Evidence suggests several causes for depression, including traumatic life events, disease, poison, and nutritional deficiencies. Many of these causes are associated with elevated levels of inflammatory biomarkers in the blood, which may in turn lead to inflammatory changes in the brain. Our authors examine what the latest research reveals about the link between inflammation in the brain and depression, and how a better understanding of that link can play a critical first step in the personalization of care.
Time-to-collision (TTC) underestimation has been interpreted as an adaptive response that allows observers to have more time to engage in a defensive behaviour. This bias seems, therefore, strongly linked to action preparation. There is evidence that the observer’s physical fitness modulates the underestimation effect so that people who need more time to react (i.e. those with less physical fitness) show a stronger underestimation effect. Here we investigated whether this bias is influenced by the momentary action capability of the observers. In the first experiment, participants estimated the time-to-collision of threatening or non-threatening stimuli while being mildly immobilized (with a chin rest) or while standing freely. Having reduced the possibility of movement led participants to show more underestimation of the approaching stimuli. However, this effect was not stronger for threatening relative to non-threatening stimuli. The effect of the action capability found in the first experiment could be interpreted as an expansion of peripersonal space (PPS). In the second experiment, we thus investigated the generality of this effect using an established paradigm to measure the size of peripersonal space. Participants bisected lines from different distances while in the chin rest or standing freely. The results replicated the classic left-to-right gradient in lateral spatial attention with increasing viewing distance, but no effect of immobilization was found. The manipulation of the momentary action capability of the observers influenced the participants’ performance in the TTC task but not in the line bisection task. These results are discussed in relation to the different functions of PPS.
The importance of obstructive sleep apnea in patients undergoing surgery with general anesthesia is well-defined, but the surgical and anesthetic implications of other sleep disorders are less clear. We sought to evaluate response to surgery with general anesthesia in patients with central disorders of hypersomnolence or restless legs syndrome. Methods: We surveyed patients on their most recent surgical procedure with general anesthesia, querying about procedure, recovery, and any changes in sleep disorder symptomatology following the procedure. Results: Forty-five patients with restless legs syndrome and 57 patients with central disorders of hypersomnolence (15 narcolepsy type 2, 1 narcolepsy type 1, 30 idiopathic hypersomnia, 1 Kleine-Levin syndrome, and 10 subjective sleepiness) completed the survey, with response rates of 45.5 and 53.8%, respectively. While patients in both groups were equally likely to report surgical complications and difficulty awakening from anesthesia, hypersomnolent patients were more likely to report worsened sleepiness (40% of the hypersomnolent group vs. 11% of the RLS group, p = 0.001) and worsening of their sleep disorder symptoms (40% of the hypersomnolent group vs. 9% of the RLS group, p = 0.0001). Conclusion: Patients with sleep disorders other than sleep apnea frequently report surgical or anesthetic complications. Patients with hypersomnolence disorders commonly perceive that their sleep disorder worsened following a procedure; whether this might be related to long term effects of general anesthesia in a particularly vulnerable clinical population requires further study.
DNA methylation may mediate persistent changes in gene function following chronic stress. To examine this hypothesis, we evaluated African American subjects matched by age and sex, and stratified into four groups by post-traumatic stress disorder (PTSD) diagnosis and history of child abuse. Total Life Stress (TLS) was also assessed in all subjects. We evaluated DNA extracted from peripheral blood using the HumanMethylation27 BeadChip and analyzed both global and site-specific methylation. Methylation levels were examined for association with PTSD, child abuse history, and TLS using a linear mixed model adjusted for age, sex, and chip effects. Global methylation was increased in subjects with PTSD. CpG sites in five genes (TPR, CLEC9A, APC5, ANXA2, and TLR8) were differentially methylated in subjects with PTSD. Additionally, a CpG site in NPFFR2 was associated with TLS after adjustment for multiple testing. Notably, many of these genes have been previously associated with inflammation. Given these results and reports of immune dysregulation associated with trauma history, we compared plasma cytokine levels in these subjects and found IL4, IL2, and TNFα levels associated with PTSD, child abuse, and TLS. Together, these results suggest that psychosocial stress may alter global and gene-specific DNA methylation patterns potentially associated with peripheral immune dysregulation. Our results suggest the need for further research on the role of DNA methylation in stress-related illnesses.
Craving for tobacco is a major challenge for people with nicotine dependence (ND) who try to quit smoking. Galanin (GAL) and its receptors (GALRs) can alter addiction-related behaviors and are therefore good candidates for modulators of behavioral parameters associated with smoking. We performed a genetic association study in 486 subjects (432 European American, EA) recruited for smoking cessation trials. Twenty-six candidate genes for ND-related phenotypes were selected based on the literature. Subjects were assessed using the Minnesota Withdrawal Scale (MWS), which included a specific item for craving, the Fagerström Scale of Nicotine Dependence (FTND), and other ND-related instruments. One single-nucleotide polymorphism (SNP) in GALR1, rs2717162, significantly associated with severity of craving in EA samples (p=6.48 × 10−6) and in the combined sample (p=9.23 × 10−6). Individuals with TT and TC genotypes had significantly higher craving scores than CC subjects. We also observed that SNPs in the CHRNA5 locus, rs16969968 and rs684513, which have been associated with ND-related phenotypes in previous studies, were nominally associated with FTND scores, although these results did not meet Bonferroni-adjusted criteria for experiment-wide significance. Our findings suggest that variation at GALR1 associates with differences in the severity of past craving for tobacco among smokers motivated to quit. Taken together with preclinical evidence, these results, if replicated, suggest that GAL and GALRs may be useful therapeutic targets for the pharmacological treatment of ND. Our results also confirm previously reported associations between variation at CHRNA5 and ND.
Corticotropin-releasing factor (CRF) is critical for the endocrine, autonomic, and behavioral responses to stressors, and it has been shown to modulate fear and anxiety. The CRF receptor is widely expressed across a variety of cell types, impeding progress toward understanding the contribution of specific CRF-containing neurons to fear dysregulation. We used a unique CRF-Cre driver transgenic mouse line to remove floxed GABA(A)α1 subunits specifically from CRF neurons [CRF-GABA(A)α1 KO]. This process resulted in mice with decreased GABA(A)α1 expression only in CRF neurons and increased CRF mRNA within the amygdala, bed nucleus of the stria terminalis (BNST) and paraventricular nucleus of the hypothalamus. These mice show normal locomotor and pain responses and no difference in depressive-like behavior or Pavlovian fear conditioning. However, CRF-GABA(A)α1 KO increased anxiety-like behavior and impaired extinction of conditioned fear, coincident with an increase in plasma corticosterone concentration. These behavioral impairments were rescued with systemic or BNST infusion of the CRF antagonist R121919. Infusion of Zolpidem, a GABA(A)α1-preferring benzodiazepine-site agonist, into the BNST of the CRF-GABA(A)α1 KO was ineffective at decreasing anxiety. Electrophysiological findings suggest a disruption in inhibitory current may play a role in these changes. These data indicate that disturbance of CRF containing GABA(A)α1 neurons causes increased anxiety and impaired fear extinction, both of which are symptoms diagnostic for anxiety disorders, such as posttraumatic stress disorder.
The changing economic and social environment of Western nations is having a profound impact on men’s lives. Men who assume a greater share of roles traditionally filled by women will experience challenges to traditional sources of male self-esteem, potentially heightening the risk for depressive disorders among men.
Stressor exposure biases decision-making strategies from those based on the relationship between actions and their consequences to others restricted by stimulus-response associations. Chronic stressor exposure also desensitizes glucocorticoid receptors (GR) and diminishes motivation to acquire food reinforcement, although causal relationships are largely not established. We show that a history of chronic exposure to the GR ligand corticosterone or acute posttraining GR blockade with RU38486 makes rodents less able to perform actions based on their consequences. Thus, optimal GR binding is necessary for the consolidation of new response-outcome learning. In contrast, medial prefrontal (but not striatal) BDNF can account for stress-related amotivation, in that selective medial prefrontal cortical Bdnf knockdown decreases break-point ratios in a progressive-ratio task. Knockdown also increases vulnerability to RU38486. Despite the role of BDNF in dendritic spine reorganization, deep-layer spine remodeling does not obviously parallel progressive-ratio response patterns, but treatment with the Na+-channel inhibitor riluzole reverses corticosteroid-induced motivational deficits and restores prefrontal BDNF expression after corticosterone. We argue that when prefrontal neurotrophin systems are compromised, and GR-mediated hypothalamic-pituitary-adrenal axis feedback is desensitized (as in the case of chronic stress hormone exposure), amotivation and inflexible maladaptive response strategies that contribute to stress-related mood disorders result.
Offspring of mothers with posttraumatic stress disorder (PTSD) are at higher risk for a range of negative developmental outcomes, including differing forms of psychopathology. This paper suggests that the multigenerational impact of trauma may be partially attributed to increased levels of stress experienced by these offspring during childhood and adolescence. Diagnostic interviews were conducted with over 800 women and their offspring. Experiences of stress were assessed using multiple measures. Results indicate that offspring of mothers with PTSD or high levels of PTSD symptoms experienced higher levels of lifetime exposure to major stress F(1, 814) = 18.04, p < .001, current chronic stress due to family relations F(1, 813) = 7.22, p = .007, and a higher level of objectively rated recent episodic life stress F(1, 758) = 5.17, p = .02, compared to offspring of women without PTSD. These findings remained significant after controlling for maternal history of depression.
Cluster A personality disorders (PD), including schizotypal personality disorder (SPD), paranoid personality disorder (PPD), and schizoid PD, are marked by odd and eccentric behaviors, and are grouped together because of common patterns in symptomatology as well as shared genetic and environmental risk factors. The DSM-IV-TR describes personality disorders as representing stable and enduring patterns of maladaptive traits, and much of what is understood about Cluster A personality disorders in particular stems from research with adult populations. Less in known about these disorders in children and adolescents, and controversy remains regarding diagnosis of personality disorders in general in youth. The current paper reviews the available research on Cluster A personality disorders in childhood and adolescence; specifically, we discuss differentiating between the three disorders and distinguishing them from other syndromes, measuring Cluster A disorders in youth, and the nature and course of these disorders throughout childhood and adolescence. We also present recent longitudinal data from a sample of adolescents diagnosed with Cluster A personality disorders from our research laboratory, and suggest directions for future research in this important but understudied area.