Linking Traumatic Brain Injury, Sleep Disruption and Post-Traumatic Headache: a Potential Role for Glymphatic Pathway Dysfunction

  • Juan PiantinoEmail author
  • Miranda M. Lim
  • Craig D. Newgard
  • Jeffrey IliffEmail author
Secondary Headache (M Robbins, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Secondary Headache


Purpose of the Review

Traumatic brain injury (TBI) is a major public health concern in the USA and worldwide. Sleep disruption and headaches are two of the most common problems reported by patients after TBI. In this manuscript, we review the current knowledge regarding the relation between post-traumatic sleep disruption and headaches. We also describe the role of the glymphatic system as a potential link between TBI, sleep, and headaches.

Recent Findings

Recent studies show a reciprocal relation between post-traumatic sleep disruption and headaches: patients with sleep disruption after TBI report more headaches, and post-traumatic headaches are a risk factor for developing disrupted sleep. Despite this clinical association, the exact mechanisms linking post-traumatic sleep disruption and headaches are not well understood. The glymphatic pathway, a newly described brain–wide network of perivascular spaces that supports the clearance of interstitial solutes and wastes from the brain, is active primarily during sleep, and becomes dysfunctional after TBI. We propose a model where changes in glymphatic function caused by TBI and post-traumatic sleep disruption may impair the clearance of neuropeptides involved in the pathogenesis of post-traumatic headaches, such as CGRP.


The relation between TBI, post-traumatic sleep disruption, and post-traumatic headaches, although well documented in the literature, remains poorly understood. Dysfunction of the glymphatic system caused by TBI offers a novel and exiting explanation to this clinically observed phenomenon. The proposed model, although theoretical, could provide important mechanistic insights to the TBI-sleep-headache association.


Glymphatic system Traumatic brain injury Concussion Headaches Sleep 



Research in the authors’ labs is supported by funding from the NIH (AG054456, NS089709, JJI; K12HL133115, JP), the Paul G. Allen Family Foundation (JJI, MML), VA Career Development Award #IK2 BX002712 (MML), and GlaxoSmithKline (JJI).

Compliance with Ethical Standards

Conflict of Interest

Juan Piantino, Miranda M. Lim, Craig D. Newgard, and Jeffrey Iliff declare no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Interpretations and conclusions are those of the authors and do not represent the views of the U.S. Department of Veterans Affairs or the United States Government.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Faul M XL, Wald MM, Coronado V. Traumatic brain injury in the United States. In: Centers for Disease Control and Prevention NCfIPaC, editor. Atlanta, GA2010.Google Scholar
  2. 2.
    VA/DoD. Clinical practice guideline for management of concussion/mild traumatic brain injury. J Rehabil Res Dev. 2009;46(6):Cp1–68.Google Scholar
  3. 3.
    Taylor CA, Bell JM, Breiding MJ, Xu L. Traumatic brain injury-related emergency department visits, hospitalizations, and deaths - United States, 2007 and 2013. Morbidity and mortality weekly report Surveillance summaries (Washington, DC : 2002). 2017;66(9):1–16. Scholar
  4. 4.
    Centers for Disease control and Prevention.What are the signs and symptoms of concussion. Accessed February 25th 2019.
  5. 5.
    Mathias JL, Alvaro PK. Prevalence of sleep disturbances, disorders, and problems following traumatic brain injury: a meta-analysis. Sleep Med. 2012;13(7):898–905. Scholar
  6. 6.
    Lew HL, Lin PH, Fuh JL, Wang SJ, Clark DJ, Walker WC. Characteristics and treatment of headache after traumatic brain injury: a focused review. Am J Phys Med Rehabil. 2006;85(7):619–27. Scholar
  7. 7.
    Lucas S, Hoffman JM, Bell KR, Dikmen S. A prospective study of prevalence and characterization of headache following mild traumatic brain injury. Cephalalgia. 2014;34(2):93–102. Scholar
  8. 8.
    Kostyun RO, Milewski MD, Hafeez I. Sleep disturbance and neurocognitive function during the recovery from a sport-related concussion in adolescents. Am J Sports Med. 2015;43(3):633–40. Scholar
  9. 9.
    Murdaugh DL, Ono KE, Reisner A, Burns TG. Assessment of sleep quantity and sleep disturbances during recovery from sports-related concussion in youth athletes. Arch Phys Med Rehabil. 2018;99(5):960–6. Scholar
  10. 10.
    •• Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Sci Transl Med. 2012;4(147):147ra11. First description of the role of the paravascular spaces in clearence of amyloid beta. CrossRefGoogle Scholar
  11. 11.
    •• Xie L, Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M et al First publication describing the increase in convective exchange of cerebrospinal fluid and interstitial fluid that occurs during sleep et al.. Science. 2013;342(6156):373–377. doi: Sleep drives metabolite clearance from the adult brain
  12. 12.
    • Iliff JJ, Chen MJ, Plog BA, Zeppenfeld DM, Soltero M, Yang L, et al. Impairment of glymphatic pathway function promotes tau pathology after traumatic brain injury. J Neurosci. 2014;34(49):16180–93. Important paper showing how traumatic brian injury impairs glimphatic function and promotes accumulation of tau. CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Schatz P, Moser RS, Covassin T, Karpf R. Early indicators of enduring symptoms in high school athletes with multiple previous concussions. Neurosurgery. 2011;68(6):1562–7; discussion 7. Scholar
  14. 14.
    Blinman TA, Houseknecht E, Snyder C, Wiebe DJ, Nance ML. Postconcussive symptoms in hospitalized pediatric patients after mild traumatic brain injury. J Pediatr Surg. 2009;44(6):1223–8. Scholar
  15. 15.
    Watson NF, Dikmen S, Machamer J, Doherty M, Temkin N. Hypersomnia following traumatic brain injury. J Clin Sleep Med. 2007;3(4):363–8.PubMedPubMedCentralGoogle Scholar
  16. 16.
    • Wickwire EM, Williams SG, Roth T, Capaldi VF, Jaffe M, Moline M, et al. Sleep, sleep disorders, and mild traumatic brain injury. What we know and what we need to know: findings from a National Working Group. Neurotherapeutics. 2016;13(2):403–17. A very good review on the current understanding of the relation between TBI and sleep disturbances. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Ouellet MC, Beaulieu-Bonneau S, Morin CM. Insomnia in patients with traumatic brain injury: frequency, characteristics, and risk factors. J Head Trauma Rehabil. 2006;21(3):199–212.CrossRefGoogle Scholar
  18. 18.
    Collen J, Orr N, Lettieri CJ, Carter K, Holley AB. Sleep disturbances among soldiers with combat-related traumatic brain injury. Chest. 2012;142(3):622–30. Scholar
  19. 19.
    Clinchot DM, Bogner J, Mysiw WJ, Fugate L, Corrigan J. Defining sleep disturbance after brain injury. Am J Phys Med Rehabil. 1998;77(4):291–5.CrossRefGoogle Scholar
  20. 20.
    Baumann CR, Bassetti CL, Valko PO, Haybaeck J, Keller M, Clark E, et al. Loss of hypocretin (orexin) neurons with traumatic brain injury. Ann Neurol. 2009;66(4):555–9. Scholar
  21. 21.
    Verma A, Anand V, Verma NP. Sleep disorders in chronic traumatic brain injury. J Clin Sleep Med. 2007;3(4):357–62.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Kempf J, Werth E, Kaiser PR, Bassetti CL, Baumann CR. Sleep-wake disturbances 3 years after traumatic brain injury. J Neurol Neurosurg Psychiatry. 2010;81(12):1402–5. Scholar
  23. 23.
    Castriotta RJ, Wilde MC, Lai JM, Atanasov S, Masel BE, Kuna ST. Prevalence and consequences of sleep disorders in traumatic brain injury. J Clin Sleep Med. 2007;3(4):349–56.PubMedPubMedCentralGoogle Scholar
  24. 24.
    Baumann CR, Werth E, Stocker R, Ludwig S, Bassetti CL. Sleep-wake disturbances 6 months after traumatic brain injury: a prospective study. Brain. 2007;130(Pt 7):1873–83. Scholar
  25. 25.
    Masel BE, Scheibel RS, Kimbark T, Kuna ST. Excessive daytime sleepiness in adults with brain injuries. Arch Phys Med Rehabil. 2001;82(11):1526–32. Scholar
  26. 26.
    Wilde MC, Castriotta RJ, Lai JM, Atanasov S, Masel BE, Kuna ST. Cognitive impairment in patients with traumatic brain injury and obstructive sleep apnea. Arch Phys Med Rehabil. 2007;88(10):1284–8. Scholar
  27. 27.
    Parcell DL, Ponsford JL, Redman JR, Rajaratnam SM. Poor sleep quality and changes in objectively recorded sleep after traumatic brain injury: a preliminary study. Arch Phys Med Rehabil. 2008;89(5):843–50. Scholar
  28. 28.
    Shekleton JA, Parcell DL, Redman JR, Phipps-Nelson J, Ponsford JL, Rajaratnam SM. Sleep disturbance and melatonin levels following traumatic brain injury. Neurology. 2010;74(21):1732–8. Scholar
  29. 29.
    Sandsmark DK, Elliott JE, Lim MM. Sleep-wake disturbances after traumatic brain injury: synthesis of human and animal studies. Sleep. 2017;40(5).
  30. 30.
    Valko PO, Gavrilov YV, Yamamoto M, Finn K, Reddy H, Haybaeck J, et al. Damage to histaminergic tuberomammillary neurons and other hypothalamic neurons with traumatic brain injury. Ann Neurol. 2015;77(1):177–82. Scholar
  31. 31.
    Baumann CR, Stocker R, Imhof HG, Trentz O, Hersberger M, Mignot E, et al. Hypocretin-1 (orexin A) deficiency in acute traumatic brain injury. Neurology. 2005;65(1):147–9. Scholar
  32. 32.
    Rye DB, Bliwise DL, Parker K, Trotti LM, Saini P, Fairley J, et al. Modulation of vigilance in the primary hypersomnias by endogenous enhancement of GABAA receptors. Sci Transl Med. 2012;4(161):161ra51. Scholar
  33. 33.
    Junger EC, Newell DW, Grant GA, Avellino AM, Ghatan S, Douville CM, et al. Cerebral autoregulation following minor head injury. J Neurosurg. 1997;86(3):425–32. Scholar
  34. 34.
    Kumar A, Loane DJ. Neuroinflammation after traumatic brain injury: opportunities for therapeutic intervention. Brain Behav Immun. 2012;26(8):1191–201. Scholar
  35. 35.
    Paparrigopoulos T, Melissaki A, Tsekou H, Efthymiou A, Kribeni G, Baziotis N, et al. Melatonin secretion after head injury: a pilot study. Brain Inj. 2006;20(8):873–8. Scholar
  36. 36.
    Seifman MA, Gomes K, Nguyen PN, Bailey M, Rosenfeld JV, Cooper DJ, et al. Measurement of serum melatonin in intensive care unit patients: changes in traumatic brain injury, trauma, and medical conditions. Front Neurol. 2014;5:237. Scholar
  37. 37.
    Tan G, Fink B, Dao TK, Hebert R, Farmer LS, Sanders A, et al. Associations among pain, PTSD, mTBI, and heart rate variability in veterans of Operation Enduring and Iraqi Freedom: a pilot study. Pain Med (Malden, Mass). 2009;10(7):1237–45. Scholar
  38. 38.
    Morin CM, Colecchi C, Stone J, Sood R, Brink D. Behavioral and pharmacological therapies for late-life insomnia: a randomized controlled trial. Jama. 1999;281(11):991–9.CrossRefGoogle Scholar
  39. 39.
    Jacobs GD, Pace-Schott EF, Stickgold R, Otto MW. Cognitive behavior therapy and pharmacotherapy for insomnia: a randomized controlled trial and direct comparison. Arch Intern Med. 2004;164(17):1888–96. Scholar
  40. 40.
    Sivertsen B, Omvik S, Pallesen S, Bjorvatn B, Havik OE, Kvale G, et al. Cognitive behavioral therapy vs zopiclone for treatment of chronic primary insomnia in older adults: a randomized controlled trial. Jama. 2006;295(24):2851–8. Scholar
  41. 41.
    Morin CM, Vallieres A, Guay B, Ivers H, Savard J, Merette C, et al. Cognitive behavioral therapy, singly and combined with medication, for persistent insomnia: a randomized controlled trial. Jama. 2009;301(19):2005–15. Scholar
  42. 42.
    Kaiser PR, Valko PO, Werth E, Thomann J, Meier J, Stocker R, et al. Modafinil ameliorates excessive daytime sleepiness after traumatic brain injury. Neurology. 2010;75(20):1780–5. Scholar
  43. 43.
    Menn SJ, Yang R, Lankford A. Armodafinil for the treatment of excessive sleepiness associated with mild or moderate closed traumatic brain injury: a 12-week, randomized, double-blind study followed by a 12-month open-label extension. J Clin Sleep Med. 2014;10(11):1181–91. Scholar
  44. 44.
    Ponsford JL, Ziino C, Parcell DL, Shekleton JA, Roper M, Redman JR, et al. Fatigue and sleep disturbance following traumatic brain injury--their nature, causes, and potential treatments. J Head Trauma Rehabil. 2012;27(3):224–33. Scholar
  45. 45.
    Blume HK, Vavilala MS, Jaffe KM, Koepsell TD, Wang J, Temkin N, et al. Headache after pediatric traumatic brain injury: a cohort study. Pediatrics. 2012;129(1):e31–9. Scholar
  46. 46.
    Nampiaparampil DE. Prevalence of chronic pain after traumatic brain injury: a systematic review. Jama. 2008;300(6):711–9. Scholar
  47. 47.
    Sufrinko A, McAllister-Deitrick J, Elbin RJ, Collins MW, Kontos AP. Family history of migraine associated with posttraumatic migraine symptoms following sport-related concussion. J Head Trauma Rehabil. 2018;33(1):7–14. Scholar
  48. 48.
    Kjeldgaard D, Forchhammer H, Teasdale T, Jensen RH. Chronic post-traumatic headache after mild head injury: a descriptive study. Cephalalgia. 2014;34(3):191–200. Scholar
  49. 49.
    Wang SJ, Fuh JL, Lu SR, Juang KD. Outcomes and predictors of chronic daily headache in adolescents: a 2-year longitudinal study. Neurology. 2007;68(8):591–6. Scholar
  50. 50.
    Headache classification Committee of the International Headache Society (IHS) the international classification of headache disorders, 3rd edition. Cephalalgia : an international journal of headache. 2018;38(1):1–211.
  51. 51.
    Lucas S, Hoffman JM, Bell KR, Walker W, Dikmen S. Characterization of headache after traumatic brain injury. Cephalalgia. 2012;32(8):600–6. Scholar
  52. 52.
    Lambru G, Matharu M. Traumatic head injury in cluster headache: cause or effect? Curr Pain Headache Rep. 2012;16(2):162–9. Scholar
  53. 53.
    Kuczynski A, Crawford S, Bodell L, Dewey D, Barlow KM. Characteristics of post-traumatic headaches in children following mild traumatic brain injury and their response to treatment: a prospective cohort. Dev Med Child Neurol. 2013;55(7):636–41. Scholar
  54. 54.
    Seifert TD, Evans RW. Posttraumatic headache: a review. Curr Pain Headache Rep. 2010;14(4):292–8. Scholar
  55. 55.
    Giza CC, Hovda DA. The new neurometabolic cascade of concussion. Neurosurgery. 2014;75(Suppl 4):S24–33. Scholar
  56. 56.
    Barkhoudarian G, Hovda DA, Giza CC. The molecular pathophysiology of concussive brain injury - an update. Phys Med Rehabil Clin N Am. 2016;27(2):373–93. Scholar
  57. 57.
    Stephens JA, Liu P, Lu H, Suskauer SJ. Cerebral blood flow after mild traumatic brain injury: associations between symptoms and post-injury perfusion. J Neurotrauma. 2018;35(2):241–8. Scholar
  58. 58.
    Kamins J, Bigler E, Covassin T, Henry L, Kemp S, Leddy JJ, et al. What is the physiological time to recovery after concussion? A systematic review. Br J Sports Med. 2017;51(12):935–40. Scholar
  59. 59.
    Zeng Z, Li Y, Lu S, Huang W, Di W. Efficacy of CoQ10 as supplementation for migraine: a meta-analysis. Acta Neurol Scand. 2019;139(3):284–93. Scholar
  60. 60.
    Zielman R, Wijnen JP, Webb A, Onderwater GLJ, Ronen I, Ferrari MD, et al. Cortical glutamate in migraine. Brain. 2017;140(7):1859–71. Scholar
  61. 61.
    Powers SW, Coffey CS, Chamberlin LA, Ecklund DJ, Klingner EA, Yankey JW, et al. Trial of amitriptyline, topiramate, and placebo for pediatric migraine. N Engl J Med. 2017;376(2):115–24. Scholar
  62. 62.
    Noruzzadeh R, Modabbernia A, Aghamollaii V, Ghaffarpour M, Harirchian MH, Salahi S, et al. Memantine for prophylactic treatment of migraine without aura: a randomized double-blind placebo-controlled study. Headache. 2016;56(1):95–103. Scholar
  63. 63.
    Mei Z, Qiu J, Alcon S, Hashim J, Rotenberg A, Sun Y, et al. Memantine improves outcomes after repetitive traumatic brain injury. Behav Brain Res. 2018;340:195–204. Scholar
  64. 64.
    Schock SC, Munyao N, Yakubchyk Y, Sabourin LA, Hakim AM, Ventureyra EC, et al. Cortical spreading depression releases ATP into the extracellular space and purinergic receptor activation contributes to the induction of ischemic tolerance. Brain Res. 2007;1168:129–38. Scholar
  65. 65.
    Burnstock G, Krugel U, Abbracchio MP, Illes P. Purinergic signalling: from normal behaviour to pathological brain function. Prog Neurobiol. 2011;95(2):229–74. Scholar
  66. 66.
    Jackson EK, Boison D, Schwarzschild MA, Kochanek PM. Purines: forgotten mediators in traumatic brain injury. J Neurochem. 2016;137(2):142–53. Scholar
  67. 67.
    Ning YL, Yang N, Chen X, Xiong RP, Zhang XZ, Li P, et al. Adenosine A2A receptor deficiency alleviates blast-induced cognitive dysfunction. J Cereb Blood Flow Metab. 2013;33(11):1789–98. Scholar
  68. 68.
    Lipton RB, Diener HC, Robbins MS, Garas SY, Patel K. Caffeine in the management of patients with headache. J Headache Pain. 2017;18(1):107. Scholar
  69. 69.
    Edvinsson L. The Trigeminovascular pathway: role of CGRP and CGRP receptors in migraine. Headache. 2017;57(Suppl 2):47–55. Scholar
  70. 70.
    Bree D, Levy D. Development of CGRP-dependent pain and headache related behaviours in a rat model of concussion: implications for mechanisms of post-traumatic headache. Cephalalgia. 2018;38(2):246–58. Scholar
  71. 71.
    Daiutolo BV, Tyburski A, Clark SW, Elliott MB. Trigeminal pain molecules, allodynia, and photosensitivity are pharmacologically and genetically modulated in a model of traumatic brain injury. J Neurotrauma. 2016;33(8):748–60. Scholar
  72. 72.
    Elliott MB, Oshinsky ML, Amenta PS, Awe OO, Jallo JI. Nociceptive neuropeptide increases and periorbital allodynia in a model of traumatic brain injury. Headache. 2012;52(6):966–84. Scholar
  73. 73.
    Tyburski AL, Cheng L, Assari S, Darvish K, Elliott MB. Frequent mild head injury promotes trigeminal sensitivity concomitant with microglial proliferation, astrocytosis, and increased neuropeptide levels in the trigeminal pain system. J Headache Pain. 2017;18(1):16. Scholar
  74. 74.
    Charles A. The pathophysiology of migraine: implications for clinical management. Lancet Neurol. 2018;17(2):174–82. Scholar
  75. 75.
    Zagami AS, Edvinsson L, Goadsby PJ. Pituitary adenylate cyclase activating polypeptide and migraine. Ann Clin Transl Neurol. 2014;1(12):1036–40. Scholar
  76. 76.
    Vink R, Gabrielian L, Thornton E. The role of substance P in secondary pathophysiology after traumatic brain injury. Front Neurol. 2017;8:304. Scholar
  77. 77.
    May A, Goadsby PJ. Substance P receptor antagonists in the therapy of migraine. Expert Opin Investig Drugs. 2001;10(4):673–8. Scholar
  78. 78.
    Lumba-Brown A, Harley J, Lucio S, Vaida F, Hilfiker M. Hypertonic saline as a therapy for pediatric concussive pain: a randomized controlled trial of symptom treatment in the emergency department. Pediatr Emerg Care. 2014;30(3):139–45. Scholar
  79. 79.
    Mittenberg W, Canyock EM, Condit D, Patton C. Treatment of post-concussion syndrome following mild head injury. J Clin Exp Neuropsychol. 2001;23(6):829–36. Scholar
  80. 80.
    Blume HK. Posttraumatic headache in pediatrics: an update and review. Curr Opin Pediatr. 2018;30(6):755–63. Scholar
  81. 81.
    Gawel MJ, Rothbart P, Jacobs H. Subcutaneous sumatriptan in the treatment of acute episodes of posttraumatic headache. Headache. 1993;33(2):96–7.CrossRefGoogle Scholar
  82. 82.
    Erickson JC. Treatment outcomes of chronic post-traumatic headaches after mild head trauma in US soldiers: an observational study. Headache. 2011;51(6):932–44. Scholar
  83. 83.
    Kamins J, Charles A. Posttraumatic headache: basic mechanisms and therapeutic targets. Headache. 2018;58(6):811–26. Scholar
  84. 84.
    Abu-Arefeh I, Russell G. Prevalence of headache and migraine in schoolchildren. Bmj. 1994;309(6957):765–9.CrossRefGoogle Scholar
  85. 85.
    Owens JA, Witmans M. Sleep problems. Curr Probl Pediatr Adolesc Health Care. 2004;34(4):154–79. Scholar
  86. 86.
    Wang J, Huang Q, Li N, Tan G, Chen L, Zhou J. Triggers of migraine and tension-type headache in China: a clinic-based survey. Eur J Neurol. 2013;20(4):689–96. Scholar
  87. 87.
    Barbanti P, Fabbrini G, Aurilia C, Vanacore N, Cruccu G. A case-control study on excessive daytime sleepiness in episodic migraine. Cephalalgia. 2007;27(10):1115–9. Scholar
  88. 88.
    Boardman HF, Thomas E, Millson DS, Croft PR. Psychological, sleep, lifestyle, and comorbid associations with headache. Headache. 2005;45(6):657–69. Scholar
  89. 89.
    Bruni O, Fabrizi P, Ottaviano S, Cortesi F, Giannotti F, Guidetti V. Prevalence of sleep disorders in childhood and adolescence with headache: a case-control study. Cephalalgia. 1997;17(4):492–8. Scholar
  90. 90.
    Miller VA, Palermo TM, Powers SW, Scher MS, Hershey AD. Migraine headaches and sleep disturbances in children. Headache. 2003;43(4):362–8.CrossRefGoogle Scholar
  91. 91.
    Barabas G, Ferrari M, Matthews WS. Childhood migraine and somnambulism. Neurology. 1983;33(7):948–9.CrossRefGoogle Scholar
  92. 92.
    Pradalier A, Giroud M, Dry J. Somnambulism, migraine and propranolol. Headache. 1987;27(3):143–5.CrossRefGoogle Scholar
  93. 93.
    Dexter JD. The relationship between stage III + IV + REM sleep and arousals with migraine. Headache. 1979;19(7):364–9.CrossRefGoogle Scholar
  94. 94.
    Tkachenko N, Singh K, Hasanaj L, Serrano L, Kothare SV. Sleep disorders associated with mild traumatic brain injury using sport concussion assessment tool 3. Pediatr Neurol. 2016;57:46–50.e1. Scholar
  95. 95.
    Jaramillo CA, Eapen BC, McGeary CA, McGeary DD, Robinson J, Amuan M, et al. A cohort study examining headaches among veterans of Iraq and Afghanistan wars: associations with traumatic brain injury, PTSD, and depression. Headache. 2016;56(3):528–39. Scholar
  96. 96.
    Hou L, Han X, Sheng P, Tong W, Li Z, Xu D, et al. Risk factors associated with sleep disturbance following traumatic brain injury: clinical findings and questionnaire based study. PLoS One. 2013;8(10):e76087. Scholar
  97. 97.
    Singh NN, Sahota P. Sleep-related headache and its management. Curr Treat Options Neurol. 2013;15(6):704–22. Scholar
  98. 98.
    Kelman L, Rains JC. Headache and sleep: examination of sleep patterns and complaints in a large clinical sample of migraineurs. Headache. 2005;45(7):904–10. Scholar
  99. 99.
    Uhlig BL, Engstrom M, Odegard SS, Hagen KK, Sand T. Headache and insomnia in population-based epidemiological studies. Cephalalgia. 2014;34(10):745–51. Scholar
  100. 100.
    Tran DP, Spierings EL. Headache and insomnia: their relation reviewed. Cranio. 2013;31(3):165–70. Scholar
  101. 101.
    Fialho LM, Pinho RS, Lin J, Minett TS, Vitalle MS, Fisberg M, et al. Sleep terrors antecedent is common in adolescents with migraine. Arq Neuropsiquiatr. 2013;71(2):83–6.CrossRefGoogle Scholar
  102. 102.
    Freedom T. Headaches and sleep disorders. Disease-a-month : DM. 2015;61(6):240–8. Scholar
  103. 103.
    Chiu YC, Hu HY, Lee FP, Huang HM. Tension-type headache associated with obstructive sleep apnea: a nationwide population-based study. J Headache Pain. 2015;16:34. Scholar
  104. 104.
    Schurks M, Winter A, Berger K, Kurth T. Migraine and restless legs syndrome: a systematic review. Cephalalgia. 2014;34(10):777–94. Scholar
  105. 105.
    Esposito M, Parisi P, Miano S, Carotenuto M. Migraine and periodic limb movement disorders in sleep in children: a preliminary case-control study. J Headache Pain. 2013;14:57. Scholar
  106. 106.
    Dahmen N, Kasten M, Wieczorek S, Gencik M, Epplen JT, Ullrich B. Increased frequency of migraine in narcoleptic patients: a confirmatory study. Cephalalgia. 2003;23(1):14–9. Scholar
  107. 107.
    Harnod T, Wang YC, Kao CH. Higher risk of developing a subsequent migraine in adults with nonapnea sleep disorders: a nationwide population-based cohort study. Eur J Intern Med. 2015;26(4):232–6. Scholar
  108. 108.
    Lateef T, Swanson S, Cui L, Nelson K, Nakamura E, Merikangas K. Headaches and sleep problems among adults in the United States: findings from the National Comorbidity Survey-Replication study. Cephalalgia. 2011;31(6):648–53. Scholar
  109. 109.
    Dosi C, Riccioni A, Della Corte M, Novelli L, Ferri R, Bruni O. Comorbidities of sleep disorders in childhood and adolescence: focus on migraine. Nat Sci Sleep. 2013;5:77–85. Scholar
  110. 110.
    Dash MB, Douglas CL, Vyazovskiy VV, Cirelli C, Tononi G. Long-term homeostasis of extracellular glutamate in the rat cerebral cortex across sleep and waking states. J Neurosci. 2009;29(3):620–9. Scholar
  111. 111.
    Kong J, Shepel PN, Holden CP, Mackiewicz M, Pack AI, Geiger JD. Brain glycogen decreases with increased periods of wakefulness: implications for homeostatic drive to sleep. J Neurosci. 2002;22(13):5581–7.CrossRefGoogle Scholar
  112. 112.
    Franken P, Dijk DJ, Tobler I, Borbely AA. Sleep deprivation in rats: effects on EEG power spectra, vigilance states, and cortical temperature. Am J Phys. 1991;261(1 Pt 2):R198–208. Scholar
  113. 113.
    Shearer WT, Reuben JM, Mullington JM, Price NJ, Lee BN, Smith EO, et al. Soluble TNF-alpha receptor 1 and IL-6 plasma levels in humans subjected to the sleep deprivation model of spaceflight. J Allergy Clin Immunol. 2001;107(1):165–70. Scholar
  114. 114.
    Vgontzas AN, Zoumakis E, Bixler EO, Lin HM, Follett H, Kales A, et al. Adverse effects of modest sleep restriction on sleepiness, performance, and inflammatory cytokines. J Clin Endocrinol Metab. 2004;89(5):2119–26. Scholar
  115. 115.
    Dodick DW, Eross EJ, Parish JM, Silber M. Clinical, anatomical, and physiologic relationship between sleep and headache. Headache. 2003;43(3):282–92.CrossRefGoogle Scholar
  116. 116.
    Lovati C, D’Amico D, Raimondi E, Mariani C, Bertora P. Sleep and headache: a bidirectional relationship. Expert Rev Neurother. 2010;10(1):105–17. Scholar
  117. 117.
    Zawilska JB, Skene DJ, Arendt J. Physiology and pharmacology of melatonin in relation to biological rhythms. Pharmacol Rep. 2009;61(3):383–410.CrossRefGoogle Scholar
  118. 118.
    Kunz D, Mahlberg R. A two-part, double-blind, placebo-controlled trial of exogenous melatonin in REM sleep behaviour disorder. J Sleep Res. 2010;19(4):591–6. Scholar
  119. 119.
    Nesbitt AD, Leschziner GD, Peatfield RC. Headache, drugs and sleep. Cephalalgia. 2014;34(10):756–66. CrossRefPubMedGoogle Scholar
  120. 120.
    Supornsilpchai W, Sanguanrangsirikul S, Maneesri S, Srikiatkhachorn A. Serotonin depletion, cortical spreading depression, and trigeminal nociception. Headache. 2006;46(1):34–9. Scholar
  121. 121.
    Garcia-Azorin D, Santos-Lasaosa S, Gago-Veiga AB, Viguera Romero J, Guerrero-Peral AL. Real world preventative drug management of migraine among Spanish neurologists. J Headache Pain. 2019;20(1):19. Scholar
  122. 122.
    Simon MJ, Iliff JJ. Regulation of cerebrospinal fluid (CSF) flow in neurodegenerative, neurovascular and neuroinflammatory disease. Biochim Biophys Acta. 2016;1862(3):442–51. Scholar
  123. 123.
    Iliff JJ, Lee H, Yu M, Feng T, Logan J, Nedergaard M, et al. Brain-wide pathway for waste clearance captured by contrast-enhanced MRI. J Clin Invest. 2013;123(3):1299–309. Scholar
  124. 124.
    Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, et al. Structural and functional features of central nervous system lymphatic vessels. Nature. 2015;523(7560):337–41. Scholar
  125. 125.
    Aspelund A, Antila S, Proulx ST, Karlsen TV, Karaman S, Detmar M, et al. A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J Exp Med. 2015;212(7):991–9. Scholar
  126. 126.
    Iliff JJ, Wang M, Zeppenfeld DM, Venkataraman A, Plog BA, Liao Y, et al. Cerebral arterial pulsation drives paravascular CSF-interstitial fluid exchange in the murine brain. J Neurosci. 2013;33(46):18190–9. Scholar
  127. 127.
    Mestre H, Hablitz LM, Xavier AL, Feng W, Zou W, Pu T, et al. Aquaporin-4-dependent glymphatic solute transport in the rodent brain. eLife. 2018;7.
  128. 128.
    Ringstad G, Vatnehol SAS, Eide PK. Glymphatic MRI in idiopathic normal pressure hydrocephalus. Brain. 2017;140(10):2691–705. Scholar
  129. 129.
    Ringstad G, Valnes LM, Dale AM, Pripp AH, Vatnehol SS, Emblem KE, et al. Brain-wide glymphatic enhancement and clearance in humans assessed with MRI. JCI Insight. 2018;3(13).
  130. 130.
    Goodman JR, Adham ZO, Woltjer RL, Lund AW, Iliff JJ. Characterization of dural sinus-associated lymphatic vasculature in human Alzheimer’s dementia subjects. Brain Behav Immun. 2018;73:34–40. Scholar
  131. 131.
    Absinta M, Ha SK, Nair G, Sati P, Luciano NJ, Palisoc M, et al. Human and nonhuman primate meninges harbor lymphatic vessels that can be visualized noninvasively by MRI. eLife. 2017;6.
  132. 132.
    Eide PK, Vatnehol SAS, Emblem KE, Ringstad G. Magnetic resonance imaging provides evidence of glymphatic drainage from human brain to cervical lymph nodes. Sci Rep. 2018;8(1):7194. Scholar
  133. 133.
    Plog BA, Dashnaw ML, Hitomi E, Peng W, Liao Y, Lou N, et al. Biomarkers of traumatic injury are transported from brain to blood via the glymphatic system. J Neurosci. 2015;35(2):518–26. Scholar
  134. 134.
    Gaberel T, Gakuba C, Goulay R, Martinez De Lizarrondo S, Hanouz JL, Emery E, et al. Impaired glymphatic perfusion after strokes revealed by contrast-enhanced MRI: a new target for fibrinolysis? Stroke. 2014;45(10):3092–6. Scholar
  135. 135.
    Bolay H, Reuter U, Dunn AK, Huang Z, Boas DA, Moskowitz MA. Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model. Nat Med. 2002;8(2):136–42. Scholar
  136. 136.
    Schain AJ, Melo-Carrillo A, Strassman AM, Burstein R. Cortical spreading depression closes paravascular space and impairs glymphatic flow: implications for migraine headache. J Neurosci. 2017;37(11):2904–15. Scholar
  137. 137.
    Yuan H, Lauritsen CG, Kaiser EA, Silberstein SD. CGRP Monoclonal antibodies for migraine: rationale and Progress. BioDrugs. 2017;31(6):487–501. CrossRefPubMedGoogle Scholar
  138. 138.
    Messlinger K, Hanesch U, Baumgartel M, Trost B, Schmidt RF. Innervation of the dura mater encephali of cat and rat: ultrastructure and calcitonin gene-related peptide-like and substance P-like immunoreactivity. Anat Embryol. 1993;188(3):219–37.CrossRefGoogle Scholar
  139. 139.
    Edvinsson L, Ekman R, Jansen I, McCulloch J, Uddman R. Calcitonin gene-related peptide and cerebral blood vessels: distribution and vasomotor effects. J Cereb Blood Flow Metab. 1987;7(6):720–8. Scholar
  140. 140.
    Eftekhari S, Salvatore CA, Calamari A, Kane SA, Tajti J, Edvinsson L. Differential distribution of calcitonin gene-related peptide and its receptor components in the human trigeminal ganglion. Neuroscience. 2010;169(2):683–96. Scholar
  141. 141.
    Lennerz JK, Ruhle V, Ceppa EP, Neuhuber WL, Bunnett NW, Grady EF, et al. Calcitonin receptor-like receptor (CLR), receptor activity-modifying protein 1 (RAMP1), and calcitonin gene-related peptide (CGRP) immunoreactivity in the rat trigeminovascular system: differences between peripheral and central CGRP receptor distribution. J Comp Neurol. 2008;507(3):1277–99. Scholar
  142. 142.
    Messlinger K. The big CGRP flood - sources, sinks and signalling sites in the trigeminovascular system. J Headache Pain. 2018;19(1):22. Scholar
  143. 143.
    Eftekhari S, Salvatore CA, Johansson S, Chen TB, Zeng Z, Edvinsson L. Localization of CGRP, CGRP receptor, PACAP and glutamate in trigeminal ganglion. Relation to the blood-brain barrier. Brain Res. 2015;1600:93–109. Scholar
  144. 144.
    Dux M, Will C, Eberhardt M, Fischer MJM, Messlinger K. Stimulation of rat cranial dura mater with potassium chloride causes CGRP release into the cerebrospinal fluid and increases medullary blood flow. Neuropeptides. 2017;64:61–8. Scholar
  145. 145.
    Bouley J, Chung DY, Ayata C, Brown RH Jr, Henninger N. Cortical spreading depression denotes concussion injury. J Neurotrauma. 2018;36:1008–17. Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pediatrics, Division of Child Neurology, Doernbecher Children’s HospitalOregon Health & Science UniversityPortlandUSA
  2. 2.Department of Neurology, Department of Medicine, Division of Pulmonary and Critical Care Medicine, Department of Behavioral NeuroscienceOregon Health & Science UniversityPortlandUSA
  3. 3.Oregon Institute of Occupational Health SciencesOregon Health and Science UniversityPortlandUSA
  4. 4.VA Portland Health Care SystemPortlandUSA
  5. 5.Center for Policy and Research in Emergency Medicine, Department of Emergency MedicineOregon Health & Science UniversityPortlandUSA
  6. 6.Department of Anesthesiology and Perioperative MedicineOregon Health & Science UniversityPortlandUSA
  7. 7.Knight Cardiovascular InstituteOregon Health & Science UniversityPortlandUSA

Personalised recommendations