Mind Body & Health

TAI CHI EFFECTS ON CHRONIC INSOMNIA IN BREAST CANCER SURVIVORS: IMMUNE MECHANISMS
PI: Michael R. Irwin, MD
NCI
Immune Mechanisms Breast cancer is the most common cancer in women. After completion of successful therapy, many behavioral symptoms persist with over 20% of breast cancer survivors reporting chronic insomnia of greater than 6 months duration that fulfils clinical diagnostic criteria with associated functional limitations, decreased quality of life, and possible effects on long-term survival. Behavioral interventions are highly efficacious in the treatment of insomnia and preferred over hypnotic medications when insomnia is chronic. However, insomnia studies conducted in cancer are scarce. The proposed research builds upon a program of study that has examined the efficacy of a mind-body intervention, Tai Chi Chih (TCC), on health outcomes including sleep impairments. Preliminary studies show that TCC, a slow moving meditation, contributes to improvements in subjective sleep quality, sleep amounts and sleep efficiency. We have further found that sleep, fatigue, and proinflammatory cytokine activity are reciprocally related and that TCC decreases proinflammatory cytokine levels. Thus, we further hypothesize that cytokine network is one physiological mechanism through which TCC carries its effects on sleep outcomes. In this randomized, controlled trial, 100 breast cancer survivors will be randomly assigned to TCC or sleep hygiene/education control (EC) over 16 weeks and followed for one year. The aims of this project are to: 1) evaluate the effects of TCC vs. EC on objective and subjective measures of sleep continuity, fatigue, and health functioning in breast cancer survivors with chronic insomnia; 2) determine the effects of TCC vs. EC on measures of proinflammatory cytokine activity; 3) evaluate whether circulating levels of proinflammatory cytokines temporally correlate with measures of sleep continuity in breast cancer survivors with insomnia over the course of the treatment trial. This project will constitute the first, randomized controlled clinical trial of the effects of TCC on sleep outcomes in breast cancer survivors, and will advance psychobiological models of insomnia treatment mechanisms.

COGNITIVE FUNCTIONING AFTER BREAST CANCER TREATMENT 
PI: Patricia Ganz, MD; Julienne Bower, PhD, Co-I
NCI
Cognitive complaints have been anecdotally reported among women receiving adjuvant chemotherapy for breast cancer, and recently this has been subjected to more rigorous study. Cerebral functioning can be assessed by self-report, standardized neuropsychological testing, and through examination of brain metabolism (all of which have been studied in our laboratory). The literature suggests a relationship between chemotherapy exposure and poorer performance on neurocognitive testing; however, patients with cognitive complaints do not necessarily test poorly and their complaints are often associated with symptoms of depression and anxiety. Preliminary work in our laboratory suggests that hormonal changes associated with menopause and adjuvant endocrine therapy for breast cancer also influence the effects of chemotherapy on cognitive functioning. Little is known about the potential mechanisms by which adjuvant endocrine therapy influences cerebral functioning after breast cancer treatment, and in this study we will address this question by studying women who have recently completed their primary breast cancer treatments (surgery, radiation, chemotherapy) and who are about to initiate adjuvant endocrine therapy (with tamoxifen or aromatase inhibitors). We will examine the potential mechanisms by which endocrine therapy affects cerebral functioning, by consideration of a comprehensive framework that includes the role of constitutional symptoms (fatigue, depression, anxiety), and immune alterations, in addition to specific cancer treatments (chemotherapy, hormonal treatments), and endogenous endocrine exposures (estrogen, cortisol). In this longitudinal, observational cohort study, we propose the following specific aims: 1)To evaluate the effects of adjuvant endocrine therapy on cognitive functioning through standardized questionnaires and neuropsychological assessments in 260 breast cancer patients at the end of primary treatment (baseline) when endocrine treatment is initiated, and one year later (follow-up). 2)To examine the association between cognitive functioning and measures of cerebral metabolism by obtaining positron emission tomography (PET) brain imaging, at rest and with a memory challenge, in close temporal proximity to the baseline assessment of cognitive functioning in a subset of 60 women, with a follow-up assessment one year later. 3)To explore the biopsychosocial mechanisms by which adjuvant endocrine therapy influences cerebral functioning by examining changes in cognitive functioning and brain metabolism, and their relationship to immune and endocrine function, mood and symptoms between the baseline and follow-up assessment one year later. Lay summary: Breast cancer is the most common cancer in women. After treatments for breast cancer, some women complain of difficulty in concentrating and thinking. This study will examine the effects of breast cancer treatments on cognitive, psychological, immune and endocrine function to try to understand the biological mechanisms of these complaints so that they may be better prevented or treated in the future.

AGING: INSOMNIA TREAMENT AND ENERGY BALANCE
PI: Sarosh Motivala, PhD
NIA
Over 50% of adults older than 65 years report problems sleeping and the prevalence of persistent insomnia is estimated to be over 30% in this population, and steadily increases with age. Behavioral treatments for chronic insomnia have demonstrated consistent improvements in self-reported sleep, but outcome assessment, including polysomnography, behavioral factors such as health functioning and biologic factors impacted by sleep have not been comprehensively examined, especially in older adults. In particular, one promising area of research is the impact of interventions on energy balance. The hormones ghrelin and leptin are thought to convey information about energy balance to the brain, and dysregulation of these hormones lead to increases in appetite and lipid accumulation. Epidemiologic studies have found that poor sleep is associated with elevated ghrelin and decreased leptin, corroborated by experimental sleep restriction studies as well. Elevated ghrelin and decreased leptin levels also correlate with increased sympathetic activity; which is seen in insomnia patients. Taken together, these findings indicate that older insomnia patients may have altered energy balance. Yet few studies have measured objective sleep assessment following insomnia interventions and no study has reported its effects on energy balance. The proposed project is an ancillary study to a newly funded NIA randomized, controlled trial comparing the effects of cognitive-behavioral therapy (CBT), Tai Chi Chih (TCC), and hygiene/education control (EC) on sleep outcomes in older insomnia patients. This K23 project is an opportunity for the PI (a health-clinical psychologist) to utilize expertise in sleep and psychophysiology assessment and previous clinical training while developing expertise in behavioral insomnia treatment research and biological effects of treatment. The unique aims of this K23 project are to: 1) evaluate the effects of CBT vs. TCC vs. EC on ghrelin and leptin levels at baseline, mid- treatment, post-treatment and 3- and 12-month follow-ups; 2) determine the effects of CBT vs. TCC vs. EC on nocturnal autonomic function (power spectral analysis of heart rate variability) during sleep assessments at the UCLA GCRC at baseline and post-treatment; 3) examine whether energy balance and autonomic function are related to improvements in objective and subjective measures of sleep over the course of the treatment trial.

BIOBEHAVIORAL INFLUENCES AND THE OVARIAN TUMOR MICROENVIRONMENT
PI: Susan Lutgendorf, PhD, Iowa PI / George Slavich, PhD, UCLA PI
NCI
Ovarian cancer is the second most common gynecologic cancer. Because of low rates of survival for the majority of ovarian cancer patients, identification of factors contributing to tumor progression is of paramount importance. Epidemiologic studies have suggested an association between biobehavioral factors such as life stress, depression, and social support and cancer progression. This study examines a novel pathway that may underlie these links in ovarian cancer, specifically, the relationship of biobehavioral factors with resident macrophages within the tumor microenvironment. It is now acknowledged that the tumor microenvironment is critical in supporting or inhibiting tumor progression. We have previously reported associations of depression and low social support with a poorer cellular immune response in ovarian cancer patients in the tumor microenvironment. We have also demonstrated direct links between biobehavioral factors and cytokines supporting angiogenesis, the formation of new blood vessels that enhance tumor growth and progression. Macrophages are major components of the tumor microenvironment where they are predominantly converted from an anti-tumor phenotype to a pro-tumor phenotype and play a key role in supporting inflammation and tumor progression. However, little is known regarding whether biobehavioral factors influence tumor associated macrophages (TAM) and interactions between TAM and tumor cells in a way that favors tumor growth. Based on compelling preliminary data, we propose that biobehavioral influences on both TAM and tumor cells in the tumor microenvironment have significant effects on production of factors supporting tumor growth and progression. We focus on TAM because of their key role in the tumor microenvironment, and because of indications of macrophage sensitivity to stress factors in the cardiovascular literature and in our preliminary data. Thus, the overarching goal of this proposal is to examine pathways by which biobehavioral factors contribute to a permissive local environment for interactions between resident cells (TAM) and tumor cells that favor tumor growth in ovarian cancer. The proposed project will prospectively examine the relationship of biobehavioral factors (life stress, depression, and social support) and TAM products (inflammatory cytokines and tumor growth factors) in the tumor microenvironment in 206 ovarian cancer patients. Association of biobehavioral factors with upregulation of gene transcripts related to inflammation and proliferation in tumor cells will also be examined. Based on preliminary data we will examine the role of adrenergic signaling as a mediator in these relationships. To determine the clinical significance of these biological alterations, the investigation will assess progression-free and overall survival during the 24 months following diagnosis. Findings will have implications for innovative behavioral and pharmacological intervention strategies for ovarian cancer patients. PUBLIC HEALTH RELEVANCE: There has been very little research examining systemic effects on the tumor microenvironment. This research examines a novel pathway by which biobehavioral factors may contribute to a permissive milieu for tumor growth and disease progression in the tumor microenvironment among ovarian cancer patients. A clearer understanding of biobehavioral risk factors and pathways by which they operate is critical for identifying targets for psychosocial and pharmacological intervention for ovarian cancer patients who may be at risk.

EMOTION REGULATION AND DEPRESSION IN BREAST CANCER SURVIVORSHIP
PI: Annette L. Stanton, PhD
NCI
Both in individuals living with cancer and in the general population, the experience of clinical depression exacts a profound psychological, physical, and economic toll. Little research has examined the unfolding risk for depressive symptoms and episodes after a breast cancer diagnosis with careful assessments repeated over time. Moreover, theory and research in depression and in emotion science have not been integrated and tested in sophisticated biopsychosocial models to advance understanding of risk and protective factors/processes for depression in cancer patients. Accordingly, this study has three specific aims. Aim 1 is to investigate how personal vulnerabilities, cancer-related (e.g., treatments/side effects) and noncancer-related stressors, and emotion regulation processes shape trajectories of depression in women following diagnosis of breast cancer. Personal vulnerabilities include general depressive diatheses (history of depression, neuroticism, harsh early environment) and emotion dysregulation diatheses (low emotional awareness and acceptance, high emotional suppression, no intimate confiding relationship). Aim 2 is to examine a diathesis- stress model, in which interactions of personal vulnerabilities, genetic factors (a functional polymorphism of the serotonin transporter gene), and stressors shape depressive response. Aim 3 is to examine a proximal model of how emotion regulation processes (approach and avoidance) mediate the effects of personal vulnerabilities on depressive symptoms and episodes. We will accomplish these aims in longitudinal research beginning within three months of diagnosis (Time 1) of 450 women (study completers) with new diagnoses of initial or recurrent invasive breast cancer and subsequent assessments every six weeks through six months (Time 2-5) and at 9 months (Time 6) and 12 months (Time 7). DNA extraction, validated questionnaires and interviews, and measures of expressive behavior will be administered. Primary dependent variables are depressive symptoms and depressive disorder. Effects of age, ethnicity, and mental health treatment receipt will be explored. Findings will influence public health by informing the next generation of targeted preventive and therapeutic interventions for depression in cancer patients, thereby reducing the disorder's health and economic burden. PUBLIC HEALTH RELEVANCE: Cancer patients are more likely than the general population to evidence depressive symptoms and clinical depression, but little is known about the factors that put individuals at risk for clinical depression when they have cancer. This project will provide information about who is at risk and factors contributing to high risk for depression, when they can be identified, and ingredients of interventions that are likely to be effective in reducing depression in women diagnosed with breast cancer. This research will help to target limited mental health resources to make the largest impact in preventing and treating depression in the face of cancer.

DAILY EXPERIENCE IN ADOLESCENCE AND BIOMARKERS OF EARLY RISK FOR ADULT HEALTH
PI: Andrew Fuligni, PhD / Michael R. Irwin, MD, Co-I
NICHD
Despite calls for the identification of early risk factors for the development of chronic health conditions, there has been little longitudinal research on biomarkers of health that has been conducted in persons younger than 25 years of age. In addition, there is only a minimal understanding of how biological indices of early risk for adult health develop among adolescents with Latin American and Asian backgrounds, the two fastest rising ethnic groups in theUnited States, who are at differential risk for adverse health outcomes as compared to European Americans. An understanding of these processes is necessary for the development of ethnically and culturally relevant prevention efforts. We propose a 3-wave longitudinal study of adolescents and their caregivers from Mexican, Chinese and European backgrounds in order to assess the impact of daily experience on biological indicators of early risk for adult health. Our focus on daily experience stems from the need to identify the mechanisms by which global social factors identified in demographic surveys, such as lower education and income, play themselves out in individuals' daily lives. Daily experiences such as social conflict, excessive demands, emotional distress, threat, and sleep behaviors have been shown to be linked to both global risk factors and multiple biological indices of health risk among adults. The project will include both intensive behavioral assessments and detailed biological markers of health risk from both adolescents and their parents in order to address the following specific aims: (1) describe the development during adolescence of biological indices of early risk for adult health; (2) assess the role of daily experience in the development of early health risk; (3) examine the existence of ethnic disparities in early health risk; and (4) explore the role of potential protective factors in the development of early health risk. Approximately 540 pairs of adolescents and primary caregivers (180 from each ethnic group) will be assessed when the adolescents are approximately 15-16, 17-18, and 19-20 years of age. Each year, both adolescents and caregivers will participate in interviews that include measures of global social factors such as socioeconomic background and potential protective factors such as social connectedness. Participants will report daily experiences using a nightly diary checklist for 9 consecutive days. Salivary cortisol will be obtained at 4 time points each day for 4 of these days in order to analyze HPA activity, and participants will wear wrist actigraphs for the same 4 days to measure objective sleep behaviors. Blood pressure, BMI, and waist/hip ratio will be assessed, and dried blood spots will be obtained for the assessment of c-reactive-protein (CRP), cholesterol, and high density lipoproteins (HDL). Finally, peripheral blood samples will be provided by a subsample of 120 families for the assessment of plasma interleukin-6 (IL-6), a pro-inflammatory cytokine, and for gene expression analyses of molecular signaling pathways driving inflammatory biology. PUBLIC HEALTH RELEVANCE: There is only a minimal understanding of how biological indices of early risk for adult health develop among adolescents with Latin American and Asian backgrounds, the two fastest rising ethnic groups in theUnited States, who are at differential risk for adverse health outcomes as compared to European American. More in-depth examinations of the daily lives of adolescents from these populations could identify both the sources of these disparities as well as unique risk and protective factors. An understanding of these processes is necessary for the development of ethnically and culturally relevant prevention efforts.

PAIN, OPIOIDS AND PRO-INFLAMMATORY IMMUNE RESPONSES
PI: Margaret Compton, PhD / Michael R. Irwin, MD, Co-I
NIDA
Separately, acute pain and opioid administration have each been shown to induce a systemic pro-inflammatory response, theoretically putting the patient at risk for, or exacerbating, diseases of inflammation (i.e., heart disease, diabetes, arthritis). Surprisingly, unknown is the expression of these inflammatory responses when pain and opioid administration co-occur, as is the common clinical case of a patient with acute pain and taking opioid analgesics. An additive model would predict that pro-inflammatory processes are increased in the presence of both, yet better health outcomes for patients whose pain is adequately treated suggests otherwise. A patient population for whom the combined effects of pain and opioids on immune function are likely to be particularly complex are the estimated 5.2 million Americans aged 12 or older who abuse prescription opioids. Not only are these individuals at risk for poor pain management due to their status as an "addict", but there is good preclinical evidence to suggest that their chronic opioid use brings with it a general state of systemic inflammation, and thus setting the patient up for a unique or enhanced inflammatory response to the combination of acute opioids and pain. To effectively maximize health outcomes in this group of patients who self-administer prescription opioids in the absence of pain, clinicians need a more comprehensive understanding of the effects of their ongoing opioid use on inflammatory outcomes. To better understand the health implications of treating acute pain with opioids in general, and in patients who abuse prescription opioids in particular, inflammatory responses to the main and interaction effects of acute pain and opioid administration will be examined in well-characterized samples of each. Specifically, we will evaluate the inflammatory and cytokine responses to: (1) experimental (cold-pressor) pain; (2) an acute opioid (IV fentanyl 1mcg/kg) challenge; and (3) the combination of opioid administration (IV fentanyl 1mcg/kg) followed by cold-pressor pain, in healthy control subjects (n=22, 11 female) and age- and gender-matched prescription opioid abusers in buprenorphine treatment (n=22, 11 female). Markers of pro-inflammatory (IL-6, IL-12, TNF1) and anti-inflammatory (IL-4, IL-10) activity, as well as a nuclear transcription factor for pro- inflammatory cytokine expression ( NF-kb), will be followed over a 3hr time period to capture the duration of opioid analgesic activity, as well as second-messenger generated changes. The proposed study is unique in evaluating immune responses in the context of pain and opioid analgesia, innovative in the inclusion of inflammatory markers and relevant molecular signaling pathways, and noteworthy in including a vulnerable population of patients, prescription opioid abusers. This work will provide valuable and novel human data on how the inflammatory effects of acute pain, opioid administration, and chronic self-administration of opioids interact, and thus have clear clinical implications for the safe and effective management of pain with opioids. PUBLIC HEALTH RELEVANCE: Separately, acute pain and opioid administration each induce a systemic pro-inflammatory response, theoretically putting the patient at risk for, or exacerbating, inflammatory disease (i.e., heart disease, diabetes, arthritis). Yet, surprisingly, the inflammatory effects of these when they co-occur, such as in the common situation of the patient in pain and taking opioid analgesics, are essentially unknown. Further, the nature of this interaction in those individuals who abuse prescription opioids in the absence of pain has not been examined. In an effort to better understand the inflammatory effects of acute and chronic opioids in persons with and without pain, pro-inflammatory immune markers will be examined in healthy controls and treatment- seeking prescription opioid abusers.

INFLAMMATION-INDUCED DEPRESSED MOOD: THE ROLE OF SOCIAL NEUROCOGNITIVE MECHANISMS
PI: Naomi Eisenberger, PhD
NIMH
This application is submitted to the NIMH DATR Mood/Sleep Research Program A2-AID. Depressive disorders occur at a high rate in patients with inflammatory disorders, with a point prevalence of 15-29%, which is two to three times greater than that observed in the general population. Substantial evidence has shown that inflammation and increases in proinflammatory cytokine activity play a critical role in the onset and perpetuation of depression and depressive symptoms (e.g. insomnia, fatigue) in those who are co-morbid for inflammatory disorders (Miller et al., 2009). Consistent with this, experimental work has shown that an inflammatory challenge can increase depressed mood in an otherwise healthy sample (Reichenberg et al., 2001). Based on these findings, there has been a growing interest in whether inflammatory processes can contribute to depression in a causal manner and how these effects might occur. Given the observation that inflammatory processes trigger social withdrawal (Dantzer, 2001; Hart, 1988), coupled with evidence that feelings of 'social disconnection' play a critical role in the onset and perpetuation of (non-inflammatory forms of) depression (Heinrich & Gullone, 2006), it is surprising that the social psychological consequences of inflammation and their contribution to depression have not been more fully explored. Here, we suggest that inflammation may increase feelings of social disconnection and that these social psychological changes may be an important contributor to inflammation-associated depression. Indeed, preliminary data demonstrated that an experimentally-induced inflammatory challenge (endotoxin) led to increases in self-reported feelings of social disconnection (e.g., "I feel disconnected from others") in addition to increases in depressed mood (Eisenberger et al., 2009b). Aside from these findings, however, there are no studies that have explored the effect of inflammatory processes on social experience in humans. The over- arching objective of this proposal is to explore the experiential and neural correlates of inflammatory- induced changes in social experience (e.g., feelings of social disconnection), which may provide a critical missing link in understanding the relationship between inflammation and depression. Participants (n=100) will be randomly assigned to receive either endotoxin or placebo and will then be monitored for the next six hours. Blood draws to assess cytokine levels as well as self-reported feelings of social disconnection and depressed mood will be collected hourly. In addition, at the time of peak cytokine response, participants will complete a neuroimaging session to examine the effect of inflammatory challenge on neural sensitivity to social rejection and social acceptance. It is hypothesized that endotoxin will increase feelings of social disconnection over time, and that the underlying neural sensitivities that give rise to these feelings (e.g., increased neural sensitivity to social rejection; decreased neural sensitivity to social acceptance) will contribute to inflammatory-induced depressed mood. PUBLIC HEALTH RELEVANCE: Although substantial evidence has demonstrated links between inflammation and depression, the mechanisms underlying this relationship are poorly understood. Based on the observation that inflammation triggers social withdrawal, coupled with evidence that feelings of social disconnection play a critical role in depression, the proposed research will examine the social psychological consequences of inflammation and their relation to depressive symptoms for the first time. In addition, the proposed research will examine the neural correlates that underlie these social psychological changes to better understand the central mechanisms that contribute to inflammatory-induced depressive symptoms.

PRO-INFLAMMATORY CYTOKINES & NEUROBEHAVIORAL SYMPTOMS IN BREAST CANCER PATIENTS
PI: Sunita Patel, PhD / Elizabeth Breen, PhD, Co-I
NCI
Pro-inflammatory cytokines and neurobehavioral symptoms in women with breast cancer. Abstract Survivors of breast cancer report debilitating behavioral symptoms, such as fatigue and neurocognitive dysfunction, which are evident in some individuals even at pre-treatment baseline. There is sufficient evidence from varied lines of research to propose that cancer-related neurobehavioral symptoms may be driven, at least in part, by activation of the pro-inflammatory cytokine network. Concentrations of specific pro-inflammatory cytokines (IL-6, TNF) and soluble receptors in serum obtained prior to treatment in breast cancer patients are significantly higher than levels found in healthy individuals and have prognostic value; however, these pre- treatment elevations have not yet been evaluated with respect to their association with either acute or chronic behavioral symptoms. Among survivors of breast cancer, elevated levels of circulating sIL-6R and IL-1ra have emerged as prominent biomarkers of persistent fatigue in cross-sectional studies of women several years post chemotherapy. No similar work has identified biomarkers of neurocognitive dysfunction in this patient population, and it is not known if the cytokine links with fatigue, or other behavioral symptoms, exist closer to the diagnosis period or evolve over time as "late effects". In this study, we will address this knowledge gap as we will evaluate this association prior to cancer treatment, and again following treatment completion. We will compare these associations in a minimum of 137 breast cancer patients relative to two comparison groups at pre-treatment, and longitudinally evaluate only the breast cancer group after treatment. Findings are expected to increase our knowledge about the possible biomarkers associated with neurobehavioral symptoms in breast cancer patients, for the purpose of better identifying and treating those at risk for such effects. PUBLIC HEALTH RELEVANCE: Findings are expected to increase knowledge about the possible biomarkers associated with neurobehavioral symptoms in breast cancer patients, for the purpose of better identifying and treating those at risk for such effects.

COMPLICATED GRIEF IN OLDER ADULTS: PHYSIOLOGICAL SUBSTRATES OF EMOTION REGULATION
PI: Mary-Frances O’Connor, PhD
NIA
Complicated Grief in Older Adults: Physiological Substrates of Emotion Regulation This application for a Career Development Award in Aging describes an integrated training plan and research project to allow the candidate to become an expert in the physiological underpinnings of emotion regulation in older adults. Conjugal bereavement is highly prevalent in older adults, with more than 900,000 people widowed each year in theU.S.Although most adjust gradually to widow(er)hood, others experience a complicated course. Complicated grief, which persists despite anti-depressant treatment, has been found to be an independent predictor of cognitive decline, poor health, depression and suicidality in older adults, making it a major public health concern. Cognitive factors, such as the inability to shift attention away from intrusive thoughts of the deceased are hypothesized to impair adjusting to a life as a widow(er). Furthermore, physiological mechanisms, such as low-grade inflammatory processes, may contribute to emotional dysregulation found in this population. The proposed research will assess neural activation, immune markers, and neuropsychological tests of attention and emotion regulation in older adults. We will recruit 135 older adults (45 with complicated grief, 45 with uncomplicated grief and 45 non-bereaved, determined by a structured interview with new consensus criteria). The specific aims are: Aim 1) To examine attentional deficits in older adults with complicated grief as measured by the e-Stroop as compared to controls (uncomplicated grief and non-bereaved); Aim 2) To examine the neural substrates of attentional deficits in a subsample of 36 older adults with fMRI in these three groups; Aim 3) To evaluate circulating markers of inflammation (e.g., sTNF-RII, IL-6, slL-6R and IL-1Ra) in older adults with complicated grief as compared to controls (uncomplicated grief and non-bereaved). The long-term goal of the project is to explore whether neural activity mediates the relationship between circulating markers of inflammation and attentional deficits. The Cousins Center for Psychoneuroimmunology at UCLA has both excellent resources (e.g. 3T imaging scanner) and excellent mentors (including Dr. Michael Irwin, MD) necessary for advanced training in bereavement, immunology, and neuroimaging research that will facilitate development of the candidate, Dr. Mary-Frances O'Connor, into an independent investigator and allow her to develop an R01 proposal to evaluate treatment for complicated grief, based on both physiological and psychological mechanisms.

FIBROMYALGIA: INTERVENTIONS FOR PAIN AND MOOD REGULATION
PI: Perry Nicassio, PhD, UCLA PI
NIAMS
Approximately 5% of women and 1.6% of men (White et al., 1999) have been diagnosed with Fibromyalgia (FM), a chronic pain condition of unknown etiology with few satisfactory treatment options. FM is characterized by widespread pain, sleep disturbance, and fatigue that frequently lead to extensive functional limitations. Although the most widely used psychological intervention for chronic pain, cognitive behavioral therapy (CBT), has successfully addressed pain management, it has not directly addressed the distinct challenges to emotion regulation faced by FM patients. Deficits in positive and negative affect regulation are salient features of the clinical profile of FM patients. An integrated approach that fortifies the therapeutic gains in pain management provided by CBT with attention to ameliorating affective regulation deficits has the potential not only to advance our knowledge of the role of emotion in chronic pain but also to provide an empirically validated treatment option not currently available for FM. This grant proposes to test the effectiveness of a cognitive-behavioral treatment for FM that supplements the pain management emphasis of existing treatments by also targeting emotion regulation. Two foci are central to the emotion regulation component: 1) minimizing the negative affective consequences of recurrent pain, including depression and anxiety symptoms, and 2) sustaining key sources of positive affect in spite of pain. FM patients (N=180) will be randomly assigned to one of three treatments: Cognitive-Behavior Therapy for Pain (CBT-P), Cognitive-Behavior Therapy for Pain and Emotion Regulation (CBT-PE), or an Education-Only Control Group (EC). Pre- and post-intervention assessments will include within-day field records of cognitive, affective, and behavioral responses to pain and naturalistic stressors, complemented by laboratory-based tests of reactivity to standardized pain and affective stimuli. Both CBT-P and CBT-PE are expected to improve pain management relative to EC, but CBT-PE is expected to have a broader impact, improving physical and psychological functioning by increasing positive affective engagement and decreasing reactivity to pain and stress. Thus, CBT-PE should enhance the capacity of FM patients to cope with stressful aspects of their illness and other areas of their lives, leading to more beneficial long-term effects on functional health and well being compared to CBT-P and EC groups.

Relevant Publications

Mitigating Cellular Inflammation in Older Adults: A Randomized Controlled Trial of Tai Chi Chih. Irwin MR, Olmstead R. Am J Geriatr Psychiatry. 2011 Sep 19. [Epub ahead of print] PMID: 21934474 

Inflammation at the intersection of behavior and somatic symptoms. Irwin MR. Psychiatr Clin North Am. 2011 Sep;34(3):605-20. No  abstract available. PMID: 21889682 

Reciprocal regulation of the neural and innate immune systems. Irwin MR, Cole SW. Nat Rev Immunol. 2011 Aug 5;11(9):625-32. doi: 10.1038/nri3042. PMID: 21818124 

Antagonistic pleiotropy at the human IL6 promoter confers genetic resilience to the pro-inflammatory effects of adverse social conditions in adolescence. Cole SW, Arevalo JM, Manu K, Telzer EH, Kiang L, Bower JE, Irwin MR, Fuligni AJ. Dev Psychol. 2011 Jul;47(4):1173-80. PMID: 21639625 

Complementary use of tai chi chih augments escitalopram treatment of geriatric depression: a randomized controlled trial. Lavretsky H, Alstein LL, Olmstead RE, Ercoli LM, Riparetti-Brown M, Cyr NS, Irwin MR. Am J Geriatr Psychiatry. 2011 Oct;19(10):839-50. doi: 10.1097/JGP.0b013e31820ee9ef. PMID: 21358389 

Inflammation-induced anhedonia: endotoxin reduces ventral striatum responses to reward. Eisenberger NI, Berkman ET, Inagaki TK, Rameson LT, Mashal NM, Irwin MR. Biol Psychiatry. 2010 Oct 15;68(8):748-54. Epub 2010 Aug 16. PMID: 20719303 

Links between behavioral factors and inflammation. O'Connor MF, Irwin MR. Clin Pharmacol Ther. 2010 Apr;87(4):479-82. Epub 2010  Feb 3. Review. PMID: 20130566 Free PMC Article 

Varicella-zoster virus-specific immune responses to herpes zoster in elderly participants in a trial of a clinically effective zoster vaccine. Weinberg A, Zhang JH, Oxman MN, Johnson GR, Hayward AR, Caulfield MJ, Irwin MR, Clair J, Smith JG, Stanley H, Marchese RD, Harbecke R, Williams HM, Chan IS, Arbeit RD, Gershon AA, Schödel F, Morrison VA, Kauffman CA, Straus SE, Schmader KE, Davis LE, Levin MJ; US Department of Veterans Affairs (VA) Cooperative Studies Program Shingles Prevention Study Investigators. J Infect Dis. 2009 Oct 1;200(7):1068-77. PMID: 19712037 Free Article 

Yoga for persistent fatigue in breast cancer survivors: results of a pilot study. Bower JE, Garet D, Sternlieb B. Evid Based Complement Alternat Med. 2011;2011:623168. Epub 2011 Jan 13. PMID: 21274288 Free PMC Article 

Prospective association between C-reactive protein and fatigue in the coronary artery risk development in young adults study. Cho HJ, Seeman TE, Bower JE, Kiefe CI, Irwin MR. Biol Psychiatry. 2009 Nov 1;66(9):871-8. Epub 2009 Jul 29. PMID: 19640510  Free PMC Article  

Social neuroscience: The social brain, oxytocin, and health. Norman GJ, Hawkley LC, Cole SW, Berntson GG, Cacioppo JT. Soc Neurosci. 2011 Jun 30. [Epub ahead of print] PMID: 21714746  

The contribution of pain and depression to self-reported sleep disturbance in patients with rheumatoid arthritis. Nicassio PM, Ormseth SR, Kay M, Custodio M, Irwin MR, Olmstead R, Weisman MH. Pain. 2011 Nov 1. [Epub ahead of print] PMID: 22051047  

An evaluation of a biopsychosocial framework for health-related quality of life and disability in rheumatoid arthritis. Nicassio PM, Kay MA, Custodio MK, Irwin MR, Olmstead R, Weisman MH. J Psychosom Res. 2011 Aug;71(2):79-85. Epub 2011 May 14. PMID: 21767687  

Psychological approaches are effective for fibromyalgia: remaining issues and challenges. Nicassio PM. Pain. 2010 Nov;151(2):245-6. Epub 2010 Aug 25. No abstract available. PMID: 20800359  

Arthritis and psychiatric disorders: disentangling the relationship. Nicassio PM. J Psychosom Res. 2010 Feb;68(2):183-5. Epub 2009 Nov 25. No abstract available. PMID: 20105701