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Trans-NIH Sleep/Pain Workshop Summary: Contribution of Sleep Disturbances to Chronic Pain

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May 29–30, 2014
Sponsored by the National Institutes of Health (NIH)
Spearheaded by the National Center for Complementary and Alternative Medicine (NCCAM)
William H. Natcher Conference Center
Bethesda, MD

On this page:

Preface

NIH thanks the workshop Co-chairs, Discussant Leaders, and Panel Members, who worked closely with NIH staff to shape the workshop in advance and contributed their expertise, insights, and time during the workshop. NCCAM also appreciates the intellectual contributions from across NIH and the financial contributions that enabled invited investigators to attend the workshop.

This workshop was dedicated to Harvey Moldofsky, M.D.

Ellen O’Donnell, science writer in the NCCAM Office of Communications, provided an initial summary. D. Lee Alekel, Ph.D., Program Director in the NCCAM Division of Extramural Research, led the writing of the final summary, and the Co-chairs, Discussant Leaders, and Panel Members, as well as members of the Trans-NIH Steering Committee, reviewed it.

The statements, conclusions, and recommendations contained in this document reflect individual and collective opinions of meeting participants and are not intended to represent the official position of NIH or the U.S. Department of Health and Human Services.

Introduction

Purpose

To foster greater collaboration between sleep and pain investigators to conduct cross-cutting research on the sleep/pain interaction, especially how sleep disturbances impact chronic pain.

Meeting Objectives

The charge to the workshop participants was to identify:

  • Mechanistic gap areas/questions on neurobiological systems that operate in sleep and pain and their convergence to exacerbate or reduce pain
  • Clinical gap areas/questions focused on
    • Experimental design and methodology, within the context of particular populations
    • Mediators and mechanisms
    • Pharmacologic and nonpharmacologic interventions, particularly the possibility that alleviating sleep disturbances might reduce chronic pain.

Rationale for the Workshop

Preliminary evidence exists for a bidirectional causal relationship between sleep disturbance and pain, but the nature of the relationship is not well understood. There is epidemiologic, basic, and clinical evidence for this interaction, but research is needed to develop a translationally meaningful understanding of how poor sleep impacts pain.

Workshop Structure

Discussant Leaders provided context, posed an initial set of key questions believed to represent knowledge gaps, and facilitated discussion. For the purposes of this summary, Session 1 has been designated as Part I, the closely related Sessions 2 and 3 were combined and designated as Part II, and Session 4 as Part III.

Workshop Process

To address the stated purpose, invited investigators and NIH scientists engaged in roundtable discussions, responded to the initial key questions, and identified additional questions for future research. In the process, participants sought to achieve the overall purpose of fostering greater collaboration between sleep and pain investigators to conduct cross-cutting research on the interaction between sleep and pain, particularly how sleep disturbances impact chronic pain. The writing team identified the most important themes that emerged from the workshop and is using them to create a framework for possible future funding opportunity announcements. As a follow-up, NIH staff will encourage additional research on sleep and pain.

Executive Summary

The purpose of the Trans-NIH Sleep/Pain Workshop was to foster greater collaboration between sleep and pain investigators to conduct cross-cutting research on sleep/pain interactions, particularly how sleep disturbances impact chronic pain. The objectives were to identify:

  • Mechanistic gap areas/questions on neurobiological systems that operate in sleep and pain, and their convergence to exacerbate or reduce pain
  • Clinical gap areas/questions focused on
    • Experimental design and methodology, within the context of particular populations
    • Mediators and mechanisms
    • Potential pharmacologic and nonpharmacologic interventions, particularly the possibility that alleviating sleep disturbances may reduce chronic pain.

Workshop participants summarized the state of the science, identified numerous knowledge gaps and major themes, and recommended research approaches.

Strong clinical evidence confirms an interaction between sleep and pain, whereas emerging evidence indicates that sleep disturbances predict chronic pain. However, little is known about the mechanisms that underlie the nature of that interaction or its clinical significance. To better understand neurobiological systems and mechanisms, investigators should consider factors that protect against and/or exacerbate sleep disturbances and chronic pain. Substantial challenges include the diversity of sleep disturbances/disorders and chronic pain conditions, their many overlaps and comorbidities, and the limitations of preclinical models. These two overlapping fields need greater standardization in methods and measurements. How sleep loss contributes to circadian misalignment and how it impacts pain processing should also be studied.

Racial, ethnic, and cultural variations in pain have long been recognized, but in sleep are just being examined. Studies typically focus on adults, but both sleep disturbances and pain also affect special populations, such as children, adolescents, and older adults. Less is known about which sleep interventions are efficacious for adolescents compared with younger children. Most experimental and clinical studies of sex differences in pain sensitivity have not included measures of sleep. Because women have a higher incidence of chronic pain and develop greater widespread pain than men, studying both male and female model organisms is essential.

Knowledge of the cells, systems, pathways, and genetic and molecular mechanisms operating at the interface of sleep and pain could lead to discovery of novel, or augment existing, nonpharmacologic and pharmacologic treatment approaches. Biomarkers should be developed to help identify the risk, serve as novel treatment-modified outcome measures, and represent targets for interventions. Cognitive-behavioral therapy (CBT) and complementary approaches1 could be further developed, perhaps in conjunction with pharmacologic approaches, to alleviate sleep disturbances and consequent pain. Current drugs that improve sleep improve pain as well, in at least one but not all pain conditions. Yet, pharmacologic (as well as nonpharmacologic) interventions should be tailored to the particular condition and target population. Treatments that can transition from testing to delivery relatively quickly, are safe and low-cost, and are effective in real-world settings are critically needed.

Part I: Participants identified the following as mechanistic knowledge gaps:

  1. Does sleep disruption increase pain and does pain disrupt sleep? If so, how? What parts of the peripheral nervous system (PNS) or central nervous system (CNS) are involved?
  2. Do the neuronal/glial systems that contribute to pain also mediate sleep dysfunction?
  3. Do the neurotransmitters and receptors involved in pain also mediate sleep?
  4. Does the immune system modulate the excitability of neurons involved in sleep and pain? Is it involved in sleep/pain interactions?
  5. Does sleep disruption affect pain in general, or do its effects differ for different types of pain (e.g., nociceptive, inflammatory, neuropathic, and chronic-widespread)?
  6. What neurobiological mechanisms related to sleep disruption contribute to the chronicity of pain?
  7. What are the heritable contributors to sleep/pain interactions, and which genes are involved?

Part II: Participants identified the following as clinical knowledge gaps:

  1. In longitudinal studies, which sleep parameters (e.g., quality, continuity, architecture, and/or microstructure) best predict pain outcomes?
  2. When studying the effects of changes in sleep, what are the most important pain-related outcomes? Which outcomes are the best markers of the sleep/pain interaction? How should researchers address the gap between existing measures of sleep and pain and clinical outcomes?
  3. What timeframe should researchers use in studying sleep and pain outcomes? Given that sleep and pain fluctuate markedly, how many measurements are needed and how quickly should we expect treatment effects?
  4. Which types of experimental sleep deprivation and disruption paradigms are most generalizable to clinical situations, and how can experimental approaches be further developed and modified to more closely reflect clinical situations?
  5. Do pain, insomnia, vigilance states, sleep physiology, and sleep disturbances operate independently or originate from one or more common alterations in the nervous system?
  6. How should we study the likely multiple, interrelated, and temporally evolving mechanisms and sequelae underlying acute and chronic sleep/pain interactions?
  7. Does long-term sleep deficiency affect mediators (and, if so, how), and do central and peripheral mediators play various roles across temporal stages of sleep deficiency? Are inflammatory markers causally involved in mediating increased pain, or do they contribute to the chronicity of pain?
  8. What are the separate, combined, and interacting effects of sex, race/ethnicity, culture, and genetics on sleep disturbances and resultant pain? How do these factors and individual variability impact the sleep-pain relationship, and do they differentially influence the effects of sleep on potential pain mediators?
  9. What mechanisms underlie the association of population factors and individual variability with both pain and sleep? Should clinical phenotyping be incorporated into clinical studies to address variability? How might researchers set up sleep and pain registry data and standardize collection methodology?

Part III: Participants identified the following as clinical knowledge gaps:

  1. To what extent do the sleep-related effects of analgesics (both positive and negative) mediate their effects on pain? Do drugs with different actions on sleep state (e.g., on REM and slow wave sleep [SWS]) have different effects on pain, and do these drugs affect biomarkers of pain (such as the proinflammatory response)?
  2. To what extent do deficient sleep and circadian dysregulation alter central pain-modulatory processes? Do changes in pain processing (e.g., in pain thresholds and/or modulation) evolve into increased clinical pain vulnerability? What are the clinical implications with respect to preventing and ameliorating chronic pain?
  3. As a cause of deficient sleep, does circadian misalignment (versus sleep duration or quality) relate to pain processing and clinical pain? Is there a relationship between central circadian timing and pain, and what is the potential role of chronobiologic interventions in managing or modifying pain?
  4. How do complementary therapies, medications, and potential substances of abuse (e.g., nicotine, alcohol, and caffeine) interact? How should researchers address their complex effects on sleep in patients with persistent pain?
  5. Can behavioral and empirically validated complementary interventions for sleep be developed, and be successfully delivered to older children and adolescents? How can youth be screened for insomnia? Is CBT for insomnia efficacious in the pediatric and adolescent chronic-pain populations?

Summary of Sessions

Workshop Co-Chairs: Daniel Clauw, M.D.; Michael Smith, Ph.D.

Part I [Session 1]: Preclinical Session To Identify Mechanistic Gap Areas in Neurobiological Systems That Operate in Sleep and Pain, and Their Convergence to Exacerbate or Reduce Pain

Discussant Leader: Clifford Woolf, M.D., Ph.D.
Panel Members: Maiken Nedergaard, M.D., D.M.Sc.; Ralph Lydic, Ph.D.; Kathleen Sluka, Ph.D.; Thomas Scammell, M.D.

Part I: Key Questions Posed to Participants

  1. What mechanisms of nociception may be impacted by sleep disruption?
  2. How might hypothalamic neurons that regulate sleep affect nociceptive pathways?
  3. Are glia (through gliotransmission) potential mediators of sleep/pain interactions?
  4. What neural/glial mechanisms are responsible for the transition from acute to chronic pain, and how might sleep affect this process?

Part I: Summary

Overlapping Neurobiology of Sleep and Pain. In this first topic area, panelists concluded that strong clinical evidence exists for an interaction between sleep and pain, but little is known about the mechanisms that underlie its nature, sites, or clinical significance. We have exciting new tools to apply to this emerging area, such as optogenetics and those being developed via the BRAIN Initiative.

Shared Neuroanatomy of Sleep and Pain in the CNS. Many systems using a variety of neurotransmitters are known to influence both sleep and pain; the anatomic areas of overlap are extensive. Ascending pain signals and descending nociceptive pathways are in close proximity to those that regulate sleep.

Research Gaps Identified by Participants

  1. Does poor sleep produce:
    • Increased afferent nociceptive signals?
    • Peripheral sensitization?
    • Central sensitization?
    • Increased ascending signals through brainstem or thalamic relays?
    • Increased microglial/astrocytic signaling?
  2. Does poor sleep reduce antinociceptive signals via action on:
    • The periaqueductal grey (PAG) to the raphe magnus?
    • Noradrenergic signals from the locus coeruleus?
    • Orexin pathways to the PAG, parabrachial nucleus (PB), and/or rostral ventrolateral medulla?
    • Amygdala pathways to the PAG or PB?
    • Other hypothalamic signals (e.g., oxytocin and corticotropin-releasing factor [CRF])?
  3. Does poor sleep alter higher-level perception of and reaction to pain, thereby causing:
    • Changes in thalamocortical responses (e.g., cingulate, insula, and prefrontal)?
    • Changes in mood, attention, and alertness?
  4. Is the change in pain specific, or are other sensory perceptions altered?

To address these gaps, animal models could be used, especially for gaps 1 and 2. Teasing apart nonspecific versus specific effects of sleep on pain is a major challenge. Specific mechanisms may vary by type of pain condition (e.g., when comparing fibromyalgia with chronic migraines).

Neurochemical Mechanisms That Modulate Sleep and Wakefulness. Sleep and pain are higher-level phenotypes regulated by lower-level phenotypes of cells and circuits, which speak to each other as the brain speaks to organs and peripheral tissues—through chemistry. Effective therapeutic approaches, whether conventional or complementary, work through brain chemistry. Imaging technology can show specific brain regions in “normal states” and a selection of neurotransmitters that can be measured relative to sleep. Current drugs for pain and/or sleep bathe the entire brain milieu, which may lead to unwanted effects. To allow more targeted therapies, we need greater understanding through measurement of these neurotransmitters/neuromodulators across states of acute pain, chronic pain, and sleep.

Imaging also can depict what is not known about the neurochemical modulation of sleep and pain. We need additional information on neuromodulators that may modulate states of sleep and pain, particularly acetylcholine, adenosine, gamma-aminobutyric acid (GABA), monoamines, and cytokines. Research on cannabinoids, oleamides, and resolvins/protectins is scant. One way to proceed would be to create a “workmanlike cartography” of all these factors and then take a functional approach.

Glia may be a major part of the answer to the linkage between sleep and pain, including the problem of the blood-brain barrier and how peripheral organs speak to the brain. One challenge is to understand the entire nervous system in toto. However, the scope should be kept manageable by focusing on one group or family of neurotransmitters, one pain condition, and/or one therapeutic agent at a time. Drugs can be administered not only systemically, but also through reverse dialysis, which can isolate the effects of drugs on specific brain regions. Both global-body and brain-specific approaches are needed, and humoral or systemic actions, as well as regional ones, should be studied.

Transition of Acute Pain to Chronic Pain. Chronic pain can be induced without excessive tissue injury by combining multiple low-intensity stimuli or stressors (rather than using a single insult). Examples include an insult to deep tissue (not merely skin surface), fatigue, physical inactivity, stress/anxiety, depression, obesity, and lack of sleep. Analogously, chronic pain leads to a constellation of symptoms, including sleep disturbances, fatigue, physical inactivity, depression, and stress/anxiety. Once a model has been developed that combines these factors, mechanisms can be examined.

Major research needs include in vitro and in vivo models that put the pieces together, studies to examine mechanisms, and interpretation of results (elucidating underlying reasons for the transition from acute to chronic pain). Because women have a higher incidence of chronic pain and develop greater widespread pain than men, studying both male and female model organisms is essential.

Known mechanisms in the transition from acute to chronic pain include enhancement of neuronal activity anywhere along the pain pathways; loss of inhibition (perhaps not only in the CNS, but in the periphery); activation of glial cells or immune cells; phosphorylation of receptors and channels; enhancement of gene transcription/upregulation of neurotransmitters, receptors, and transporters; and alteration of connectivity within the nervous system. For both sleep and pain, these mechanisms seem to occur in many of the same neurons, neurotransmitters, and pathways. A major question is whether sleep and pain use these mechanisms together, in parallel, or in distinct or convergent ways.

There are many ways to induce and disrupt sleep, just as there are a variety of distinct sleep disorders. Pain presents situations that are analogous. To understand the underlying mechanisms and biological pathways, investigators should consider factors that protect against both chronic pain and sleep disturbances that produce pain. Heritability, gender, age, and racial/cultural factors may influence sleep disturbances and pain conditions. Animal models present challenges, but they alone provide opportunities to interrogate mechanisms at the cellular and molecular levels.

Overlap Among Wakefulness, Neuronal-Glial Interactions, and Pain. A conceptual model developed by Tononi and Cirelli states that sleep downscales synapses and deletes those not needed for what the person learned that day. If sleep is insufficient, the person starts the day with already-increased excitability, which triggers a chain response with respect to pain.

The effect that sleep has on gene transcription, which in turn may impact sleep and wakefulness, is potentially important. Pain can be considered a form of extreme wakefulness because of increased neuronal excitability. In wakefulness, norepinephrine inhibits the short-term potassium pump in glial cell traffic, which in turn affects important processes of fluid flux. It may be worthwhile to examine not only the duration of wakefulness, but also its intensity.

Another discussion topic in Part I was that of negative study results. The consensus was that negative results should be published, as publishing only positive results can lead to bias and to thinking that effects are larger than they are in reality.

Part I: Key Knowledge Gaps Identified by Participants

  1. Does disruption of sleep enhance pain and does pain disrupt sleep? If so, how? What parts of the PNS or CNS are involved?
  2. Do the neuronal/glial systems that contribute to pain also mediate sleep dysfunction?
  3. Do the neurotransmitters and receptors involved in pain also mediate sleep?
  4. Does the immune system modulate the excitability of neurons involved in sleep and pain? Is it involved in sleep/pain interactions?
  5. Does sleep disruption affect pain in general, or do effects differ for different types of pain (e.g., nociceptive, inflammatory, neuropathic, and chronic-widespread)?
  6. What is responsible for gender differences in the interaction between sleep and pain?
  7. What are the heritable contributors to sleep/pain interactions, and which genes are involved?

Part I: Major Themes and Recommended Research Approaches Identified by Participants

  1. Clinical understanding of sleep and its disturbances, and of its relationship to chronic pain, has significantly advanced in recent years. However, mechanistic understanding of the relationship between these two states is very limited and urgently needs to be addressed if new therapeutic approaches are to be developed.
    1. The relationship between sleep disorders and pain is complex and bidirectional, and how it occurs at a cellular or systems level is essentially unknown. How sleep disturbances contribute to chronic pain and whether sleep disorders increase pain sensitivity are of particular merit.
    2. New neurobiological, bioinformatics, and genomic technologies provide tools to examine how sleep impacts pain. Preclinical research will complement and provide mechanistic insights into descriptive clinical studies and potentially identify novel therapeutic targets.
  2. The challenges to understanding the sleep-pain interaction are substantial, including the diversity of sleep disturbances/disorders and chronic-pain conditions, their many overlaps and comorbidities, and the limitations in preclinical models and methods.
    1. Modern neurobiological technology, including the BRAIN Initiative, offers new avenues to probe the nature of sleep, how it may be disrupted, and how this disruption affects pain processing and the risk for development of chronic pain.
    2. Researchers can identify which cells and circuits are involved; their phenotypic characteristics, modifiability, and emergent properties; and how these properties intersect with cognitive and other higher brain functions. Biological targets for future experimental work include:
      • Identity, connectivity, function, and plasticity of neurons and circuits within the periphery, spinal cord, brainstem, hypothalamus, thalamus, and cortex
      • Alterations in glial cells, neurons, and neuronal circuitry in disease
      • Molecular mechanisms including ion channels, neurotransmitters, receptors, transporters, and their transcriptional and post-translational processing
      • Genetic determinants and risk factors related to heritability of sleep and pain disorders
      • Phenotypes for mechanistic studies and drug screens, and neuroimmune interactions.
  3. Increasing knowledge of the cells, systems, pathways, and genetic and molecular mechanisms operating at the intersection of sleep and pain could lead to discovery of new treatment approaches or augmentation of existing ones, both pharmacologic and nonpharmacologic. Enormous opportunities exist to increase understanding and explore novel interventions.
  4. Investigators identified exciting opportunities for new, focused research approaches to address the knowledge gaps and elucidate the mechanisms underlying sleep/pain interactions. Examples include:
    1. Live population imaging of neuronal/glial activity
    2. Multielectrode array electrophysiology to deconvolute the cellular and systems activity driving EEG signals
    3. Optogenetic tools to activate and silence specific sets of neurons
    4. The neuronal connectivity underlying pain and sleep and its dynamic plasticity
    5. Genome editing to introduce mutations or reporters, and enable conditional knockout or expression of genes
    6. Intersectional transgenics to target specific sets of neurons in pain and sleep circuits
    7. Interrogation of spontaneous and preferred behavior over prolonged periods using fully automated technology and analysis algorithms
    8. Next-generation profiling of specific neurons and glia
    9. Phenotypic screens
    10. Using techniques to disrupt sleep that model human disorders.

Part II [Sessions 2 and 3]: Clinical Gap Areas Focused on Experimental Design and Methodology and on Mediators and Mechanisms, in the Context of Particular Populations, for Sleep/Pain Research

Discussant Leaders: Gilles Lavigne, DM.D., Ph.D.; Roger Fillingim, Ph.D.
Panel Members: Carol Landis, Ph.D., RN; Robert Edwards, Ph.D.; Monika Haack, Ph.D.; Linda LeResche, Sc.D.

Part II: Key Questions Posed to Participants

  1. What issues in experimental design and methodology do we need to consider for particular research questions in the area of sleep (e.g., on its quantity and quality) and chronic pain?
  2. How are different forms of sleep disturbance associated with pain?
  3. Following sleep loss, what mediators and mechanisms (e.g., inflammation, pain sensitization, or circadian misalignment) may be responsible for the accompanying pain?
  4. In the context of these issues, do population differences (age, sex, race/ethnicity, etc.) or individual differences matter?

Part II: Summary

Sleep is a unique physiological and behavioral state distinct from coma and anesthesia, and it provides a window to further understand the mechanism(s) of pain. A sleeping brain processes sensory inputs and pain; this processing occurs differently across sleep stages and over sleep periods. Because many factors influence sleep, many issues must be considered in study design, including:

  1. How to assess pain-related disruption in sleep continuity or quality over its fragmentation by arousal, breathing, or movement; scoring of normal and disturbed breathing; lifestyle (e.g., exercise/fitness, work and sleep schedules, and food and fluid intake); and mood (e.g., anxiety and depression)
  2. How to account for the persistence of placebo analgesia conditioning during sleep when assessing management efficacy or efficiency
  3. How to define and measure nonrestorative sleep
  4. How to take into account the influences of comorbidities (e.g., insomnia, sleep-disordered breathing, and movement disorders); sociocultural differences in sleep perception and pain-relief expectation; and phenotyping (age, sex, race/ethnicity, etc.).

Three additional issues needing consideration are sleep comorbidities (e.g., that reduce total sleep time or increase limb movements); comparability of different types of sleep recording devices (e.g., full polygraphy versus limited channels and variables, and conduction in the laboratory versus home); and use of nonequivalent outcomes (e.g., the apnea-hypopnea index; respiratory disturbance index; oximetry with or without sleep arousal) to diagnose sleep breathing disorders.

Population and Individual Differences. While the hoped-for goal of research is to improve sleep, reduce pain, and enhance quality of life for people with chronic pain, several issues with respect to population and individual differences hinder progress:

  • Researchers do not know what works, for whom, and under what conditions.
  • All pain is not the same. The etiology or type of pain (e.g., musculoskeletal or neuropathic) matters with respect to sleep duration and quality. Sleep disturbances in musculoskeletal types of pain have been most studied; minimal data exist on neuropathic pain.

Age, sex, race/ethnicity, and individual differences matter in sleep duration and quality among people with chronic pain. Most studies focus on adults, but both sleep disturbances and pain also affect special populations such as children, adolescents, and older adults. Cross-study comparisons of participants similar in age are challenging, mainly because of variability in measures and reliance on self-reported data. Women of every ethnicity complain more of pain and insomnia than men do, but gender differences in sleep have not been studied as extensively as they have in pain. Most experimental and clinical studies of sex differences in pain sensitivity have not included measures of sleep. Racial, ethnic, and cultural variations in pain have long been recognized, but those in sleep are just beginning to be examined. Individual variability in pain sensitivity and sleep disturbance exists, but has been little studied. Social and environmental variables, individual variability, and the impact of genetic background on individual variability need further study as well.

If identified, biomarkers could be developed that might help identify risk for pain originating from sleep disturbance, serve as novel treatment outcome measures, and represent important targets for interventions. Factors such as age and sex may moderate associations between sleep and pain. Mechanisms that mediate the sleep/pain relationship may vary qualitatively across populations, suggesting the need to tailor treatment and take individual differences into account. Psychosocial factors—such as depression, anxiety, pain history, abuse or stress exposure, and cognitive function— also might modify the sleep/pain relationship.

Inflammation. In experimental models of deficient sleep (e.g., of total sleep deprivation or sleep restriction), increased concentrations of proinflammatory markers, such as IL-6, TNF-α, and PGE2, have been noted in serum/plasma, urine, or monocytes. Upregulation of inflammatory markers has been reported in insomnia and breathing-related disorders.

Pain sensitization. Deficient sleep (as in experimental total sleep deprivation, restriction, or fragmentation, or insomnia disorder) increases sensitivity to thermal or mechanical nociceptive stimulation. Experimental sleep fragmentation or insomnia disorder can alter central pain inhibitory and facilitatory pathways (thus also altering, for example, conditioned pain modulation and temporal summation of pain).

Circadian misalignment occurs in shift work and jet lag, but likely is experienced by a much broader segment of the population due to increased light exposure and/or “social jet lag” (i.e., a discrepancy between an individual’s social schedules and biological cycles). It impacts systems involved in cardiometabolic health in humans, and upregulates inflammatory markers in animal models independent of sleep loss. Thus far, animal and human studies in this area have focused mostly on cardiometabolic health. Many people who have deficient sleep during the week but sleep in on weekends or have frequent jet lag from travel do not think they experience harm, but animal and human studies indicate otherwise. Two of the knowledge gaps in circadian misalignment are (1) whether that misalignment, as distinct from sleep duration or quality, relates to pain processing and clinical pain, and (2) the degree of sleep loss that occurs.

Part II: Knowledge Gaps Identified by Participants

  1. What sleep parameters (e.g., quality, continuity, architecture, and microstructure) are most predictive of pain outcomes longitudinally?
  2. What experimental approach is the best analog to the actual sleep disturbance experienced by pain patients (study of increased sleep latency, prolonged awakenings, reduced SWS, disrupted circadian patterns, etc.)?
  3. How should researchers handle the complex effects of medications, complementary treatments, nicotine, alcohol, and caffeine on sleep in studies of patients with persistent pain? Should participants continue their medications?
  4. What pain-related outcomes are most important? Can they be standardized without inhibiting innovation?
  5. During what timeframe should sleep and pain outcomes be studied? Given that sleep and pain fluctuate substantially, how many measurements are needed in a specific time period, and how quickly should treatment effects be expected?
  6. How should we study the interrelated potential mechanisms underlying sleep/pain interactions?
  7. Do sleep disturbances and pain covariates explain the variability in outcome data?
  8. How do population factors and individual variability impact the sleep/pain relationship?
  9. What are the combined effects of population factors (e.g., the interactions of age, sex, and race/ethnicity)?
  10. What mechanisms underlie the association of population factors and individual variability with both pain and sleep?
  11. Do population factors and individual variability differentially impact the effects of sleep on potential pain mediators (e.g., inflammation and pain sensitization)?
  12. In the context of deficient sleep, what are the mechanisms involved in central pain modulatory pathways, and how do changes in pain processing relate to increased clinical pain vulnerability? What is the clinical relevance of sleep-induced changes in pain processing? Are inflammatory markers causally involved in mediating increased pain?
  13. What are the sources of inflammatory markers in the context of deficient sleep (e.g., monocytes, adipocytes, glia/astrocytes, and endothelial cells)?
  14. What are the effects of sleep on analgesic mediators (e.g., anti-inflammatory cytokines, opioids, and resolvins)?
  15. How does long-term sleep deficiency affect mediators, and do mediators play different roles across temporal stages of sleep deficiency?
  16. How do experimental pain-related changes documented with sleep deficiency relate to clinical findings of chronic pain and increased vulnerability to chronic pain?

Part II: Major Themes and Recommended Research Approaches Identified by Participants

  1. Chronic pain and chronic insomnia are overlapping health epidemics with intersecting prevalence. Although patients with chronic pain show disruption in numerous aspects of sleep, many studies assess only one component, whereas multiple aspects of sleep must be explored to understand the sleep/pain relationship over time.
  2. Sleep deprivation studies use many experimental approaches, including total sleep deprivation, restriction, fragmentation, etc. Should these manipulations attempt to mimic sleep disturbances experienced by chronic-pain patients, and what sleep parameters are most important to disrupt?
  3. Patients with sleep disruption and persistent pain often take many medications with documented effects on sleep, have variable compliance rates, and have above-average rates of using (for example) complementary treatments, nicotine, alcohol, and caffeine. How do these factors interact? Discussion ensued in favor of study designs that include patients taking their medications on a consistent basis throughout the study and control for medication effects in the analysis. The main question being studied will determine the best approach.
  4. Past studies use examples of nighttime pain, daily pain intensity, disability, physical function, mood, quality of life, analgesic benefits, and pain sensitivity as measured through quantitative sensory testing (QST). Various interventions differentially impact these outcomes. Standardization is critical, but must not stifle innovation in assessing the sleep/pain interaction.
  5. CBT often produces benefits that gradually increase over time, whereas sedative-hypnotics may produce sizable short-term benefits that decline over time.
  6. Changes in sleep, such as improvements or disruptions, are likely to affect systems that can be assessed at many levels (e.g., gene expression, neurotransmitter binding, functional connectivity in the brain, heart rate variability, health behaviors, and psychosocial states). The mechanisms are generally interrelated, and most studies evaluate only a few at most, resulting in limited data interpretation and extrapolation.
  7. A wide range of biopsychosocial mediators and mechanisms have been implicated in studies of individual sleep disorders and pain conditions. However, at the intersection of sleep loss with pain, the evidence for those mediators and mechanisms is limited to studies with small sample sizes, thereby reducing the clinical relevance.
  8. Substantial knowledge gaps remain regarding how sleep and sleep disturbances impact pain.
  9. There are neurobiological similarities among pain, insomnia, vigilance states, sleep physiology, and sleep disturbances, but it is uncertain whether these conditions operate as independent, synergistic phenomena or originate from common alterations in the nervous system.
  10. Researchers need a better understanding of the degree to which human experimental research paradigms are generalizable to the clinical situation and how experimental approaches may be modified to more closely reflect clinical situations.
  11. Developing tools to measure sleep/pain interactions requires a better understanding of those interactions. More consistent, validated, and standardized measures and methodologies are needed. Related questions include: What are the most important items to assess? Which outcomes are the best markers of the interaction between sleep and pain? How should research address the gap between existing measures and clinical outcomes?
  12. Further research is needed to understand the critical role of inflammation as a trigger or factor that maintains the chronicity in the sleep/pain relationship.
  13. Both population factors and individual differences mediate and moderate sleep disorders and pain conditions, thereby likely influencing the intersection between sleep and pain. Insufficient statistical power has also been a challenge. Two examples of topics that need to be studied are age, particularly in combination with sex, and individual differences, especially within population subgroups. Panelists expressed caution about combining sex/gender across age groups, particularly in studying coexistent comorbidities (e.g., apnea-hypopnea or periodic limb movement), including those dependent on sex and age, such as menopausal symptoms.
  14. Issues for clinical trials include variability and statistical power. Clinical phenotyping could help address variability. Multicenter pain and sleep registry data should be merged, and standardized collection methodologies are needed.
  15. Clinical research on management, efficacy, or effectiveness should not underestimate the roles of age, sex/gender, lifestyle, social and environmental factors, comorbidities, and personal perceptions about sleep, expectation of pain relief, etc. Many mechanisms or biopsychosocial influences are persistent or altered from wake to sleep.
  16. Future research on sleep/pain relationships will need to be large in scale and cooperative in nature, and might best be suited to a collaborative, interdisciplinary, multisite approach.

Part III [Session 4]: Clinical Gap Areas To Address Pharmacologic and Nonpharmacologic Interventions, Particularly the Potential of Alleviating Sleep Disturbances to Reduce Chronic Pain

Discussant Leaders: Timothy Roehrs, Ph.D.; Michael Vitiello, Ph.D.
Panel Members: Thomas Roth, Ph.D.; Jennifer Haythornthwaite, Ph.D.; Helen Burgess, Ph.D.; Tonya Palermo, Ph.D.

Part III: Key Questions Posed to Participants

  1. What are the benefits and risks of current pharmacological treatment approaches to sleep and pain, and what populations might be more vulnerable?
  2. What are the current sleep-oriented interventions/approaches (e.g., CBT) to alleviate sleep disturbances and pain, and are particular populations more appropriate for such approaches?
  3. What are the potential complementary and integrative approaches to alleviate sleep disturbances that hold promise in reducing chronic pain?

Part III: Summary

Introduction to Approaches to Alleviate Sleep Disturbances to Reduce Chronic Pain. Participants noted that studies have not examined tactile sensitivity, vis à vis pain sensitivity, until recently. A recent systematic review of sleep/pain interactions described the bidirectional association, but reported that sleep disturbance is a stronger predictor of development and maintenance of chronic pain.

To analyze sleep and examine very complex brain states, researchers often use measures that date back many decades but can be less sensitive than more advanced measures, such as REM density or slow-wave activity, in specific sleep contexts. Some measures are considered crude (e.g., slow-wave activity and REM pressure), but classic measures of sleep stages and REM minutes still have a purpose, mainly for comparison across studies. The ability to automate older methods should be explored. Measuring sleep continuity and exploring the use of Big Data methods to accumulate profiles over time and across individuals may be valuable. EEG is not sleep, and imaging is not pain—yet they are valuable tools.

Discussion focused on what outcomes to measure and how to measure them. Pain and sleep have many components. Function is an important outcome; for example, researchers should consider patients’ perceptions of their own functioning and ability to respond to daily demands. How investigators think about sleep and pain may be quite different from how patients think and what they value. Potentially useful measures of function may be found, for example, in relation to osteoarthritis and self-efficacy. Recruitment source is important to consider; for example, patients in primary care will differ from those in a tertiary care pain clinic. The temporal dynamics of pain have not been well addressed.

Part III: Summary of Pharmacologic Interventions

Drugs that improve sleep improve pain as well, in at least one but not all pain conditions. This nonspecific effect is evident across drugs with diverse mechanisms of action. Given this universality, the analgesic activity of drugs is mediated, at least in part, by sleep. This sleep/pain interaction may contribute to the variable effects of drugs. Many drugs known to have analgesic properties improve sleep not only in pain patients, but in other patient populations without pain (e.g., sedating tricyclics and NSAIDs). These effects are not necessarily mediated by pain changes. This complex matrix of analgesic effects (whether positive, negative, or none) was illustrated for the following drugs: opioids (which appear to disturb sleep), anticonvulsants, GABAA modulators, triptans, cannabis, sodium oxybate, sedating tricyclic antidepressants, and SSRI and SNRI antidepressants.

Part III: Knowledge Gaps Identified by Participants: Pharmacologic Interventions

  1. Do drugs with different actions on sleep state (i.e., REM or SWS) have different effects on pain?
  2. How much of the effect of analgesics is mediated by either positive or negative effects on sleep?
  3. What is the effect of various sleep-promoting drugs on biomarkers of pain?
  4. Does the sleep effect of analgesics (both positive and negative) mediate their effects on pain?
  5. Large-scale randomized controlled trials are needed in a variety of painful conditions, with pain and sleep as primary outcomes. These would identify patient characteristics that yield best outcomes in particular settings (community, primary, tertiary, etc.) and evaluate cost savings.
  6. Do these interventions enhance or reduce the need for pharmacologic treatment for pain?

Part III: Summary of Nonpharmacologic Sleep-oriented Approaches

The evidence varies widely for nonpharmacologic interventions in various sleep and/or pain conditions. Nonpharmacologic approaches in alleviating sleep disturbances and pain include CBT (as an intervention for both insomnia and pain) and complementary approaches (e.g., relaxation, hypnosis, biofeedback, mindfulness, meditative movement, exercise, acupuncture, PENS/TENS/SCS,2 and brain stimulation3). The typically short testing periods for nonpharmacologic interventions present challenges, particularly in assessing total sleep improvement. The effects of sleep fragmentation appear very powerful in terms of pain modulation; increases in sleep consolidation and efficiency may be important markers for decreased pathology in sleep patterns. Behavioral interventions are almost always tested in the context of usual care. However, waitlist care and usual care are not appropriate controls for most nonpharmacologic interventions, as they do not account for nonspecific effects that may accompany treatment. Attention controls are needed to more accurately assess treatment efficacy.

Studies of behavioral interventions have generally had small sample sizes, and many have been hampered by design issues. Researchers need to consider dosing variability and delivery mode (e.g., whether delivered by telephone, distance, or Internet), as well as interventionist expertise. One question is whether professionals with doctoral-level training are always needed, or whether paraprofessionals and health coaches are sufficient. Pain researchers have not adequately addressed the translation of interventions into the real world. Self-help is common, and an empirically derived, stepped-care model is needed.

Efficacy trials should consider whether the results will be deployable in real-world settings. Internet- or smartphone-based programs (which patients like) can be put into practice relatively quickly. Studies need not always be purely efficacy driven. Appropriate controls in behavioral intervention trials are essential, but can be very difficult to design and should be guided by the hypothesis. Determining placebo effects and nonspecific effects, particularly in behavioral trials, is challenging.

Circadian Rhythms. Questions addressed included: 1) What is the role of circadian rhythms in mediating sleep disturbances; might they affect consequent pain? 2) Do circadian approaches to alleviate sleep disturbances (e.g., light therapy and melatonin) hold promise in reducing chronic pain?

Research indicates that about 70 percent of humans have endogenous circadian periods greater than 24 hours. This results in a natural tendency for circadian timing to drift later each day (i.e., phase delay). Light exerts the strongest influence on the timing of circadian rhythms. Morning light shifts the clock earlier (i.e., phase advance), helps overcome the natural tendency to phase delay, and realigns circadian timing to more closely match the external environment. Thus, morning light is the most critical light that humans receive every day. Conversely, evening light phase-delays circadian timing, exacerbating circadian misalignment. There is increasing recognition of the negative effects of evening light exposure, which often co-occurs with later bedtimes. Evidence suggests that circadian timing influences mood and sleep, which in turn influence pain; circadian-controlled melatonin reduces pain via opioid receptors; and circadian afferents directly affect central pain centers. Researchers are interested in the direct circadian control of substance P and inflammatory markers involved in pain.

One of the studies discussed was a small pilot study of light treatment in fibromyalgia. Measures used in this research include effects of time of day on drug dosing, whether self-care measures (e.g., exercise and dietary intake) affect circadian timing, and whether exercise or limiting light exposure in the evening from electronic devices improves insomnia and pain.

Part III: Knowledge Gaps Identified by Participants: Nonpharmacologic Circadian Interventions

  1. Delayed circadian timing likely is associated with worse pain and mood. Is there a relationship between central circadian timing and pain? Related to this, are timing of (1) dim-light melatonin onset (DLMO) and (2) circadian phase angle (DLMO-sleep midpoint) associated with pain?
  2. What is the relationship between peripheral clock timing and pain?
  3. Treatments that phase-advance, or shift the clock earlier, may improve pain and mood. Can treatments that shift circadian timing modify pain? Examples include bright light treatment, exogenous melatonin, and sleep/wake scheduling.

Nonpharmacologic Approaches in Children and Adolescents. Questions addressed included whether there are unique considerations and challenges in certain populations, such as children and adolescents. Children have a similar prevalence of pain and disability as adults; yet, the types of pain conditions and their distribution by sex/gender at various ages are different. Sleep problems in children are less clearly defined, in part due to different terminology and to placing various ages under the same rubric. Less is known about which sleep interventions are efficacious for adolescents compared with younger children. Evidence is limited on the interrelation of pain and sleep in children, but current knowledge includes the following:

  1. Insomnia is the most common sleep problem in youth with chronic pain. Insomnia symptoms persist over time and are associated with negative consequences including poor function, low quality of life, high health-care utilization, and adverse impact on the family.
  2. Sleep quality (as assessed by actigraphy) affects next-day pain in a daily temporal relationship, suggesting that sleep interventions may reduce subsequent pain.
  3. Nonpharmacologic interventions, particularly CBT, reduce pain and related disability in children with chronic pain. It is not known whether sleep actually changes, as sleep has rarely been assessed as an outcome of pain therapies. Pilot data show that sleep does not improve with CBT as a pain intervention, and poor sleep is a risk factor for less improvement in pain outcomes following CBT for chronic pain.
  4. Participants discussed the importance of sleep hygiene for children and adolescents (e.g., avoidance of media in the bedroom and late at night); the need for a consistent definition of insomnia in adolescents; where adolescents receive care for sleep issues (usually, a comorbidity brings them to care); and the importance of the family context. A further question is whether the same mechanisms are at play when these problems first emerge in younger years, compared with later life.

Part III: Knowledge Gaps Identified by Participants: Studying Children

  1. Pediatric sleep intervention research has lagged behind adult research and primarily focused on bedtime problems in children under age 7 years. Can sleep interventions be successfully delivered to older children and adolescents?
  2. Validated tools are not available for diagnosing insomnia in children and adolescents; these tools are needed to define clinical trial populations. How can youth be screened for insomnia?
  3. Nonpharmacologic sleep treatments need to be evaluated in youth with chronic-pain conditions using validated sleep and pain measures as primary outcomes. Is CBT for insomnia efficacious in healthy and ill pediatric populations?

Part III: Major Themes and Recommended Research Approaches Identified by Participants

  1. Outcomes, measurement, and measures remain key gap areas. The research community needs consistent, validated terminology and measures.
  2. There are common challenges between studies of interventions for sleep disorders, pain conditions, and their intersection, and between pharmacologic and nonpharmacologic interventions for these conditions (e.g., nonspecific effects). Both types of interventions have complexities, and studies must address knowledge gaps.
  3. There is a compelling need for nonpharmacologic treatments that can move from testing to delivery relatively quickly, are safe and low-cost, and are likely to be effective in real-world settings.
  4. Comparative effectiveness studies and dissemination science are needed to determine strategies for optimizing outcomes in the real world.
  5. Function in the real world is important to patients and should be included in data collection.
  6. The role of circadian rhythms in sleep and health (including in pain) is of great interest and has begun to be investigated. Better understanding of how disruption of circadian rhythms affects sleep and pain may lead to better approaches for management and treatment.
  7. Sleep problems and the sleep/pain intersection, as well as appropriate treatments, have had very little study in children and adolescents, yet these problems may be widespread.
  8. The sleep/pain relationship also has been inadequately studied in relation to age in young and elderly populations.

1 Examples include relaxation, hypnosis, biofeedback, mindfulness, meditative movement, exercise, acupuncture, percutaneous electrical nerve stimulation (PENS), transcutaneous electrical nerve stimulation (TENS), spinal cord stimulation (SCS), and brain stimulation (such as transcranial direct current stimulation (tDCS), percutaneous transcranial electrical stimulation (TES), and transcranial magnetic stimulation [TMS]). Back

2 Includes percutaneous electrical nerve stimulation (PENS), transcutaneous electrical nerve stimulation (TENS), and spinal cord stimulation (SCS). Back

3 Includes transcranial direct current stimulation (tDCS), percutaneous transcranial electrical stimulation (TES), and transcranial magnetic stimulation (TMS). Back

Appendix A: Agenda

Trans-NIH Sleep/Pain Workshop, May 29–30, 2014

Welcome: D. Lee Alekel, Ph.D., Program Director of Women’s Health, NCCAM
Introductory Remarks: Josephine Briggs, M.D., Director of NCCAM
Co-Chairs: Daniel Clauw, M.D.; Michael Smith, Ph.D.

Part I [Session 1]: Preclinical Session To Identify Mechanistic Gap Areas in Neurobiological Systems That Operate in Sleep and Pain, and Their Convergence to Exacerbate or Reduce Pain

Discussant Leader: Clifford Woolf, M.D., Ph.D.
Panel Members: Maiken Nedergaard, M.D., D.M.Sc.; Ralph Lydic, Ph.D.; Kathleen Sluka, Ph.D.; Thomas Scammell, M.D.
Key Questions Posed to Participants:

  1. What mechanisms of nociception may be impacted by sleep disruption?
  2. How might hypothalamic neurons that regulate sleep affect nociceptive pathways? Are glia (through gliotransmission) potential mediators of sleep/pain interactions?
  3. What neural/glial mechanisms are responsible for the transition from acute to chronic pain, and how might sleep affect this process?

Part II [Sessions 2 and 3]: Clinical Gap Areas Focused on Experimental Design and Methodology and on Mediators and Mechanisms, in the Context of Particular Populations, for Sleep/Pain Research

Discussant Leaders: Gilles Lavigne, D.M.D., Ph.D.; Roger Fillingim, Ph.D.
Panel Members: Carol Landis, Ph.D., R.N.; Robert Edwards, Ph.D.; Monika Haack, Ph.D.; Linda LeResche, Sc.D.
Key Questions Posed to Participants:

  1. What issues in experimental design and methodology do we need to consider for particular research questions in the area of sleep (quantity and quality) and chronic pain?
  2. How are different forms of sleep disturbance associated with pain?
  3. Following sleep loss, what mediators and mechanisms (e.g., inflammation, pain sensitization, or circadian misalignment) may be responsible for the accompanying pain?
  4. In the context of these issues, do population differences (age, sex, race/ethnicity, etc.) or individual differences matter?

Part III [Session 4]: Clinical Gap Areas To Address Pharmacologic and Nonpharmacologic Interventions, Particularly the Potential of Alleviating Sleep Disturbances to Reduce Chronic Pain

Discussant Leaders: Timothy Roehrs, Ph.D.; Michael Vitiello, Ph.D.
Panel Members: Thomas Roth, Ph.D.; Jennifer Haythornthwaite, Ph.D.; Helen Burgess, Ph.D.; Tonya Palermo, Ph.D.
Key Questions Posed to Participants:

  1. Pharmacologic approaches: What are the benefits and risks of current pharmacological treatment approaches to sleep and pain, and what populations might be more vulnerable?
  2. Non-pharmacologic approaches: What are the current sleep-oriented interventions/approaches (e.g., cognitive-behavioral therapy) to alleviate sleep disturbances and pain, and are particular populations more appropriate for such approaches?
  3. Non-pharmacologic approaches: What are the potential complementary and integrative approaches to alleviate sleep disturbances that hold promise in reducing chronic pain?

Appendix B: List of Sponsoring/Participating Institutes, Centers, and Offices

Sponsoring Institutes/Centers/Offices:

National Center for Complementary and Alternative Medicine
National Cancer Institute
National Institute on Aging
National Institute of Nursing Research
National Institute on Drug Abuse
National Institute of Neurological Disorders and Stroke
Office of Research on Women’s Health
Eunice Kennedy Shriver National Institute of Child Health and Human Development
National Institutes of Health Office of Pain Policy

Additional participating Institutes:

National Institute of Dental and Craniofacial Research
National Institute of Arthritis and Musculoskeletal and Skin Diseases
National Institute on Alcohol Abuse and Alcoholism
National Heart, Lung, and Blood Institute
National Institutes of Health Clinical Center

Appendix C: Roster of Meeting Panelists

Helen Burgess, Ph.D.
Professor
Department of Behavioral Sciences, Department of Internal Medicine
Rush University Medical Center
Biological Rhythms Research Laboratory
Chicago, IL

Daniel J. Clauw, M.D.
Professor
Department of Anesthesiology, Medicine (Rheumatology), and Psychiatry
University of Michigan
Ann Arbor, MI

Robert R. Edwards, Ph.D.
Associate Professor
Department of Anesthesiology
Brigham & Women’s Hospital
Boston, MA

Roger B. Fillingim, Ph.D.
Professor
College of Dentistry
University of Florida
Gainesville, FL

Monika Haack, Ph.D.
Assistant Professor
Neurology
Beth Israel Deaconess Medical Center
Boston, MA

Jennifer A. Haythornthwaite, Ph.D.
Professor
Psychiatry & Behavioral Sciences
Johns Hopkins University
Baltimore, MD

Carol A. Landis, Ph.D., R.N., FAAN
Professor
Biobehavioral Nursing & Health Systems, School of Nursing
University of Washington
Seattle, WA

Gilles Lavigne, D.M.D., Ph.D., FRCDc, hc
Professor and Dean
Faculty of Dental Medicine
Universite de Montreal
Montreal, Canada

Linda LeResche, Sc.D.
Professor, Department of Oral Medicine
Associate Dean for Research, School of Dentistry
University of Washington
Seattle, WA

Ralph Lydic, Ph.D.
Robert H. Cole Endowed Professor of Neuroscience
Departments of Anesthesiology and Psychology
University of Tennessee
Knoxville, TN

Maiken Nedergaard, M.D., D.M.Sc
Frank P. Smith Professor of Neurosurgery
Co-Director, Center for Translational Neuromedicine
University of Rochester Medical Center
Rochester, NY

Tonya M. Palermo, Ph.D.
Professor
Anesthesiology & Pain Medicine
University of Washington and Seattle Children’s Research Institute
Seattle, WA

Timothy Roehrs Ph.D.
Professor, Department of Psychiatry & Behavioral Neuroscience
Wayne State University, School of Medicine
Senior Biomedical Scientist and Director of Research
Internal Medicine, Sleep Disorders Center
Henry Ford Health System
Detroit, MI

Thomas Roth, Ph.D.
Director
Sleep Disorders and Research Center
Henry Ford Hospital
Detroit MI

Thomas Scammell, M.D.
Professor
Department of Neurology
Beth Israel Deaconess Medical Center & Boston Children’s Hospital
Boston, MA

Kathleen A Sluka, P.T., Ph.D., FAPTA
Professor
Department of Physical Therapy and Rehabilitation Science
Carver College of Medicine, College of Nursing
University of Iowa
Iowa City, IA

Michael T. Smith, Ph.D.
Professor, Psychiatry, Neurology, and Nursing
Director, Center for Behavior and Health
Co-Director, Center for Sleep-Related Symptom Science
Dept. of Psychiatry and Behavioral Sciences, Behavioral Medicine Division
Johns Hopkins University, School of Medicine
Baltimore, MD

Michael V. Vitiello, Ph.D.
Professor
Psychiatry & Behavioral Sciences, Gerontology & Geriatric Medicine, and Biobehavioral Nursing
University of Washington, School of Medicine
Seattle WA

Clifford Woolf, M.D., Ph.D.
Professor
Director, F.M. Kirby Neurobiology Center
Neurology/Neurobiology
Boston Children’s Hospital
Boston, MA

This page last modified September 24, 2017