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Item (506) The complex relationship between pain intensity and physical functioning in fibromyalgia: the mediating role of depression(The Journal of Pain, 2016) Steiner, Jennifer L.; Bigatti, Silvia M.; Slaven, James E.; Ang, Dennis C.Fibromyalgia (FM) is typically associated with the experience of diffuse pain and physical impairment. Depression also commonly co-exists in patients with FM, and it has been correlated with pain intensity and physical functioning. Previous research suggests an association between pain intensity and physical functioning; however, the direct causal relationship between improvements in pain intensity and in functioning is not observed in many FM patients. This may suggest that another factor such as depression is mediating this relationship. The present work examined the possibility of a mediating role of depression in the relationship between pain intensity and functioning over the course of time. 216 patients with FM completed self-report measures of pain intensity, depression, and physical impairment as part of a larger longitudinal study which investigated interventions to increase physical activity among FM patients. Assessments were completed at baseline, 12 weeks, 24 weeks, and 36 weeks. Longitudinal mediational analyses indicated that depression is a statistically significant partial mediator of the relationship between pain intensity and self-reported physical functioning at all four assessment points. To the authors’ knowledge, this is the first study to explicitly examine this relationship in a sample of FM patients, as well as the first to do so using a longitudinal design; this may significantly add to our understanding of the complexities behind creating improvements in physical functioning in this population. Clinical implication for these findings include focusing on depression and psychological correlates of depression as first line therapeutic targets in improving physical functioning of patients with FM, and treating co-morbid depression in patients with fibromyalgia earlier in the course of treatment to prevent engagement in and the perpetuation of the cycle of disability. This work was a secondary data analysis from a study funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases.Item Activin acutely sensitizes dorsal root ganglion neurons and induces hyperalgesia via PKC-mediated potentiation of transient receptor potential vanilloid I(Society for Neuroscience, 2007-12-12) Zhu, Weiguo; Xu, Pin; Cuascut, Fernando X.; Hall, Alison K.; Oxford, Gerry S.; Pharmacology and Toxicology, School of MedicinePain hypersensitivity is a cardinal sign of tissue damage, but how molecules from peripheral tissues affect sensory neuron physiology is incompletely understood. Previous studies have shown that activin A increases after peripheral injury and is sufficient to induce acute nociceptive behavior and increase pain peptides in sensory ganglia. This study was designed to test the possibility that the enhanced nociceptive responsiveness associated with activin involved sensitization of transient receptor potential vanilloid I (TRPV1) in primary sensory neurons. Activin receptors were found widely distributed among adult sensory neurons, including those that also express the capsaicin receptor. Whole-cell patch-clamp recording from sensory neurons showed that activin acutely sensitized capsaicin responses and depended on activin receptor kinase activity. Pharmacological studies revealed that the activin sensitization of capsaicin responses required PKCepsilon signaling, but not PI3K (phosphoinositide 3-kinase), ERK (extracellular signal-regulated protein kinase), PKA, PKCalpha/beta, or Src. Furthermore, activin administration caused acute thermal hyperalgesia in wild-type mice, but not in TRPV1-null mice. These data suggest that activin signals through its own receptor, involves PKCepsilon signaling to sensitize the TRPV1 channel, and contributes to acute thermal hyperalgesia.Item Agreement between older adult patient and caregiver proxy symptom reports(Springer, 2022-05-14) Kroenke, Kurt; Stump, Timothy E.; Monahan, Patrick O.; Medicine, School of MedicineBackground: Proxy report is essential for patients unable to complete patient-reported outcome (PRO) measures themselves and potentially beneficial when the caregiver perspective can complement patient report. In this study, we examine agreement between self-report by older adults and proxy report by their caregivers when completing PROs for pain, anxiety, depression, and other symptoms/impairments. Methods: Four PROs were administered by telephone to older adults and their caregivers followed by re-administration within 24 h in a random subgroup. The PROs included the PHQ-9 depression, GAD-7 anxiety, PEG pain, and SymTrak multi-dimensional symptom and functional status scales. Results: The sample consisted of 576 older adult and caregiver participants (188 patient-caregiver dyads, 200 patients without identified caregiver). The four measures had good internal (Cronbach's alpha, 0.76 to 0.92) and test-retest (ICC, 0.63 to 0.92) reliability whether completed by patients or caregivers. Total score and item-level means were relatively similar for both patient and caregiver reports. Agreement for total score as measured by intraclass correlation coefficient (ICC) was better for SymTrak-23 (0.48) and pain (0.58) than for anxiety (0.28) and depression (0.25). Multinomial modeling showed higher (worse) patient-reported scale scores were associated with caregiver underreporting, whereas higher caregiver task difficulty was associated with overreporting. Conclusion: When averaged over individuals at the group level, proxy reports of PRO scores by caregivers tend to approximate patient reports. For individual patients, proxy report should be interpreted more cautiously for psychological symptoms as well as when patient-reported symptoms are more severe, or caregiver task difficulty is high.Item Analysis of INSPPIRE-2 Cohort: Risk Factors and Disease Burden in Children with Acute Recurrent or Chronic Pancreatitis(Wiley, 2022) Uc, Aliye; Cress, Gretchen A.; Wang, Fuchenchu; Abu-El-Haija, Maisam; Ellery, Kate M.; Fishman, Douglas S.; Gariepy, Cheryl E.; Gonska, Tanja; Lin, Tom K.; Liu, Quin Y.; Mehta, Megha; Maqbool, Asim; McFerron, Brian A.; Morinville, Veronique D.; Ooi, Chee Y.; Perito, Emily R.; Schwarzenberg, Sarah Jane; Sellers, Zachary M.; Serrano, Jose; Shah, Uzma; Troendle, David M.; Wilschanski, Michael; Zheng, Yuhua; Yuan, Ying; Lowe, Mark E.; Pediatrics, School of MedicineObjectives: The objective of this study is to investigate risk factors and disease burden in pediatric acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP). Methods: Data were obtained from INternational Study group of Pediatric Pancreatitis: In search for a cuRE-2 (INSPPIRE-2), the largest multi-center prospective cohort study in pediatric patients with ARP or CP. Results: Of 689 children, 365 had ARP (53%), 324 had CP (47%). CP was more commonly associated with female sex, younger age at first acute pancreatitis (AP) attack, Asian race, family history of CP, lower BMI%, genetic and obstructive factors, PRSS1 mutations and pancreas divisum. CFTR mutations, toxic-metabolic factors, medication use, hypertriglyceridemia, Crohn disease were more common in children with ARP. Constant or frequent abdominal pain, emergency room (ER) visits, hospitalizations, medical, endoscopic or surgical therapies were significantly more common in CP, episodic pain in ARP. A total of 33.1% of children with CP had exocrine pancreatic insufficiency (EPI), 8.7% had diabetes mellitus. Compared to boys, girls were more likely to report pain impacting socialization and school, medical therapies, cholecystectomy, but no increased opioid use. There was no difference in race, ethnicity, age at first AP episode, age at CP diagnosis, duration of disease, risk factors, prevalence of EPI or diabetes between boys and girls. Multivariate analysis revealed that family history of CP, constant pain, obstructive risk factors were predictors of CP. Conclusions: Children with family history of CP, constant pain, or obstructive risk factors should raise suspicion for CP.Item Analysis of the efficacy of EPIONE therapies to treat phantom limb pain(2017-03) Comoglio, Caleb C.; Yoshida, KenThe primary objectives of this thesis are (1) to discuss the current understanding of phenomena associated with, proposed mechanisms of, and suggested treatments for amputation related pain, (2) to describe the software developed for analyzing results of a clinical study for the treatment of phantom limb pain (PLP), (3) to discuss the methods for a multi-center trial by the EPIONE consortium along with presenting preliminary results, and (4) to discuss the methods and results of a case study involving a new therapy modality for alleviating PLP. Each objective has been expanded into a chapter as described below. Chapter 1 serves as a literature review introducing the topic of amputation, associ- ated phenomena, and proposed mechanisms. The chapter also discusses the currently available treatments and the instruments used to measure PLP. Key topics include the definition of PLP, the prevalence of PLP, current treatment options for PLP, and experimental measurement of PLP. The final objective of this chapter is to introduce topics related to the investigation paradigm utilized for the studies following in Chapter 4 and Chapter 5. Therefore, a minor emphasis has been put on surface electrical stimulation (SES) and operant conditioning. As with any multi-center clinical study, coordination is key. Chapter 2 introduces the common clinical protocol (CCP) and methods of analysis for the clinical trials conducted by the EPIONE consortium. In order to analyze results in an automated fashion, a software tool was developed. This tool, the EPIONE Extraction Program (EEP) along with its extension the Group Analysis Module (GAM), is the focus of Chapter 3. A high-level overview of the requirements, process flow, and software testing are described. This chapter also discusses the methods of analysis for several self-report instruments used to determine effect size in Chapter 4 and Chapter 5. The outputs of the software tools make up the results presented and described in these chapters. In addition to the details included in Chapter 3, supplemental information is available in Appendix A and Appendix B, which are the detailed User Guides for the EEP and GAM. Chapter 4 reviews the pilot study data conducted by the EPIONE consortium. The primary and two secondary instruments used for analysis are discussed. This chapter provides a brief overview of results from the group. Each clinical site used slightly different variations of a common clinical protocol to better understand what effectively drives alleviation of PLP and to allow comparison of results. The work done at Indiana University - Purdue University Indianapolis (IUPUI) represents a small part of several other universities involved in the EPIONE consortium. Chapter 5 focuses on a case study at IUPUI with a more in-depth review of data collected throughout the study period. Using SES, we seek to reverse cortical reorganization by giving meaningful stimuli through existing circuitry. In this chapter the present work is discussed by introducing a case study in detail with an analysis of psychophysical data.Item Anxiety sensitivity as a transdiagnostic risk factor for trajectories of adverse posttraumatic neuropsychiatric sequelae in the AURORA study(Elsevier, 2022-12) Short , Nicole A.; van Rooij , Sanne J. H.; Murty, Vishnu P.; Stevens, Jennifer S.; An , Xinming; Ji , Yinyao; McLean , Samuel A.; House , Stacey L.; Beaudoin, Francesca L.; Zeng, Donglin; Neylan, Thomas C.; Clifford, Gari D.; Linnstaedt, Sarah D.; Germine, Laura T.; Bollen, Kenneth A.; Rauch , Scott L.; Haran , John P.; Lewandowski, Christopher; Musey Jr., Paul I.; Hendry , Phyllis L.; Sheikh , Sophia; Jones , Christopher W.; Punches, Brittany E.; Swor , Robert A.; McGrath , Meghan E.; Hudak , Lauren A.; Pascual , Jose L.; Seamon , Mark J.; Datner , Elizabeth M.; Pearson , Claire; Peak , David A.; Merchant , Roland C.; Domeier , Robert M.; Rathlev, Niels K.; O'Neil, Brian J.; Sergot, Paulina; Sanchez, Leon D.; Bruce, Steven E.; Pietrzak, Robert H.; Joormann, Jutta; Barch, Deanna M.; Pizzagalli , Diego A.; Sheridan, John F.; Smoller, Jordan W.; Harte, Steven E.; Elliott, James M.; Kessler, Ronald C.; Koenen, Karestan C .; Jovanovic , Tanja; Emergency Medicine, School of MedicineAnxiety sensitivity, or fear of anxious arousal, is cross-sectionally associated with a wide array of adverse posttraumatic neuropsychiatric sequelae, including symptoms of posttraumatic stress disorder, depression, anxiety, sleep disturbance, pain, and somatization. The current study utilizes a large-scale, multi-site, prospective study of trauma survivors presenting to emergency departments. Hypotheses tested whether elevated anxiety sensitivity in the immediate posttrauma period is associated with more severe and persistent trajectories of common adverse posttraumatic neuropsychiatric sequelae in the eight weeks posttrauma. Participants from the AURORA study (n = 2,269 recruited from 23 emergency departments) completed self-report assessments over eight weeks posttrauma. Associations between heightened anxiety sensitivity and more severe and/or persistent trajectories of trauma-related symptoms identified by growth mixture modeling were analyzed. Anxiety sensitivity assessed two weeks posttrauma was associated with severe and/or persistent posttraumatic stress, depression, anxiety, sleep disturbance, pain, and somatic symptoms in the eight weeks posttrauma. Effect sizes were in the small to medium range in multivariate models accounting for various demographic, trauma-related, pre-trauma mental health-related, and personality-related factors. Anxiety sensitivity may be a useful transdiagnostic risk factor in the immediate posttraumatic period identifying individuals at risk for the development of adverse posttraumatic neuropsychiatric sequelae. Further, considering anxiety sensitivity is malleable via brief intervention, it could be a useful secondary prevention target. Future research should continue to evaluate associations between anxiety sensitivity and trauma-related pathology.Item Aromatase inhibitors augment nociceptive behaviors in rats and enhance the excitability of sensory neurons(Elsevier, 2016-07) Robarge, Jason D.; Duarte, Djane B.; Shariat, Behzad; Wang, Ruizhong; Flockhart, David A.; Vasko, Michael R.; Pharmacology and Toxicology, School of MedicineAlthough aromatase inhibitors (AIs) are commonly used therapies for breast cancer, their use is limited because they produce arthralgia in a large number of patients. To determine whether AIs produce hypersensitivity in animal models of pain, we examined the effects of the AI, letrozole, on mechanical, thermal, and chemical sensitivity in rats. In ovariectomized (OVX) rats, administering a single dose of 1 or 5mg/kg letrozole significantly reduced mechanical paw withdrawal thresholds, without altering thermal sensitivity. Repeated injection of 5mg/kg letrozole in male rats produced mechanical, but not thermal, hypersensitivity that extinguished when drug dosing was stopped. A single dose of 5mg/kg letrozole or daily dosing of letrozole or exemestane in male rats also augmented flinching behavior induced by intraplantar injection of 1000nmol of adenosine 5'-triphosphate (ATP). To determine whether sensitization of sensory neurons contributed to AI-induced hypersensitivity, we evaluated the excitability of neurons isolated from dorsal root ganglia of male rats chronically treated with letrozole. Both small and medium-diameter sensory neurons isolated from letrozole-treated rats were more excitable, as reflected by increased action potential firing in response to a ramp of depolarizing current, a lower resting membrane potential, and a lower rheobase. However, systemic letrozole treatment did not augment the stimulus-evoked release of the neuropeptide calcitonin gene-related peptide (CGRP) from spinal cord slices, suggesting that the enhanced nociceptive responses were not secondary to an increase in peptide release from sensory endings in the spinal cord. These results provide the first evidence that AIs modulate the excitability of sensory neurons, which may be a primary mechanism for the effect of these drugs to augment pain behaviors in rats.Item Associations between Loneliness and Cancer Patients’ Pain and Fatigue(Office of the Vice Chancellor for Research, 2015-04-17) Stout, Madison E.; Adams, Rebecca N.; Mosher, Catherine E.Introduction: Pain and fatigue occur at higher rates in cancer patients than in the general population. One study found that loneliness predicted both pain and fatigue in cancer patients; however, the study only focused on patients with breast or colon cancer. The goal of the current study is to examine whether loneliness is associated with pain and fatigue in a sample of patients with various cancer types, including more rare diagnoses. We hypothesized that loneliness would be positively correlated with pain and fatigue, controlling for demographic and medical characteristics. Methods: Participants (N=44) were 60 years old (SD=12) on average, 68% Caucasian, and 59% female. All participants had received treatment for cancer at the Indiana University Simon Cancer Center or another Indiana University Hospital since 2013. Participants were recruited from the Indiana Tumor Registry, and after consenting, they were mailed a survey to complete at home that included measures of loneliness, pain, and fatigue. To test our hypothesis, we computed correlations between loneliness and each symptom (i.e., pain and fatigue), controlling for age, gender, and time since diagnosis. Results: As hypothesized, we found a large, positive correlation between loneliness and fatigue (r =0.51, p=0.001), controlling for demographic and medical characteristics. In addition, loneliness was positively correlated with pain, but this result fell just short of statistical significance (r=0.28, p=0.09). Conclusions: Results from this study suggest that greater loneliness is associated with greater fatigue in cancer patients, consistent with the results of one prior study. Although the association between loneliness and pain was more modest, it may reach statistical significance as the study sample size increases. If future longitudinal research shows that greater loneliness predicts cancer patients’ pain and fatigue, it would suggest that interventions to reduce loneliness may also reduce their physical symptoms.Item The AURORA Study: A Longitudinal, Multimodal Library of Brain Biology and Function after Traumatic Stress Exposure(Springer Nature, 2020-02) McLean, Samuel A.; Ressler, Kerry; Koenen, Karestan Chase; Neylan, Thomas; Germine, Laura; Jovanovic, Tanja; Clifford, Gari D.; Zeng, Donglin; An, Xinming; Linnstaedt, Sarah; Beaudoin, Francesca; House, Stacey; Bollen, Kenneth A.; Musey, Paul; Hendry, Phyllis; Jones, Christopher W.; Lewandowski, Christopher; Swor, Robert; Datner, Elizabeth; Mohiuddin, Kamran; Stevens, Jennifer S.; Storrow, Alan; Kurz, Michael Christopher; McGrath, Meghan E.; Fermann, Gregory J.; Hudak, Lauren A.; Gentile, Nina; Chang, Anna Marie; Peak, David A.; Pascual, Jose L.; Seamon, Mark J.; Sergot, Paulina; Peacock, W. Frank; Diercks, Deborah; Sanchez, Leon D.; Rathlev, Niels; Domeier, Robert; Haran, John Patrick; Pearson, Claire; Murty, Vishnu P.; Insel, Thomas R.; Dagum, Paul; Onnela, Jukka-Pekka; Bruce, Steven E.; Gaynes, Bradley N.; Joormann, Jutta; Miller, Mark W.; Pietrzak, Robert H.; Buysse, Daniel J.; Pizzagalli, Diego A.; Rauch, Scott L.; Harte, Steven E.; Young, Larry J.; Barch, Deanna M.; Lebois, Lauren A. M.; van Rooij, Sanne J. H.; Luna, Beatriz; Smoller, Jordan W.; Dougherty, Robert F.; Pace, Thaddeus W. W.; Binder, Elisabeth; Sheridan, John F.; Elliott, James M.; Basu, Archana; Fromer, Menachem; Parlikar, Tushar; Zaslavsky, Alan M.; Kessler, Ronald; Emergency Medicine, School of MedicineAdverse posttraumatic neuropsychiatric sequelae (APNS) are common among civilian trauma survivors and military veterans. These APNS, as traditionally classified, include posttraumatic stress, postconcussion syndrome, depression, and regional or widespread pain. Traditional classifications have come to hamper scientific progress because they artificially fragment APNS into siloed, syndromic diagnoses unmoored to discrete components of brain functioning and studied in isolation. These limitations in classification and ontology slow the discovery of pathophysiologic mechanisms, biobehavioral markers, risk prediction tools, and preventive/treatment interventions. Progress in overcoming these limitations has been challenging because such progress would require studies that both evaluate a broad spectrum of posttraumatic sequelae (to overcome fragmentation) and also perform in-depth biobehavioral evaluation (to index sequelae to domains of brain function). This article summarizes the methods of the Advancing Understanding of RecOvery afteR traumA (AURORA) Study. AURORA conducts a large-scale (n = 5000 target sample) in-depth assessment of APNS development using a state-of-the-art battery of self-report, neurocognitive, physiologic, digital phenotyping, psychophysical, neuroimaging, and genomic assessments, beginning in the early aftermath of trauma and continuing for 1 year. The goals of AURORA are to achieve improved phenotypes, prediction tools, and understanding of molecular mechanisms to inform the future development and testing of preventive and treatment interventions.Item CaMKII Controls Whether Touch Is Painful(Society for Neuroscience, 2015-10-21) Yu, Hongwei; Pan, Bin; Weyer, Andy; Wu, Hsiang-En; Meng, Jingwei; Fischer, Gregory; Vilceanu, Daniel; Light, Alan R.; Stucky, Cheryl; Rice, Frank L.; Hudmon, Andy; Hogan, Quinn; Department of Biochemistry & Molecular Biology, IU School of MedicineThe sensation of touch is initiated when fast conducting low-threshold mechanoreceptors (Aβ-LTMRs) generate impulses at their terminals in the skin. Plasticity in this system is evident in the process of adaption, in which a period of diminished sensitivity follows prior stimulation. CaMKII is an ideal candidate for mediating activity-dependent plasticity in touch because it shifts into an enhanced activation state after neuronal depolarizations and can thereby reflect past firing history. Here we show that sensory neuron CaMKII autophosphorylation encodes the level of Aβ-LTMR activity in rat models of sensory deprivation (whisker clipping, tail suspension, casting). Blockade of CaMKII signaling limits normal adaptation of action potential generation in Aβ-LTMRs in excised skin. CaMKII activity is also required for natural filtering of impulse trains as they travel through the sensory neuron T-junction in the DRG. Blockade of CaMKII selectively in presynaptic Aβ-LTMRs removes dorsal horn inhibition that otherwise prevents Aβ-LTMR input from activating nociceptive lamina I neurons. Together, these consequences of reduced CaMKII function in Aβ-LTMRs cause low-intensity mechanical stimulation to produce pain behavior. We conclude that, without normal sensory activity to maintain adequate levels of CaMKII function, the touch pathway shifts into a pain system. In the clinical setting, sensory disuse may be a critical factor that enhances and prolongs chronic pain initiated by other conditions. SIGNIFICANCE STATEMENT: The sensation of touch is served by specialized sensory neurons termed low-threshold mechanoreceptors (LTMRs). We examined the role of CaMKII in regulating the function of these neurons. Loss of CaMKII function, such as occurred in rats during sensory deprivation, elevated the generation and propagation of impulses by LTMRs, and altered the spinal cord circuitry in such a way that low-threshold mechanical stimuli produced pain behavior. Because limbs are protected from use during a painful condition, this sensitization of LTMRs may perpetuate pain and prevent functional rehabilitation.