Affect labeling: a promising new neuroscience-based approach to treating combat-related PTSD in veterans.

Introduction: A significant portion of individuals exposed to combat-related trauma will develop posttraumatic stress disorder (PTSD), a severe, debilitating disorder with adverse impacts on both mental and physical functioning. Current treatments are effective for many individuals, however, there is a need for new treatment approaches to improve outcomes in PTSD and address the many existing barriers to seeking or completing treatment. Methods: In this open trial pilot study, we tested a novel, brief, computer-based intervention for PTSD utilizing "affect labeling" that was inspired by recent advances in neuroscience with U.S. veterans. Results: As expected, pre-intervention clinical and fMRI neuroimaging data indicated that U.S. veterans with combat-related PTSD (N = 20) had significantly higher PTSD symptoms, depression symptoms, and amygdala reactivity to trauma cues than trauma-exposed healthy control veterans (N = 20). Veterans with PTSD who completed the affect labeling intervention (N = 13) evidenced reduced PTSD symptoms and these reductions were correlated with reductions in amygdala reactivity. Discussion: Results from this initial proof-of-concept study are intriguing and suggest that affect labeling training offers significant potential as a novel, cost-effective, computer-based intervention for PTSD. Implications and next steps for further developing affect labeling interventions for PTSD are discussed. Clinical Trial Registration: https://clinicaltrials.gov/, identifier NCT05924399.

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 (ßs ≥ 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.

Major stress in early childhood strengthens the association between peripheral inflammatory activity and corticostriatal responsivity to reward.

BACKGROUND: Severe, chronic stress during childhood accentuates vulnerability to mental and physical health problems across the lifespan. To explain this phenomenon, the neuroimmune network hypothesis proposes that childhood stressors amplify signaling between peripheral inflammatory cells and developing brain circuits that support processing of rewards and threats. Here, we conducted a preliminary test of the basic premises of this hypothesis. METHODS: 180 adolescents (mean age = 19.1 years; 68.9 % female) with diverse racial and ethnic identities (56.1 % White; 28.3 % Hispanic; 26.1 % Asian) participated. The Childhood Trauma Interview was administered to quantify early adversity. Five inflammatory biomarkers were assayed in antecubital blood - C-reactive protein, tumor necrosis factor-a, and interleukins-6, -8, and -10 - and were averaged to form a composite score. Participants also completed a functional MRI task to measure corticostriatal responsivity to the anticipation and acquisition of monetary rewards. RESULTS: Stress exposure and corticostriatal responsivity interacted statistically to predict the inflammation composite. Among participants who experienced major stressors in the first decade of life, higher inflammatory activity covaried with lower corticostriatal responsivity during acquisition of monetary rewards. This relationship was specific to participants who experienced major stress in early childhood, implying a sensitive period for exposure, and were evident in both the orbitofrontal cortex and the ventral striatum, suggesting the broad involvement of corticostriatal regions. The findings were independent of participants' age, sex, racial and ethnic identity, family income, and depressive symptoms. CONCLUSIONS: Collectively, the results are consistent with hypotheses suggesting that major stress in childhood alters brain-immune signaling.

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.

BACKGROUND: Although 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. METHOD: Female 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. RESULTS: Compared 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. LIMITATIONS: A cross-sectional study design and relatively small, Western sample. CONCLUSIONS: These 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.

Neural and peripheral markers of reward during positive social evaluation are associated with less clinician-rated depression symptom severity in adolescence.

Although blunted sensitivity to reward is thought to play a key role in promoting risk for depression, most research on this topic has utilized monetary reward paradigms and focused on currently depressed adults. To address this issue, we analyzed neural reward and ß-endorphin data from the Psychobiology of Stress and Adolescent Depression (PSY SAD) Study, which recruited a well-characterized sample of adolescent girls at high vs. low risk for major depressive disorder (MDD) (N = 52, M age = 14.90, SD = 1.35) based on their mothers' lifetime history of MDD. As hypothesized, greater striatal activity while receiving positive (vs. neutral) social evaluation was associated with lower depression symptom severity as independently assessed by the Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS). This association was present for girls at high but not low risk for MDD, suggesting that this neural response may represent a pre-clinical marker of risk for depression. Consistent with these results, higher post-social evaluation levels of a peripheral marker of reward sensitivity, ß-endorphin, were related to lower clinician-rated depression symptom severity. Together, these results indicate that neural and peripheral markers of responsivity to social reward are both related to depression severity, which may have implications for understanding the pathophysiology of depression.

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

BACKGROUND: Recent 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. METHODS: Using 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. RESULTS: Early-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. CONCLUSIONS: Early-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.

Fear-potentiated startle predicts longitudinal change in transdiagnostic symptom dimensions of anxiety and depression.

BACKGROUND: Elevated defensive responding, through startle reflex (SR) and skin conductance response (SCR), may contribute to onset and maintenance of depression and anxiety. Most work examining SR and SCR has predicted psychiatric diagnoses. There is a paucity of research examining links between SR or SCR and dimensional measures of psychopathology. METHODS: We used latent growth curve modeling to predict longitudinal change in three symptom factors (i.e., General Distress, Fears, Anhedonia-Apprehension) from SR and SCR measured during a fear-potentiated startle paradigm among adolescents oversampled for neuroticism (N = 129). RESULTS: Elevated SCR in danger phases before and after an unpleasant muscle contraction predicted increasing Fears over time. Elevated SR in safe phases post-contraction also predicted increasing Fears over time. Attenuated SR in safe phases post-contraction predicted elevated General Distress longitudinally. Attenuated SCR pre-contraction in danger phases predicted elevated Anhedonia-Apprehension over time. LIMITATIONS: Our non-clinical sample may limit generalizability of results. Additionally, we did not assess change in SR and SCR over time. CONCLUSIONS: The present study demonstrates that SR and SCR during a fear-potentiated startle paradigm predict longitudinal change in dimensional anxiety and depression symptom factors and relatedly, that SR and SCR may represent risk factors for the exacerbation of symptomatology.

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, Mage  = 14.72 years, SD = 1.38) at risk for psychopathology completed assessments of salivary cortisol and pro-inflammatory cytokines (i.e., tumor necrosis factor-α, interleukin-1ß, 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.

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.

Prospective examination of pre-trauma anhedonia as a risk factor for post-traumatic stress symptoms.

Background: Anhedonia, the reduction of pleasure and reward-seeking behaviour, is a transdiagnostic symptom with well-described neural circuit mediators. Although typically observed during disease state, extant hypotheses suggest that anhedonia may also be an early risk factor for development of psychopathology. Understanding the contribution of anhedonia to the trauma-response trajectory may bolster inferences about biological mechanisms contributing to pre-trauma risk versus trauma-related symptom expression, knowledge of which could aid in targeted interventions. Objective: Using a prospective, longitudinal design in a population at risk for trauma disorders, we tested the hypothesis that anhedonia may be a pre-trauma risk factor for post-traumatic stress disorder (PTSD) symptoms. Methods: Adult male participants from the Marine Resilience Study (N = 2,593) were assessed across three time-points (pre-deployment, 3-month and 6-month post-deployment). An anhedonia factor was extracted from self-report instruments pre-trauma and tested for its relationship with development of PTSD re-experiencing symptoms after deployment. Results: Higher pre-deployment anhedonia predicted increased PTSD intrusive re-experiencing symptoms at 3- and 6-months post-deployment when controlling for pre-trauma PTSD and depression symptoms. Depression symptoms were not significant predictors of subsequent PTSD intrusive re-experiencing symptoms. Anhedonia at 3 mo also robustly predicted maintenance of PTSD intrusive re-experiencing symptoms at the 6 mo time point. Conclusions: Pre-deployment anhedonia may be a pre-trauma risk factor for PTSD, not simply a state-dependent effect of trauma exposure and PTSD symptom expression. Anhedonia may contribute to persistence and/or chronicity of re-experiencing symptoms after the emergence of PTSD symptoms.

Antecedentes: La anhedonia, reducción del placer y del comportamiento de búsqueda de recompensa, es un síntoma transdiagnóstico con circuitos neurales mediadores bien descritos. Aunque es observada típicamente durante estados patológicos, hipótesis existentes sugieren que la anhedonia puede ser también un factor de riesgo temprano para el desarrollo de psicopatología. La comprensión de la contribución de la anhedonia a la trayectoria de la respuesta al trauma puede reforzar las inferencias sobre los mecanismos biológicos que contribuyen al riesgo pre-trauma versus la expresión sintomática relacionada al trauma, conocimiento que puede ayudar en intervenciones dirigidas.Objetivo: Utilizando un diseño longitudinal prospectivo en una población de riesgo para trastornos traumáticos, probamos la hipótesis de que la anhedonia puede ser un factor de riesgo pre-trauma para síntomas de trastorno de estrés postraumático (TEPT).Métodos: Participantes masculinos adultos del Estudio de Resiliencia de la Marina (N = 2,593) fueron evaluados a lo largo de 3 puntos temporales (antes del despliegue, a los 3 meses, y a los 6 meses post-despliegue). Se extrajo un factor para anhedonia a partir de instrumentos auto-aplicados pre-trauma y fue evaluado por su relación con el desarrollo de síntomas de re-experimentación del TEPT después del despliegue.Resultados: Una anhedonia más alta pre-despliegue predijo un aumento de síntomas de TEPT a los 3 y 6 meses post-despliegue, al controlar con síntomas de TEPT y de depresión pre-trauma. Los síntomas depresivos no fueron predictores significativos de síntomas de TEPT posteriores. La anhedonia a los 3 meses predijo también de forma robusta la mantención de síntomas de TEPT a los 6 meses.Conclusiones: La anhedonia pre-despliegue puede ser un factor de riesgo pre-trauma para TEPT, no sólo como un efecto dependiente del estado de la exposición al trauma y la expresión de síntomas de TEPT. La anhedonia puede contribuir a la persistencia y/o cronicidad de síntomas de re-experimentación tras el inicio de los síntomas de TEPT.

Anhedonia in Posttraumatic Stress Disorder: Prevalence, Phenotypes, and Neural Circuitry.

Anhedonia, the reduction of pleasure and reward-seeking behavior, is a transdiagnostic construct associated with a range of important health outcomes. As with other psychiatric disorders, anhedonia is a relatively common, though understudied, feature of posttraumatic stress disorder (PTSD) that is not adequately targeted by existing treatments. The purpose of this review is to describe the current state of the literature on anhedonia in PTSD and highlight areas for future research based on gaps in the existing evidence base. First, we review evidence for anhedonia symptoms as a distinct PTSD symptom factor and its associations with psychiatric comorbidity, disease trajectory, and quality of life outcomes, as well as describe theories that seek to explain the occurrence of anhedonia among individuals with PTSD. Second, we review evidence for behavioral and neural alterations in reward processing and circuitry, a marker of anhedonia, among individuals with PTSD and in animal models relevant to this disorder. Finally, we discuss key gaps in our understanding of anhedonia in PTSD and suggest areas for future research. Specifically, the timing of anhedonia symptom development and underlying circuit dysfunction in the trauma response trajectory, as well as potential differential associations of facets of anhedonia on clinical outcomes, remain unclear. Additionally, further research is needed to determine potential moderators of anhedonia, as well as the efficacy and effectiveness of psychotherapeutic, psychopharmacological, and device-based interventions targeting anhedonia among individuals with PTSD. A more thorough understanding of these topics will ultimately improve prevention and intervention efforts for PTSD.

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.

Dysregulation of threat neurociruitry 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.

Neuroticism and interpretive bias as risk factors for anxiety and depression.

Neuroticism has been associated with depression and anxiety both cross-sectionally and longitudinally. Interpretive bias has been associated with depression and anxiety, primarily in cross-sectional and bias induction studies. The purpose of the current study was to examine the role of interpretive bias as a prospective risk factor and a mediator of the relation between neuroticism and depressive and anxious symptoms in young adults assessed longitudinally. Neuroticism significantly predicted a broad general distress dimension, but not intermediate fears and anhedonia-apprehension dimensions, nor a narrow social fears dimension. Neuroticism also significantly predicted negative interpretive bias for social scenarios. Negative interpretive bias for social scenarios did not significantly predict dimension scores, nor did it mediate the relation between neuroticism and general distress or social fears. These results suggest that although neuroticism relates to negative interpretive bias, its risk for symptoms of depression and anxiety is at most weakly conferred through negative interpretive bias.

Using Neuroscience to Augment Behavioral Interventions for Depression.

Depression is both prevalent and costly, and many individuals do not adequately respond to existing psychopharmacological and behavioral interventions. The current article describes the use of neuroscience in augmenting behavioral interventions for depression in two primary areas: anhedonia and cognitive deficits/biases. Neuroscience research has increased our understanding of the neural bases of reward processing and regulation of positive affect, and anhedonia among depressed samples can be related to deficits in each of these domains. Treatments that specifically target reward processing and regulation of positive affect in order to reduce anhedonia represent a recent advance in the field. Depression is also associated with aberrant processes relating to working memory, autobiographical memory, attentional bias, and interpretive bias. Neuroscience findings have increasingly been leveraged to augment the efficacy of cognitive-training and bias-modification interventions in these domains. The use of neuroscience to inform the development and augmentation of behavioral interventions for depression is a promising avenue of continued research.

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.