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.
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Raymond L. Ownby;
Drenna Waldrop-Valverde;
Deborah L. Jones;
Sunil Sharma;
Ritu Nehra;
Adarsh M. Kumar;
Sudesh Prabhakar;
Amaillis Acevedo;
Mahendra Kumar
An evaluation of the effects of HIV infection on neurocognition over time is important for understanding disease progression. Changes in cognitive function can be evaluated longitudinally by using neuropsychological testing at repeated intervals. The assessment of change over time, however, is complicated by the potentially confounding influence of learning on repeated test administrations, often referred to as practice effect. In this study, we present data on testing of persons with or without HIV infection on a battery administered at study baseline and repeated 1 year later. Results suggest that practice effects may be diminished in persons with HIV infection compared to without it. This appears to be true even among those with relatively intact immune functioning as measured by CD4 count.
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Don C. Des Jarlais;
Kamyar Arasteh;
Courtney McKnight;
Jonathan Feelemyer;
Aimee N. C. Campbell;
Susan Tross;
Hannah Cooper;
Holly Hagan;
David C. Perlman
Background and aims: HIV has reached high prevalence in many non-injecting drug user (NIDU) populations. The aims of this study were to (1) examine the trend in HIV prevalence among non-injecting cocaine and heroin NIDUs in New York City, (2) identify factors potentially associated with the trend and (3) estimate HIV incidence among NIDUs. Design: Serial-cross sectional surveys of people entering drug treatment programs. People were permitted to participate only once per year, but could participate in multiple years. Setting: Mount Sinai Beth Israel drug treatment programs in New York City, USA. Participants: We recruited 3298 non-injecting cocaine and heroin users from 2005 to 2014. Participants were 78.7% male, 6.1% white, 25.7% Hispanic and 65.8% African American. Smoking crack cocaine was the most common non-injecting drug practice. Measures: Trend tests were used to examine HIV prevalence, demographics, drug use, sexual behavior and use of antiretroviral treatment (ART) by calendar year; χ 2 and multivariable logistic regression were used to compare 2005–10 versus 2011–14. Findings: HIV prevalence declined approximately 1% per year (P < 0.001), with a decline from 16% in 2005–10 to 8% in 2011–14 (P < 0.001). The percentages of participants smoking crack and having multiple sexual partners declined and the percentage of HIV-positive people on ART increased. HIV incidence among repeat participants was 1.2 per 1000 person-years (95% confidence interval = 0.03/1000–7/1000). Conclusions: HIV prevalence has declined and a high percentage of HIV-positive non-injecting drug users (NIDUs) are receiving antiretroviral treatment, suggesting an end to the HIV epidemic among NIDUs in New York City. These results can be considered a proof of concept that it is possible to control non-injecting drug use related sexual transmission HIV epidemics.
A cascade of neuroendocrine events regulates the initiation and progression of female puberty. However, the factors that determine the timing of these events across individuals are still uncertain. While the consequences of puberty on subsequent emotional development and adult behavior have received significant attention, what is less understood are the social and environmental factors that actually alter the initiation and progression of puberty. In order to more fully understand what factors influence pubertal timing in females, the present study quantified social and emotional behavior; stress physiology; and growth and activity measures in juvenile female rhesus monkeys to determine what best predicts eventual puberty. Based on previous reports, we hypothesized that increased agonistic behavior resulting from subordinate status in their natal group, in combination with slowed growth, reduced prosocial behavior, and increased emotional reactivity would predict delayed puberty. The analyses were restricted to behavioral and physiological measures obtained prior to the onset of puberty, defined as menarche. Together, our findings indicate that higher rates of aggression but lower rates of submission received from group mates; slower weight gain; and greater emotional reactivity, evidenced by higher anxiety, distress and appeasing behaviors, and lower cortisol responsivity in response to a potentially threatening situation, predicts delayed puberty. Together the combination of these variables accounted for 58% of the variance in the age of menarche, 71% in age at first ovulation, and 45% in the duration of adolescent sterility. While early puberty may be more advantageous for the individual from a fertility standpoint, it presents significant health risks, including increased risk for a number of estrogen dependent cancers and as well as the emergence of mood disorders during adulthood. On the other hand, it is possible that increased emotional reactivity associated with delayed puberty could persist, increasing the risk for emotional dysregulation to socially challenging situations. The data argue for prospective studies that will determine how emotional reactivity shown to be important for pubertal timing is affected by early social experience and temperament, and how these stress-related variables contribute to body weight accumulation, affecting the neuroendocrine regulation of puberty.
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William C Reeves;
Christine Heim;
Elizabeth M Maloney;
Laura Solomon Youngblood;
Elizabeth Robinson Unger;
Michael J Decker;
James F Jones;
David Rye
Background
The etiology and pathophysiology of chronic fatigue syndrome (CFS) remain inchoate. Attempts to elucidate the pathophysiology must consider sleep physiology, as unrefreshing sleep is the most commonly reported of the 8 case-defining symptoms of CFS. Although published studies have consistently reported inefficient sleep and documented a variable occurrence of previously undiagnosed primary sleep disorders, they have not identified characteristic disturbances in sleep architecture or a distinctive pattern of polysomnographic abnormalities associated with CFS.
Methods
This study recruited CFS cases and non-fatigued controls from a population based study of CFS in Wichita, Kansas. Participants spent two nights in the research unit of a local hospital and underwent overnight polysomnographic and daytime multiple sleep latency testing in order to characterize sleep architecture.
Results
Approximately 18% of persons with CFS and 7% of asymptomatic controls were diagnosed with severe primary sleep disorders and were excluded from further analysis. These rates were not significantly different. Persons with CFS had a significantly higher mean frequency of obstructive apnea per hour (p = .003); however, the difference was not clinically meaningful. Other characteristics of sleep architecture did not differ between persons with CFS and controls.
Conclusion
Although disordered breathing during sleep may be associated with CFS, this study generally did not provide evidence that altered sleep architecture is a critical factor in CFS. Future studies should further scrutinize the relationship between subjective sleep quality relative to objective polysomnographic measures.
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Sudeepa Bhattacharyya;
Ahmed T. Ahmed;
Matthias Arnold;
Duan Liu;
Chunqiao Luo;
Hongjie Zhu;
Siamak Mahmoudiandehkordi;
Drew Neavin;
Gregory Louie;
Boadie Dunlop;
Mark A. Frye;
Liewei Wang;
Richard M. Weinshilboum;
Ranga R. Krishnan;
A. John Rush;
Rima Kaddurah-Daouk
Metabolomics provides valuable tools for the study of drug effects, unraveling the mechanism of action and variation in response due to treatment. In this study we used electrochemistry-based targeted metabolomics to gain insights into the mechanisms of action of escitalopram/citalopram focusing on a set of 31 metabolites from neurotransmitter-related pathways. Overall, 290 unipolar patients with major depressive disorder were profiled at baseline, after 4 and 8 weeks of drug treatment. The 17-item Hamilton Depression Rating Scale (HRSD17) scores gauged depressive symptom severity. More significant metabolic changes were found after 8 weeks than 4 weeks post baseline. Within the tryptophan pathway, we noted significant reductions in serotonin (5HT) and increases in indoles that are known to be influenced by human gut microbial cometabolism. 5HT, 5-hydroxyindoleacetate (5HIAA), and the ratio of 5HIAA/5HT showed significant correlations to temporal changes in HRSD17 scores. In the tyrosine pathway, changes were observed in the end products of the catecholamines, 3-methoxy-4-hydroxyphenylethyleneglycol and vinylmandelic acid. Furthermore, two phenolic acids, 4-hydroxyphenylacetic acid and 4-hydroxybenzoic acid, produced through noncanconical pathways, were increased with drug exposure. In the purine pathway, significant reductions in hypoxanthine and xanthine levels were observed. Examination of metabolite interactions through differential partial correlation networks revealed changes in guanosine–homogentisic acid and methionine–tyrosine interactions associated with HRSD17. Genetic association studies using the ratios of these interacting pairs of metabolites highlighted two genetic loci harboring genes previously linked to depression, neurotransmission, or neurodegeneration. Overall, exposure to escitalopram/citalopram results in shifts in metabolism through noncanonical pathways, which suggest possible roles for the gut microbiome, oxidative stress, and inflammation-related mechanisms.
Summary
PTSD symptoms are associated with heightened fear responses in laboratory fear conditioning paradigms. This study examined the effects of dexamethasone administration on hypothalamic–pituitary–adrenal (HPA) function and fear-potentiated startle (FPS) in trauma-exposed individuals with and without PTSD. We used an established fear discrimination procedure, in which one visual stimulus (CS+, danger cue) was paired with aversive airblasts to the throat (unconditioned stimulus, US), and another stimulus (CS−, safety cue) was presented without airblasts. In addition to FPS, the dexamethasone suppression test (DST) was performed. The study sample (N = 100) was recruited from a highly traumatized civilian population in Atlanta, GA. Half of the subjects (n = 54, 16 PTSD, 38 controls) underwent conditioning at baseline and the other half (n = 46, 17 PTSD, 29 controls) after DST, in a cross-sectional design. We found a significant interaction effect of diagnostic group and dexamethasone treatment. Under baseline conditions, subjects with PTSD showed more than twice as much fear-potentiated startle to the danger cue compared to traumatized controls, F(1,53) = 8.08, p = 0.006. However, there was no group difference in subjects tested after dexamethasone suppression. Furthermore, there was a significant treatment effect in PTSD subjects but not in controls, with dexamethasone reducing fear-potentiated startle to the CS+, F(1,32) = 4.00, p = 0.05. There was also a positive correlation between PTSD subjects’ FPS and cortisol levels, r = 0.46, p = 0.01. These results suggest that transient suppression of HPA function via dexamethasone suppression may reduce exaggerated fear in patients with PTSD.
Posttraumatic Stress Disorder (PTSD) is an anxiety disorder which can develop as a result of exposure to a traumatic event and is associated with significant functional impairment. Family and twin studies have found that risk for PTSD is associated with an underlying genetic vulnerability and that more than 30% of the variance associated with PTSD is related to a heritable component. Using a fear conditioning model to conceptualize the neurobiology of PTSD, three primary neuronal systems have been investigated – the hypothalamic-pituitary-adrenal axis, the locus coeruleus-noradrenegic system, and neurocircuitry interconnecting the limbic system and frontal cortex. The majority of the initial investigations into main effects of candidate genes hypothesized to be associated with PTSD risk have been negative, but studies examining the interaction of genetic polymorphisms with specific environments in predicting PTSD have produced several positive results which have increased our understanding of the determinants of risk and resilience in the aftermath of trauma. Promising avenues of inquiry into the role of epigenetic modification have also been proposed to explain the enduring impact of environmental exposures which occur during key, often early, developmental periods on gene expression. Studies of PTSD endophenotypes, which are heritable biomarkers associated with a circumscribed trait within the more complex psychiatric disorder, may be more directly amenable to analysis of the underlying genetics and neural pathways and have provided promising targets for elucidating the neurobiology of PTSD. Knowledge of the genetic underpinnings and neuronal pathways involved in the etiology and maintenance of PTSD will allow for improved targeting of primary prevention amongst vulnerable individuals or populations, as well as timely, targeted treatment interventions.
Calcitonin gene-related peptide (CGRP) acting within the bed nucleus of the stria terminalis (BNST) increases anxiety as well as neural activation in anxiety-related structures, and mediates behavioral stress responses. Similar effects have been described following intra-ventricular as well as intra-BNST infusions of the stress-responsive neuropeptide, corticotropin releasing factor (CRF). Interestingly, CGRP-positive terminals within the lateral division of the BNST form perisomatic baskets around neurons that express CRF, suggesting that BNST CGRP could exert its anxiogenic effects by increasing release of CRF from these neurons. With this in mind, the present set of experiments was designed to examine the role of CRFR1 signaling in the anxiogenic effects of CGRP within the BNST and to determine whether CRF from BNST neurons contributes to these effects. Consistent with previous studies, we found that 400 ng CGRP infused bilaterally into the BNST increased the acoustic startle response and induced anxiety-like behavior in the elevated plus maze compared to vehicle. Both of these effects were attenuated by 10 mg/kg PO of the CRFR1 antagonist, GSK876008. GSK876008 alone did not affect startle. An intra-BNST infusion of the CRFR1 antagonist CP376395 (2 μg) also blocked increases in acoustic startle induced by intra-BNST infusion of CGRP, as did virally-mediated siRNA knockdown of CRF expression locally within the BNST. Together, these results suggest that the anxiogenic effects of intra-BNST CGRP may be mediated by CRF from BNST neurons acting at local CRFR1 receptors.
Brain–derived neurotrophic factor (BDNF) is critically involved in synaptic plasticity and neurotransmission. Our lab has previously found that BDNF activation of TrkB is required for fear memory formation and that GABAA receptor subunits and the GABAA clustering protein gephyrin are dynamically regulated during fear memory consolidation. We hypothesize that TrkB-dependent internalization of GABAA receptors may partially underlie a transient period of amygdala hyperactivation during fear memory consolidation. We have previously reported that BDNF modulates GABAA receptor α1 subunit sequestration in cultured hippocampal and amygdala neurons by differential phosphorylation pathways. At present, no studies have investigated the regulation of gephyrin and GABAA receptor α1 subunits following BDNF activation in amygdala. In this study, we confirm the association of GABAA receptor α1 and γ2 subunits with gephyrin on mouse amygdala neurons by coimmunoprecipitation and immunocytochemistry. We then demonstrate that rapid BDNF treatment, as well as suppression of gephyrin protein levels on amygdala neurons, induced sequestration of surface α1 subunits. Further, we find that rapid exposure of BDNF to primary amygdala cultures produced decreases in gephyrin levels, whereas longer exposure resulted in an eventual increase. While total α1 subunit levels remained unchanged, gephyrin was downregulated in whole cell homogenates, but enhanced in complexes with GABAA receptors. Our data with anisomycin suggest that BDNF may rapidly induce gephyrin protein degradation, with subsequent gephyrin synthesis occurring. Together, these findings suggest that gephyrin may be a key factor in BDNF-dependent GABAA receptor regulation in amygdala. This work may inform future studies aimed at elucidating the pathways connecting BDNF, GABAA systems, gephyrin, and their role in underlying amygdala-dependent learning.