Publications by Year: 2019
Mackey S, Greely HT, Martucci KT. Neuroimaging-based pain biomarkers: definitions, clinical and research applications, and evaluation frameworks to achieve personalized pain medicine. Pain Rep. 2019;4(4):e762.
One of the key ambitions of neuroimaging-based pain biomarker research is to augment patient and clinician reporting of clinically relevant phenomena with neural measures for prediction, prognosis, and detection of pain. Despite years of productive research on the neuroimaging of pain, such applications have seen little advancement. However, recent developments in identifying brain-based biomarkers of pain through advances in technology and multivariate pattern analysis provide some optimism. Here, we (1) define and review the different types of potential neuroimaging-based biomarkers, their clinical and research applications, and their limitations and (2) describe frameworks for evaluation of pain biomarkers used in other fields (eg, genetics, cancer, cardiovascular disease, immune system disorders, and rare diseases) to achieve broad clinical and research utility and minimize the risks of misapplication of this emerging technology. To conclude, we discuss future directions for neuroimaging-based biomarker research to achieve the goal of personalized pain medicine.
Martucci KT, MacNiven KH, Borg N, Knutson B, Mackey SC. Apparent Effects of Opioid Use on Neural Responses to Reward in Chronic Pain. Sci. Rep. 2019;9(1):9633.
Neural responses to incentives are altered in chronic pain and by opioid use. To understand how opioid use modulates the neural response to reward/value in chronic pain, we compared brain functional magnetic resonance imaging (fMRI) responses to a monetary incentive delay (MID) task in patients with fibromyalgia taking opioids (N = 17), patients with fibromyalgia not taking opioids (N = 17), and healthy controls (N = 15). Both groups of patients with fibromyalgia taking and not taking opioids had similar levels of pain, psychological measures, and clinical symptoms. Neural responses in the nucleus accumbens to anticipated reward and non-loss outcomes did not differ from healthy controls in either fibromyalgia group. However, neural responses in the medial prefrontal cortex differed, such that patients with fibromyalgia not taking opioids demonstrated significantly altered responses to anticipated rewards and non-loss outcomes compared to healthy controls, but patients with fibromyalgia taking opioids did not. Despite limitations including the use of additional non-opioid medications by fibromyalgia patients taking opioids, these preliminary findings suggest relatively “normalized” neural responses to monetary incentives in chronic pain patients who take opioids versus those who do not.
Rosenberg GM, Shearer EJ, Zion SR, et al. Implementation Challenges Using a Novel Method for Collecting Patient-Reported Outcomes After Injury. J. Surg. Res. 2019;241:277-284.
BACKGROUND: Monitoring longitudinal patient-reported outcomes after injury is important for comprehensive trauma care. Current methodologies are resource-intensive and struggle to engage patients. MATERIALS AND METHODS: Patients \$\geq\$18 y old admitted to the trauma service were prospectively enrolled. The following inclusion criteria were used: emergency operation, ICU length of stay \$\geq\$2 midnights, or hospital length of stay \$\geq\$4 d. Validated and customized questionnaires were administered using a novel internet-based survey platform. Three-month follow-up surveys were administered. Contextual field notes regarding barriers to enrollment/completion of surveys and challenges faced by participants were recorded. RESULTS: Forty-seven patients were eligible; 26 of 47 (55%) enrolled and 19 of 26 (73%) completed initial surveys. The final sample included 14 (74%) men and 5 (26%) women. Primary barriers to enrollment included technological constraints and declined participation. Contextual field notes revealed three major issues: competing hospital tasks, problems with technology, and poor engagement. The average survey completion time was 43 \$\pm\$ 27 min-21% found this too long. Seventy-four percent reported the system “easy to use” and 95% reported they would “very likely” or “definitely” respond to future surveys. However, 10 of 26 (38%) patients completed 3-mo follow-up. CONCLUSIONS: Despite a well-rated internet-based survey platform, study participation remained challenging. Lack of email access and technological issues decreased enrollment and the busy hospitalization posed barriers to completion. Despite a thoughtful operational design and implementation plan, the trauma population presented a challenging group to engage. Next steps will focus on optimizing engagement, broadening access to survey reminders, and enhancing integration into clinical workflows.
Swarm RA, Paice JA, Anghelescu DL, et al. Adult Cancer Pain, Version 3.2019, NCCN Clinical Practice Guidelines in Oncology. J. Natl. Compr. Canc. Netw. 2019;17(8):977-1007.
In recent years, the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Adult Cancer Pain have undergone substantial revisions focusing on the appropriate and safe prescription of opioid analgesics, optimization of nonopioid analgesics and adjuvant medications, and integration of nonpharmacologic methods of cancer pain management. This selection highlights some of these changes, covering topics on management of adult cancer pain including pharmacologic interventions, nonpharmacologic interventions, and treatment of specific cancer pain syndromes. The complete version of the NCCN Guidelines for Adult Cancer Pain addresses additional aspects of this topic, including pathophysiologic classification of cancer pain syndromes, comprehensive pain assessment, management of pain crisis, ongoing care for cancer pain, pain in cancer survivors, and specialty consultations.
Weber KA, Smith AC, Wasielewski M, et al. Deep Learning Convolutional Neural Networks for the Automatic Quantification of Muscle Fat Infiltration Following Whiplash Injury. Sci. Rep. 2019;9(1):7973.
Muscle fat infiltration (MFI) of the deep cervical spine extensors has been observed in cervical spine conditions using time-consuming and rater-dependent manual techniques. Deep learning convolutional neural network (CNN) models have demonstrated state-of-the-art performance in segmentation tasks. Here, we train and test a CNN for muscle segmentation and automatic MFI calculation using high-resolution fat-water images from 39 participants (26 female, average = 31.7 \$\pm\$ 9.3 years) 3 months post whiplash injury. First, we demonstrate high test reliability and accuracy of the CNN compared to manual segmentation. Then we explore the relationships between CNN muscle volume, CNN MFI, and clinical measures of pain and neck-related disability. Across all participants, we demonstrate that CNN muscle volume was negatively correlated to pain (R = -0.415, p = 0.006) and disability (R = -0.286, p = 0.045), while CNN MFI tended to be positively correlated to disability (R = 0.214, p = 0.105). Additionally, CNN MFI was higher in participants with persisting pain and disability (p = 0.049). Overall, CNN s may improve the efficiency and objectivity of muscle measures allowing for the quantitative monitoring of muscle properties in disorders of and beyond the cervical spine.
Aguiniga LM, Yang W, Yaggie RE, Schaeffer AJ, Klumpp DJ, Group MAPPRNS. Acyloxyacyl hydrolase modulates depressive-like behaviors through aryl hydrocarbon receptor. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2019;317(2):R289—R300.
Corticotropin-releasing factor (CRF) regulates stress responses, and aberrant CRF signals are associated with depressive disorders. Crf expression is responsive to arachidonic acid (AA), where CRF is released from the hypothalamic paraventricular nucleus (PVN) to initiate the hypothalamic-pituitary-adrenal axis, culminating in glucocorticoid stress hormone release. Despite this biological and clinical significance, Crf regulation is unclear. Here, we report that acyloxyacyl hydrolase, encoded by Aoah, is expressed in the PVN, and Aoah regulates Crf through the aryl hydrocarbon receptor (AhR). We previously showed that AOAH-deficient mice mimicked interstitial cystitis/bladder pain syndrome, a condition frequently associated with comorbid anxiety and depression. With the use of novelty-suppressed feeding and sucrose preference assays to quantify rodent correlates of anxiety/depression, AOAH-deficient mice exhibited depressive behaviors. AOAH-deficient mice also had increased CNS AA, increased Crf expression in the PVN, and elevated serum corticosterone, consistent with dysfunction of the hypothalamic-pituitary-adrenal axis. The human Crf promoter has putative binding sites for AhR and peroxisome proliferator-activated receptor (PPARγ). PPARγ did not affect AA-dependent Crf expression in vitro, and conditional Pparγ knockout did not alter the AOAH-deficient depressive phenotype, despite previous studies implicating PPARγ as a therapeutic target for depression. In contrast, Crf induction was mediated by AhR binding sites in vitro and increased by AhR overexpression. Furthermore, conditional Ahr knockout rescued the depressive phenotype of AOAH-deficient mice. Finally, an AhR antagonist rescued the AOAH-deficient depressive phenotype. Together, our results demonstrate that Aoah is a novel genetic regulator of Crf mediated through AhR, and AhR is a therapeutic target for depression.
Ackerman L, Anger JT, Khalique MU, et al. Optimization of DNA extraction from human urinary samples for mycobiome community profiling. PLoS One. 2019;14(4):e0210306.
INTRODUCTION: Recent data suggest the urinary tract hosts a microbial community of varying composition, even in the absence of infection. Culture-independent methodologies, such as next-generation sequencing of conserved ribosomal DNA sequences, provide an expansive look at these communities, identifying both common commensals and fastidious organisms. A fundamental challenge has been the isolation of DNA representative of the entire resident microbial community, including fungi. MATERIALS AND METHODS: We evaluated multiple modifications of commonly-used DNA extraction procedures using standardized male and female urine samples, comparing resulting overall, fungal and bacterial DNA yields by quantitative PCR. After identifying protocol modifications that increased DNA yields (lyticase/lysozyme digestion, bead beating, boil/freeze cycles, proteinase K treatment, and carrier DNA use), all modifications were combined for systematic confirmation of optimal protocol conditions. This optimized protocol was tested against commercially available methodologies to compare overall and microbial DNA yields, community representation and diversity by next-generation sequencing (NGS). RESULTS: Overall and fungal-specific DNA yields from standardized urine samples demonstrated that microbial abundances differed significantly among the eight methods used. Methodologies that included multiple disruption steps, including enzymatic, mechanical, and thermal disruption and proteinase digestion, particularly in combination with small volume processing and pooling steps, provided more comprehensive representation of the range of bacterial and fungal species. Concentration of larger volume urine specimens at low speed centrifugation proved highly effective, increasing resulting DNA levels and providing greater microbial representation and diversity. CONCLUSIONS: Alterations in the methodology of urine storage, preparation, and DNA processing improve microbial community profiling using culture-independent sequencing methods. Our optimized protocol for DNA extraction from urine samples provided improved fungal community representation. Use of this technique resulted in equivalent representation of the bacterial populations as well, making this a useful technique for the concurrent evaluation of bacterial and fungal populations by NGS.
Barad M, Sturgeon JA, Fish S, Dexter F, Mackey S, Flood PD. Response to BotulinumtoxinA in a migraine cohort with multiple comorbidities and widespread pain. Reg. Anesth. Pain Med. 2019;44(6):660-668.
BACKGROUND: The phase III research evaluating migraine prophylaxis therapy (PREEMPT) protocol was developed in low-risk migraine patients. We studied longitudinal response to treatment in a sequential retrospective observational cohort to evaluate predictors of effectiveness in patients with multiple overlapping pain syndromes treated in a quaternary pain management clinic. METHODS: We evaluated indicators of individual response in 402 consecutive chronic migraine patients who provided demographic information and used the Collaborative Health Outcomes Information Registry. RESULTS: The patients were middle aged 47 (38-56) median (IQR) years old and 83% women. They reported multiple complex pain problems with 11 (6-18) regions represented on a pain body map. Evaluated with National Institutes of Health Patient-Reported Outcomes Measurement Information System measures, they reported higher scores for sleep impairment and disturbance, anxiety, depression, fatigue, pain behavior, pain interference and worse function and satisfaction with social roles compared with the general US population; p\textless0.001 for all domains. Within 120 days of treatment, 62% of patients reported reduced headache frequency. The best multivariable model developed for prediction of reduced headache frequency in response to treatment included lower treatment number, lower pain interference score, and less depression (p=0.001, 0.002, and 0.009). Depression may have been an obstacle to successful treatment; there was no association between depression score and number of treatments (p=0.54). CONCLUSIONS: Our findings point to the importance of identifying and addressing pain interference and depression early in chronic migraine management and, more broadly, highlights the importance of multidisciplinary evaluation and treatment in chronic migraine.