Kevin M Hellman , PhD

BS, Computer Science, University of Wisconsin-Madison
PhD, Neuroscience, The University of Pennsylvania
Postdoctoral Scholar, The University of Chicago

     I am the principal investigator of an NIH funded grant that studies the physiology and treatment of women's health conditions. Dysmenorrhea, period pain, is the leading cause of school/work absence and foremost risk factor for chronic visceral pain in reproductive aged women. Our laboratory has developed new animal models, investigated novel diagnostic methods, and conducted treatment studies. My goal is to systematically define the pathophysiology of dysmenorrhea and develop new treatments, while simultaneously training a cadre of future investigators to revolutionize the study of visceral pain. Our research is essential because there are few other laboratories dedicated to eradicating dysmenorrhea, one of the most frequent causes of suffering and gender disparity worldwide. Our recent review article on dysmenorrhea http://doi.org/10.1016/j.ajog.2017.08.108  was reading for board recertification and provides a roadmap for developing effective treatments for menstrual pain.  

See our lab website http://cureperiodpain.org for more information

Chronic visceral pelvic pain disorders cause substantial morbidity and cost upwards of 50 billion dollars in lost US wages and health care expenditures.Visceral pelvic pain conditions, such as endometriosis-associated pelvic pain, irritable bowel syndrome, bladder pain syndrome, are common (~25% prevalence in women), but predictable and may be preventable. The causes of visceral pain are poorly understood because diagnostic tests do not exist to distinguish pain due to primary nociceptor activation, referred abdominal muscular activity, organ perfusion, and oxygenation issues. Development of effective treatments for disruptive chronic pelvic pain conditions like dysmenorrhea and bladder pain syndrome are hindered by this lack of mechanistic understanding.

To address these limitations, I joined NorthShore University HealthSystem and created the Gynecological Research Laboratory (GyRL). Dr. Frank Tu is my primary collaborator (and also a minimally invasive surgeon specializing in pelvic pain). Dr. Tu’s expertise has been vital for recruiting and examining over 500 participants, interpreting anatomical ultrasound/MRI findings and bridging the translational science I have conducted in the GyRL. My expertise in basic pain research, computational analytical methods, paradigms for studying spontaneous pain and the science of electrophysiology was essential for the development of robust assessment of the physiological bases for pelvic pain. The innovation of my work requires clinical phenotyping to complement my research methodology and statistical modeling and this combination has been essential to discovering novel insights into female pelvic pain.

I have developed a method to study visceral pain by noninvasively evaluating physiological factors while simultaneously assessing spontaneous pain. This approach has led to the identification of how uterine and non-uterine components contribute to menstrual pain. There are few other laboratories dedicated to eradicating dysmenorrhea, one of the most frequent causes of suffering and gender disparity worldwide. Early attention to pain evolution is essential if we are to transform current, antiquated tertiary care paradigms in chronic pain management, including opioid use, which have produced the worst health epidemic of the decade.  

1. Systematic definition of the mechanisms responsible for menstrual cramping pain:“Why are girls still missing so many days because of their menstrual cycle?”-Michelle Obama tweeting on barriers to girl’s education in 2016.  As highlighted by the former First Lady, a hidden, personal, and painful reality of many women is severe, gut-wrenching menstrual cramps occurring every 3-5 minutes for several days each month. This misery is a leading cause of missed school and work. These cramps are hallmarks of dysmenorrhea and are not sufficiently relieved by nonsteroidal anti-inflammatories (NSAIDs) in roughly 15% of reproductive age women. My analysis of over 1000 adult women found that the severity of dysmenorrhea along with self-report of sensory sensitivity predict nearly 75% of the participants who experience high levels of overall pelvic pain (odds ratio:13).   Thus, developing effective treatments for menstrual pain is imperative to reducing gender disparity and chronic pelvic pain.

              However, scientific demonstration of the mechanisms responsible for menstrual pain remains limited by in vitro methods, irrelevant models, or failure to use precise methods to assess contractility, perfusion, oxygenation, and pain. Therefore, to address this limitation, I developed novel methods for clarifying the mechanisms responsible for menstrual cramps.

              a. I developed an in vivo mouse model to clarify the pathophysiological mechanisms responsible for dysmenorrhea and to allow for the testing of new therapeutics. My model allowed us to characterize the effects of candidate molecules while simultaneously using novel optical methods to monitor uterine perfusion and oxygenation (Exp pub#2). Our model demonstrated that prostaglandin and Platelet Activating Factor (PAF) could directly elicit visceral pain and pelvic hyperalgesia via uterine hypercontractility and uterine ischemia. These results challenged the dogma that uterine ischemia never occurs. Furthermore, since PAF is not inhibited by NSAIDS it represents a new potential druggable target for NSAID-resistant dysmenorrhea. This animal model provided the fundamental conceptual foundation for the mechanisms (inflammation, contractility and ischemic pain) underlying menstrual pain that I subsequently tested in humans as described below.

              b. I have developed novel MRI and pain testing methods for clarifying pathophysiological mechanisms responsible for dysmenorrhea in humans. The use of invasive methods to study dysmenorrhea (e.g., intrauterine catheters and tissue biopsy) inherently confounds understanding of the mechanisms underlying pain and has limited utility for clinic-based diagnostic tests. In addition, I recognized a key gap in the dysmenorrhea research field was a lack of attention to the temporal relationship between myometrial activity and pain. Improving on these study design limitations was a key focus, as spontaneous cramps are the primary phenomenon reported by dysmenorrhea sufferers. Discerning the temporal relationship between the perception of pain and uterine physiological changes is also essential for establishing causality. To clarify whether myometrial contractile-induced ischemia is responsible for cramping symptoms, I developed a real-time method for monitoring spontaneous pain with fMRI. In this paradigm participants were instructed to squeeze a bulb every time they felt a severe menstrual cramp. Simultaneously, acquired pelvic MRI signals demonstrated that decreases in myometrial signal occurred either coincident with pain report or 30-70 seconds before. The location and directionality of signal change and its temporal relationship to pain onset lead me to hypothesize that cramping pain results from a combination of uterine pressure and hemodynamic dysfunction. My study is unique in demonstrating the underlying physiology in an internal pelvic organ, time-locked to the report of spontaneous pain. Thus, as a new technical method it holds promise as a technique for identifying the cause of pelvic pain and other visceral pain disorders that are amenable to fMRI interrogation.  

              c. I further adapted this method of studying spontaneous cramping to identify neurological mechanisms responsible for referred pelvic pain, which could allow for clinical phenotyping of dysmenorrhea. By evaluating the relationship between abdominal muscle activity and spontaneous pain, I was able to provide evidence linking distinct abdominal muscle activity to reported spontaneous cramps in primary dysmenorrhea.  In contrast, women with chronic pelvic pain were less likely to have abdominal muscle activity preceding cramping pain, had widespread mechanical hypersensitivity and responded poorly to naproxen. The phenotyping methods described in this manuscript provide a strategy for characterizing nociceptive mechanisms in cyclical uterine pain and may ultimately predict treatment responsiveness.

2. Development of novel paradigm to prevent the transition to chronic pelvic pain. To extend my work on menstrual pain, I have extensively collaborated with Dr. Frank Tu. His clinical expertise in chronic pelvic pain and experience in quantitative sensory testing and my background in basic pain research has resulted in a research program that studies women with dysmenorrhea at risk for the development of chronic pelvic pain.   

              a. Dr. Tu and I validated a noninvasive bladder task that can identify participants with enhanced visceral sensitivity prior to the development of chronic pelvic pain. Since treatments for chronic pelvic pain have low efficacy, it is critical to develop prevention methods. A first step would be to identify at-risk women for prevention trials.  The prior use of invasive visceral tasks (such as colorectal distension) had greatly limited research because it deterred participation and was vulnerable to fear-related factors. Therefore, Dr. Tu developed a noninvasive task in which women are asked to promote diuresis by drinking water, followed by structured measurement of their level of bladder pain as their bladder fills, with serial monitoring of this process with ultrasonography. Together, we performed additional experiments, and I performed the necessary analyses for validation of these findings to confirm my hypothesis that women with dysmenorrhea are more likely to have bladder sensitivity. We have confirmed our original novel finding that a subset of women with severe dysmenorrhea (~25%) have significant bladder pain (even off menses) without having any symptomatology resembling chronic pelvic pain . We have also validated our task and shown that it is less confounded by psychological factors than even questionnaire methods .The development and validation of this bladder task has led to its use as a tool for identifying preventable factors responsible for the transition from episodic menstrual pain to chronic pelvic pain. This task serves as the foundation for our NIH-funded chronic pelvic pain prevention program, and a variation has been adapted for the six site NIDDK U01 research program, “Multi-Disciplinary Approach to the Study of Chronic Pelvic Pain.”

              b. Dr. Tu and I have demonstrated that multisensory hypersensitivity, independent of anxiety and depression, is a key predictor of visceral pain, but not dysmenorrhea. Multisensory hypersensitivity (also known as somatization) was associated with pelvic pain in our studies .Conversely, the role of somatization in dysmenorrhea has been overemphasized— we have confirmed this by demonstrating clear peripheral mechanisms that overshadow limited psychosomatic mechanisms.Furthermore, the implication that psychosomatic factors solely underlie the chronic pain experience is often regarded as offensive by patients, and can represent a major barrier to promoting biopsychosocial treatments. Clearly, the role of somatization in pain is an important problem and these observations have generated a great deal of interest from clinicians with requests for grand rounds presentations from all of the major psychology and psychiatry programs in Chicago.

              c. Dr. Tu and I have also established a simple, physical exam-centered, risk factor for pelvic pain. Women with pelvic pain have a combination of lower mechanical stimulation thresholds and increased duration of afterpain. Our results imply that if clinicians could consistently document pelvic floor tenderness ratings, along with recording the presence of prolonged pain following pelvic exam (>5 minutes), vulnerable subgroups of women could be identified for prospective trajectory studies of future pelvic pain risk. The response threshold and afterpain differences imply that two different alterations may occur in chronic pelvic pain. The decrease in mechanical thresholds likely reflects increased excitability (i.e., sensitization) in peripheral mechanically-sensitive class A-fibers (which respond on a rapid time scale) responsible for perception of “first pain”. In contrast, our observed aftersensation differences point to aberrant C-fiber activity, which typically relays information in response to noxious or extreme temperature stimuli. These C fibers are primarily implicated in sustained perception of noxious stimuli, a phenomenon labeled “second pain.” As each class of fibers are differentially modulated by given treatment modalities (A-fibers are preferentially blocked by compression/ischemia, while C-fiber activity is reduced by DMSO or anticonvulsants), this suggests future confirmatory studies of these mechanistic classifications to determine if certain groups selectively respond to physical therapy (A-fiber predominant) vs. neuromodulating drugs (C-fiber predominant).

• 1994: Frank Academic Scholar
• 1995: University of Wisconsin Honor Society
• 1997: Neuroscience Training Program award for Outstanding Research in Neurobiology
• 2000: National Institute of Health, National Research Service Award
• 2004: Elliot Stellar Scholar
• 2004: U.W. Madison Neuropsychology Travel Fellowship
• 2006: American Academy of Sleep Medicine Faculty Research Award
• 2012: Best abstract on pelvic pain, AAGL Global Congress
• 2012: Honorable mention poster award, International Pelvic Pain Society
• 2013: Best abstract on pelvic pain, AAGL Global Congress
• 2013: Best poster award, International Pelvic Pain Society
• 2014: New investigator of the year, NorthShore University HealthSystem
• 2016: Spotlighted abstract, Society for Affective Science
• 2017: Best paper award, Chicago Gynecological Society
• 2018: Faculty of 1000 recommended paper: Nonsteroidal antiinflammatory drug resistance in dysmenorrhea: epidemiology, causes, and treatment. 
• 2019: Poster Award: International Association for the Study of Pain—Abdominal and Pelvic Pain SIG

• Society for Reproductive Investigation (formerly SGI)
• American Academy of Sleep Medicine
• Society for Neuroscience
• Faculty of 1000
• International Pelvic Pain Society
• International Association for the Study of Pain 

Peer-reviewed scientific publications in the primary literature, exclusive of abstracts :

1. Lytton WW, Hellman KM, Sutula TP. Computer models of hippocampal circuit changes of the kindling model of epilepsy. (1998) Artificial Intelligence in Medicine. 13(1-2):81-97.  http://dx.doi.org/10.1016/S0933-3657(98)00005-0

2. Graves LA, Hellman KM, Veasey S, Blendy JA, Pack AI, Abel T. Genetic Evidence for a Role of CREB in Sustained Cortical Arousal. (2003) Journal of Neurophysiology 90(2):1152-9. http://jn.physiology.org/cgi/content/full/90/2/1152

3. Ouyang M, Hellman KM, Abel T, Thomas SA. Adrenergic Signaling Plays a Critical Role in the Maintenance of Waking and in the Regulation of REM Sleep. (2004) Journal of Neurophysiology. 92(4):2071-82 http://jn.physiology.org/cgi/content/full/92/4/2071

4. Keeley MB, Wood MA, Isiegas C, Stein J, Hellman KM, Hannenhalli S, Abel T. Differential Transcriptional Response to Non-Associative and Associative Components of Classical Fear Conditioning in the Amygdala and Hippocampus. (2006) Learning and Memory 13(2):135-42.  http://learnmem.cshlp.org/content/13/2/135.long

5. Brink TS, Hellman KM, Lambert AM, Mason P.  Raphe magnus neurons help protect reactions to visceral pain from interruption by cutaneous pain. (2006) Journal of Neurophysiology 96(6):3423-32. http://jn.physiology.org/cgi/content/full/96/6/3423

6. Hellman KM, Abel T.  Fear Conditioning Increases NREM sleep. (2007) Behavioral Neuroscience 121(2):310-323. http://psycnet.apa.org/journals/bne/121/2/310.pdf

7. Hellman KM, Brink TS, Mason P.  Activity of murine raphe magnus cells predicts tachypnea and on-going nociceptive responsiveness. (2007) Journal of Neurophysiology 98(6):3121-33.  http://jn.physiology.org/cgi/content/full/98/6/3121

8. Hellman KM, Mendelson SJ, Mendez-Duarte MA, Russell JL, Mason P. Opioid microinjection into raphe magnus modulates cardiorespiratory function in mice and rats. (2009) American Journal of Physiology 297(5): R1400-8 http://ajpregu.physiology.org/cgi/reprint/00140.2009v1.pdf

9. Hellman KM, Hernandez P, Young A, Park A, Abel T. Genetic Evidence that Protein Kinase A Regulates Thalamocortical Oscillations during NREM Sleep. (2010) Sleep 33(1):19-28. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2802244/

10. Tu FF, Hellman KM, Backonja M.   Gynecological Management of Neuropathic Pain. (2011) American Journal of Obstetrics & Gynecology 205(5):435-43. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3205239/

11. Hellman KM, Mason P. Opioids disrupt pro-nociceptive modulation mediated by raphe magnus. (2012) Journal of Neuroscience 40:13668-78. http://www.jneurosci.org/content/32/40/13668.long

12. Tu FF, Epstein AE, Pozolo KE, Sexton DL, Melnyk AI, Hellman KM. A Non-Invasive Bladder Sensory Test Supports a Role for Dysmenorrhea Increasing Bladder Noxious Mechanosensitivity.  (2013) Clinical Journal of Pain 29(10):883-90. http://dx.doi.org/10.1097/AJP.0b013e31827a71a3

13. Westling AM, Tu F, Griffith JW, Hellman KM. The association of dysmenorrhea with noncyclic pelvic pain accounting for psychological factors. (2013) American Journal of Obstetrics & Gynecology 209(5): 422.e1-422.e10  http://dx.doi.org/10.1016/j.ajog.2013.08.020

14. Hellman KM, Patanwala IY, Pozolo KE, Tu FF. Multimodal nociceptive mechanisms underlying chronic pelvic pain. (2015) American Journal of Obstetrics & Gynecology 213(6):827.e1-9. http://dx.doi.org/10.1016/j.ajog.2015.08.038

15. Tu FF, Kane J, Hellman KM. Non-invasive experimental bladder pain assessment in painful bladder syndrome. (2016) British Journal of Obstetrics & Gynecology 124(2):283-291. http://dx.doi.org/10.1111/1471-0528.14433     

16. Hellman KM, Yu PY, Oladosu, FA Segel C, Han A, Prasad PV, Jilling T, Tu FF. The Effects of Platelet-Activating Factor on Uterine Contractility, Perfusion, Hypoxia, and Pain in Mice. (2017) Reproductive Sciences 25(3):384-394 http://doi.org/10.1177/1933719117715122

17. Oladosu FA, Tu FF, Hellman KM. Nonsteroidal antiinflammatory drug resistance in dysmenorrhea: epidemiology, causes, and treatment. (2017) American Journal of Obstetrics & Gynecology 218(4):390-400 http://doi.org/10.1016/j.ajog.2017.08.108

18. Hellman KM, Kuhn CS, Tu FF, Dillane KE, Shlobin NA, Senapati S, Zhou X, Li W, Prasad PV. CINE MRI During Spontaneous Cramps in Women with Menstrual Pain. (2018) American Journal of Obstetrics & Gynecology. 218(5):506.e1-506.e8       http://doi.org/10.1016/j.ajog.2018.01.035

19. Zuckerman RM, Silton RL, Tu FF, Eng JS, Hellman KM. Somatic Symptoms in Women with Dysmenorrhea and Noncyclic Pelvic Pain. Archives of Women’s Mental Health. (2018).   http://doi.org/10.1007/s00737-018-0823-4

20. Hellman KM, Datta A, Steiner ND, Kane J, Garrison EF, Clauw DJ, Tu FF. Identification of experimental bladder sensitivity among dysmenorrhea sufferers. (2018) American Journal of Obstetrics & Gynecology. 219(1):84.e1-84.e8.http://doi.org/10.1016/j.ajog.2018.04.030     

21. Oladosu FA,Tu FF, Farhan S, Garrison EF, Steiner ND, Roth GE, Hellman KM. Abdominal skeletal muscle activity precedes spontaneous menstrual cramping pain in primary dysmenorrhea (2018) American Journal of Obstetrics & Gynecology. 219(1):91.e1-91.e7.http://doi.org/10.1016/j.ajog.2018.04.050

22. Oladosu FA, Hellman KM, Ham PJ, Kochlefl L, Datta A, Garrison EF, Steiner ND, Roth GE, Tu FF. Persistent autonomic dysfunction and bladder sensitivity in primary dysmenorrhea (2019) Scientific Reports 18;9(1):2194. http://doi.org/10.1038/s41598-019-38545-3

23.Tu FF, Datta A, Atashroo D, Senapati S, Roth G, Clauw D,Hellman KM. Clinical Profile of Comorbid Dysmenorrhea and Bladder Sensitivity: A Cross-Sectional Analysis. (2020) American Journal of Obstetrics & Gynecology.  http://10.1016/j.ajog.2019.12.010

24. Oladosu FA, Tu FF, Garfield LB, Garrison EF, Steiner ND, Roth GE, Hellman KM. Low serum oxytocin concentrations are associated with painful menstruation. (2020) Reproductive Sciences. 27(2):668-674.  http://doi.org/10.1007/s43032-019-00071-y

25. Hellman KM, Roth GE, Dillane, KE, Garrison EF, Clauw D, Tu FF. Dysmenorrhea subtypes exhibit differential quantitative sensory assessment profiles. (2020) PAIN. 161(6):1227-1236.http://doi.org/10.1097/j.pain.0000000000001826

26. Oladosu FA, Tu FF, Garrison EF, Dillane, KE, Roth GE, Hellman KM. Low Serum Naproxen Concentrations Are Associated With Minimal Pain Relief: A Preliminary Study in Women With Dysmenorrhea. (2020) Pain Medicine. http://doi.org/10.1093/pm/pnaa133

27. Kantarovich D, Vollbrecht HB, Cruz SA, Castillo H, Lee CS, Kushner J, Leng JX, Morgan VK, Hellman KM. Wikipedia: A Medical Student Educational Project to Edit Wikipedia in Preparation for Practicing Evidence-Based Pain Medicine. (2020) Journal of Medical Education and Curricular Development. https://doi.org/10.1177%2F2382120520959691

28. Britto K, Shilpa I, Hellman KM, Laveaux S.  Racial Distribution and Characterization of Pelvic Organ Prolapse in a Hospital-Based Subspecialty Clinic. Female Pelvic Medicine & Reconstructive Surgery. (2021) Female Pelvic Medicine & Reconstructive Surgery 27.3: 147-150. https://doi.org/10.1097/SPV.0000000000001016

29. Wilson SH, Hellman KM, James D, Adler AC, Chandrakantan A.  Mechanisms, diagnosis, prevention and management of perioperative opioid-induced hyperalgesia. (2021) Pain Management  11(4):405-417. https://doi.org/10.2217/pmt-2020-0105

30. Tu FF, Hellman KM, Roth GE, Dillane KE, Walker LS. Noninvasive bladder testing of adolescent females to assess visceral hypersensitivity. (2021) Pain. In press https://doi.org/10.1097/j.pain.0000000000002311

31. Hellman KM, Oladosu FA, Garrison EF, Dillane, KE, Roth GE, Tu FF. Circulating sex steroids and bladder pain sensitivity in dysmenorrhea (2021). Molecular Pain. In press

32. Kmiecik MJ, Tu FF, Silton RL, Dillane KE, Roth GE, Harte SE, Hellman KM.  Cortical Mechanisms of Visual Hypersensitivity in Women at Risk for Chronic Pelvic Pain. (2021) Pain. In press  https://doi.org/10.1101/2020.12.03.20242032

Letter, commentaries and editorials

1. Mason P, Hellman KM review of Changes in expression of NMDA-NR1 receptor subunits in the rostral ventromedial medulla modulate pain behaviors. Faculty of 1000: http://f1000.com/prime/6657956

2. Mason P, Hellman KM review of Acetate causes alcohol hangover headache in rats. Faculty of 1000: http://f1000.com/prime/8249956

3. Mason P, Hellman KM review of Unmasking the tonic-aversive state in neuropathic pain. Faculty of 1000: http://f1000.com/prime/1168048

4. Hellman KM, Summary of relevant findings at SFN 2016. Pelvic Pain Special Interest Group Newsletter (January 2016)

5. Hellman KM, Tu FF, Reply to Ruan et al.  Multimodal nociceptive mechanisms underlying chronic pelvic pain. American Journal of Obstetrics & Gynecology, Volume 215, Issue 1, 132 – 133. http://dx.doi.org/10.1016/j.ajog.2016.02.051

6. Hellman K, Tu F,  Primary Dysmenorrhea: Diagnosis and Therapy. Obstetrics & Gynecology. (2021) 137(4):752. https://doi.org/10.1097/aog.0000000000004341