Publications by authors named "Michael R Irwin"

279 Publications

Trait positive affect buffers the association between experimental sleep disruption and inflammation.

Psychoneuroendocrinology 2021 Apr 28;129:105240. Epub 2021 Apr 28.

Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background: Sleep disturbances and insufficient sleep are highly prevalent. Both clinical sleep disorders and multiple forms of experimental sleep loss predict heightened inflammation. As such, it is necessary to investigate potential protective factors. Given that trait positive affect (PA) is associated with reduced inflammation, and buffers the proinflammatory effects of stress, it is possible that high trait positive affect might protect individuals from an inflammatory response to sleep disruption. The present study tested this hypothesis in an experimental sleep disruption paradigm with assessment of cellular inflammation.

Methods: Data were drawn from good sleeping adults (n = 79) who participated in a randomized, within-subjects crossover experiment comparing the effects of two nights of sleep disruption versus two nights of uninterrupted sleep. Stimulated monocytic production of intracellular proinflammatory cytokines tumor necrosis factor (TNF) and interleukin-6 (IL-6) were assayed using flow cytometric methods and indexed as the percentage of monocytes expressing TNF, IL-6, or co-expressing both. Hypotheses were evaluated using linear mixed effects models.

Results: Controlling for negative affect, body mass index, age, and sex, PA significantly moderated the associations between sleep condition and stimulated monocyte production of IL-6 (b = -1.03, t = -2.02, p = .048) and its co-expression with TNF (b = -0.93, t = -2.00, p = .049), such that inflammatory responses were blunted among those high in PA with increases principally among those low in PA. The effect on TNF was similar in terms of effect size, but marginally significant.

Conclusions: Activation of cellular inflammation in response to sleep disruption is buffered by PA independent of negative affect. Interventions that promote PA might protect persons from the inflammatory activation following sleep loss, with the potential to mitigate the adverse health consequences of sleep disturbance.
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http://dx.doi.org/10.1016/j.psyneuen.2021.105240DOI Listing
April 2021

Sex Differences, Sleep Disturbance and Risk of Persistent Pain Associated With Groin Hernia Surgery: A Nationwide Register-Based Cohort Study.

J Pain 2021 May 5. Epub 2021 May 5.

Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden; Department of Surgery, Skåne University Hospital, Malmö, Sweden.

Persistent pain after groin hernia repair is a major health problem. Sleep disturbance is associated with heightened pain sensitivity. The main objective of this study was to examine the role of sleep disturbance in the development and long-term maintenance of chronic postherniorrhaphy inguinal pain (CPIP), with exploration of sex differences. From 2012-2017, a national cohort of patients with prior groin hernia repair (n=2084;45.8% females) were assessed for the development of CPIP 12 months after surgery. Patients then underwent long-term (median 5.0 years) follow-up to evaluate the contribution of sex and sleep disturbance on the maintenance of CPIP. Associations between pre- and postoperative sleep problems (assessed at long-term follow-up) and CPIP were tested using logistic regression. Females had higher rates of CPIP with negative impact on daily activities 12 months after surgery as compared to males (14.6 vs 9.2%,p<0.0005), and were more likely to have moderate-severe CPIP in the long-term (3.1 vs 1.2%,p=0.003). Preoperative sleep problems predicted development of CPIP 12 months after surgery (adjusted odds ratio (aOR) 1.76 (95%CI 1.26-2.46),p=0.001) and CPIP in the long-term (aOR 2.20 (1.61-3.00),p<0.0001). CPIP was associated with insomnia and depression. Sleep disturbance may increase the risk for CPIP, and contribute to maintenance of postsurgical pain. PERSPECTIVE: Females are at heightened risk for CPIP as compared to males. Increased severity of pain symptoms are linked to poorer sleep and psychiatric morbidity. Given the robust associations between sleep disturbance and CPIP, interventions which consolidate and promote sleep, especially in females, may improve long-term pain control.
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http://dx.doi.org/10.1016/j.jpain.2021.04.008DOI Listing
May 2021

Exploring neural mechanisms of the health benefits of gratitude in women: A randomized controlled trial.

Brain Behav Immun 2021 Apr 28. Epub 2021 Apr 28.

Department of Psychology, University of California, Los Angeles, 502 Portola Plaza, Los Angeles, CA 90095, United States. Electronic address:

Background: Gratitude has received growing interest as an emotion that can bring greater happiness and health. However, little is known about the effects of gratitude on objective measures of physical health or the neural mechanisms that underlie these effects. Given strong links between gratitude and giving behavior, and giving and health, it is possible that gratitude may benefit health through the same mechanisms as giving to others. Thus, this study investigated whether gratitude activates a neural 'caregiving system' (e.g., ventral striatum (VS), septal area (SA)), which can downregulate threat responding (e.g., amygdala) and possibly cellular inflammatory responses linked to health.

Methods: A parallel group randomized controlled trial examined the effect of a six-week online gratitude (n = 31) vs. control (n = 30) writing intervention on neural activity and inflammatory outcomes. Pre- and post-intervention, healthy female participants (ages 35-50) reported on support-giving behavior and provided blood samples to assess circulating plasma levels and stimulated monocytic production of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6)). Post-intervention, participants completed a gratitude task and a threat reactivity task in an fMRI scanner.

Results: There were no significant group differences (gratitude vs. control intervention) in neural responses (VS, SA, or amygdala) to the gratitude or threat tasks. However, across the entire sample, those who showed larger pre- to- post-intervention increases in self-reported support-giving showed larger reductions in amygdala reactivity following the gratitude task (vs. control task). Additionally, those who showed larger reductions in amygdala reactivity following the gratitude task showed larger pre-to-post reductions in the stimulated production of TNF-α and IL-6. Importantly, gratitude-related reductions in amygdala reactivity statistically mediated the relationship between increases in support-giving and decreases in stimulated TNF-α production.

Conclusion: The observed relationships suggest that gratitude may benefit health (reducing inflammatory responses) through the threat-reducing effects of support-giving.
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http://dx.doi.org/10.1016/j.bbi.2021.04.019DOI Listing
April 2021

The long shadow of childhood trauma for depression in midlife: examining daily psychological stress processes as a persistent risk pathway.

Psychol Med 2021 Mar 26:1-10. Epub 2021 Mar 26.

Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, CA, USA.

Background: Childhood trauma (CT) increases the risk of adult depression. Buffering effects require an understanding of the underlying persistent risk pathways. This study examined whether daily psychological stress processes - how an individual interprets and affectively responds to minor everyday events - mediate the effect of CT on adult depressive symptoms.

Methods: Middle-aged women (N = 183) reported CT at baseline and completed daily diaries of threat appraisals and negative evening affect for 7 days at baseline, 9, and 18 months. Depressive symptoms were measured across the 1.5-year period. Mediation was examined using multilevel structural equation modeling.

Results: Reported CT predicted greater depressive symptoms over the 1.5-year time period (estimate = 0.27, s.e. = 0.07, 95% CI 0.15-0.38, p < 0.001). Daily threat appraisals and negative affect mediated the effect of reported CT on depressive symptoms (estimate = 0.34, s.e. = 0.08, 95% CI 0.22-0.46, p < 0.001). Daily threat appraisals explained more than half of this effect (estimate = 0.19, s.e. = 0.07, 95% CI 0.08-0.30, p = 0.004). Post hoc analyses in individuals who reported at least moderate severity of CT showed that lower threat appraisals buffered depressive symptoms. A similar pattern was found in individuals who reported no/low severity of CT.

Conclusions: A reported history of CT acts as a latent vulnerability, exaggerating threat appraisals of everyday events, which trigger greater negative evening affect - processes that have important mental health consequences and may provide malleable intervention targets.
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http://dx.doi.org/10.1017/S0033291721000921DOI Listing
March 2021

Which came first, obstructive sleep apnoea or hypertension? A retrospective study of electronic records over 10 years, with separation by sex.

BMJ Open 2021 Mar 23;11(3):e041179. Epub 2021 Mar 23.

UCLA School of Nursing, University of California, Los Angeles, Los Angeles, California, USA

Objectives: Obstructive sleep apnoea (OSA) is a risk factor for hypertension (HTN), but the clinical progression of OSA to HTN is unclear. There are also sex differences in prevalence, screening and symptoms of OSA. Our objective was to estimate the time from OSA to HTN diagnoses in females and males.

Design: Retrospective analysis of electronic health records (EHR) over 10 years (2006-2015 inclusive).

Setting: University of California Los Angeles (UCLA) Health System in Los Angeles, California, USA.

Participants: 4848 patients: females n=2086, mean (SD) age=52.8 (13.2) years; males n=2762, age=53.8 (13.5) years. These patients were selected from 1.6 million with diagnoses in the EHR who met these criteria: diagnoses of OSA and HTN; in long-term care defined by ambulatory visits at least 1 year prior and 1 year subsequent to the first OSA diagnosis; no diagnosis of OSA or HTN at intake; and a sleep study performed at UCLA.

Primary And Secondary Outcome Measures: The primary outcome measure in each patient was time from the first diagnosis of OSA to the first diagnosis of HTN (OSA to HTN days). Since HTN and OSA are progressive disorders, a secondary measure was the relationship between OSA to HTN time and age (OSA to HTN=β×Age+β).

Results: The median (lower and upper quartiles) days from OSA to HTN were: all -532 (-1439, -3); females -610 (-1579, -42); and males -451 (-1358, 0). Older age in both sexes was associated with less time to a subsequent HTN diagnosis or more time from a prior HTN diagnosis (β days/year: all -16.9, females -18.3, males -15.9).

Conclusions: HTN was on average diagnosed years prior to OSA, with a longer separation in females. Our findings are consistent with underscreening of OSA, more so in females than males. Undiagnosed OSA may delay treatment for the sleep disorder and perhaps affect the development and progression of HTN.
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http://dx.doi.org/10.1136/bmjopen-2020-041179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993176PMC
March 2021

Night shift schedule alters endogenous regulation of circulating cytokines.

Neurobiol Sleep Circadian Rhythms 2021 May 5;10:100063. Epub 2021 Mar 5.

Sleep and Performance Research Center, Washington State University, Spokane, WA, 99202, USA.

Night shift work is a risk factor for viral infection, suggesting that night shift schedules compromise host defense mechanisms. Prior studies have investigated changes in the temporal profiles of circulating cytokines important for priming and restraining the immune response to infectious challenges from night shift work, but not by way of a 24-h constant routine of continuous wakefulness devoid of behavioral or environmental influences. Hence the true pattern of cytokines, and the combined effect of sleep loss and circadian misalignment on these cytokines remains unknown. Here, 14 healthy young men and women underwent three days of either a simulated night shift or a simulated day shift schedule under dim light in a controlled in-laboratory environment. This was followed by a 24-h constant routine protocol during which venous blood was collected at 3-h intervals. Those who had been in the night shift schedule showed lower mean circulating TNF-α (t = -6.03, p < 0.001), without any significant differences in IL-1β, IL-8 and IL-10, compared with those who had been in the day shift (i.e., control) schedule. Furthermore, circulating IL-6 increased with time awake in both shift work conditions (t = 6.03, p < 0.001), such that temporal changes in IL-6 were markedly shifted relative to circadian clock time in the night shift condition. These results indicate that night shift work compromises host defense by creating cytokine conditions that initially impede anti-viral immunity (lower TNF-α) and may eventually promote autoimmunity (mistimed rise in IL-6).
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http://dx.doi.org/10.1016/j.nbscr.2021.100063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970107PMC
May 2021

Depression treatment response to ketamine: sex-specific role of interleukin-8, but not other inflammatory markers.

Transl Psychiatry 2021 Mar 15;11(1):167. Epub 2021 Mar 15.

Cousins Center for Psychoneuroimmunology, University of California at Los Angeles, Los Angeles, CA, USA.

Inflammation plays a role in depression pathophysiology and treatment response, with effects varying by sex and therapeutic modality. Lower levels of interleukin(IL)-8 predict depression response to antidepressant medication and to electroconvulsive therapy (ECT), although ECT effects are specific to females. Whether IL-8 predicts depression response to ketamine and in a sex-specific manner is not known. Here, depressed patients (n = 46; female, n = 17) received open label infusion of ketamine (0.5 mg/kg over 40 min; NCT02165449). Plasma levels of IL-8 were evaluated at baseline and post-treatment. Baseline levels of IL-8 had a trending association with response to ketamine, depending upon sex (responder status × sex interaction: p = 0.096), in which lower baseline levels of IL-8 in females (p = 0.095) but not males (p = 0.96) trended with treatment response. Change in levels of IL-8 from baseline to post-treatment differed significantly by responder status (defined as ≥50% reduction in Hamilton Depression Rating Scale [HAM-D] Score), depending upon sex (responder status × sex × time interaction: F(1,42)=6.68, p = 0.01). In addition, change in IL-8 interacted with sex to predict change in HAM-D score (β = -0.63, p = 0.003); increasing IL-8 was associated with decreasing HAM-D score in females (p = 0.08) whereas the inverse was found in males (p = 0.02). Other inflammatory markers (IL-6, IL-10, tumor necrosis factor-α, C-reactive protein) were explored with no significant relationships identified. Given these preliminary findings, further evaluation of sex differences in the relationship between IL-8 and treatment response is warranted to elucidate mechanisms of response and aid in the development of personalized approaches to depression treatment.
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http://dx.doi.org/10.1038/s41398-021-01268-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7960960PMC
March 2021

Vulnerability to inflammation-related depressive symptoms: Moderation by stress in women with breast cancer.

Brain Behav Immun 2021 May 9;94:71-78. Epub 2021 Mar 9.

Department of Psychology, UCLA, Los Angeles, CA, United States; Department of Psychiatry and Biobehavioral Sciences, UCLA, Los Angeles, CA, United States; Cousins Center for Psychoneuroimmunology, Semel Institute for Neuroscience and Human Behavior, UCLA, Los Angeles, CA, United States.

Background: Stress precipitates depression and may do so in part by increasing susceptibility to inflammation-induced depressive symptoms. However, this has not been examined among individuals facing a major life stressor. Accordingly, the present study tested the moderating role of stress on the longitudinal association between inflammation and depressive symptoms among women with breast cancer.

Methods: Women recently diagnosed with early-stage breast cancer (N = 187) were enrolled before starting adjuvant/neoadjuvant treatment. Blood draws and self-reported depressive symptoms were collected pre-treatment, post-treatment, and at 6, 12, and 18-month post-treatment follow ups. C-reactive protein (CRP) was used to index inflammation. Measures of psychological stress, including cancer-related stress, general stress perceptions, and childhood stress, were administered pre-treatment.

Results: Stress moderated the association between CRP and depressive symptoms, such that higher levels of CRP were associated with elevated depressive symptoms only among women who reported high cancer-related stress (β = 0.080, p = .002) and perceived stress (β = 0.053, p = .044); childhood stress effects were non-significant. Moreover, elevated CRP was associated with increased odds of exhibiting clinically significant depressive symptoms (OR = 1.64, p < .001) among women who reported high cancer-related stress. Results were independent of age, BMI, race and cancer-related covariates.

Conclusions: Stress was found to heighten sensitivity to inflammation-associated depressive symptoms over a 2-year period, with notably stronger effects for subjective stress responses to a concurrent life event. Individuals who are most distressed following a major life event may exhibit the greatest risk for inflammation-induced depression.
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http://dx.doi.org/10.1016/j.bbi.2021.03.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058308PMC
May 2021

Preoperative sleep quality and adverse pain outcomes after total hip arthroplasty.

Eur J Pain 2021 Mar 8. Epub 2021 Mar 8.

Clinical Memory Research Unit, Faculty of Medicine, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden.

Background: Sleep disturbance is thought to aggravate acute postoperative pain. The influence of preoperative sleep problems on pain control in the long-term and development of chronic postsurgical pain is largely unknown.

Methods: This prospective, observational study aimed to examine the links between preoperative sleep disturbance (Pittsburgh Sleep Quality Index, PSQI) and pain severity (Brief Pain Inventory, BPI) 6 months postoperative (primary outcome), objective measures of pain and postoperative pain control variables (secondary outcomes). Patients (n = 52) with disabling osteoarthritis (OA) pain undergoing total hip arthroplasty (THA) were included. Quantitative sensory testing (QST) was performed preoperatively on the day of surgery to evaluate pain objectively. Clinical data, as well as measures of sleep quality and pain, were obtained preoperatively and longitudinally over a 6-month period.

Results: Preoperatively, sleep disturbance (i.e., PSQI score >5) occurred in 73.1% (n = 38) of THA patients, and pain severity was high (BPI pain severity 5.4 ± 1.3). Regression models, adjusting for relevant covariates, showed that preoperative PSQI score predicted pain severity 6 months postoperative (β = 0.091 (95% CI 0.001-0.181), p = .048, R  = 0.35). Poor sleep quality was associated with increased pressure pain sensitivity and impaired endogenous pain inhibitory capacity (R range 0.14-0.33, all p's < 0.04). Moreover, preoperative sleep disturbance predicted increased opioid treatment during the first 24 hr after surgery (unadjusted β = 0.009 (95% CI 0.002-0.015) mg/kg, p = .007, R  = 0.15).

Conclusions: Preoperative sleep disturbance is prevalent in THA patients, is associated with objective measures of pain severity, and independently predicts immediate postoperative opioid treatment and poorer long-term pain control in patients who have undergone THA.

Significance: Poor sleep quality and impaired sleep continuity are associated with heightened pain sensitivity, but previous work has not evaluated whether preoperative sleep problems impact long-term postoperative pain outcomes. Here, we show that sleep difficulties prior to total hip arthroplasty adversely predict postoperative pain control 6 months after surgery. Given sleep difficulties robustly predict pain outcomes, targeting and improving sleep may have salutary effects on postoperative pain reports and management.
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http://dx.doi.org/10.1002/ejp.1761DOI Listing
March 2021

Associations between peripheral inflammation and resting state functional connectivity in adolescents.

Brain Behav Immun 2021 Feb 23. Epub 2021 Feb 23.

Department of Psychology, University of California, Davis, CA, United States.

Relatively little is known about associations between peripheral inflammation and neural function in humans. Neuroimaging studies in adults have suggested that elevated peripheral inflammatory markers are associated with altered resting state functional connectivity (rsFC) in several brain networks associated with mood and cognition. Few studies have examined these associations in adolescents, yet scarce data from adolescents point to different networks than adult studies. The current study examined the associations between peripheral inflammation and rsFC in a community sample of adolescents (n = 70; age, 12-15 years; 32 female, 36 male, 2 nonbinary). After blood sampling, an fMRI scan was performed to assess rsFC. Assay for serum inflammatory markers, including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and C-reactive protein (CRP), was performed. Results indicated that higher TNF-α was associated with altered rsFC between the right amygdala and left striatum and between the right inferior frontal gyrus and left parietal cortex (p < 0.05 whole-brain corrected). Associations with IL-6 and CRP were not significant. In contrast with findings in adults, inflammation may have unique links with the connectivity of the developing adolescent brain. Results have implications for understanding how peripheral inflammation may influence connectivity during adolescence, when neural networks are undergoing major developmental changes.
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http://dx.doi.org/10.1016/j.bbi.2021.02.018DOI Listing
February 2021

Do all patients with cancer experience fatigue? A longitudinal study of fatigue trajectories in women with breast cancer.

Cancer 2021 Apr 19;127(8):1334-1344. Epub 2021 Feb 19.

Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, California.

Background: Fatigue is a common and expected side effect of cancer treatment. However, the majority of studies to date have focused on average levels of fatigue, which may obscure important individual differences in the severity and course of fatigue over time. The current study was designed to identify distinct trajectories of fatigue from diagnosis into survivorship in a longitudinal study of women with early-stage breast cancer.

Methods: Women with stage 0 to stage IIIA breast cancer (270 women) were recruited before (neo)adjuvant therapy with radiotherapy, chemotherapy, and/or endocrine therapy and completed assessments at baseline; posttreatment; and at 6 months, 12 months, and 18 months of follow-up. Growth mixture modeling was used to identify trajectories of fatigue, and differences among the trajectory groups with regard to demographic, medical, and psychosocial variables were examined.

Results: Five distinct trajectories of fatigue were identified: Stable Low (66%), with low levels of fatigue across assessments; Stable High (13%), with high fatigue across assessments; Decreasing (4%), with high fatigue at baseline that resolved over time; Increasing (9%), with low fatigue at baseline that increased over time; and Reactive (8%), with increased fatigue after treatment that resolved over time. Both psychological and treatment-related factors were found to be associated with fatigue trajectories, with psychological factors most strongly linked to high fatigue at the beginning of and over the course of treatment.

Conclusions: There is considerable variability in the experience of fatigue among women with early-stage breast cancer. Although the majority of women report relatively low fatigue, those with a history of depression and elevated psychological distress may be at risk of more severe and persistent fatigue.
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http://dx.doi.org/10.1002/cncr.33327DOI Listing
April 2021

Sleep-Wake Timings in Adolescence: Chronotype Development and Associations with Adjustment.

J Youth Adolesc 2021 Apr 19;50(4):628-640. Epub 2021 Feb 19.

Department of Psychology, UCLA, Los Angeles, CA, 90095, USA.

Adolescent sleep research has focused heavily on duration and quality with less work examining chronotype, defined as individual differences in sleep-wake timings driven by the circadian rhythm. This study filled a gap in the literature by utilizing actigraphy-based sleep estimates in an accelerated longitudinal design in order to better understand the developmental trajectory and individual stability of chronotype during adolescence, as well as the associations between chronotype with risky behaviors, substance use, and depressive symptoms. A total of 329 adolescents (57% female; 21% Asian American, 31% European American, 41% Latino, 7% other ethnicity) provided actigraphy-based estimates of sleep and completed questionnaires at up to three time points, two years apart, beginning at 14-17 years of age. Multilevel modeling revealed a non-linear developmental trend in chronotype whereby eveningness increased from 14 to 19 years of age followed by a trend toward morningness. Individual differences in chronotype exhibited modest stability during adolescent development. Furthermore, greater evening chronotype was associated with more risky behaviors and substance use among males, and more substance use among older adolescents, whereas depressive symptoms were not associated with chronotype. The findings from this study may have practical implications for adolescent behavioral health interventions targeted at reducing risky behaviors and substance use among youth.
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http://dx.doi.org/10.1007/s10964-021-01407-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993411PMC
April 2021

Effects of Tai Chi or Exercise on Sleep in Older Adults With Insomnia: A Randomized Clinical Trial.

JAMA Netw Open 2021 02 1;4(2):e2037199. Epub 2021 Feb 1.

Cousins Center for Psychoneuroimmunology and Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles.

Importance: Previous studies that have shown tai chi to improve sleep were mainly based on subjective assessments, which might have produced results confounded by self-reporting bias.

Objective: To compare the effectiveness of tai chi for improving sleep in older adults with insomnia with conventional exercise and a passive control group using actigraphy-based objective measurements.

Design, Setting, And Participants: This randomized, 3-arm, parallel group, assessor-masked clinical trial was conducted at a single research unit in Hong Kong between August 2014 and August 2018. Eligible participants, aged 60 years or older and with chronic insomnia, were randomly allocated into tai chi training, exercise, and control groups.

Interventions: 12-week tai chi training, 12-week conventional exercise, and no intervention control.

Main Outcomes And Measures: Primary outcomes were measures taken from actigraphy sleep assessment. Secondary outcomes included remission of insomnia, insomnia treatment response, Pittsburgh Sleep Quality Index score, Insomnia Severity Index score, and self-reported sleep using a 7-day sleep diary. Assessments were performed at baseline, end of the intervention (postintervention), and 24 months after the intervention (follow-up). Data analysis was performed from September 2018 to August 2020.

Results: A total of 320 participants (mean [SD] age, 67.3 [6.8] years; mean [SD] insomnia duration, 124.4 [134.5] months; 256 [80.0%] women) were randomly allocated into control (110 participants), exercise (105 participants), and tai chi (105 participants) groups and included in the data analysis. Compared with the control group, the exercise and tai chi groups showed improved sleep efficiency (exercise vs control: adjusted mean difference, +3.5%; 95% CI, 1.8-5.2; P < .001; tai chi vs control: adjusted mean difference, +3.4%; 95% CI, 1.6-5.1; P < .001) and reductions of wake time after sleep onset (exercise vs control: -17.0 minutes; 95% CI, -24.9 to -9.0; P < .001; tai chi vs control: -13.3 minutes; 95% CI, -21.3 to -5.2; P = .001) and number of awakenings (exercise vs control: -2.8 times; 95% CI, -4.0 to -1.6; P < .001; tai chi vs control: -2.2 times; 95% CI, -3.5 to -1.0; P < .001) as assessed by actigraphy at postintervention; although there were no significant differences between the exercise and tai chi groups. The actigraphy-assessed beneficial effects were maintained in both intervention groups at follow-up.

Conclusions And Relevance: Conventional exercise and tai chi improved sleep and the beneficial effects sustained for 24 months, although the absolute improvements in sleep parameters were modest. Improvements in objective sleep parameters were not different between the tai chi and exercise groups, suggesting that tai chi can be an alternative approach for managing insomnia.

Trial Registration: ClinicalTrials.gov Identifier: NCT02260843.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.37199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885034PMC
February 2021

Anti-inflammatory effects of melatonin: A systematic review and meta-analysis of clinical trials.

Brain Behav Immun 2021 Mar 10;93:245-253. Epub 2021 Feb 10.

UCLA Insomnia Clinic, Cousins Center for Psychoneuroimmunology, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, United States.

Chronic inflammation contributes to multiple diseases including cardiovascular diseases, autoimmune disorders, metabolic disorders, and psychiatric conditions. Melatonin, a hormone responsible for circadian rhythm, plays a complex role within the immune system, including having an anti-inflammatory effect. While there are numerous animal studies demonstrating this effect, few human clinical trials have been conducted. This systematic review of clinical trials examined whether exogenous melatonin reduces levels of inflammatory markers in humans. We searched PubMed, Embase, Cochrane Library, Scopus, and PsycINFO, and the references of the identified articles for randomized and non-randomized placebo-controlled trials. Data were extracted from the articles and meta-analyses were conducted using a random effects model to calculate standardized mean differences (SMDs, i.e., Cohen's d). From an initial search result of 4548 references, 31 studies met the inclusion criteria and were included involving 1517 participants. Melatonin had significant anti-inflammatory effects on interleukin (IL)-1 (SMD -1.64; 95% confidence interval [CI] -2.86, -0.43; p = 0.008), IL-6 (-3.84; -5.23, -2.46; p < 0.001), IL-8 (-21.06; -27.27, -14.85; p < 0.001), and tumor necrosis factor (TNF) (-1.54; -2.49, -0.58; p = 0.002), but not on C-reactive protein (CRP) (-0.18; -0.91, 0.55; p = 0.62). Trimming outlier studies with large effect sizes eliminated publication bias, and summary effect sizes were significant for IL-1 (SMD -1.11; 95% CI -1.90, -0.32; p = 0.006), IL-6 (-1.91; -2.98, -0.83; p = 0.001), and IL-8 (-13.46; -18.88, -8.04; p < 0.001), but not for TNF (-0.45; -1.13, 0.23; p = 0.19). Exogenous melatonin reduced levels of inflammatory markers and may be useful for prevention and adjuvant treatment of inflammatory disorders. Melatonin is safe with few side effects, which makes it an excellent agent for prevention of inflammatory disorders. Because chronic inflammation increases with aging and inflammation plays a role in the etiology of numerous diseases that affect older populations, melatonin has the potential to be widely used particularly in older adults.
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http://dx.doi.org/10.1016/j.bbi.2021.01.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979486PMC
March 2021

Replicable association between human cytomegalovirus infection and reduced white matter fractional anisotropy in major depressive disorder.

Neuropsychopharmacology 2021 04 26;46(5):928-938. Epub 2021 Jan 26.

Laureate Institute for Brain Research, Tulsa, OK, USA.

Major depressive disorder (MDD) is associated with reductions in white matter microstructural integrity as measured by fractional anisotropy (FA), an index derived from diffusion tensor imaging (DTI). The neurotropic herpesvirus, human cytomegalovirus (HCMV), is a major cause of white matter pathology in immunosuppressed populations but its relationship with FA has never been tested in MDD despite the presence of inflammation and weakened antiviral immunity in a subset of depressed patients. We tested the relationship between FA and HCMV infection in two independent samples consisting of 176 individuals with MDD and 44 healthy controls (HC) (Discovery sample) and 88 participants with MDD and 48 HCs (Replication sample). Equal numbers of HCMV positive (HCMV+) and HCMV negative (HCMV-) groups within each sample were balanced on ten different clinical/demographic variables using propensity score matching. Anti-HCMV IgG antibodies were measured using a solid-phase ELISA. In the Discovery sample, significantly lower FA was observed in the right inferior fronto-occipital fasciculus (IFOF) in HCMV+ participants with MDD compared to HCMV- participants with MDD (cluster size 1316 mm; p < 0.05, d = -0.58). This association was confirmed in the replication sample by extracting the mean FA from this exact cluster and applying the identical statistical model (p < 0.05, d = -0.45). There was no significant effect of diagnosis or interaction between diagnosis and HCMV in either sample. The effect of chronic HCMV infection on white matter integrity may-in at-risk individuals-contribute to the psychopathology of depression. These findings may provide a novel target of intervention for a subgroup of patients with MDD.
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http://dx.doi.org/10.1038/s41386-021-00971-1DOI Listing
April 2021

The IL-6 antagonist tocilizumab is associated with worse depression and related symptoms in the medically ill.

Transl Psychiatry 2021 01 18;11(1):58. Epub 2021 Jan 18.

Section of BMT & Cellular Therapies; Division of Hematology/Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.

Because medical illness is associated with increased inflammation and an increased risk for treatment-resistant major depressive disorder, anti-cytokine therapy may represent a novel, and especially efficacious, treatment for depression. We hypothesized that blockade of the interleukin (IL)-6 signaling pathway with tocilizumab would decrease depression and related symptomatology in a longitudinal cohort of allogeneic hematopoietic stem cell transplantation (HCT) patients, a medically ill population with a significant inflammation and psychopathology. Patients undergoing allogeneic HCT received either a single dose of tocilizumab one day prior to HCT (n = 25), or HCT alone (n = 62). The primary outcome included depressive symptoms at 28 days post HCT; anxiety, fatigue, sleep, and pain were assessed at pretreatment baseline and days +28, +100, and +180 post HCT as secondary outcomes. Multivariate regression demonstrated that preemptive treatment with tocilizumab was associated with significantly higher depression scores at D28 vs. the comparison group (β = 5.74; 95% CI 0.75, 10.73; P = 0.03). Even after adjustment for baseline depressive symptoms, propensity score, and presence of acute graft-versus-host disease (grades II-IV) and other baseline covariates, the tocilizumab-exposed group continued to have significantly higher depression scores compared to the nonexposed group at D28 (β = 4.73; 95% CI 0.64, 8.81; P = 0.02). Despite evidence that IL-6 antagonism would be beneficial, blockade of the IL-6 receptor with tocilizumab among medically ill patients resulted in significantly more-not less-depressive symptoms.
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http://dx.doi.org/10.1038/s41398-020-01164-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812704PMC
January 2021

Testing a mindfulness meditation mobile app for the treatment of sleep-related symptoms in adults with sleep disturbance: A randomized controlled trial.

PLoS One 2021 7;16(1):e0244717. Epub 2021 Jan 7.

Cousins Center for Psychoneuroimmunology and Mindful Awareness Research Center, Jane and Terry Semel Insitute for Neuroscience and Human Behavior, at UCLA, Los Angeles, California, United States of America.

The objective of this randomized controlled trial was to test whether a commercially available, mindfulness meditation mobile app, (i.e., Calm app), was effective in reducing fatigue (primary outcome), pre-sleep arousal, and daytime sleepiness (secondary outcomes) in adults with sleep disturbance (Insomnia Severity Index Score >10) as compared to a wait-list control group. Associations between the use of the Calm app (i.e., adherence to the intervention) and changes in sleep quality was also explored in the intervention group only. Adults with sleep disturbance were recruited (N = 640). Eligible and consenting participants (N = 263) were randomly assigned to the intervention (n = 124) or a wait-list control (n = 139) group. Intervention participants were asked to meditate using the Calm app ≥10 minutes/day for eight weeks. Fatigue, daytime sleepiness, and pre-sleep arousal were assessed at baseline, mid- (4-weeks) and post-intervention (8-weeks) in both groups, whereas sleep quality was evaluated only in the intervention group. Findings from intent-to-treat analyses suggest the use of the Calm app for eight weeks significantly decreased daytime fatigue (p = .018) as well as daytime sleepiness (p = .003) and cognitive (p = .005) and somatic (p < .001) pre-sleep arousal as compared to the wait-list control group. Within the intervention group, use of the Calm app was associated with improvements in sleep quality (p < .001). This randomized controlled trial demonstrates that the Calm app can be used to treat fatigue, daytime sleepiness, and pre-sleep arousal in adults with sleep disturbance. Given that the Calm app is affordable and widely accessible, these data have implications for community level dissemination of a mobile app to improve sleep-related symptoms associated with sleep disturbance. Trial registration: ClinicalTrials.gov NCT04045275.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244717PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790277PMC
May 2021

Behavioral activation therapy for depression is associated with a reduction in the concentration of circulating quinolinic acid.

Psychol Med 2020 Nov 25:1-10. Epub 2020 Nov 25.

Laureate Institute for Brain Research, Tulsa, OK, USA.

Background: An inflammation-induced imbalance in the kynurenine pathway (KP) has been reported in major depressive disorder but the utility of these metabolites as predictive or therapeutic biomarkers of behavioral activation (BA) therapy is unknown.

Methods: Serum samples were provided by 56 depressed individuals before BA therapy and 29 of these individuals also provided samples after 10 weeks of therapy to measure cytokines and KP metabolites. The PROMIS Depression Scale (PROMIS-D) and the Sheehan Disability Scale were administered weekly and the Beck depression inventory was administered pre- and post-therapy. Data were analyzed with linear mixed-effect, general linear, and logistic regression models. The primary outcome for the biomarker analyses was the ratio of kynurenic acid to quinolinic acid (KynA/QA).

Results: BA decreased depression and disability scores (p's < 0.001, Cohen's d's > 0.5). KynA/QA significantly increased at post-therapy relative to baseline (p < 0.001, d = 2.2), an effect driven by a decrease in QA post-therapy (p < 0.001, uncorrected, d = 3.39). A trend towards a decrease in the ratio of kynurenine to tryptophan (KYN/TRP) was also observed (p = 0.054, uncorrected, d = 0.78). The change in KynA/QA was nominally associated with the magnitude of change in PROMIS-D scores (p = 0.074, Cohen's f2 = 0.054). Baseline KynA/QA did not predict response to BA therapy.

Conclusion: The current findings together with previous research show that electronconvulsive therapy, escitalopram, and ketamine decrease concentrations of the neurotoxin, QA, raise the possibility that a common therapeutic mechanism underlies diverse forms of anti-depressant treatment but future controlled studies are needed to test this hypothesis.
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http://dx.doi.org/10.1017/S0033291720004389DOI Listing
November 2020

A hidden menace? Cytomegalovirus infection is associated with reduced cortical gray matter volume in major depressive disorder.

Mol Psychiatry 2020 Nov 22. Epub 2020 Nov 22.

Laureate Institute for Brain Research, Tulsa, OK, USA.

Human cytomegalovirus (HCMV) infection is associated with neuropathology in patients with impaired immunity and/or inflammatory diseases. However, the association between gray matter volume (GMV) and HCMV has never been examined in major depressive disorder (MDD) despite the presence of inflammation and impaired viral immunity in a subset of patients. We tested this relationship in two independent samples consisting of 179 individuals with MDD and 41 healthy controls (HC) (sample 1) and 124 MDD participants and 148 HCs (sample 2). HCMV positive (HCMV+) and HCMV negative (HCMV-) groups within each sample were balanced on up to 11 different clinical/demographic variables using inverse probability of treatment weighting. GMV of 87 regions was measured with FreeSurfer. There was a main effect of HCMV serostatus but not diagnosis that replicated across samples. Relative to HCMV- subjects, HCMV+ subjects in sample 1 showed a significant reduction of volume in six regions (p < 0.05). The reductions in GMV of the right supramarginal gyrus (standardized beta coefficient (SBC) = -0.26) and left fusiform gyrus (SBC = -0.25) in sample 1 were replicated in sample 2: right supramarginal gyrus (p < 0.05, SBC = -0.32), left fusiform gyrus (P < 0.01, SBC = -0.51). Posthoc tests revealed that the effect of HCMV was driven by differences between the HCMV+ and HCMV- MDD subgroups. HCMV IgG level, a surrogate marker of viral activity, was correlated with GMV in the left fusiform gyrus (r = -0.19, P = 0.049) and right supramarginal gyrus (r = -0.19, p = 0.043) in the HCMV+ group of sample 1. Conceivably, HCMV infection may be a treatable source of neuropathology in vulnerable MDD patients.
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http://dx.doi.org/10.1038/s41380-020-00932-yDOI Listing
November 2020

Experimental sleep disruption attenuates morphine analgesia: findings from a randomized trial and implications for the opioid abuse epidemic.

Sci Rep 2020 11 18;10(1):20121. Epub 2020 Nov 18.

Cousins Center for Psychoneuroimmunology, UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles, CA, 90024, USA.

Preclinical studies demonstrate that sleep disruption diminishes morphine analgesia and modulates reward processing. We sought to translate these preclinical findings to humans by examining whether sleep disruption alters morphine's analgesic and hedonic properties. We randomized 100 healthy adults to receive morphine versus placebo after two nights of undisturbed sleep (US) and two nights of forced awakening (FA) sleep disruption. Sleep conditions were counterbalanced, separated by a two-week washout. The morning after both sleep conditions, we tested cold pressor pain tolerance before and 40-min after double-blind injection of .08 mg/kg morphine or placebo. The primary outcome was the analgesia index, calculated as the change in cold pressor hand withdrawal latency (HWL) before and after drug injection. Secondary outcomes were ratings of feeling "high," drug "liking," and negative drug effects. We found a significant sleep condition by drug interaction on the analgesia index (95% CI - 0.57, - 0.001). After US, subjects receiving morphine demonstrated significantly longer HWL compared to placebo (95% CI 0.23, 0.65), but not after FA (95% CI - 0.05, 0.38). Morphine analgesia was diminished threefold under FA, relative to US. After FA, females (95% CI - 0.88, - 0.05), but not males (95% CI - 0.23, 0.72), reported decreased subjective "high" effects compared to US. After FA, females (95% CI 0.05, 0.27), but not males (95% CI - 0.10, 0.11), administered morphine reported increased negative drug effects compared to US. These data demonstrate that sleep disruption attenuates morphine analgesia in humans and suggest that sleep disturbed males may be at greatest risk for problematic opioid use.
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http://dx.doi.org/10.1038/s41598-020-76934-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674501PMC
November 2020

Use of the Consumer-Based Meditation App Calm for Sleep Disturbances: Cross-Sectional Survey Study.

JMIR Form Res 2020 Nov 13;4(11):e19508. Epub 2020 Nov 13.

Integrated Brain Health Clinical and Research Program, Department of Psychiatry, Massachusetts General Hospital/Harvard Medical School, Cambridge, MA, United States.

Background: Over 30% of Americans report regular sleep disturbance, and consumers are increasingly seeking strategies to improve sleep. Self-guided mindfulness mobile apps may help individuals improve their sleep. Despite the recent proliferation of sleep content within commercially available mindfulness apps, there is little research on how consumers are using these apps for sleep.

Objective: We conducted a cross-sectional survey among subscribers to Calm, a popular, consumer-based, mindfulness-based meditation app, and described and compared how good sleepers, poor sleepers, and those with self-reported insomnia use the app for sleep.

Methods: Participants who were paying subscribers of Calm and had used a sleep component of Calm in the last 90 days were invited to complete an investigator-developed survey that included questions about sleep disturbance and the use of Calm for sleep. Based on self-reports of sleep disturbances and of insomnia diagnosis, participants were categorized as "good sleepers," "poor sleepers," or "those with insomnia diagnosis." Chi-square tests compared reasons for downloading the app and usage patterns across participants with and without sleep disturbance.

Results: There was a total of 9868 survey respondents. Approximately 10% of participants (1008/9868, 10.21%) were good sleepers, 78% were poor sleepers (7565/9868, 77.66%), and 11% reported a diagnosis of insomnia (1039/9868, 10.53%). The sample was mostly White (8185/9797, 83.55%), non-Hispanic (8929/9423, 94.76%), and female (8166/9578, 85.26%). The most common reasons for sleep disturbances were racing thoughts (7084/8604, 82.33%), followed by stress or anxiety (6307/8604, 73.30%). Poor sleepers and those with insomnia were more likely than good sleepers to have downloaded Calm to improve sleep (χ=1548.8, P<.001), reduce depression or anxiety (χ=15.5, P<.001), or improve overall health (χ=57.6, P<.001). Respondents with insomnia used Calm most often (mean 5.417 days/week, SD 1.936), followed by poor sleepers (mean 5.043 days/week, SD 2.027; F=21.544, P<.001). The most common time to use Calm was while lying down to sleep (7607/9686, 78.54%), and bedtime use was more common among poor sleepers and those with insomnia (χ=382.7, P<.001). Compared to good and poor sleepers, those with insomnia were more likely to use Calm after waking up at night (χ=410.3, P<.001). Most participants tried to use Calm on a regular basis (5031/8597, 58.52%), but regular nighttime use was most common among those with insomnia (646/977, 66.1%), followed by poor sleepers (4040/6930, 58.30%; χ=109.3, P<.001).

Conclusions: Of the paying subscribers to Calm who have used one of the sleep components, approximately 90% have sleep difficulties, and 77% started using Calm primarily for sleep. These descriptive data point to areas of focus for continued refinement of app features and content, followed by prospective trials testing efficacy of consumer-based meditation mobile apps for improving sleep.
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http://dx.doi.org/10.2196/19508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695531PMC
November 2020

Insomnia and Susceptibility to Depressive Symptoms and Fatigue in Diverse Breast Cancer Survivors.

J Womens Health (Larchmt) 2020 Oct 9. Epub 2020 Oct 9.

Cousins Center for Psychoneuroimmunology, UCLA Semel Institute for Neuroscience and Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.

Nearly 40% of breast cancer survivors have insomnia, yet, information how this condition affects their quality of life is lacking. We examined the association between insomnia and depressive symptoms and fatigue in breast cancer survivors. Participants were recruited from a community health plan. We conducted a cross-sectional analysis to examine the association between current insomnia (using Insomnia Severity Index [ISI]) and current depressive symptoms (using Inventory of Depressive Symptomology [IDS]) and fatigue (using Fatigue Symptom Inventory [FSI]) in 315 breast cancer survivors who did not have major depressive disorder. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using multivariable logistic regression. The cohort included 30% minority women whose median time since breast cancer diagnosis was 6 years. Survivors with current insomnia symptoms (ISI ≥8) had a sixfold greater odds of current depressive symptoms (IDS >14, OR = 5.98, 95% CI: 3.04-11.76), after adjusting for lifetime insomnia history (OR = 2.01, 95% CI: 1.03-3.94) and perceived stress (OR = 6.37, 95% CI: 2.48-16.32). Insomnia symptoms were markedly associated with moderate fatigue (FSI >3, OR = 5.02, 95% CI: 2.66-9.44). Ever use of antidepressants or sleep medications post-breast cancer diagnosis was not associated with lower odds of current depressive symptoms or feeling fatigued in those with insomnia symptoms. Current insomnia symptoms were strongly correlated with current depressive symptoms and fatigue. Survivorship care plans should consider incorporating insomnia screening to that may potentially enhance quality of life domains.
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http://dx.doi.org/10.1089/jwh.2019.8135DOI Listing
October 2020

Sleep and Inflammation During Adolescents' Transition to Young Adulthood.

J Adolesc Health 2020 12 23;67(6):821-828. Epub 2020 Jun 23.

Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California; Cousins Center for Psychoneuroimmunology, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, California; Department of Psychology, University of California Los Angeles, Los Angeles, California.

Purpose: This study investigated the extent to which multiple sleep dimensions are associated with inflammation during adolescents' transition to young adulthood, a developmental period when sleep difficulties and systemic inflammation levels are on the rise. Additionally, the moderating roles of socioeconomic status (SES) and ethnicity were explored.

Methods: A total of 350 Asian American, Latino, and European American youth participated at two-year intervals in wave 1 (n = 316, M = 16.40), wave 2 (n = 248 including 34 new participants to refresh the sample, M = 18.31), and wave 3 (n = 180, M = 20.29). Sleep duration (weekday and weekend) and variability in duration (nightly and weekday/weekend) were obtained from eight nights of wrist actigraphy. Subjective sleep quality was assessed using the Pittsburgh Sleep Quality Index. Levels of C-reactive protein (CRP), a biomarker of systemic inflammation, were assayed from dried blood spots obtained from finger pricks.

Results: Multilevel models demonstrated that greater weekday/weekend sleep variability and worse sleep quality were associated with higher CRP; shorter weekend duration was associated with higher CRP only at younger ages. Shorter weekday duration was associated with higher CRP only among high-SES youth, whereas greater nightly variability was associated with higher CRP only among European American youth.

Conclusions: Aspects of poor sleep may contribute to the rise of CRP during adolescents' transition to young adulthood, especially in earlier years. In addition, some sleep-CRP associations may vary as a function of youth's SES and ethnicity.
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http://dx.doi.org/10.1016/j.jadohealth.2020.04.015DOI Listing
December 2020

Motivation and sensitivity to monetary reward in late-life insomnia: moderating role of sex and the inflammatory marker CRP.

Neuropsychopharmacology 2020 09 16;45(10):1664-1671. Epub 2020 Jun 16.

Department of Psychiatry and Biobehavioral Sciences, Norman Cousins Center for Psychoneuroimmunology, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.

Insomnia is a well-established risk factor for late-life depression, yet the intermediary mechanisms are not known. One plausible mechanism is dysregulation of the reward system, a common feature of depression. The main objective of the current study was to determine whether late-life insomnia is associated with reduced motivation and reduced sensitivity for monetary reward. Secondary exploratory objectives were to test for sex-specific effects and whether elevated inflammation potentiated these associations. Nondepressed community dwelling older adults (n = 104; aged 60-80) who either met (n = 31) or did not meet (n = 73) criteria for insomnia disorder as assessed by the Structured Clinical Interview for DSM-5 completed the Effort Expenditure for Rewards Task and provided blood samples for the assessment of C-reactive protein (CRP). Older adults with late-life insomnia showed reduced reward motivation 95% CI [-0.955, -0.569] and reduced reward sensitivity 95% CI [-0.430, -0.075] relative to comparison controls. In secondary exploratory analyses, late-life insomnia was associated with reduced motivation to a greater degree in males than in females 95% CI [0.072, 0.775], particularly when CRP was also elevated 95% CI [0.672, 1.551]. Late-life insomnia is associated with reduced motivation and sensitivity for monetary reward, which suggests insomnia may confer risk for late-life depression by dysregulation of reward mechanisms. Exploratory analyses suggest that older males with insomnia and elevated CRP may be particularly vulnerable to deficits in reward motivation. Although in need of replication and further study, results suggest that interventions that target insomnia or deficits in reward processing may mitigate the risk of depression in nondepressed older adults, especially older males with insomnia.
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http://dx.doi.org/10.1038/s41386-020-0735-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419294PMC
September 2020

Sleep, inflammation, and perception of sad facial emotion: A laboratory-based study in older adults.

Brain Behav Immun 2020 10 9;89:159-167. Epub 2020 Jun 9.

Cousins Center for Psychoneuroimmunology, Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, United States; Department of Psychology, College of Arts and Sciences, University of California, Los Angeles, United States. Electronic address:

Background: Facial emotion perception (FEP) is pivotal for discriminating salient emotional information. Accumulating data indicate that FEP responses, particularly to sad emotional stimuli, are impaired in depression. This study tests whether sleep disturbance and inflammation, two risk factors for depression, contribute to impaired FEP to sad emotional stimuli.

Methods: In older adults (n = 40, 71.7 ± 6.8y, 56.4% female), disturbance of sleep maintenance (i.e., wake time after sleep onset [WASO]) was evaluated by polysomnography. In the morning, plasma concentrations of two markers of systemic inflammation were evaluated (i.e., interleukin [IL]-6, tumor necrosis factor [TNF]-α), followed by two FEP tasks, which assessed delays in emotion recognition (ER) and ratings of perceived emotion intensity (EI) in response to sad facial emotional stimuli, with exploration of FEP responses to happiness and anger. Linear regression models tested whether WASO, IL-6, and TNF-α would be associated with impaired FEP to sad emotional stimuli. In addition, moderation tests examined whether inflammation would moderate the link between sleep disturbance and impaired FEP to sad emotional stimuli.

Results: Longer WASO predicted longer ER delays (p < 0.05) and lower EI ratings in response to sad faces (p < 0.01). Further, higher TNF-α (p < 0.05) but not IL-6 predicted longer ER delays for sad faces, whereas higher IL-6 (p < 0.01) but not TNF-α predicted lower EI ratings for sad faces. Finally, TNF-α moderated the relationship between longer WASO and longer ER delays to sad faces (p < 0.001), while IL-6 moderated the relationship between longer WASO and lower EI ratings to sad faces (p < 0.01). Neither sleep nor inflammatory measures were associated with FEP responses to happiness or anger.

Conclusion: In older adults, disturbance of sleep maintenance is associated with impaired FEP to sad emotion, a relationship that appears to be moderated by inflammation. These data indicate that sleep disturbance and inflammation converge and contribute to impaired FEP with implications for risk for late-life depression.
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http://dx.doi.org/10.1016/j.bbi.2020.06.011DOI Listing
October 2020

Inflammation and depression treatment response to electroconvulsive therapy: Sex-specific role of interleukin-8.

Brain Behav Immun 2020 10 29;89:59-66. Epub 2020 May 29.

Cousins Center for Psychoneuroimmunology, United States; Jane and Terry Semel Institute for Neuroscience and Human Behavior at UCLA, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, United States.

Females suffer from depression at twice the rate of males and have differential neural and emotional responses to inflammation. However, sex-specific evaluation of relationships between inflammation and response to depression treatments are lacking. Some data suggest that interleukin(IL)-8 predicts treatment response to antidepressants and has a relationship with depressive symptom severity. This study examines whether IL-8 predicts treatment response to electroconvulsive therapy (ECT), and whether there are sex specific effects. In 40 depressed patients (22 female), plasma levels of IL-8, as well as other markers of inflammation including IL-6, IL-10, tumor necrosis factor (TNF)-α, and C-reactive protein (CRP) were obtained prior to administration of ECT and after completion of the index treatment series. Depression treatment response was defined as ≥ 50% reduction in Hamilton Depression Rating Scale (HAM-D) Score. Baseline levels of IL-8 differed by responder status, depending on sex (group × sex interaction: β = -0.571, p = 0.04), with female responders having lower levels of IL-8 at baseline as compared to female non-responders [t(20) = 2.37, p = 0.03]. Further, IL-8 levels from baseline to end of treatment differed by responder status, depending on sex (group × sex × time interaction: [F(1,36) = 9.48, p = 0.004]), and change in IL-8 from baseline to end of treatment was negatively correlated with percentage change in HAM-D score in females (β = -0.458, p = 0.03), but not in males (β = 0.315, p = 0.20). Other inflammatory markers did not differ in relation to responder status and sex. Further evaluation of sex differences in the relationship between IL-8, depression, and treatment response, across disparate treatment modalities, may inform mechanisms of response and aid in development of personalized medicine strategies.
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http://dx.doi.org/10.1016/j.bbi.2020.05.069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572496PMC
October 2020

Mindfulness meditation and exercise both improve sleep quality: Secondary analysis of a randomized controlled trial of community dwelling adults.

Sleep Health 2020 12 22;6(6):804-813. Epub 2020 May 22.

David Geffen School of Medicine, Psychiatry, University of California - Los Angeles, United States.

Objectives: To assess the benefits of training in mindfulness-based stress reduction (MBSR) or moderate intensity exercise (EX) for improving sleep quality.

Design: Randomized controlled trial.

Setting: Outpatient, community-based.

Participants: Healthy adults (n = 413) aged 30-69 who did not regularly exercise or practice meditation, and who had no known prior sleep problems.

Interventions: 1) 8-weeks of MBSR training; 2) matched EX training; or 3) wait-list control.

Measurements: The Pittsburgh Sleep Quality Index (PSQI) was administered at baseline and at 1, 3, 5, and 7-month follow-up visits.

Analysis: Total PSQI scores and three PSQI factors (perceived sleep quality; daily disturbance, sleep efficiency) were assessed using linear mixed effects regression models for longitudinal data.

Results: Compared to controls, PSQI global scores improved significantly for EX (mean change -0.98 points [95% CI -1.56, -0.41] p = 0.001) and marginally for MBSR (-0.53 [-1.10, 0.04] p = 0.07). The perceived sleep quality factor improved for both EX (-0.18 [-0.30, -0.07] p = 0.002) and MBSR (-0.12 [-0.24, -0.01] p = 0.035). The daily disturbance factor improved slightly more for MBSR (-0.13 [-0.22, -0.033] p = 0.008) than EX (-0.09 [-0.19, 0.004] p = 0.06). The sleep efficiency factor did not improve after MBSR (0.08 [-0.045, 0.21] p = 0.2) or EX (-0.07 [-0.20, 0.06] p = 0.3). Improvements in the sleep quality were sustained over 7 months for both groups.

Conclusions: Training in MBSR and EX produced small but statistically significant and sustained improvements in sleep quality. For EX participants, this improvement was due primarily to improvements in perceived sleep quality. For MBSR, the decrease in daily disturbance was more important.
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http://dx.doi.org/10.1016/j.sleh.2020.04.003DOI Listing
December 2020

Differential expression of cerebrospinal fluid neuroinflammatory mediators depending on osteoarthritis pain phenotype.

Pain 2020 09;161(9):2142-2154

Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Faculty of Medicine, Lund University, Lund, Sweden.

Abstract: Neuroinflammation is implicated in the development and maintenance of persistent pain states, but there are limited data linking cerebrospinal fluid (CSF) inflammatory mediators with neurophysiological pain processes in humans. In a prospective observational study, CSF inflammatory mediators were compared between patients with osteoarthritis (OA) who were undergoing total hip arthroplasty due to disabling pain symptoms (n = 52) and pain-free comparison controls (n = 30). In OA patients only, detailed clinical examination and quantitative sensory testing were completed. Cerebrospinal fluid samples were analyzed for 10 proinflammatory mediators using Meso Scale Discovery platform. Compared to controls, OA patients had higher CSF levels of interleukin 8 (IL-8) (P = 0.002), intercellular adhesion molecule 1 (P = 0.007), and vascular cell adhesion molecule 1 (P = 0.006). Osteoarthritis patients with central sensitization possibly indicated by arm pressure pain detection threshold <250 kPa showed significantly higher CSF levels of Fms-related tyrosine kinase 1 (Flt-1) (P = 0.044) and interferon gamma-induced protein 10 (IP-10) (P = 0.024), as compared to subjects with PPDT above that threshold. In patients reporting pain numerical rating scale score ≥3/10 during peripheral venous cannulation, Flt-1 was elevated (P = 0.025), and in patients with punctate stimulus wind-up ratio ≥2, CSF monocyte chemoattractant protein 1 was higher (P = 0.011). Multiple logistic regression models showed that increased Flt-1 was associated with central sensitization, assessed by remote-site PPDT and peripheral venous cannulation pain, and monocyte chemoattractant protein-1 with temporal summation in the area of maximum pain. Multiple proinflammatory mediators measured in CSF are associated with persistent hip OA-related pain. Pain phenotype may be influenced by specific CSF neuroinflammatory profiles.
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http://dx.doi.org/10.1097/j.pain.0000000000001903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431139PMC
September 2020

Mindfulness Meditation Activates Altruism.

Sci Rep 2020 04 16;10(1):6511. Epub 2020 Apr 16.

Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, CA, 90095, United States.

Clinical evidence suggests that mindfulness meditation reduces anxiety, depression, and stress, and improves emotion regulation due to modulation of activity in neural substrates linked to the regulation of emotions and social preferences. However, less was known about whether mindfulness meditation might alter pro-social behavior. Here we examined whether mindfulness meditation activates human altruism, a component of social cooperation. Using a simple donation game, which is a real-world version of the Dictator's Game, we randomly assigned 326 subjects to a mindfulness meditation online session or control and measured their willingness to donate a portion of their payment for participation as a charitable donation. Subjects who underwent the meditation treatment donated at a 2.61 times higher rate than the control (p = 0.005), after controlling for socio-demographics. We also found a larger treatment effect of meditation among those who did not go to college (p < 0.001) and those who were under 25 years of age (p < 0.001), with both subject groups contributing virtually nothing in the control condition. Our results imply high context modularity of human altruism and the development of intervention approaches including mindfulness meditation to increase social cooperation, especially among subjects with low baseline willingness to contribute.
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http://dx.doi.org/10.1038/s41598-020-62652-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7162971PMC
April 2020

Childhood maltreatment and monocyte gene expression among women with breast cancer.

Brain Behav Immun 2020 08 2;88:396-402. Epub 2020 Apr 2.

UCLA Department of Psychiatry and Biobehavioral Sciences, United States; Cousins Center for Psychoneuroimmunology, Semel Institute for Neuroscience and Human Behavior, United States; Jonsson Comprehensive Cancer Center, United States; UCLA Department of Medicine, United States.

Background: Childhood adversity is reliably associated with immune alterations in adulthood, including increases in inflammatory processes. However, relatively few studies have investigated these associations in clinical populations such as cancer patients who are at risk for negative immune-related health outcomes. The current study tested the hypothesis that childhood maltreatment would be associated with alterations in immune-related gene expression in monocytes from women with breast cancer.

Methods: Women (n = 86) were recruited after diagnosis with early-stage breast cancer but before onset of adjuvant therapy with radiation, chemotherapy, and/or endocrine therapy. Participants completed questionnaires to assess childhood maltreatment (Childhood Trauma Questionnaire; CTQ) and depressive symptoms (Center for Epidemiologic Studies Depression Scale; CES-D) and provided blood samples for immune assessment. CD14+ monocytes were isolated for RNA extraction and gene expression analyses.

Results: Based on responses to the CTQ, 28% of participants were classified as experiencing physical and/or emotional abuse or neglect and 7% as experiencing sexual abuse. Genome-wide transcriptional profiling of isolated monocytes identified 202 gene transcripts that differed in average expression level by > 25% over the range of maltreatment exposure. Bioinformatics analyses of those gene transcripts identified a significantly greater prevalence of NF-κB-binding motifs within the promoters of up-regulated vs. down-regulated genes (p = .028) in women exposed to childhood maltreatment, indicating greater inflammatory signaling. Parallel analyses of Type I interferon signaling also indicated greater prevalence of Interferon Response Factor (IRF)-related binding sites in women with a childhood maltreatment history (p = .020). Results remained significant in analyses controlling for current depression; however, NF-κB and IRF-related gene expression was higher in women with both maltreatment exposure and current depression.

Conclusions: In women recently diagnosed with early-stage breast cancer, childhood maltreatment was associated with increases in the classical NF-kB-related pro-inflammatory signaling pathway and with increases in the Type I interferon system. These results suggest a broad pattern of chronic immunologic activation in breast cancer patients with a history of childhood maltreatment, particularly those who are currently experiencing clinically significant depressive symptoms. These findings have implications for the long-term health and well-being of maltreatment exposed breast cancer patients.
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http://dx.doi.org/10.1016/j.bbi.2020.04.001DOI Listing
August 2020