Does the Association Between Psychosocial Factors and Opioid Use After Elective Spine Surgery Differ by Sex in Older Adults?

Purpose: Psychosocial disorders have been linked to chronic postoperative opioid use and the development of postoperative pain. The potential interaction between sex and psychosocial factors with respect to opioid use after elective spine surgery in the elderly has not yet been evaluated. Our aim was to assess whether any observed association of anxiety or depression indicators with opioid consumption in the first 72 hours after elective spine surgery varies by sex in adults ≥65 years. Patients and Methods: Secondary analysis of a retrospective cohort of 647 elective spine surgeries performed at Brigham and Women's Hospital, July 1, 2015-March 15, 2017, in patients ≥65. Linear mixed-effects models were used to test whether history of anxiety, anxiolytic use, history of depression, and antidepressant use were associated with opioid consumption 0-24, 24-48, and 48-72 post surgery, and whether these potential associations differed by sex. Results: History of anxiety, anxiolytic use, history of depression, and antidepressant use were more common among women (51.3% of the sample). During the first 24 hours after surgery, men with a preoperative history of anxiety consumed an adjusted mean of 19.5 morphine milligram equivalents (MME) (99.6% CI: 8.1, 31.0) more than men without a history of anxiety; women with a history of anxiety only consumed an adjusted mean 2.9 MME (99.6% CI: -3.1, 8.9) more than women without a history of anxiety (P value for interaction between sex and history of anxiety <0.001). No other interactions were detected between sex and psychosocial factors with respect to opioid use after surgery. Conclusion: Secondary analysis of this retrospective cohort study found minimal evidence that the association between psychosocial factors and opioid consumption after elective spine surgery differs by sex in adults ≥65.

Childhood trauma and clinical high risk for psychosis.

As a risk factor for psychosis, childhood trauma rates are elevated in the clinical-high-risk (CHR) syndrome compared to the general population. However, it is unknown whether trauma is typically experienced in childhood or adolescence/young adulthood, whether it occurred prior to CHR syndrome onset, and how severe trauma relates to presenting symptoms. In this study, we examined the relationship of trauma history to symptoms and functioning in individuals diagnosed with the CHR syndrome on the Structured Interview for Psychosis-Risk Syndromes (N = 103). Trauma, defined as meeting the DSM-IV A1 criterion of actual or threatened death or injury, was assessed by semi-structured interview. A large proportion of CHR participants (61%) reported trauma exposure, including interpersonal trauma, trauma prior to CHR onset, and childhood trauma prior to age 12. Those with a trauma history (versus those without trauma) were rated as having more severe perceptual disturbances, general/affective symptoms and more impairment on the Global Assessment of Functioning Scale. The number of traumatic events correlated with more severe ratings in those three domains. Additionally, the number of interpersonal traumas was correlated with ratings of suspiciousness. Trauma was unrelated to specific measures of social and role functioning. A small proportion of CHR participants were diagnosed with formal PTSD (14%), which was unrelated to symptom severity or functioning. Thus, we demonstrate that trauma exposure is often early in life (before age 12), occurs prior to the onset of the CHR syndrome, and is related to both positive and affective symptoms.

The Role of Trauma and Stressful Life Events among Individuals at Clinical High Risk for Psychosis: A Review.

The experience of childhood trauma (CT) and stressful life events (SLEs) is associated with subsequent development of a variety of mental health conditions, including psychotic illness. Recent research identifying adolescents and young adults at clinical high risk (CHR) for psychosis allows for prospective evaluation of the impact of trauma and adverse life events on psychosis onset and other outcomes, addressing etiological questions that cannot be answered in studies of fully psychotic or non-clinical populations. This article provides a comprehensive review of the current emerging literature on trauma and adverse life events in the CHR population. Up to 80% of CHR youth endorse a lifetime history of childhood traumatic events and victimization (e.g., bullying). Several studies have shown that the experience of CT predicts psychosis onset among CHR individuals, while the literature on the influence of recent SLEs (e.g., death of a loved one) remains inconclusive. Multiple models have been proposed to explain the link between trauma and psychosis, including the stress-vulnerability and stress-sensitivity hypotheses, with emphases on both cognitive processes and neurobiological mechanisms (e.g., the hypothalamic-pituitary-adrenal axis). Despite the preponderance of CHR individuals who endorse either CT or SLEs, no clinical trials have been conducted evaluating interventions for trauma in CHR youth to date. Furthermore, the current process of formal identification and assessment of trauma, SLEs, and their impact on CHR youth is inconsistent in research and clinical practice. Recommendations for improving trauma assessment, treatment, and future research directions in the CHR field are provided.

Effect of restorative yoga vs. stretching on diurnal cortisol dynamics and psychosocial outcomes in individuals with the metabolic syndrome: the PRYSMS randomized controlled trial.

PURPOSE: Chronic stimulation and dysregulation of the neuroendocrine system by stress may cause metabolic abnormalities. We estimated how much cortisol and psychosocial outcomes improved with a restorative yoga (relaxation) versus a low impact stretching intervention for individuals with the metabolic syndrome. METHODS: We conducted a 1-year multi-center randomized controlled trial (6-month intervention and 6-month maintenance phase) of restorative yoga vs. stretching. Participants completed surveys to assess depression, social support, positive affect, and stress at baseline, 6 months and 12 months. For each assessment, we collected saliva at four points daily for three days and collected response to dexamethasone on the fourth day for analysis of diurnal cortisol dynamics. We analyzed our data using multivariate regression models, controlling for study site, medications (antidepressants, hormone therapy), body mass index, and baseline cortisol values. RESULTS: Psychosocial outcome measures were available for 171 study participants at baseline, 140 at 6 months, and 132 at 1 year. Complete cortisol data were available for 136 of 171 study participants (72 in restorative yoga and 64 in stretching) and were only available at baseline and 6 months. At 6 months, the stretching group had decreased cortisol at waking and bedtime compared to the restorative yoga group. The pattern of changes in stress mirrored this improvement, with the stretching group showing reductions in chronic stress severity and perseverative thoughts about their stress. Perceived stress decreased by 1.5 points (-0.4; 3.3, p=0.11) at 6 months, and by 2.0 points (0.1; 3.9, p=0.04) at 1 year in the stretching compared to restorative yoga groups. Post hoc analyses suggest that in the stretching group only, perceived increases in social support (particularly feelings of belonging), but not changes in stress were related to improved cortisol dynamics. CONCLUSIONS: We found significant decreases in salivary cortisol, chronic stress severity, and stress perception in the stretching group compared to the restorative yoga group. Group support during the interactive stretch classes may have contributed to these changes.

Stretching of the back improves gait, mechanical sensitivity and connective tissue inflammation in a rodent model.

The role played by nonspecialized connective tissues in chronic non-specific low back pain is not well understood. In a recent ultrasound study, human subjects with chronic low back pain had altered connective tissue structure compared to human subjects without low back pain, suggesting the presence of inflammation and/or fibrosis in the low back pain subjects. Mechanical input in the form of static tissue stretch has been shown in vitro and in vivo to have anti-inflammatory and anti-fibrotic effects. To better understand the pathophysiology of lumbar nonspecialized connective tissue as well as potential mechanisms underlying therapeutic effects of tissue stretch, we developed a carrageenan-induced inflammation model in the low back of a rodent. Induction of inflammation in the lumbar connective tissues resulted in altered gait, increased mechanical sensitivity of the tissues of the low back, and local macrophage infiltration. Mechanical input was then applied to this model as in vivo tissue stretch for 10 minutes twice a day for 12 days. In vivo tissue stretch mitigated the inflammation-induced changes leading to restored stride length and intrastep distance, decreased mechanical sensitivity of the back and reduced macrophage expression in the nonspecialized connective tissues of the low back. This study highlights the need for further investigation into the contribution of connective tissue to low back pain and the need for a better understanding of how interventions involving mechanical stretch could provide maximal therapeutic benefit. This tissue stretch research is relevant to body-based treatments such as yoga or massage, and to some stretch techniques used with physical therapy.

Sensory innervation of the nonspecialized connective tissues in the low back of the rat.

Chronic musculoskeletal pain, including low back pain, is a worldwide debilitating condition; however, the mechanisms that underlie its development remain poorly understood. Pathological neuroplastic changes in the sensory innervation of connective tissue may contribute to the development of nonspecific chronic low back pain. Progress in understanding such potentially important abnormalities is hampered by limited knowledge of connective tissue's normal sensory innervation. The goal of this study was to evaluate and quantify the sensory nerve fibers terminating within the nonspecialized connective tissues in the low back of the rat. With 3-dimensional reconstructions of thick (30-80 µm) tissue sections we have for the first time conclusively identified sensory nerve fiber terminations within the collagen matrix of connective tissue in the low back. Using dye labeling techniques with Fast Blue, presumptive dorsal root ganglia cells that innervate the low back were identified. Of the Fast Blue-labeled cells, 60-88% also expressed calcitonin gene-related peptide (CGRP) immunoreactivity. Based on the immunolabeling with CGRP and the approximate size of these nerve fibers (≤2 µm) we hypothesize that they are Aδ or C fibers and thus may play a role in the development of chronic pain.

Hybridization between mtDNA-defined phylogeographic lineages of black ratsnakes (Pantherophis sp.).

Phylogeographic analyses using mitochondrial DNA (mtDNA) have revealed many examples of apparently deep historical subdivisions ('phylogroups') within many vertebrates. It remains unclear whether these phylogroups represent independently evolving, adaptively differentiated lineages or groups that show little functional differentiation and, hence, will merge on contact. Here, we use mtDNA sequence data to evaluate the phylogeographic relationships between two of the northernmost populations of black ratsnakes (Pantherophis obsoletus complex) in Ontario, Canada and previously analysed populations in the United States. We then use population-level analyses to evaluate the level of adaptive divergence between previously established mtDNA phylogroups. Phylogenetic analyses show that southern Ontario snakes have mtDNA haplotypes that fall within the Central mtDNA phylogroup, as designated by Burbrink et al. (2000). In contrast, snakes in eastern Ontario carry either Central or Eastern-specific haplotypes. Within the hybrid region, we found highly variable frequencies of mtDNA haplotypes among isolated sub-populations, no association between variation in cytonuclear (mtDNA) and nuclear (microsatellite DNA) markers, no difference in survival or reproductive success among snakes with different mtDNA haplotypes, and no effect of mate similarity in mtDNA on female clutch size. These results argue that the Eastern and Central phylogroups have merged in this region, likely due to a lack of adaptive differentiation between individuals in each lineage. Hence, in these snakes, phylogeographic structure in mtDNA is more a reflection of historical isolation rather than adaptive divergence. The observed reticulation between lineages and lack of evidence for hybrid disgenesis also bears on the classification of these lineages as distinct species.

Identification of T lymphocytes in simian immunodeficiency virus encephalitis: distribution of CD8+ T cells in association with central nervous system vessels and virus.

T lymphocytes are found within brains infected with human immunodeficiency virus (HIV) or simian immunodeficiency virus (SIV) where they are a minor, but consistently identified, population. However, little analysis of their phenotypes has been done, and questions concerning whether or not they are viral antigen specific has not been thoroughly examined. We investigated the central nervous system (CNS) of SIV-infected rhesus macaques to identify T-lymphocyte subsets in relation to virus-infected cells and brain microvessels. We have found that a sensitive antigen-retrieval technique greatly enhanced immunohistochemical detection of CD4+ and CD8+ T lymphocytes in control studies. In encephalitic brains of SIV-infected monkeys with acquired immunodeficiency syndrome (AIDS), we found a significant accumulation of CD8+ T lymphocytes but little-to-no accumulation of CD4+ T lymphocytes. CD4+ cells, when detected, were mostly monocyte/macrophages closely associated with CNS vessels. Using a combination of in situ hybridization for SIV RNA, and immunohistochemistry for CD8+ T lymphocytes and/or Glut-1 for endothelial cells on brain microvessels, we found CD8+ T lymphocytes with an angiocentric distribution often adjacent to virus-infected cells. In the CNS of animals with SIV encephalitis, there was a trend of CD8+ T lymphocytes that were not directly juxtaposed with CNS vessels. These data suggest that in brains of SIV-infected monkeys and HIV-infected humans, CD8+ T lymphocytes traffic to and are retained in the CNS in an angiocentric and possibly antigen-specific manner.

Monocyte/macrophage traffic in HIV and SIV encephalitis.

This short review focuses on the role of central nervous system (CNS) perivascular macrophages as targets of productive infection of the CNS. Data discussed include the importance of these cells as early targets of infection and their productive infection with AIDS. Many of the immune molecules on perivascular macrophages are also found on subsets of blood monocyte/macrophages, some of which are expanded during human immunodeficiency virus (HIV) infection. These observations paired with the known bone marrow (BM) origin of perivascular macrophages and the BM as a site of HIV infection underscore the importance of the study of monocyte populations in the BM and blood, which are activated and infected as a source of virus that enters the CNS. Data presented and discussed herein suggest a role of HIV-infected BM-derived monocytes as "Trojan horse" cells that traffic to the CNS to become perivascular macrophages. The study of such cells including their timing of infection, activation, and traffic and the role of HIV-specific immune responses controlling their accumulation in the CNS warrant study with regard to CNS neuropathogenesis.

Proliferating cellular nuclear antigen expression as a marker of perivascular macrophages in simian immunodeficiency virus encephalitis.

Brain perivascular macrophages are a major target of simian immunodeficiency virus (SIV) infection in rhesus macaques and HIV infection in humans. Perivascular macrophages are distinct from parenchymal microglia in their location, morphology, expression of myeloid markers, and turnover in the CNS. In contrast to parenchymal microglia, perivascular macrophages are continuously repopulated by blood monocytes, which undergo maturation to macrophages on entering the central nervous system (CNS). We studied differences in monocyte/macrophages in vivo that might account for preferential infection of perivascular macrophages by SIV. In situ hybridization for SIV and proliferating cellular nuclear antigen (PCNA) immunohistochemistry demonstrated that SIV-infected and PCNA-positive cells were predominantly found in perivascular cuffs of viremic animals and in histopathological lesions that characterize SIV encephalitis (SIVE) in animals with AIDS. Multilabel techniques including double-label immunohistochemistry and combined in situ hybridization and immunofluorescence confocal microscopy revealed numerous infected perivascular macrophages that were PCNA-positive. Outside the CNS, SIV-infected, PCNA-expressing macrophage subpopulations were found in the small intestine and lung of animals with AIDS. While PCNA is used as a marker of cell proliferation it is also strongly expressed in non-dividing cells undergoing DNA synthesis and repair. Therefore, more specific markers for cell proliferation including Ki-67, topoisomerase IIalpha, and bromodeoxyuridine (BrdU) incorporation were used which indicated that PCNA-positive cells within SIVE lesions were not proliferating. These observations are consistent with perivascular macrophages as terminally differentiated, non-dividing cells and underscores biological differences that could potentially define mechanisms of preferential, productive infection of perivascular macrophages in the rhesus macaque model of neuroAIDS. These studies suggest that within CNS and non-CNS tissues there exist subpopulations of macrophages that are SIV-infected and express PCNA.