Differential effects of early life stress on hippocampus and amygdala volume as a function of emotional abilities

Early life stress (ELS) is known to have considerable influence on brain development and affective functioning. Previous studies in clinical populations have shown that hippocampus and amygdala, two central structures of limbic emotion processing circuits, are predominantly affected by early stress exposure. Given the inconsistent findings on ELS‐related effects in healthy populations and the associations of ELS and affective functioning, the question arises which additional emotion‐relevant variables need to be considered to better understand the effects of ELS. We, therefore, investigated the volume of hippocampus and amygdala in 25 high alexithymic (h‐ALEX) and 25 low alexithymic (l‐ALEX) individuals, which were matched with regard to ELS, but significantly differed in their degree of emotional functioning. Volumetric analyses were performed using FSL‐FIRST, a method to automatically segment subcortical structures on T1‐weighted magnetic resonance images. Alexithymia was assessed using the Toronto Alexithymia Scale and Bermond–Vorst Alexithymia Questionnaire. ELS was assessed by Childhood Trauma Questionnaire (CTQ) and Early Trauma Inventory. Our data showed that ELS was negatively associated with right hippocampus volume in h‐ALEX individuals, while there was no such association in the l‐ALEX group. Furthermore, ELS was positively associated with left amygdala volume in l‐ALEX individuals, but not in individuals with high levels of alexithymia. The present study emphasizes a substantial relationship between intrapersonal factors, such as alexithymia and neural alterations related to the experience of ELS. Longitudinal study designs are necessary to pursue the question of how emotional abilities interact with individual adaptations to early stress exposure on the neural level. © 2014 Wiley Periodicals, Inc.     

Early life stress followed by subsequent adult chronic stress potentiates anxiety and blunts hippocampal structural remodeling

Early life stress produces long‐term alterations in cognition, emotionality, and stress responsiveness. The stress‐sensitive hippocampal formation plays a role in producing many of these alterations. We report that adult male rats exposed to early life stress, in the form of maternal separation (MS), exhibit baseline impairment of hippocampal dependent memory and following three weeks of chronic restraint stress (CRS) exhibit heightened anxiety‐like behavior and alterations in the morphology of hippocampal CA3 pyramidal neurons. Specifically, as measured by the object placement task, MS offspring demonstrated impaired spatial memory compared with nonmaternally separated rats (NMS). Moreover, compared with NMS rats, subsequent CRS exposure of MS rats increased novelty‐induced corticosterone secretion and potentiated anxiety‐like behavior as measured by the elevated plus maze. Further, CRS exposed MS rats did not exhibit shortening of apical dendritic length compared with nonstressed MS rats, whereas CRS exposed NMS rats did show significant dendritic shrinkage compared with nonstressed NMS rats. The blunted CRS‐induced remodeling of apical dendritic length in MS rats is likely due to a baseline deficiency in dendritic length; MS rats exhibit a trend towards shorter apical dendrites in comparison to NMS rats. CRS exposure in both MS and NMS rats, however, induced a reduction in apical dendritic branching. Finally, there was a significant correlation between apical dendritic length and novelty‐induced corticosterone level, while there was not a significant correlation with anxiety‐like behavior. Overall, our results suggest preserved but blunted hippocampal structural plasticity in MS rats that is not sufficient to compensate for hippocampal dysfunction and hypersensitivity to CRS. © 2010 Wiley Periodicals, Inc., Inc.     

Reward-related neural correlates of early life stress in school-aged children

ObjectivesEarly life stress likely contributes to dysfunction in neural reward processing systems. However, studies to date have focused almost exclusively on adolescents and adults, measured early life stress retrospectively, and have often failed to control for concurrent levels of stress. The current study examined the contribution of prospectively measured cumulative life stress in preschool-age children on reward-related neural activation and connectivity in school-age children.MethodsChildren (N = 46) and caregivers reported children’s exposure to early life stress between birth and preschool age (mean = 4.8 years, SD = 0.80). At follow-up (mean age = 7.52 years, SD = .78), participants performed a child-friendly monetary incentive delay task during functional magnetic resonance imaging.ResultsChildren with higher levels of cumulative early life stress, controlling for concurrent stressful life events, exhibited aberrant patterns of neural activation and connectivity in reward- and emotion-related regions (e.g., prefrontal cortex, temporal pole, culmen), depending on the presence of a potential reward and whether or not the target was hit or missed.ConclusionsFindings suggest that stress exposure during early childhood may impact neural reward processing systems earlier in development than has previously been demonstrated. Understanding how early life stress relates to alterations in reward processing could guide earlier, more mechanistic interventions.     

Early life stress modulates oxytocin effects on limbic system during acute psychosocial stress

Early life stress (ELS) is associated with altered stress responsivity, structural and functional brain changes and an increased risk for the development of psychopathological conditions in later life. Due to its behavioral and physiological effects, the neuropeptide oxytocin (OXT) is a useful tool to investigate stress responsivity, even though the neurobiological underpinnings of its effects are still unknown. Here we investigate the effects of OXT on cortisol stress response and neural activity during psychosocial stress. Using functional magnetic resonance imaging in healthy subjects with and without a history of ELS, we found attenuated hormonal reactivity and significantly reduced limbic deactivation after OXT administration in subjects without a history of ELS. Subjects who experienced ELS showed both blunted stress reactivity and limbic deactivation during stress. Furthermore, in these subjects OXT had opposite effects with increased hormonal reactivity and increased limbic deactivation. Our results might implicate that reduced limbic deactivation and hypothalamic–pituitary–adrenal axis responsivity during psychosocial stress are markers for biological resilience after ELS. Effects of OXT in subjects with a history of maltreatment could therefore be considered detrimental and suggest careful consideration of OXT administration in such individuals.     

Antidepressant drug-induced stimulation of mouse hippocampal neurogenesis is age-dependent and altered by early life stress

The continuous generation of new neurons in the adult hippocampus exhibits remarkable plasticity. Decreased neurogenesis is thought to underlie depression-like behaviors, and increased neurogenesis is thought to occur following antidepressant drug treatment. Studies on different strains of mice, however, yielded contrasting results with regard to the link between behavioral modifications induced by antidepressant drugs or environmental enrichment and changes in adult hippocampal neurogenesis. Therefore, we conducted a comparative study on the inbred strains Balb/c and C57Bl/6 that differ substantially in emotionality, stress reactivity, and behavioral responses to chronic antidepressant drugs. Quantitative assessments of progenitor cell proliferation and immature neuronal differentiation in the dentate gyrus revealed that, despite significantly different basal proliferation rates between both strains, neither strain exhibited changes in adult neurogenesis after exposure to early life stress or adult chronic fluoxetine treatment. A stimulatory effect of fluoxetine on adult hippocampal neurogenesis was only detected when treatment was initiated during adolescence, and this effect was abolished in mice exposed to early life stress, a prominent risk factor for developing adult-onset depression-like behaviors. Thus, in both strains of mice neither adult fluoxetine treatment nor adolescent fluoxetine treatment following early life stress exposure increased the proliferation and early differentiation of adult neural progenitor cells.     

Long term effects of stress on hippocampal function: Emphasis on early life stress paradigms and potential involvement of neuropeptide Y

The brain is both central in orchestrating the response to stress, and, a very sensitive target when such response is not controlled. In fact, stress has long been associated with the onset and/or exacerbation of several neuropsychiatric disorders such as anxiety, depression, and drug addiction. The hippocampus is a key brain region involved in the response to stress, not only due to its anatomical connections with the hypothalamic‐pituitary‐adrenal axis but also as a major target of stress mediators. The hippocampal dentate gyrus (DG)‐CA3 circuit, composed of DG granule cells axons (mossy fibers) synapsing onto CA3 pyramidal cells, plays an essential role in memory encoding and retrieval, functions that are vulnerable to stress. Although naturally excitatory, this circuit is under the inhibitory control of GABAergic interneurons that maintain the excitation/inhibition balance. One subgroup of such interneurons produces neuropeptide Y (NPY), which has emerged as a promising endogenous stress “resilience molecule” due to its anxiolytic and anti‐epileptic properties. Here we examine existing evidence that reveals a potential role for hilar NPY+ interneurons in mediating stress‐induced changes in hippocampal function. We will focus specifically on rodent models of early life stress (ELS), defined as adverse conditions during the early postnatal period that can have profound consequences for neurodevelopment. Collectively, these findings suggest that the long‐lasting effects of ELS might stem from the loss of GABAergic NPY+ cells, which then can lead to reduced inhibition in the DG‐CA3 pathway. Such change might then lead to hyperexcitability and concomitant hippocampal‐dependent behavioral deficits.     

Pattern separation of emotional information in hippocampal dentate and CA3

Emotional arousal, mediated by the amygdala, is known to modulate episodic memories stored by the hippocampus, a region involved in pattern separation (the process by which similar representations are independently stored). While emotional modulation and pattern separation have been examined independently, this study attempts to link the two areas of research to propose an alternative account for how emotion modulates episodic memory. We used an emotional discrimination task designed to tax pattern separation of emotional information by concurrently varying emotional valence and similarity of stimuli. To examine emotional modulation of memory at the level of hippocampal subfields, we used high‐resolution fMRI (1.5 mm isotropic) of the medial temporal lobe. Consistent with prior reports, we observed engagement of the hippocampal dentate gyrus (DG) and CA3 during accurate discrimination of highly similar items (behavioral correlate of pattern separation). Furthermore, we observed an emotional modulation of this signal (negative > neutral) specific to trials on which participants accurately discriminated similar emotional items. The amygdala was also modulated by emotion, regardless of the accuracy of discrimination. Additionally, we found aberrant amygdala‐hippocampal network activity in a sample of adults with depressive symptoms. In this sample, amygdala activation was enhanced and DG/CA3 activation was diminished during emotional discrimination compared to those without depressive symptoms. Depressive symptom severity was also negatively correlated with DG/CA3 activity. This study suggests a novel mechanistic account for how emotional information is processed by hippocampal subfields as well as how this network may be altered in mood disorders. © 2014 Wiley Periodicals, Inc.     

How do academic stress and leisure activities influence college students' emotional well-being? A daily diary investigation

China has one of the largest bodies of college students who face growing academic stress that influences their well-being. Using a daily diary method in a group of Chinese college students (n = 139, mean age = 19.50 years, 27% males) who reported their daily positive and negative emotion consecutively for two weeks, this study investigated the dynamic relations between daily academic stress, leisure activities engagement, and emotion, and further examined the moderation of sex on these links. The results showed that at both between- and within-person level, academic stress was positively associated with negative emotion, and leisure activities engagement was positively associated with positive emotion. The association between leisure activities engagement and positive emotion were stronger among female students than among male students. These results suggest that effectively reducing academic stress and actively engaging in leisure activities are both important in promoting and enhancing daily emotional well-being.     

Associations between the COMT Val/Met polymorphism, early life stress, and personality among healthy adults

Efforts to identify genetic factors that confer an increased risk for the expression of psychiatric symptoms have focused on polymorphisms in variety of candidate genes, including the catechol-O-methyltransferase (COMT) gene. Results from previous studies that have examined associations between the functional COMT polymorphism (Val158Met) and mental health have been mixed. In the present study, we examined the relationships between COMT, early life stress, and personality in a healthy adult sample. Consistent with previous studies, we hypothesized that individuals with the low-activity genotype would have higher neuroticism and lower extraversion and that this effect would be more pronounced in females. In addition, we extended the previous literature by investigating the potential influence of early life stress. A total of 486 healthy adults underwent genetic testing and personality assessment. Results revealed that individuals homozygous for the COMT low enzyme activity allele had lower extraversion on the NEO-FFI and demonstrated a trend toward greater neuroticism. These relationships were not influenced by sex or the presence of reported early life stress. The finding that COMT genotype was associated with extraversion, and more weakly with neuroticism, is consistent with previous studies. Future research to clarify the influence of sex and gene–environmental interactions is warranted.     

Functional imaging of emotional memory in bipolar disorder and schizophrenia

Objectives: Although in current diagnostic criteria there exists a distinction between bipolar disorder and schizophrenia, many patients manifest features of both disorders, and it is unclear which aspects, if any, confer diagnostic specificity. In the present study, we investigate whether there are differences in medial temporal lobe (MTL) activation in bipolar disorder and schizophrenia. We also investigate associations between activation levels and symptom severity across the disorders. Methods: Functional magnetic resonance imaging scans were conducted on 14 healthy controls, 14 patients with bipolar disorder, and 15 patients with schizophrenia undergoing an emotional memory paradigm. Results: All groups demonstrated the expected pattern of behavioural responses during encoding and retrieval, and there were no significant group differences in performance. Robust MTL activation was seen in all three groups during viewing of emotional scenes, which correlated significantly with recognition memory for emotional stimuli. The bipolar group demonstrated relatively greater increases in activation for emotional versus neutral scenes in the left hippocampus than both controls and patients with schizophrenia. There was a significant positive correlation between mania scores and activation in the anterior cingulate, and a significant negative correlation between depression scores and activation in the dorsolateral prefrontal cortex. Conclusion: These results provide evidence that there are distinct patterns of activation in the MTL during an emotional memory task in bipolar disorder and schizophrenia. They also demonstrate that different mood states are associated with different neurobiological responses to emotion across the patient groups.     

Look at me, I'll remember you: the perception of self-relevant social cues enhances memory and right hippocampal activity

Being looked at by a person enhances the subsequent memorability of her/his identity. Here, we tested the specificity of this effect and its underlying brain processes. We manipulated three social cues displayed by an agent: Gaze Direction (Direct/Averted), Emotional Expression (Anger/Neutral), and Pointing gesture (Presence/Absence). Our behavioral experiment showed that direct as compared with averted gaze perception enhanced subsequent retrieval of face identity. Similar effect of enhanced retrieval was found when pointing finger was absent as compared with present but not for anger as compared with neutral expression. The fMRI results revealed amygdala activity for both Anger and Direct gaze conditions, suggesting emotional arousal. Yet, the right hippocampus, known to play a role in self-relevant memory processes, was only revealed during direct gaze perception. Further investigations suggest that right hippocampal activity was maximal for the most self-relevant social event (i.e. actor expressing anger and pointing toward the participant with direct gaze). Altogether, our results suggest that the perception of self-relevant social cues such as direct gaze automatically prompts "self-relevant memory" processes.     

The association between hippocampal volume and life events in healthy twins

Hippocampal volume deficits have been linked to life stress. However, the degree to which genes and environment influence the association between hippocampal volume and life events is largely unknown. In total, 123 healthy twins from monozygotic and dizygotic twin pairs underwent magnetic resonance imaging (MRI), and 57 healthy twins were interviewed with the Life Events and Difficulties Schedule (LEDS), with an overlap of 54 twins undergoing both MRI and the life events interview. Hippocampal volumes were segmented with Freesurfer software. Data were analyzed with OpenMx software. Smaller hippocampal volume was associated with higher severe life event load (r_ph= ?0.39), where shared environmental factors influencing both measures fully explained the association. Hippocampal volume was not associated with total or mild life event load. Hippocampal volume showed high heritability (range, h²: 57%–81%) whereas life event measures were influenced by shared (c²) and unique (e²) environmental factors only (range, c²:40%–64%, e²: 36%–60%). The results suggested that shared environmental factors influenced the relationship between smaller hippocampal volume and severe (but not mild) stress. This indicated that particularly severe life events that were shared between twins were associated with smaller hippocampal volume. Furthermore, it is suggested to distinguish between mild and severe life events in life event research. © 2016 Wiley Periodicals, Inc.     

Neural correlates of the classic color and emotional stroop in women with abuse-related posttraumatic stress disorder.

BACKGROUND: The anterior cingulate and medial prefrontal cortex play an important role in the inhibition of responses, as measured by the Stroop task, as well as in emotional regulation. Dysfunction of the anterior cingulate/medial prefrontal cortex has been implicated in posttraumatic stress disorder (PTSD). The purpose of this study was to use the Stroop task as a probe of anterior cingulate function in PTSD. METHODS: Women with early childhood sexual abuse-related PTSD (n = 12) and women with abuse but without PTSD (n = 9) underwent positron emission tomographic measurement of cerebral blood flow during exposure to control, color Stroop, and emotional Stroop conditions. RESULTS: Women with abuse with PTSD (but not abused non-PTSD women) had a relative decrease in anterior cingulate blood flow during exposure to the emotional (but not color) classic Stroop task. During the color Stroop there were also relatively greater increases in blood flow in non-PTSD compared with PTSD women in right visual association cortex, cuneus, and right inferior parietal lobule. CONCLUSIONS: These findings add further evidence for dysfunction of a network of brain regions, including anterior cingulate and visual and parietal cortex, in abuse-related PTSD.     

The potential of infant fMRI research and the study of early life stress as a promising exemplar

Functional magnetic resonance imaging (fMRI) research with infants and toddlers has increased rapidly over the past decade, and provided a unique window into early brain development. In the current report, we review the state of the literature, which has established the feasibility and utility of task-based fMRI and resting state functional connectivity MRI (rs-fcMRI) during early periods of brain maturation. These methodologies have been successfully applied beginning in the neonatal period to increase understanding of how the brain both responds to environmental stimuli, and becomes organized into large-scale functional systems that support complex behaviors. We discuss the methodological challenges posed by this promising area of research. We also highlight that despite these challenges, early work indicates a strong potential for these methods to influence multiple research domains. As an example, we focus on the study of early life stress and its influence on brain development and mental health outcomes. We illustrate the promise of these methodologies for building on, and making important contributions to, the existing literature in this field.     

The influence of early and recent life stress on severity of depression

The influence of life stressors arising in different life stages on the severity of depression was examined in a sample of 123 depressive women, ranging from 22 to 64 years of age. In an interview, information was obtained on the incidence of certain life stressors in early and recent periods. The severity of depression was measured using the Beck Depression Inventory. The results indicate that experience of physical or sexual abuse before the age of 19 is strongly associated with severity of depression. Also, most women suffering from severe depression had previous and recent difficulties in their relationships with parents, partner or others and recent problems with self-esteem. A hypothetical model for predicting the severity of depression was evaluated. Difficulties experienced one year prior to assessment appeared to directly predict severity of depression. Difficulties with social relationships whose origin could be traced back to early periods and that had a continuing effect throughout life were found to be crucial factors for indirectly predicting the severity of depression.