Introduction

I would like to speculate on how high altitude may limit the brain and how, as a consequence, the brain might limit the body it occupies at high altitude. Such limitations will be more apparent at extremely high altitudes, by which I mean above approximately 7000–8000m. To characterize the territory we will wander, I will share a personal experience, one of those pivotal moments that can change the direction of a life in unexpected ways.

Shortly before 19:00h on 22 May 1963, Willi Unsoeld and I departed the summit of Mount Everest (8850m). We had ascended another way, hence, were descending what for us was unknown terrain.

‘We almost ran along the crest, trusting Lute and Barrel’s tracks to keep us a safe distance from the cornice edge. Have to reach the South Summit before dark, I thought, or we’ll never find the way. The sun dropped below the jagged horizon. We didn’t need goggles any more. There was a loud hiss. Damn! Something’s broken. I reached back and turned off the valve. Without oxygen, I tried to keep pace with the rope disappearing over the edge ahead. Vision dimmed, the ground began to move. I stopped till things cleared, waved my arms and shouted into the wind for Willi to hold up. The taught rope finally stopped him. I tightened the regulator, then moved the oxygen on. No hiss! To my relief it had only been jarred loose. On oxygen again I could move rapidly’.     Thomas F. Hornbein, Everest, the West Ridge     (Hornbein, 1998)

Thinking back on this moment, and recalling descriptions of similar experiences, a number of thoughts, and questions, occur.

First, although an acclimatized lowlander can survive for a time on the summit of Everest without supplemental oxygen, one is so close to the limit that even a modicum of excess exertion may impair brain function. In my case, the visual cortex seemed to be the prime target; this same dimming was experienced the evening before while digging a tent platform a bit too strenuously at 8320m while not using supplemental oxygen. Lionel Terray, indulging in the same activity at approximately 7400m on Annapurna in 1950, wrote: ‘At times I would force so much that a black veil began to form in front of my eyes and I fell to my knees, panting like an overdriven beast’ (Terray, 1963). Descriptions of hallucinations at these extreme heights are not uncommon in the literature. Two questions were provoked by this experience. (i) Might lack of oxygen to the brain limit maximum physical performance at these extremely high altitudes? (ii) If brain oxygenation near the summit of Everest is so close to the threshold where function is actually inhibited, could such exposure also cause residual brain injury following return to sea level?

This second question has been a matter of speculation and concern since humans first contemplated venturing to these great heights. By now, a fairly extensive literature exists that describes how a low partial pressure of oxygen affects the brain, both acutely and after varying durations of acclimatization. We also have some information on the aftereffects of hypoxia.

Consequences of hypoxia: real time

Consequences of hypoxia: aftereffects

In this same paper Ryn also provided the first report of behavioral abnormalities persisting after returning to low altitude (Ryn, 1971). Since that time, a small but mostly consistent literature has documented neurobehavioral changes following exposure to very high altitude. I will describe two of these works briefly, that of Hornbein, Schoene and Townes (Hornbein et al., 1989) and the observations reported by Regard et al. (Regard et al., 1989). We studied mainly members of the American Medical Research Expedition to Mount Everest (AMREE) in 1981 and subjects participating in Operation Everest II, a chamber simulation performed in 1985. Comparing performance following hypoxic exposure with that prior to ascent, we found decrements in short-term memory, aphasic deficits and decreased finger-tapping speed. When AMREE members were tested a year later, memory and aphasia deficits were no longer apparent, but in 13 of 16 participants finger-tapping speed remained impaired. Regard et al. studied eight ‘world-class’ mountaineers, all of whom had climbed above 8500m one or more times without the use of supplemental oxygen (Regard et al., 1989). Neuropsychometric tests were performed 2–10 months after return to low altitude. All eight showed some performance decrements compared with a matched group of climbers who had no such high-altitude exposure. Five individuals seemed to be particularly affected, with mild impairment of concentration, short-term memory and cognitive flexibility (the ability to shift concepts and control errors). Three of these five showed electroencephalographic (EEG) abnormalities. Garrido et al. have reported magnetic resonance imaging (MRI) abnormalities in some individuals after return from these high altitudes (Garrido et al., 1993). Other literature is summarized by Raichle and Hornbein (Raichle and Hornbein, 2001).

The conclusions from these observations are that, even without a loss of consciousness or overt evidence of impaired function while at extreme altitude, some individuals show evidence of brain injury, at least for a time, after return to sea level. Individuals seem to vary considerably in their vulnerability. One factor associated with such variability is the ventilatory response to hypoxia (HVR). Curiously, individuals with a higher HVR appeared to sustain greater impairment in spite of a higher arterial oxygen saturation and a greater capacity to perform work while at high altitude (Masuyama et al., 1986; Schoene et al., 1984). I will return to the possible significance of this observation in the next section.

A sea-level counterpart to these high-altitude mountaineers may be individuals with arterial hypoxemia consequent to chronic obstructive pulmonary disease. These individuals show similar impairment on neuropsychometric tests (Grant et al., 1982), and the progression of this impairment can be prevented, perhaps even reversed, by long-term continuous oxygen therapy to ameliorate the hypoxemia (Grant and Heaton, 1985). These findings too support the presumption that even non-life-threatening hypoxia may hurt the brain if sustained long enough.

What is going on?

High altitude slows the brain and can injure the brain, and brain hypoxia may play a role in limiting physical performance at extreme elevations. How do these changes come about? I would like to speculate on two interconnected questions. (i) Does brain hypoxia limit work capacity, at least at extremely high altitude? If so, what mechanisms might provoke sufficient hypoxia of the relevant neuronal pathways? (ii) Noting the general belief, based upon extensive laboratory investigations in non-human primates, that inspired hypoxia alone does not cause brain injury, how might we explain the residual deficits observed in apparently normally functioning high-altitude mountaineers and chronically hypoxemic sea-level dwellers?

Concluding remarks

We know that the human brain at extremely high altitude exists in an environment close to the limits of what is needed for it to function. Both real-time and residual impairments occur. What we do not know yet is whether brain hypoxia limits the capacity to perform work near the summit of Mount Everest. Nor do we understand how hypoxia of a degree that appears to allow fairly normal function (such as climbing Everest without oxygen) leaves in its wake a residual injury to the brain.