Thaddeus W. W. Pace

IFN-Alpha-Induced Cortical and Subcortical Glutamate Changes Assessed by Magnetic Resonance Spectroscopy

Cytokine effects on behavior may be related to alterations in glutamate metabolism. We therefore measured glutamate concentrations in brain regions shown to be affected by inflammatory stimuli including the cytokine interferon (IFN)-alpha. IFN-alpha is known to alter neural activity in the dorsal anterior cingulate cortex (dACC) and basal ganglia in association with symptoms of depression and increases in peripheral cytokines including the tumor necrosis factor (TNF) and its soluble receptor. Single-voxel magnetic resonance spectroscopy (MRS) was employed to measure glutamate concentrations normalized to creatine (Glu/Cr) in dACC and basal ganglia of 31 patients with hepatitis C before and after ∼1 month of either no treatment (n=14) or treatment with IFN-alpha (n=17). Depressive symptoms were measured at each visit using the Inventory of Depressive Symptoms-Clinician Rating (IDS-C) and the Multidimensional Fatigue Inventory. IFN-alpha was associated with a significant increase in Glu/Cr in dACC and left basal ganglia. Increases in dACC Glu/Cr were positively correlated with scores on the IDS-C in the group as a whole, but not in either group alone. Glu/Cr increases in left basal ganglia were correlated with decreased motivation in the group as a whole and in IFN-alpha-treated subjects alone. No Glu/Cr changes were found in the right basal ganglia, and no significant correlations were found between Glu/Cr and the inflammatory markers. IFN-alpha-induced increases in glutamate in dACC and basal ganglia are consistent with MRS findings in bipolar depression and suggest that inflammatory cytokines may contribute to glutamate alterations in patients with mood disorders and increased inflammation.

Epigenetic changes associated with inflammation in breast cancer patients treated with chemotherapy.

Inflammation has been associated with fatigue during and after various types of breast cancer treatments. We examined whether prior chemotherapy was associated with DNA methylation patterns that could explain persisting inflammation and/or fatigue in women treated for breast cancer. Prior to breast radiation therapy, DNA was extracted from peripheral blood mononuclear cells (PBMCs) of 61 Stage 0-IIIA breast cancer patients who had received partial mastectomy with or without chemotherapy. DNA methylation was assessed at >485,000 CpG sites across the genome along with fatigue and plasma inflammatory markers previously associated with fatigue. Compared to non-chemotherapy-treated, women who had received chemotherapy exhibited significantly decreased methylation at eight CpG sites (p<1.03×10(-7)) including four in exon 11 of transmembrane protein 49 (TMEM49), which demonstrated the largest decreases in methylation. Lower methylation at each identified CpG site was associated with increased plasma soluble tumor necrosis factor receptor 2 (sTNFR2) and interleukin (IL)-6 and mediated the relationship between chemotherapy and increases in these inflammatory biomarkers adjusting for multiple clinical and treatment characteristics. sTNFR2, but not CpG methylation status, was correlated with fatigue. Six months after breast radiation therapy, DNA methylation, inflammatory biomarkers and fatigue assessments were repeated in a subset of subjects (N=39). Reduced methylation in 4 of the 8 identified CpG sites was still observed in chemotherapy versus non-chemotherapy-treated patients, albeit with some decay indicating the dynamic and potentially reversible nature of the changes. Reduced methylation in these 4 CpG sites also continued to correlate with either increased sTNFR2 or IL-6, but not fatigue. In conclusion, prior chemotherapy treatment was associated with decreased methylation of CpG sites in DNA from PBMCs of breast cancer patients, which correlated with increased inflammatory markers prior to and 6months after radiation therapy. Persisting epigenetic changes secondary to chemotherapy may be one factor that contributes to inflammation and its consequences including cancer-related fatigue in vulnerable breast cancer patients.

Mechanistic insights into corticosteroids in multiple sclerosis: War horse or chameleon?☆

OBJECTIVESnRelapse management is a crucial component of multiple sclerosis (MS) care. High-dose corticosteroids (CSs) are used to dampen inflammation, which is thought to hasten the recovery of MS relapse. A diversity of mechanisms drive the heterogeneous clinical response to exogenous CSs in patients with MS. Preclinical research is beginning to provide important insights into how CSs work, both in terms of intended and unintended effects. In this article we discuss cellular, systemic, and clinical characteristics that might contribute to intended and unintended CS effects when utilizing supraphysiological doses in clinical practice. The goal of this article is to consider recent insights about CS mechanisms of action in the context of MS.nnnMETHODSnWe reviewed relevant preclinical and clinical studies on the desirable and undesirable effects of high-dose corticosteroids used in MS care.nnnRESULTSnPreclinical studies reviewed suggest that corticosteroids may act in unpredictable ways in the context of autoimmune conditions. The precise timing, dosage, duration, cellular exposure, and background CS milieu likely contribute to their clinical heterogeneity.nnnCONCLUSIONnIt is difficult to predict when patients will respond favorably to CSs, both in terms of therapeutic response and tolerability profile. There are specific cellular, systemic, and clinical characteristics that might merit further consideration when utilizing CSs in clinical practice, and these should be explored in a translational setting.

Feasibility of Cognitively-Based Compassion Training (CBCT) for breast cancer survivors: a randomized, wait list controlled pilot study.

PurposeThis study assessed the feasibility of a meditation-based program called Cognitively-Based Compassion Training (CBCT) with breast cancer survivors. Enrollment and participant satisfaction with a novel intervention, adherence to program requirements, and differences between the intervention group and wait list controls on self-report measures were also assessed. Additionally, cortisol, a stress-related endocrine biomarker, was assessed.MethodsParticipants (nxa0=xa033) were randomly assigned to CBCT or the wait list. CBCT provided eight weekly, 2-h classes and a “booster” CBCT session 4xa0weeks later. CBCT participants were expected to attend classes and meditate between classes at least three times per week. Pre-/post-intervention and follow-up questionnaires measured symptom change (depression, intrusive thoughts, perceived stress, fear of cancer recurrence, fatigue/vitality, loneliness, and quality of life). Saliva samples were collected at the same periods to assess the slope of diurnal cortisol activity.ResultsEnrollment, class attendance, home practice time, and patient satisfaction exceeded expectations. Compared to controls, post-intervention, the CBCT group showed suggestions of significant improvements in depression, avoidance of intrusive thoughts, functional impairment associated with fear of recurrence, mindfulness, and vitality/fatigue. At follow-up, less perceived stress and higher mindfulness were also significant in the CBCT group. No significant changes were observed on any other measure including diurnal cortisol activity.ConclusionsWithin the limits of a pilot feasibility study, results suggest that CBCT is a feasible and highly satisfactory intervention potentially beneficial for the psychological well-being of breast cancer survivors. However, more comprehensive trials are needed to provide systematic evidence.RelevanceCBCT may be very beneficial for improving depression and enhancing well-being during breast cancer survivorship.

Re-evaluating the treatment of acute optic neuritis

Clinical case reports and prospective trials have demonstrated a reproducible benefit of hypothalamic-pituitary-adrenal (HPA) axis modulation on the rate of recovery from acute inflammatory central nervous system (CNS) demyelination. As a result, corticosteroid preparations and adrenocorticotrophic hormones are the current mainstays of therapy for the treatment of acute optic neuritis (AON) and acute demyelination in multiple sclerosis. Despite facilitating the pace of recovery, HPA axis modulation and corticosteroids have failed to demonstrate long-term benefit on functional recovery. After AON, patients frequently report visual problems, motion perception difficulties and abnormal depth perception despite ‘normal’ (20/20) vision. In light of this disparity, the efficacy of these and other therapies for acute demyelination require re-evaluation using modern, high-precision paraclinical tools capable of monitoring tissue injury. In no arena is this more amenable than AON, where a new array of tools in retinal imaging and electrophysiology has advanced our ability to measure the anatomic and functional consequences of optic nerve injury. As a result, AON provides a unique clinical model for evaluating the treatment response of the derivative elements of acute inflammatory CNS injury: demyelination, axonal injury and neuronal degeneration. In this article, we examine current thinking on the mechanisms of immune injury in AON, discuss novel technologies for the assessment of optic nerve structure and function, and assess current and future treatment modalities. The primary aim is to develop a framework for rigorously evaluating interventions in AON and to assess their ability to preserve tissue architecture, re-establish normal physiology and restore optimal neurological function.

A mindful eating intervention: A theory-guided randomized anti-obesity feasibility study with adolescent Latino females

UNLABELLEDnWhile pediatric anti-obesity lifestyle interventions have received considerable attention, few show sustained impact on body mass index (BMI). Using the Information-Motivation-Behavioral Skills Theory as a framework, we examined the effects of a satiety-focused mindful eating intervention (MEI) on BMI, weight and mindful awareness.nnnMETHODnnnnDESIGN AND SETTINGnUtilizing a two-group, repeated measures design, 37 adolescent females with a BMIu2009>90th percentile, recruited from a public high school in a Latino community in the Southwestern United States, were randomized 2:1, one third to the group receiving a 6-week MEI and two thirds to the comparison group (CG) receiving the usual care (nutrition and exercise information).nnnINTERVENTIONnDuring six weekly 90-min after school MEI group sessions, the behavioral skills of slow intentional eating were practiced with foci on satiety cues and triggers to overeat.nnnOUTCOMESnFeasibility and acceptability were measured as participant retention (goal ≥55%) and evaluative comments from those in the MEI group, respectively. BMI and mindful awareness were measured on site at baseline, immediately post intervention, and at 4-week follow-up (week 10).nnnRESULTSnFifty-seven and 65% of those in the MEI and CG were retained throughout the study, respectively. MEI participants showed significantly lowered BMI compared with CG participants, whose weight increased (p<0.001). At six weeks, the MEI group BMI decreased by 1.1kg/m(2) (BMI continued to decline to 1.4kg/m(2) by week 10); while CG BMI increased by 0.7kg/m(2) (consistent with BMI >90th percentile standard growth projections).nnnCONCLUSIONSnInitial and sustained decline of BMI in the MEI group supports further study of this theory-guided approach, and the value of practicing satiety-focused mindful eating behavioral skills to facilitate health behavior change.

Natural language indicators of differential gene regulation in the human immune system

Significance Social genomics research has identified a conserved transcriptional response to adversity (CTRA) that may contribute to social disparities in health. This study identified systematic individual differences in natural language use that track CTRA gene expression more closely than do conventional self-report measures of stress, anxiety, or depression. These language style markers may provide a useful behavioral indicator of the neurobiological processes that mediate social influences on gene expression in immune cells. Adverse social conditions have been linked to a conserved transcriptional response to adversity (CTRA) in circulating leukocytes that may contribute to social gradients in disease. However, the CNS mechanisms involved remain obscure, in part because CTRA gene-expression profiles often track external social–environmental variables more closely than they do self-reported internal affective states such as stress, depression, or anxiety. This study examined the possibility that variations in patterns of natural language use might provide more sensitive indicators of the automatic threat-detection and -response systems that proximally regulate autonomic induction of the CTRA. In 22,627 audio samples of natural speech sampled from the daily interactions of 143 healthy adults, both total language output and patterns of function-word use covaried with CTRA gene expression. These language features predicted CTRA gene expression substantially better than did conventional self-report measures of stress, depression, and anxiety and did so independently of demographic and behavioral factors (age, sex, race, smoking, body mass index) and leukocyte subset distributions. This predictive relationship held when language and gene expression were sampled more than a week apart, suggesting that associations reflect stable individual differences or chronic life circumstances. Given the observed relationship between personal expression and gene expression, patterns of natural language use may provide a useful behavioral indicator of nonconsciously evaluated well-being (implicit safety vs. threat) that is distinct from conscious affective experience and more closely tracks the neurobiological processes involved in peripheral gene regulation.

The plasma interleukin-6 response to acute psychosocial stress in humans is detected by a magnetic multiplex assay: comparison to high-sensitivity ELISA

Abstract Circulating concentrations of interleukin (IL)-6, an inflammatory biomarker widely assessed in humans to study the inflammatory response to acute psychological stress, have for decades been quantified using enzyme-linked immunosorbent assay (ELISA). However, biobehavioral researchers are increasingly using cytokine multiplex assays instead of ELISA to measure IL-6 and other cytokines. Despite this trend, multiplex assays have not been directly compared to ELISA for their ability to detect subtle stress-induced changes of IL-6. Here, we tested the prediction that a high-sensitivity multiplex assay (human Magnetic Luminex Performance Assay, R&D Systems, Minneapolis, MN) would detect changes in IL-6 as a result of acute stress challenge in a manner comparable to high-sensitivity ELISA. Blood was collected from 12 healthy adults immediately before and then 90 and 210u2009min after the start of the Trier Social Stress Test (TSST), an acute laboratory psychosocial stress challenge. In addition to quantifying IL-6 concentrations in plasma with both multiplex and ELISA, we also assessed concentrations of tumor necrosis factor-alpha, IL-8, IL-10, IL-5, and IL-2 with multiplex. The multiplex detected IL-6 in all samples. Concentrations strongly correlated with values determined by ELISA across all samples (ru2009=u20090.941, pu2009<u2009.001) as well as among samples collected at individual TSST time points. IL-6 responses to the TSST (i.e. area under the curve) captured by multiplex and ELISA were also strongly correlated (rsu2009=u20090.937, pu2009<u2009.001). While other cytokines were detected by multiplex, none changed as a result of TSST challenge at time points examined. These results suggest high-sensitivity magnetic multiplex assay is able to detect changes in plasma concentrations of IL-6 as a result of acute stress in humans.

A Dyadic Analysis of Stress Processes in Latinas with Breast Cancer and Their Family Caregivers

Breast cancer diagnosis and treatment negatively affect quality of life for survivors and their family caregivers. The stress process model has been useful for describing the cascade of social and psychological experiences that culminate in degraded quality of life for both survivors and their family caregivers. This study is designed to test theoretically specified predictors of negative psychosocial outcomes in a dyadic context.

Emotion Dysregulation and Inflammation in African-American Women with Type 2 Diabetes

C-reactive protein (CRP), a marker of systemic inflammation, has been associated with major depressive disorder (MDD) and posttraumatic stress disorder (PTSD). Emotion dysregulation is a transdiagnostic risk factor for many psychological disorders associated with chronic inflammatory state. The objective of this study was to determine whether inflammation is associated with emotion dysregulation in women with type 2 diabetes mellitus (T2DM). We examined associations between trauma exposure, MDD, PTSD, emotion dysregulation, and CRP among 40 African-American women with T2DM recruited from an urban hospital. Emotion dysregulation was measured using the Difficulties in Emotion Regulation Scale. PTSD and MDD were measured with structured clinical interviews. Child abuse and lifetime trauma load were also assessed. Analyses showed that both emotion dysregulation and current MDD were significantly associated with higher levels of CRP (p < 0.01). Current PTSD was not significantly related to CRP. In a regression model, emotion dysregulation was significantly associated with higher CRP (p < 0.001) independent of body mass index, trauma exposure, and MDD diagnosis. These findings suggest that emotion dysregulation may be an important risk factor for chronic inflammation beyond already known risk factors among women with T2DM, though a causal relationship cannot be determined from this study.