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Research

Our research focuses on the role of sleep disturbances in the following intersecting areas:

  • Pain and pain processing
  • Inflammatory and inflammatory resolution processes.
  • Sexual differences in the prevalence of pain- and immune-related diseases.

Research Area Pain

Pain is one of greatest health burden across the United States and the world, with an estimated 20% of adults experiencing chronic pain. There is a continued urgent need to identify factors and mechanisms that contribute to pain development and persistence with the goal to stop the enormous impact on people’s life. Seventy-two percent of chronic pain patients suffer from insomnia. This high comorbidity is not surprising, given that pain is a powerful disruptor of sleep. But also, there is strong evidence that insomnia predisposes to the development of a wide range of diseases involving chronic pain, including headache disorders, musculoskeletal disorders, back/neck pain, autoimmune disorders, chronic infectious disorders, as well as post acute infections syndromes.

Our research:

  • Patients who fulfill criteria for insomnia experience pain twice as much, are much more sensitive to pain than good sleepers, and show abnormalities in central pain-modulatory pathways. Over time, such somatosensory changes are likely to transition into more severe pain states that impact quality of life and require pharmacological control. To better understand the mechanisms driving the sleep-pain relationship, we are using the controlled laboratory setting in the Clinical Research Center to mimic sleep disturbance patterns that are common in the general and clinical populations. For example, we expose healthy individuals to repeated nights of disrupted and shortened sleep with intermittent better sleep nights as frequently observed in pain populations, and assess changes in various pain domains, including spontaneous pain, sensitivity to evoked pain, and changes in central pain processing. See Simpson et al., 2018; Haack et al., 2023.
  • We are also investigating the sleep-pain relationship in individuals with Long COVID, using wearable and EEG-based sleep monitoring, to understand the role of sleep in pain severity and persistence in Long COVID. Both sleep disturbances and pain are frequently among the top 5 most common and debilitating symptoms reported by patients with Long COVID (NIH/NINDS R21NS128815).
  • We are investigating whether targeting inflammatory pathways, for example through acetylic salicylic acid, can reduce pain and pain processing changes as a consequence of sleep disturbances. The development of therapeutic targets that complement sleep improvement therapies are very much needed to better mitigate pain in insomnia, and, in the long term to prevent the transitioning into chronic pain states (NIH/NHLBI R01HL136310).

Research Area Inflammation

One of the cardinal signs of the acute inflammatory response to infection or tissue damage is pain, resulting from the activation of pro-inflammatory and proalgesic acting mediators that mainly derive from the NF-kB and cyclooxygenase (COX) pathways. Counter- and pro-resolving mediators come into play to limit and/or resolve inflammation and to promote the return to homeostasis. These include the specialized pro-resolving mediators (SPMs) that derive from diet-derived omega-3 and -6 fatty acids. Failure to adequately mount inflammatory resolution processes can result in unresolved inflammation. Almost all of these inflammatory mediators are dysregulated by disturbed sleep or sleep that is too short. Such inflammatory dysregulations are likely one mechanism through which disturbed or short sleep increases risk of the many disorders involving immunopathology. An improved understanding of the pathways and mediators activated by sleep disturbances can provide therapeutic targets aimed at preventing the many consequences of unresolved inflammation.

Our Research:

  • The exposure to experimental sleep disturbance patterns in the controlled laboratory setting leads to activation of multiple pathways involved in the generation and persistence of pain, including the NF-kB pathway, the cyclooxygenase (COX) pathway, and the central pain-modulatory pathways. See Besedovsky et al., 2019; Besedovsky et al., 2022; Haack et al., 2023. 
  • Prolonged experimental sleep disturbances in healthy humans profoundly downregulate certain inflammatory resolution mediators, in particular the D-series resolvins that derive from the Omega-3 fatty acid. This effect suggest that sleep disturbances may prevent the return to inflammatory homeostasis by compromising the resolution of inflammation. See Engert et al., 2023. Dr. Larissa Engert is currently investigating whether sleep disturbances contribute to dysregulation of inflammatory resolution pathways in Long COVID, funded by the Sleep Research Society  Foundation.
  • We are investigating whether pharmacologically targeting the inflammatory resolution pathways can mitigate the inflammatory consequences of sleep disturbances. We probing inflammation with low-dose acetylic acid, which has the ability to target multiple pro-inflammatory and inflammatory resolution pathways. NIH/NHLBI R01HL136310.

Research Area Sex

Numerous chronic diseases are characterized by a pronounced sexual dimorphism. The majority of individuals with chronic pain disorders are women. This is also true for autoimmune disorders and several post-acute infection syndromes, including Long COVID. Women also present with a disproportionate greater disease burden and experience symptoms as more severe and more persistent, including pain. Sleep disturbances are highly comorbid with chronic disease conditions and furthermore, they increase the risk for developing such conditions by up to 3-fold. There is emerging evidence that sleep disturbances may affect women and men differently in terms of symptom burden and pathways involved in pain initiation and persistence. While there is still a paucity of studies focusing on sex differences, this knowledge holds promise for more personalized and precision therapeutics that could complement classical sleep improvement therapies to more effectively manage pain, in particular in females.

Our Research:

  • The exposure to experimental sleep disturbances amplifies symptoms of pain and fatigue to a greater extent in females than males. Specifically, females need longer to recover from fatigue induced by disturbed sleep and consistently respond with greater severity of localized pain (e.g., headache, back pain), and non-localized widespread pain. Besedovsky et al., 2022; Olia et al., submitted.
  • Experimental sleep disturbances dysregulate inflammatory and central pain-modulatory pathways in a sex-dependent manner, suggesting that the mechanistic pathways through which sleep disturbances contributes to pain and other health-damaging effects are not the same for both sexes. Besedovsky et al 2022; Haack et al., 2023, Haack & Sethna, under review.
  • We are obtaining funding to specifically investigate sex differences in the biological consequences of sleep disturbances, to generate the knowledge needed for personalized therapeutics to better manage pain and stop the transitioning into chronic pain in the many women and men suffering from sleep disturbances.

Laboratory Collaborations

Dr. Janet Mullington, Professor of Neurology, Harvard Medical School, Department of Neurology, Beth Israel Deaconess Medical Center

Dr. Navil Sethna, Professor of Anesthesiology, Harvard Medical School, Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children’s Hospital

Dr. Charles Serhan, Simon Gelman Professor of Anesthesia (Biochemistry and Molecular Pharmacology), Harvard Medical School and Professor of Oral Medicine, Infection & Immunity, Harvard University

Dr. Suzanne Bertisch, Assistant Professor of Medicine, Harvard Medical School, Department of Sleep Medicine, Brigham Mass General.

Dr. Wolfgang Junger, Professor of Surgery, University of California San Diego.

Dr. Luciana Besedovsky, Professor, Institute of Medical Psychology, Ludwig-Maximillians University Munich Germany