CMDAT Research Foundation
CMDAT Research Foundation 

Association between major types of headaches and geographic altitude:  a preliminary report

Headaches remain a worldwide concern affecting people of all ages, races, income levels and geographical areas. For example, about one billion people suffer from migraine worldwide1, 2.Approximately 2% of the world population suffers from chronic migraine1, 2.Regional variations for headaches are significant and rates of migraine, for instance, are somewhat lower in Asia and Africa compared to Europe where this type of headache affects up to 28% of people at some point in their lives. At the same time, about 140 million people live above 2,500 meters worldwide. In the US, the mean altitude of Juneau, the capital of Alaska is 0 feet while some US large cities are located at high altitude such as Denver (5,278 feet), Cheyenne (6,062 feet) or Santa Fe (7,000 feet) etc.3


Previous large population-based studies found that residents of areas situated at 1500 m or above have longer life expectancies as compared to those who reside at sea level4. This large population-based study also found lower rates for ischemic heart disease and higher rates of COPD in the high altitude area. Our previous research indicates that the rate of hospitalizations for some conditions can be affected by altitude levels as well. For instance, we examined hospitalizations rates for Alzheimer’s disease (AD) and we found that rates of AD are significantly lower in the “mountain” states of the US as compared to the states in the lowland area. For example, the proportion of AD discharges to all discharges in low altitude South Carolina or in lowland Maryland is more than 4-fold bigger than such proportion in high altitude Utah (0.017 versus 0.004 respectively)5. On the other hand, we hypothesized that high altitude can trigger many negative post-traumatic brain injury (TBI) outcomes such as post-traumatic headache (PTH)6.


Therefore, it is biologically plausible that elevation may affect population rates of complex diseases affecting brain and central nervous system such as migraine or PTH.

Research evidence suggests that high altitude may increase risk of certain headaches (in the absence of TBI); however, little is known about epidemiology and overall association between headaches and altitude level. Some people are known to suffer from headaches who either reside or travel to high altitude areas and who often seek validation for the cause of their headaches. In a recent prospective trial, Broessner et al determined that normobaric hypoxia is a trigger for high altitude headache and migraine-like headache attacks even in healthy volunteers. The largest relevant study we are aware of is an acute mountain sickness (AMS) analysis of 168 athletes with neurological impairment 7. Kamaraj et al found that neurological impairment, prior history of occurrence of AMS, and prior occurrence of headache at high altitude could be used as predictors for AMS, with the most common symptoms being headache and fatigue8. However, this study considered only the general category of “headache,” and was underpowered statistically to draw significant conclusions.


Therefore, although several epidemiologic studies have examined the prevalence of migraine and headaches at various populations, there are no large, population-based studies that examined the association between specific types of headaches (i.e. migraine or post-traumatic headaches (PTH)) and altitude level. On one hand, cellular hypoxia is caused by decreased barometric pressure, leading to headache. High elevation results in lowered partial pressure of oxygen and the human brain responds to it by changing the responsiveness of cerebral circulation. In addition, exposure to hypoxia has been shown to result in multiple changes to central nervous system physiology and behavior, such as verbal working and short-term memory impairment, hippocampal atrophy, neurodegeneration,significant differences in the middle, posterior cerebral and basilar artery flow velocity9, and alterations in the blood brain barrier (BBB)10. Additional autonomic system alterations secondary to neurological impairment (e.g. cardiovascular and metabolic) could hinder compensatory mechanisms, thereby contributing to the occurrence of headache at altitude11, 12.


On the other hand, hypoxia can also trigger some potentially beneficial physiological reactions to protect human organism from damage. One potentially beneficial reaction is the higher production of erythropoietin (EPO) by human kidneys. Previous research evidence suggests that subtle hypoxia can result in moderate production of EPO while presence at 3,000 m above the sea level may result in a sharp, almost 2-fold renal EPO production13. EPO has been shown to possess multiple neuroprotective properties14. EPO was also shown to protect the astroglial space by reducing the concentration of extracellular glutamate14. In addition, EPO was shown to be effective agent protecting and repairing many important processes in the nervous system. Furthermore, synthesis of EPO in astrocytes could protect them against apoptogenic chemicals or even low oxygen pressure14. Overall, EPO is currently viewed as a substance that can sustain antiapoptotic responses in many tissues there it can be regarded as a general tissues-protective cytokine.


Therefore, it is unclear whether high altitude is a risk factor for various forms of headaches including migraine or PTH and no large population based studies have been conducted to examine the rate of hospitalizations for various types of headache at high altitude so far.


1.      Unger J. Migraine headaches: A historical prospective, a glimpse into the future, and migraine epidemiology. Dis Mon. 2006;52:367-384

2.         Lipton RB, Stewart WF. Migraine headaches: Epidemiology and comorbidity. Clin Neurosci. 1998;5:2-9


4.         Ezzati M, Horwitz ME, Thomas DS, Friedman AB, Roach R, Clark T, Murray CJ, Honigman B. Altitude, life expectancy and mortality from ischaemic heart disease, stroke, copd and cancers: National population-based analysis of us counties. J Epidemiol Community Health. 2012;66:e17

5.         Ismailov RM. Erythropoietin and epidemiology of alzheimer disease. Alzheimer Dis Assoc Disord. 2013;27:204-206

6.         Ismailov RM, Lytle JM. Traumatic brain injury, its outcomes and high altitude. J Spec Oper Med, in press

7.         Broessner G, Rohregger J, Wille M, Lackner P, Ndayisaba JP, Burtscher M. Hypoxia triggers high-altitude headache with migraine features: A prospective trial. Cephalalgia. 2015

8.         Kamaraj DC, Dicianno BE, Cooper RA, Hunter J, Tang JL. Acute mountain sickness in athletes with neurological impairments. J Rehabil Res Dev. 2013;50:253-262

9.         Singh SB, Thakur L, Anand JP, Panjwani U, Yadav D, Selvamurthy W. Effect of high altitude (ha) on event related brain potentials. Indian J Physiol Pharmacol. 2003;47:52-58

10.       Merkelbach S, Haensch CA, Hemmer B, Koehler J, Konig NH, Ziemssen T. Multiple sclerosis and the autonomic nervous system. J Neurol. 2006;253 Suppl 1:I21-25

11.       Bravo G, Guizar-Sahagun G, Ibarra A, Centurion D, Villalon CM. Cardiovascular alterations after spinal cord injury: An overview. Curr Med Chem Cardiovasc Hematol Agents. 2004;2:133-148

12.       Greve MW, Zink BJ. Pathophysiology of traumatic brain injury. Mt Sinai J Med. 2009;76:97-104

13.       Eckardt KU, Boutellier U, Kurtz A, Schopen M, Koller EA, Bauer C. Rate of erythropoietin formation in humans in response to acute hypobaric hypoxia. J Appl Physiol (1985). 1989;66:1785-1788

14.       Joyeux-Faure M. Cellular protection by erythropoietin: New therapeutic implications? J Pharmacol Exp Ther. 2007;323:759-762





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Did you know that life expectancy in the United States has declined? It happened again following last year's decline and for the first time in more than two decades!


Did you also know that the oldest man on Earth (who is  now 123) lives in the mountains at an altitude of more than 12,000 feet?


But did you also know that previous large population-based studies found that residents of areas situated at 1500 m or above have longer life expectancy as compared to those who reside at sea level.


Read more about our research on aging and altitude. Answers that are yet to be found!

CMDAT stands for Complex Mechanisms of Disease, Aging and Trauma.


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