studies modeled instances of adversity according to the dimensions of threat and deprivation as proposed by McLaughlin and Sheridan’s dimensional model of adversity and psychopathology. Study 1 found that a deprivation adversity composite was significantly associated with neural activation in regions of interest during the acquisition phase of a differential fear conditioning paradigm, but that this neural activation did not predict subsequent anxiety symptoms. Study 2 found that the deprivation adversity composite was significantly associated with neural activation in the ventral striatum during reward consumption, but that neural activation during reward processing did not predict subsequent depressive symptoms. Study 3 found that the threat adversity composite was significantly associated with working memory task performance for both neutral and negative verbal stimuli, and that slower mean reaction time for a block of mixed neutral and negative words predicted lesser subsequent anxiety symptoms. Peripheral inflammation was not significantly associated with early adversity, neural activation during fear conditioning or reward processing, or working memory. The current studies tested recent theoretical models in early life adversity research, providing insight into the neural, cognitive and inflammatory processes thought to underlie the association between early adversity and psychiatric symptomatology

Heightened neural activity and functional connectivity responses to social rejection in female adolescents at risk for depression: Testing the Social Signal Transduction Theory of Depression

BackgroundAlthough social rejection is among the strongest proximal precipitants of major depressive disorder (MDD), little is known about the underlying neurobiological mechanisms and whether neural sensitivity to social rejection may help explain differences in MDD risk. To address this issue, we tested whether neural responses to social threat differed in female adolescents at high vs. low maternal risk for MDD.MethodFemale adolescents with (high-risk; n = 22, Mage = 14.68) and without (low-risk; n = 30, Mage = 15.07) a maternal history of depression were experimentally exposed to negative and neutral social evaluation while undergoing an fMRI scan. Neural responses were assessed by event-related activity and functional connectivity, as well as multivoxel pattern analysis. Activity and functional connectivity analyses focused on a priori-selected regions of interest implicated in self-referential processing and emotion regulation.ResultsCompared to low-risk female adolescents, high-risk female adolescents exhibited greater increases in self-reported depression and social disconnection following social evaluation. Moreover, compared to low-risk female adolescents, high-risk female adolescents exhibited greater amygdala responses to negative social evaluation and a differential pattern of functional connectivity in brain regions related to emotion regulation, self-referential processing, and negative affect. Additionally, these markers of neural threat reactivity were related to depressive symptoms.LimitationsA cross-sectional study design and relatively small, Western sample.ConclusionsThese results suggest that exaggerated neural reactivity to social threat-and an atypical pattern of related functional connectivity-is evident in individuals with a preclinical risk factor for depression. Targeting such responding may thus be a fruitful strategy for preventing depression in at-risk youth

Reduced autobiographical memory specificity affects general distress through poor social support

Sharing specific autobiographical events is likely to influence the support people give us; a person who shares little detail of their lives may be unlikely to attract social support and this may in turn contribute towards anxious and depressive symptoms. Participants (N = 142) reported memories evoked by negative and positive cue words and these memories were coded for whether or not they referred to a specific event lasting less than 24 h. At this time (T1) and one year later (T2), participants also completed the UCLA Life Stress Interview (LSI), which includes a measure of social support, and measures of depression and anxiety comprising a general distress latent construct. The tendency to recall fewer specific memories was associated with lower social support given by friends and romantic partners and this was in turn associated with elevated general distress at T2, even when accounting for T1 social support and general distress. Our findings contribute to the literature regarding the social function of memory and suggest another route via which reduced specificity contributes to emotional disorders

Individual differences in threat and reward neural circuitry activation:Testing dimensional models of early adversity, anxiety and depression

Altered functioning of the brain's threat and reward circuitry has been linked to early life adversity and to symptoms of anxiety and depression. To date, however, these relationships have been studied largely in isolation and in categorical‐based approaches. It is unclear to what extent early life adversity and psychopathology have unique effects on brain functioning during threat and reward processing. We examined functional brain activity during a face processing task in threat (amygdala and ventromedial prefrontal cortex) and reward (ventral striatum and orbitofrontal cortex) regions of interest among a sample (N = 103) of young adults (aged 18–19 years) in relation to dimensional measures of early life adversity and symptoms of anxiety and depression. Results demonstrated a significant association between higher scores on the deprivation adversity dimension and greater activation of reward neural circuitry during viewing of happy faces, with the largest effect sizes observed in the orbitofrontal cortex. We found no significant associations between the threat adversity dimension, or symptom dimensions of anxiety and depression, and neural activation in threat or reward circuitries. These results lend partial support to theories of adversity‐related alterations in neural activation and highlight the importance of testing dimensional models of adversity and psychopathology in large sample sizes to further our understanding of the biological processes implicated

Psychobiology of Stress and Adolescent Depression (PSY SAD) Study: Protocol overview for an fMRI-based multi-method investigation.

Depression is a common, often recurrent disorder that causes substantial disease burden worldwide, and this is especially true for women following the pubertal transition. According to the Social Signal Transduction Theory of Depression, stressors involving social stress and rejection, which frequently precipitate major depressive episodes, induce depressive symptoms in vulnerable individuals in part by altering the activity and connectivity of stress-related neural pathways, and by upregulating components of the immune system involved in inflammation. To test this theory, we recruited adolescent females at high and low risk for depression and assessed their psychological, neural, inflammatory, and genomic responses to a brief (10 minute) social stress task, in addition to trait psychological and microbial factors affecting these responses. We then followed these adolescents longitudinally to investigate how their multi-level stress responses at baseline were related to their biological aging at baseline, and psychosocial and clinical functioning over one year. In this protocol paper, we describe the theoretical motivations for conducting this study as well as the sample, study design, procedures, and measures. Ultimately, our aim is to elucidate how social adversity influences the brain and immune system to cause depression, one of the most common and costly of all disorders

Childhood unpredictability is associated with increased risk for long- and short-term depression and anhedonia symptoms following combat deployment.

High unpredictability has emerged as a dimension of early-life adversity that may contribute to a host of deleterious consequences later in life. Early-life unpredictability affects development of limbic and reward circuits in both rodents and humans, with a potential to increase sensitivity to stressors and mood symptoms later in life. Here, we examined the extent to which unpredictability during childhood was associated with changes in mood symptoms (anhedonia and general depression) after two adult life stressors, combat deployment and civilian reintegration, which were assessed ten years apart. We also examined how perceived stress and social support mediated and /or moderated links between childhood unpredictability and mood symptoms. To test these hypotheses, we leveraged the Marine Resiliency Study, a prospective longitudinal study of the effects of combat deployment on mental health in Active-Duty Marines and Navy Corpsman. Participants (N = 273) were assessed for depression and anhedonia before (pre-deployment) and 3-6 months after (acute post-deployment) a combat deployment. Additional assessment of depression and childhood unpredictability were collected 10 years post-deployment (chronic post-deployment). Higher childhood unpredictability was associated with higher anhedonia and general depression at both acute and chronic post-deployment timepoints (βs ≥ 0.16, ps ≤.007). The relationship between childhood unpredictability and subsequent depression at acute post-deployment was partially mediated by lower social support (b = 0.07, 95% CI [0.03, 0.15]) while depression at chronic post-deployment was fully mediated by a combination of lower social support (b = 0.14, 95% CI [0.07, 0.23]) and higher perceived stress (b = 0.09, 95% CI [0.05, 0.15]). These findings implicate childhood unpredictability as a potential risk factor for depression in adulthood and suggest that increasing the structure and predictability of childhood routines and developing social support interventions after life stressors could be helpful for preventing adult depression

Exploring joint HPA-inflammatory stress response profiles in adolescent girls : implications for developmental models of neuroendocrine dysregulation

Prior research has struggled to differentiate cortisol stress response patterns reflective of well-regulated versus dysregulated hypothalamic-pituitary-adrenal (HPA) axis function among adolescents. Here, we show how exploring profiles of joint HPA-inflammatory stress responsivity, and linking those profiles to pubertal development and peer stress exposure may aid such distinction. Adolescent girls (N = 157, M-age( )= 14.72 years, SD = 1.38) at risk for psychopathology completed assessments of salivary cortisol and pro-inflammatory cytokines (i.e., tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6) prior to and following the Trier Social Stress Test. Adolescents, a close friend, and a caregiver completed questionnaire measures of peer stress and pubertal status. Multitrajectory modeling of adolescents' cortisol and cytokine levels revealed three profiles: low cortisol response-stably low cytokine (n = 75), high cortisol response-stably moderate cytokine (n = 47), and low cortisol response-stably high cytokine (n = 35). Relative to low cortisol response-stably low cytokine, adolescents exhibiting the high cortisol response-stably moderate cytokine profile were more advanced in their pubertal development, but presented with similarly low levels of peer stress exposure. Despite showing cortisol responses that were indistinguishable from low cortisol response-stably low cytokine, adolescents exhibiting the low cortisol response-stably high cytokine profile were more pubertally advanced, but also more likely to have experienced chronic peer strain (self-report) and relational peer victimization (close friend-report). These findings thus illustrate the potential value of taking a multisystem approach to studying adolescent stress responsivity and underscore the importance of considering developmental and social factors when interpreting cortisol stress response patterns. Ultimately, such work may help inform developmental models of neuroendocrine dysregulation and related risk for psychopathology

Contribution of early-life unpredictability to neuropsychiatric symptom patterns in adulthood.

BackgroundRecent studies in both human and experimental animals have identified fragmented and unpredictable parental and environmental signals as a novel source of early-life adversity. Early-life unpredictability may be a fundamental developmental factor that impacts brain development, including reward and emotional memory circuits, affecting the risk for psychopathology later in life. Here, we tested the hypothesis that self-reported early-life unpredictability is associated with psychiatric symptoms in adult clinical populations.MethodsUsing the newly validated Questionnaire of Unpredictability in Childhood, we assessed early-life unpredictability in 156 trauma-exposed adults, of which 65% sought treatment for mood, anxiety, and/or posttraumatic stress disorder (PTSD) symptoms. All participants completed symptom measures of PTSD, depression and anhedonia, anxiety, alcohol use, and chronic pain. Relative contributions of early-life unpredictability versus childhood trauma and associations with longitudinal outcomes over a 6-month period were determined.ResultsEarly-life unpredictability, independent of childhood trauma, was significantly associated with higher depression, anxiety symptoms, and anhedonia, and was related to higher overall symptom ratings across time. Early-life unpredictability was also associated with suicidal ideation, but not alcohol use or pain symptoms.ConclusionsEarly-life unpredictability is an independent and consistent predictor of specific adult psychiatric symptoms, providing impetus for studying mechanisms of its effects on the developing brain that promote risk for psychopathology

Dysregulation of threat neurocircuitry during fear extinction: the role of anhedonia

Dimensional models of anxiety and depression highlight common and distinct symptom clusters that are thought to reflect disruptions in underlying functional processes. The current study investigated how functioning of threat neurocircuitry relates to symptom dimensions of anxiety and depression. Participants were aged 18-19 years (n = 229, 158 female) and were selected to ensure a range of scores on symptom measures. Symptom dimensions of "General Distress" (common to anxiety disorders and depression), "Fears" (more specific to anxiety disorders), and "Anhedonia-apprehension" (more specific to depression) were evaluated. Participants underwent functional magnetic resonance imaging during a Pavlovian fear conditioning paradigm. Multilevel modeling analyses estimated relationships between symptom dimensions and activation in threat neural circuitry. Exploratory whole brain analyses were also conducted. Threat-related neural activity was not associated with General Distress or Fears. Anhedonia-apprehension was associated with activation of bilateral amygdala, anterior insula and dACC during late extinction. We found no evidence to support an association between symptom dimensions of General Distress or Fears with threat circuitry activation in a large sample of young adults. We did, however, find that the symptom dimension of Anhedonia-apprehension was significantly associated with threat-related neural activation during fear extinction. This effect requires replication in future work but may reflect anhedonic impairments in learning when contingencies are altered, possibly linked to the rewarding relief of an unexpectedly absent threat