Bruce S. Rabin

Chronic stress, glucocorticoid receptor resistance, inflammation, and disease risk

We propose a model wherein chronic stress results in glucocorticoid receptor resistance (GCR) that, in turn, results in failure to down-regulate inflammatory response. Here we test the model in two viral-challenge studies. In study 1, we assessed stressful life events, GCR, and control variables including baseline antibody to the challenge virus, age, body mass index (BMI), season, race, sex, education, and virus type in 276 healthy adult volunteers. The volunteers were subsequently quarantined, exposed to one of two rhinoviruses, and followed for 5 d with nasal washes for viral isolation and assessment of signs/symptoms of a common cold. In study 2, we assessed the same control variables and GCR in 79 subjects who were subsequently exposed to a rhinovirus and monitored at baseline and for 5 d after viral challenge for the production of local (in nasal secretions) proinflammatory cytokines (IL-1β, TNF-α, and IL-6). Study 1: After covarying the control variables, those with recent exposure to a long-term threatening stressful experience demonstrated GCR; and those with GCR were at higher risk of subsequently developing a cold. Study 2: With the same controls used in study 1, greater GCR predicted the production of more local proinflammatory cytokines among infected subjects. These data provide support for a model suggesting that prolonged stressors result in GCR, which, in turn, interferes with appropriate regulation of inflammation. Because inflammation plays an important role in the onset and progression of a wide range of diseases, this model may have broad implications for understanding the role of stress in health.

Types of Stressors That Increase Susceptibility to the Common Cold in Healthy Adults

Two-hundred seventy-six volunteers completed a life stressor interview and psychological questionnaires and provided blood and urine samples. They were then inoculated with common cold viruses and monitored for the onset of disease. Although severe acute stressful life events (less than 1 month long) were not associated with developing colds, severe chronic stressors (1 month or longer) were associated with a substantial increase in risk of disease. This relation was attributable primarily to under- or unemployment and to enduring interpersonal difficulties with family or friends. The association between chronic stressors and susceptibility to colds could not be fully explained by differences among stressed and nonstressed persons in social network characteristics, personality, health practices, or prechallenge endocrine or immune measures.

Loneliness, Social Network Size, and Immune Response to Influenza Vaccination in College Freshmen.

Antibody response to the influenza immunization was investigated in 83 1st-semester healthy university freshmen. Elevated levels of loneliness throughout the semester and small social networks were independently associated with poorer antibody response to 1 component of the vaccine. Those with both high levels of loneliness and a small social network had the lowest antibody response. Loneliness was also associated with greater psychological stress and negative affect, less positive affect, poorer sleep efficiency and quality, and elevations in circulating levels of cortisol. However, only the stress data were consistent with mediation of the loneliness-antibody response relation. None of these variables were associated with social network size, and hence none were potential mediators of the relation between network size and immunization response.

Induction of c-Fos immunoreactivity in the rat forebrain by conditioned and unconditioned aversive stimuli.

The protein product of the c-fos proto-oncogene was immunocytochemically localized in forebrain regions of adult male Lewis rats subjected to a physically aversive footshock stimulus or a Pavlovian-conditioned, non-aversive, auditory stimulus. Animals receiving the conditioned stimulus were first conditioned by repeatedly pairing electric footshock, the unconditioned stimulus (US), with an auditory cue, the conditioned stimulus (CS). These animals were later tested with the CS in the absence of the US, a procedure which, like footshock itself, suppresses immune function. In animals exposed to the conditioned or unconditioned stressor, c-Fos was strongly expressed in cells of the paraventricular nuclei (PVN) of the hypothalamus, some of which contain corticotropin-releasing hormone (CRH), and other forebrain areas directly associated with autonomic function, the ventral lateral septal nuclei (LSV), the medial amygdaloid nuclei (AME), the sensorimotor cortex, the basal ganglia and thalamic nuclei. Control animals exhibited very little or no c-Fos in the above areas. The identified forebrain nuclei can now be targeted for further study aimed at elucidating their role in stress-induced immune alteration.

Individual Differences in Cellular Immune Response to Stress

Correlational studies suggest that psychological stress suppresses cellular immune function in some, but not all, individuals. Here, effects of acute mental stress on lymphocyte subpopulations and T-lymphocyte mitogenesis were examined experimentally in healthy young adults. CD8 (T-suppressor/cytotoxic) lymphocytes increased in number and T-cell response to stimulation by phytohemagglutinin was attenuated following exposure to a 20-min laboratory stressor, but only in persons who also showed heightened catecholamine and cardiovascular reactions to stress. Hence, individuals differ substantially in their immunologic responsivity to behavioral stimuli, and such differences parallel (and may be predicted by) interindividual variability in stress-induced sympathetic nervous system activation.

Serum interleukin-6 concentration in schizophrenia: Elevation associated with duration of illness

Using an enzyme immunoassay (ELISA), we measured serum interleukin-6 (IL-6) concentration in 128 schizophrenic patients (24 of whom were never medicated) and in 110 normal control subjects. Mean serum IL-6 concentration was significantly higher in the schizophrenic patients as compared with the control subjects (p = 0.009). Comparisons within the patient group revealed that serum IL-6 was significantly correlated with duration of illness (r = 0.32, p = 0.0004). After covariation for duration of illness, there was no relationship between IL-6 levels and the production of autoantibodies, clinical state, or medication status. Thus, elevated serum IL-6 levels in schizophrenia develop during the course of illness and may be related to treatment or to disease progression.

Psychological stress and antibody response to immunization: a critical review of the human literature.

Objective The objective of this review was to evaluate the evidence for the hypothesis that psychological stress influences antibody response to immunization in humans. Methods A critical review of the literature was conducted. Results The evidence supports an association between psychological stress and suppression of humoral immune (antibody) response to immunization. This association is convincing in the case of secondary immune response but weak for primary response. The lack of consistent evidence for a relation with primary response may be attributed to a failure to consider the critical points when stress needs to be elevated in the course of the production of antibody. Lower secondary antibody responses were found among patients with chronically high levels of stress (severe enduring problems or high levels of trait negative affect). These responses were found most consistently among older adults. Lower secondary responses were also found for those reporting acute stress or negative affect, but only in studies of secretory immunoglobulin A antibody in which psychological and antibody measures were linked very closely in time. Health practices did not mediate relations between stress and antibody responses; however, there were indications that elevated cortisol levels among stressed patients could play a role. Evidence also suggests the possible influences of dispositional stress-reactivity and low positive affect in the inhibition of antibody production. Conclusions The literature supports a relationship between psychological stress and antibody responses to immunizations. The data are convincing in the case of secondary response but weak for primary response. More attention to the kinetics of stress and antibody response and their interrelations is needed in future research.

CHRONIC SOCIAL STRESS, SOCIAL STATUS, AND SUSCEPTIBILITY TO UPPER RESPIRATORY INFECTIONS IN NONHUMAN PRIMATES

Objective The objective of the study was to assess the roles of social stress and social status in susceptibility to upper respiratory infection. Method: Sixty male cynomolgus monkeys were randomly assigned to stable or unstable social conditions for 15 months. Two markers of social status, social rank and percent of behaviors that were submissive, were assessed at independent observation periods. Endocrine, immune, and behavioral responses were each assessed (at 3-month intervals) during the 9th through 14th months of the study. At the beginning of the 15th month, all animals were exposed to a virus (adenovirus) that causes a common-cold-like illness. The primary outcome was whether or not an animal developed an infection (shed virus) after viral exposure. Results: Although the social instability manipulation was associated with increased agonistic behavior as indicated by minor injuries and elevated norepinephrine responses to social reorganizations, the manipulation did not influence the probability of being infected by the virus. However, low social status (as assessed by either marker) was associated with a substantially greater probability of being infected. It was also associated with less body weight, greater elevated cortisol responses to social reorganizations, and less aggressive behavior. However, none of these characteristics could account for the relation between social status and infection. Conclusions: Social stress was not associated with susceptibility to infection. However, animals with lower social status were at higher risk than high social status animals.

The effect of sunlight on postoperative analgesic medication use: A prospective study of patients undergoing spinal surgery

Objective: Exposure to natural sunlight has been associated with improvement in mood, reduced mortality among patients with cancer, and reduced length of hospitalization for patients who have experienced myocardial infarction. Our aim was to evaluate whether the amount of sunlight in a hospital room modifies a patient’s psychosocial health, the quantity of analgesic medication used, and the pain medication cost. Methods: A prospective study of pain medication use was conducted in 89 patients undergoing elective cervical and lumbar spinal surgery where they were housed on either the “bright” or “dim” side of the same hospital unit. Analgesic medication was converted to standard morphine equivalents for interpatient comparison. The intensity of sunlight in each hospital room was measured daily and psychologic questionnaires were administered on the day after surgery and at discharge. Results: Patients staying on the bright side of the hospital unit were exposed to 46% higher-intensity sunlight on average (p = .005). Patients exposed to an increased intensity of sunlight experienced less perceived stress (p = .035), marginally less pain (p = .058), took 22% less analgesic medication per hour (p = .047), and had 21% less pain medication costs (p = .047). Age quartile was the only other variable found to be a predictor of analgesic use, with a significant negative correlation (p <.001). However, patients housed on the bright side of the hospital consistently used less analgesic medications in all age quartiles. Conclusion: The exposure postoperatively of patients who have undergone spinal surgery to increased amounts of natural sunlight during their hospital recovery period may result in decreased stress, pain, analgesic medication use, and pain medication costs. ACCF = anterior cervical corpectomy and fusion; ACDF = anterior cervical discectomy and fusion; AEDET = Achieving Excellence Design Evaluation Toolkit; CES-D = Center for Epidemiological Studies–Depression Scale; CNS = central nervous system; DS = degenerative spondylolisthesis; LOS = length of stay; LOT-R = Life Orientation Test-Revised; LS = lumbar stenosis; MPQ = McGill Pain Questionnaire; OR = operating room; PACU = postanesthesia care unit; PCA = patient-controlled analgesia; PFI = Private Finance Initiative; POMS = Reduced POMS–Anxiety Scale; PRN = as needed; PSS = Perceived Stress Scale; SAD = seasonal affective disorder; TCAs = tricyclic antidepressants; UK = United Kingdom.

Characterization of the central nervous system innervation of the rat spleen using viral transneuronal tracing.

Splenic immune function is modulated by sympathetic innervation, which in turn is controlled by inputs from supraspinal regions. In the present study, the characterization of central circuits involved in the control of splenic function was accomplished by injecting pseudorabies virus (PRV), a retrograde transynaptic tracer, into the spleen and conducting a temporal analysis of the progression of the infection from 60 hours to 110 hours postinoculation. In addition, central noradrenergic cell groups involved in splenic innervation were characterized by dual immunohistochemical detection of dopamine‐β‐hydroxylase and PRV. Infection in the CNS first appeared in the spinal cord. Splenic sympathetic preganglionic neurons, identified in rats injected with Fluoro‐Gold i.p. prior to PRV inoculation of the spleen, were located in T3–T12 bilaterally; numerous infected interneurons were also found in the thoracic spinal cord (T1–T13). Infected neurons in the brain were first observed in the A5 region, ventromedial medulla, rostral ventrolateral medulla, paraventricular hypothalamic nucleus, Barringtons nucleus, and caudal raphe. At intermediate survival times, the number of infected cells increased in previously infected areas, and infected neurons also appeared in lateral hypothalamus, A7 region, locus coeruleus, subcoeruleus region, nucleus of the solitary tract, and C3 cell group. At longer postinoculation intervals, infected neurons were found in additional hypothalamic areas, Edinger‐Westphal nucleus, periaqueductal gray, pedunculopontine tegmental nucleus, caudal ventrolateral medulla, and area postrema. These results demonstrate that the sympathetic outflow to the spleen is controlled by a complex multisynaptic pathway that involves several brainstem and forebrain nuclei. J. Comp. Neurol. 439:1–18, 2001.