1. A novel MRI diagnostic test for ischemic pain INTRODUCTION ► The peripheral physiological events responsible for cramps for most visceral pain conditions are unknown. ► Menstrual pain is an ideal visceral pain to study because patients can be scheduled at a time point when they anticipate severe spontaneous pain. ► In uterine pain such, as menstrual pain, there are reports of elevated levels of inflammatory cytokines, high-pressure uterine contractions, reduced vascular flow, ischemia and involuntary visceral-motor responses. However, the principal causes of uterine pain have yet to be determined much like other forms of visceral pain. ► There is an urgent need to understand which peripheral physiological phenomena (inflammatory cytokines, muscular contractions, mechanical sensitivity, vascular flow, tissue oxygenation, and involuntary abdominal muscle activity) primarily underlie visceral pain in both general and subtypes of uterine dysfunction. ► To develop new methods for evaluating visceral pain, we have instrumented human subjects with EMGs and performed MRI imaging during episodes of menstrual pain. ► Preliminary analyses were performed during the SPARK research experience to develop algorithms for building diagnostic tests. Methods ►Subjects (n=15) with menstrual pain, or healthy controls (n=3) were scheduled to participate during menses and on control non-menstrual day. ►Subjects were instrumented with EMG electrodes and were instructed to continuously report pain using a squeeze bulb. ►Sagittal MRI was performed while simultaneously recording EMG activity and bulb squeezes. ►EPI-BOLD movies(Flip Angle:90, FoV: 255*340, Echo: 30, Repeat: 2000, 10 minutes) were acquired in a Siemens Magnetom Verio 3T scanner to measure uterine oxygenation. ►HASTE movies (Flip Angle:150, FoV: 206*300, Echo: 80, Repeat: 2000, 10 minutes) were acquired to measure uterine contractility. ►90 minutes after Naproxen, an analgesic often effective for menstrual pain, subjects underwent a repeat episodes of scanning ►After the repeat scan, subjects were given supplemental oxygen at 10 liters/minute for 2 minutes ►ImageJ was used to quantify image intensity in regions of interest and compared to pain report using Microsoft Excel. CONCLUSIONS ► EPI-BOLD can measure reliably measure uterine oxygenation. (see panel 2) ► Episodes of transient uterine ischemia were associated more frequently before NSAIDs and more frequently on days with menstrual pain. (panel 5) ► Episodes of transient uterine ischemia were more often observed in women diagnosed with dysmenorrhea. (panel 5) ► Our results demonstrate that MRI can be used to diagnose the role of ischemia in visceral pain to facilitate development of therapeutics that ameliorate ischemia. 1. Diagram of MRI protocol Nathan A. Shlobin Evanston Hospital With assistance from Kevin Hellman (mentor), Wei Li, Gene, Eugene Dunkle, and Pottumarthi Prasad Naproxen 440 mg Repeat EPI-BOLD and HASTE sequence First EPI- BOLD and HASTE sequence Localize Uterus with MRI Start60 minutes 150 minutes Supplemental O 2 for validation 2. Supplemental O 2 increases EPI-BOLD signal, demonstrating that measurements indicate uterine oxygenation 4.Cyclical changes in EPI-BOLD signal were not observed on control days DysmenorrheaControl MensesNon-MensesMensesNon-Menses Before9/122/110/3 Repeat Scan/NSAIDS4/101/110/3 5. Transient episodes of uterine ischemia were observed more frequently in women in pain 3.Large cyclical changes in EPI-BOLD signal were often associated with cramps 10 minutes Acknowledgements: This research was supported by a pilot grant (NorthShore University HealthSystem) and the National Institute for Child and Human Development. References: Hallac, R. R., Ding, Y., Yuan, Q., McColl, R. W., Lea, J., Sims, R. D.,... & Mason, R. P. (2012). Oxygenation in cervical cancer and normal uterine cervix assessed using blood oxygenation level ‐ dependent (BOLD) MRI at 3T. NMR in Biomedicine, 25(12), 1321-1330. Kido, A., Koyama, T., Kataoka, M., Yamamoto, A., Saga, T., Turner, R., & Togashi, K. (2007). Physiological changes of the human uterine myometrium during menstrual cycle: preliminary evaluation using BOLD MR imaging. Journal of Magnetic Resonance Imaging, 26(3), 695-700.