General changes in cerebrovascular function during hypoxia

In spite of a great deal of research over the last few decades, a clear understanding of the effect of hypoxia on the brain remains elusive (see Ainslie et al. 2014; Ainslie et al. 2016; Haddad and Jiang 1993; Hoiland et al. 2016; Hossmann 1999; Raichle and Hornbein 2001; Siesjö 1992a; Siesjö 1992b). Nevertheless, there are three consistent findings from the existing body of research. First, whole human brain oxygen consumption remains constant with changing levels of oxygenation, even with severe degrees of hypoxia. To maintain this equilibrium, an increase in blood flow commensurate to the severity of hypoxia must occur. Second, in spite of constant oxygen consumption, hypoxia accelerates local glucose utilization and lactate production suggesting an increase in glycolytic flux by nerve cells. However, utilization is depressed during severe hypoxemia while oxygen consumption remains the same. In clinical states of severe ischemia, the hippocampus, white matter, superior colliculus, and lateral geniculates appear particularly sensitive to reductions in tissue PO₂. Third, brain tissue concentrations of ATP, ADP, and AMP, markers of the energy state of the tissue, remain close to normal even during severe hypoxia, comparable to elevations above 8000 m. While the brain is very sensitive to a decrease in oxygen supply, as evidenced by the changes in blood flow and glucose metabolism, examples from nature demonstrate some species’ phenomenal resistance to profound hypoxia, such as the turtle (Perez-Pinzon et al. 1992), the harbor seal (Kerem and Elsner 1973), and the bar-headed goose (Faraci and Fedde 1986; Laguë 2017; Scott et al. 2015). Albeit to a lesser extent than these hypoxia-resistant animals, high altitude populations, such as Tibetans and Sherpa of the Nepal Himalaya, have also demonstrated increased tolerance to hypoxia (Garrido et al. 1993).

Ionic and neurotransmitter changes in the brain during hypoxia

It is clear that hypoxia has dramatic effects on the central nervous system that are mediated, to a large extent, by the activity of ion channels. Although influenced by a variety of methodological issues such as the duration of hypoxia, cell type, experimental conditions, and age of the animals, most investigators describe an initial hyperpolarization of nerve cells followed by severe depolarization and influx (and hence elevation) of calcium [Ca²⁺]_i during hypoxia (Diarra et al. 1999; Lukyanetz et al. 2003; Tjong et al. 2007; Yao and Haddad 2004). These observations are important as it is widely held that the increase in [Ca²⁺]_i results in cell death. The initial, transient hyperpolarization observed in response to hypoxia in hippocampal and dorsal vagal neurons is due to the opening of ATP-sensitive K⁺ (K_ATP) channels (Trapp and Ballanyi 1995). At normal cellular ATP levels, the K_ATP channels are inactive, but as ATP is depleted during hypoxia, increased activity of these channels leads to K⁺ efflux and hyperpolarization, perhaps in an effort to protect the cells and minimize hypoxia-induced damage by reducing neuronal input (Fujimura et al. 1997; Huang et al. 2006; Yamamoto et al. 1997). A few studies suggest that large conductance calcium-activated potassium channels, perhaps activated by release of Ca²⁺ from internal stores, may also participate in the initial hyperpolarization (Erdemli et al. 1998; Silver and Erecińska 1990; Yamamoto et al. 1997). However, sustained hypoxia/anoxia leads to depolarization in hippocampal (Raley-Susman et al. 2001) and hypoglossal (Haddad and Donnelly 1990) neurons. Similar to the effects reported in neurons, sustained hypoxia/anoxia also leads to depolarization (Ballanyi et al. 1996) and increased [Ca²⁺]_i in glia. The mechanisms underlying this depolarization, which have been reviewed in detail elsewhere (Shimoda and Polak 2010), are complex and unresolved.

Although there is also evidence that global oxygen delivery to the brain is sufficient to maintain overall metabolism and energetics, other extramitochondrial cellular processes are more sensitive to even small hypoxic insults. Specifically, the synthesis of enzymes (e.g., prolyl hydroxylase, tryptophan hydroxylase, and tyrosine hydroxylase) and related neurotransmitters (e.g., glutamate, serotonin, acetylcholine, and dopamine) is very oxygen sensitive (Pulsinelli 1985). The oxygen partial pressures at which these enzymatic reactions proceed at half the normal activity (K_m) for oxygen are within the physiological range of PO₂ values (e.g., 30–60 mmHg) experienced during exposure to hypoxia (Pulsinelli 1985). The differential brain responses to hypoxia, along with variability in neuronal vulnerability, probably explain the dose-dependent changes in neurological symptoms and deficits (Pulsinelli 1985). For example, animal studies have reported that brainstem parenchymal PO₂ is ∼25 mmHg, some ∼70 mmHg lower than arterial PO₂ even during normoxia (Marina et al. 2015). However, a recent magnetic resonance proton spectroscopy study during which humans were acutely exposed to 40 minutes of poikilocapnic hypoxia (F_IO₂ 0.10), reported small elevations in cerebral metabolic rate of O₂ (∼8%) and reductions in creatine and phosphocreatine concentrations of ∼15% (Vestergaard et al. 2016). The authors speculated that a shift toward creatine-mediated ATP catalysis as a manifestation of hypoxia could reflect a defense mechanism.

Vascular endothelial growth factor and hypoxia

As mentioned in Chapter 21, certain factors, such as hypoxia-induced vascular endothelial growth factor, are known to induce fluid leak from capillaries in the brain (Fischer et al. 1999; Schoch et al. 2002), an effect known to occur with acute hypoxic exposure. The mechanism of the stimulation of vascular endothelial growth factor (VEGF) has been identified, and the beneficial effects to the brain in terms of improvement of oxygen delivery have been established.

The response of the brain to chronic hypoxia and ischemia is one of survival, which takes the forms of angiogenesis and neuroprotection, respectively. The initiation of these events depends on the stimulation of the transcription factor, hypoxia-inducible factor 1 (HIF-1) (Semenza 2019). The alpha portion of the heterodimer is the one that acts as an immediate transcription factor for a number of growth factors, one of which is VEGF (see Chapter 6). HIF-1α is present in many tissues and responds immediately and transiently to hypoxia and/or ischemia. HIF-1α targets mRNA genes and stimulates the induction of the VEGF gene, which, along with the synergistic effect of glycolytic metabolism, induces angiogenesis in the insulted cerebral tissue (Bergeron et al. 2000; Marti et al. 2000).

With several weeks of exposure to hypoxia, rats demonstrate rapid and sustained increase in HIF-1α (Chavez et al. 2000), which stimulates VEGF. This, together with other growth factors, results in angiogenesis and vascular remodeling such that there is an increase in capillary density. While increases in cerebral blood flow, discussed later in the chapter, act to maintain convective oxygen delivery and offset reductions in brain tissue PO₂ levels in the acute phase, the later onset angiogenic response is crucial for increasing capillary density and reducing diffusional distance of O₂ as cerebral blood flow returns to normal values following acclimatization. As brain tissue PO₂ is quite low, even in normal conditions (∼25 mmHg), the diffusive transport of O₂ would be otherwise markedly reduced in the absence of such angiogenesis (Boero et al. 1999; Dor et al. 2001; LaManna et al. 2004; Pichiule and LaManna 2002). This body of work, which has been reviewed in detail elsewhere (LaManna et al. 2004; Semenza 2000; Xu and LaManna 2006), is an impressive example of the quest to understand down to the genetic level the adaptation to hypoxia that minimizes the effects of decreased oxygen availability, whether that results from exposure to high altitude or clinical disease.

Hypoxia and the electroencephalogram

Acute exposure to simulated high altitude has a profound effect on electroencephalography (EEG) activity. Above 6000 m, slowing of EEG activity, which manifests as increased power at lower frequencies, has been typically reported (Kraaier et al. 1988; Ozaki et al. 1995; Papadelis et al. 2007; Rozhkov et al. 2009), with increased synchronization and decreased entropy of the signal (Papadelis et al. 2007; Rozhkov et al. 2009). Starting from 3000 m, the degree of slowing of cortical activity seems to be progressively related to the degree of hypoxia (Ozaki et al. 1995). In addition, while at lower simulated altitudes (3000 m and 4000 m) the decrease in spectral power at relatively higher frequencies (>10 Hz) of the EEG signal is uniform across every brain region, at a simulated altitude of 6000 m, there is complete suppression of this component in the posterior area of the brain (Ozaki et al. 1995). Functionally, slowing and synchronization of the EEG signal are thought to represent decreased synaptic transmission in neurons that are not hypoxic resistant, leading to their electrophysiological isolation from neurons that are hypoxic resistant (Goodall et al. 2014a; Papadelis et al. 2007; Pincus 1994). Interestingly, during an abstract thinking task at a simulated altitude of 4000 m, increased high-frequency activity over the frontal lobe precentral gyrus was detected compared to the same task in normoxia (Decroix et al. 2018). Here, the authors also reported that abstract thinking performance did not deteriorate in the simulated altitude condition, which was interpreted as evidence that large activation of the frontal lobe precentral gyrus in hypoxia is required to preserve cognitive performance in face of decreased neuronal efficiency (Decroix et al. 2018).

Altitude-related changes in EEG activity persist during acclimatization. Travel to and stay at altitudes between 3650 m and 4300 m for 11 to 30 days is associated with increased power of the higher frequency components (>12 Hz) of the EEG in the middle posterior parietal and occipital areas (Gritti et al. 2012; Zhao et al. 2016), while treks from 3440 m to 5050 m over 14 to 15 days, with seven to eight days over 5000 m, are associated with similar changes in the frontal area (Feddersen et al. 2015). Interestingly, mountaineers who developed acute mountain sickness (AMS) showed increased power of the frontal and occipital activity signal after two days at 3440 m for frequencies of the EEG signal above 8 Hz (Feddersen et al. 2015).

Evoked potentials and hypoxia

Acute hypoxia has effects on cerebral visual and auditory processing capabilities.

Cerebral blood flow under normal physiologic conditions

Under normal conditions, the cerebral vasculature is sensitive to changes in C_aO₂. This sensitivity occurs below a P_aO₂ of ∼55 mmHg, whereby further reductions in P_aO₂ lead to an accelerated reduction in arterial oxygen saturation (Figure 12.2). This response characteristic is due to the shape of the oxyhemoglobin dissociation curve and its impact on the relationship between P_aO₂ and C_aO₂. The cerebrovascular response to changes in C_aO₂ is dependent on the prevailing P_aCO₂; hypercapnia increases and hypocapnia decreases cerebrovascular sensitivity to hypoxia (Mardimae et al. 2012). The cerebral vasculature is also highly sensitive to small changes in P_aCO₂. Studies employing a range of different experimental techniques for the assessment of CBF, which have been reviewed elsewhere (Ainslie et al. 2016; Hoiland et al. 2014; Hoiland et al. 2016), all show an approximate 6–8% increase and/or 3–4% decrease in flow per millimeter of mercury change in P_aCO₂ above and below eupneic P_aCO₂, respectively. Studies of hypoxic cerebrovascular reactivity are thus confounded by the ventilatory response to hypoxia, which produces hypocapnia and elicits a cerebrovascular vasoconstrictive response (i.e., poikilocapnic).

As reviewed elsewhere (Ainslie and Subudhi 2014; Hoiland et al. 2018), studies incorporating a range of techniques to assess the CBF response to isocapnic hypoxia have reported CBF reactivities ranging from a 0.5% to 2.5% increase in CBF per percentage point reduction in arterial oxygen saturation_. For a given severity of isocapnic hypoxia, the percent increase in blood flow to the brainstem is greater than that to the middle and anterior regions, as assessed by flow through the vertebral and internal carotid arteries, respectively (Ogoh et al. 2013; Willie et al., 2012). Congruous positron emission tomography (PET) scan data collected during isocapnic hypoxia reveal that cortical blood flow is less responsive to hypoxia than phylogenetically older areas of the brain (Binks et al. 2008). In addition to dilation of the arteries throughout the cerebrovascular with hypoxia and hypercapnia, venous capacitance vessels also dilate (Lawley et al. 2014; Weinbrecht et al. 1986; Wilson et al. 2013), thus also increasing the volume of cerebral venous blood. Increased cerebral blood volume is important as it may mediate increases in intracranial pressure and play a role in the pathophysiology of high altitude headache and cerebral edema (Lawley et al. 2015), as discussed in Chapters 20 and 21. Unlike the response to P_aCO₂, however, the CBF response to oxygen appears to be determined by the content rather than the partial pressure of oxygen per se (Ainslie et al. 2016; Hoiland et al. 2016 2018). It is unknown if the venous capacitance vessels are also regulated via oxygen content. However, in conscious animals and humans, the hyperventilation caused by hypoxemia causes a reduction in P_aCO₂ and an increase in pH, which elicits a cerebral vasoconstrictive stimulus. Therefore, the results shown in Figure 12.2 cannot be applied directly to the climber at extreme altitude, as discussed next.

Cerebral blood flow at high altitude

During ascent and initial stay at high altitude, increases in CBF are elicited via reductions in C_aO₂ and consequent hypoxic cerebral vasodilation (Hoiland et al. 2016). The magnitude of this increase in CBF is altitude dependent and contingent on the countervailing influences of hypoxemia, decreased C_aO₂, and hypocapnia. The resulting cerebral vasodilation occurs throughout the cerebral vasculature from the large extracranial cerebral conduit arteries (i.e., internal carotid and vertebral arteries), large intracranial arteries (e.g., middle cerebral artery), through to pial vessels and is adequate to maintain CDO₂ (Figure 12.3).

While hyperventilation mitigates the drop in C_aO₂ at high altitude, it leads to concomitant reductions in P_aCO₂ resulting in an increased blood and CSF pH (Lahiri and Milledge 1967) as discussed in Chapter 9. As the cerebral vasculature is highly sensitive to alterations in pH (Kety and Schmidt 1948; Willie et al. 2012, 2015), decreased P_aCO₂ and increased pH produce a marked vasoconstrictor stimulus (Willie et al. 2014) that counteracts the hypoxic vasodilatory stimulus, although the hypoxic stimulus maintains a net vasodilatory outcome (Willie et al. 2015). Given the interplay of C_aO₂ and P_aCO₂ on CBF regulation at altitude, overall regulation appears to be dependent on four primary factors: 1) the hypoxic ventilatory response (HVR), 2) the ventilatory response to changes in CO₂ (HCVR), 3) hypoxic cerebral vasodilation, and 4) hypocapnic cerebral vasoconstriction. The HVR and HCVR determine the prevailing arterial blood gas stimuli (see Chapter 9), while hypoxic cerebral vasodilation and hypocapnic vasoconstriction determine the magnitude by which the cerebral vasculature responds to the arterial blood gas stimuli.

Hypoxic cerebral vasodilation notably occurs via several pathways but appears to be primarily regulated by deoxyhemoglobin-mediated release of ATP and nitric oxide (reviewed in Hoiland et al. 2018). These signaling processes alleviate cerebral hypoxemia by facilitating increased CBF (Doctor and Stamler 2011; Ellsworth et al. 2009; Gladwin et al. 2006; Hoiland et al. 2016). Another important consideration in the regulation of CBF at altitude is sympathetic nervous system activity (Brassard et al. 2017). However, a laboratory study demonstrates no influence of α₁-adrenoceptor blockade on CBF during six hours of exposure to hypoxia (F_IO₂ 0.11) (Lewis et al. 2014). Conversely, at high altitude, combined α₁– and nonselective β-adrenoceptor blockade reduces CBF, although this is likely due to a marked drop in mean arterial pressure (∼25 mmHg) (Ainslie et al. 2012) and does not appear to have a direct influence on cerebrovascular tone.

As time at high altitude progresses, CBF stabilizes and starts decreasing toward baseline values within two to three days after arrival (Figure 12.3) (Ainslie and Subudhi 2014). This is a result of both systemic adaptations affecting C_aO₂ and altered sensitivity of the cerebral vasculature (Lucas et al. 2011). Comprising the relevant systemic adaptations are three factors: 1) altitude-induced diuresis whereby HCO₃⁻ is excreted at an elevated rate in an attempt to compensate for respiratory alkalosis (Ge et al. 2006); 2) a substantial loss of plasma volume, decreasing total blood volume but eliciting a significant increase in hematocrit and hemoglobin concentration within days of exposure to high altitude (Pugh 1964). This particular physiological response is a key factor, in addition to ventilatory acclimatization, that drives the early increase in C_aO₂ from initial hypoxic exposure and thus contributes to the progressive decrease in CBF); and 3) following ∼1 week at high altitude, erythropoiesis then increases hemoglobin mass leading to further increases in hematocrit (Ryan et al. 2014; Siebenmann et al. 2015, 2017). Another necessary consideration is the influence of the concentration of hemoglobin on blood viscosity and the potential implications of viscosity in regulating CBF at high altitude. To our knowledge, no data have specifically examined the influence of viscosity on CBF at high altitude; however, the existing data in humans at sea level indicates a likely negligible influence of viscosity on CBF in hypoxia (Hoiland et al. 2016). It should be noted, of course, that excessive polycythemia is extremely detrimental to physiological function and health at high altitude, especially in those with chronic mountain sickness (Dante and Javier 2007; Villafuerte and Corante 2016).

Alterations in cerebral vascular reactivity to both oxygen and carbon dioxide may also be implicated in CBF regulation at high altitude (Lucas et al. 2011). Both increases (Lucas et al. 2011; Flück et al. 2015) and no change (Rupp et al. 2014; Willie et al. 2015) in hypocapnic cerebral vasoconstriction have been demonstrated upon ascent to and acclimatization at altitude. Therefore, given methodological (technical and logistical) differences between studies, physiological differences (e.g., acid–base balance) and the consequent inconsistency of results, it remains relatively unclear how altered hypocapnic vasoconstriction contributes to the progressively reduced CBF throughout acclimatization. Related to cerebral sensitivity to oxygen, one study to date has conducted repeated measures indicating that hypoxic cerebral vasodilation is increased at high altitude (Jensen et al. 1996), a result which has been corroborated by more well-controlled laboratory studies (Poulin et al. 2002). Yet, changes in hypoxic vasodilation with acclimatization have not been examined using volumetric measures of CBF, necessitating judicious interpretation of the currently available data. Nonetheless, the observed increase in hypoxic cerebral vasodilation may counteract the vasoconstrictor stimulus consequent to reduced P_aCO₂ and underscore the net vasodilatory stimulus and maintained CDO₂ observed upon exposure to high altitude. Collectively, global CBF at high altitude mirrors changes in C_aO₂ and although P_aCO₂ is a very potent regulator of tone, following initial exposure to altitude, arterial pH is minimally altered. Therefore, it appears C_aO₂ is the primary factor governing the pattern by which CBF changes following initial exposure to high altitude. Potential alterations in reactivity at high altitude may further “fine tune” the observed changes in CBF.

Although global changes in CBF have been shown to maintain CDO₂ in hypobaric hypoxia throughout ascent and stay at high altitude, regional differences in the flow response to high altitude have been demonstrated (Hoiland et al. 2017; Subudhi et al. 2013). These high altitude studies and those conducted in well-controlled laboratory settings (Binks et al. 2008; Hoiland et al. 2017; Lawley et al. 2016; Subudhi et al. 2013) display preferential blood flow distribution to the posterior circulation, which perfuses brain regions such as the brainstem, hypothalamus, thalamus, and cerebellum (Binks et al. 2008). Despite no relationship between global CBF and AMS (Ainslie and Subudhi 2014) and failure of globally maintained CDO₂ to explain cognitive deficits in hypoxia, the aforementioned regionalization of CBF is suggested to be responsible for AMS (Feddersen et al. 2015) as well as cognitive impairment (Lawley et al. 2016) at high altitude. However, given the number of inconsistent studies (Ainslie and Subudhi 2014; Liu et al. 2017), sufficient data are still lacking with regard to the intricacies of regionalized CBF regulation and its consequent impact(s). Nevertheless, regionally differential distribution of blood flow likely occurs as a survival mechanism to prioritize delivery to the posterior areas of the brain, including the brainstem, responsible for controlling functional and homeostatic processes while consequently reducing delivery to areas responsible for higher cognitive function.

Acute hypoxia and cognitive function

It is generally believed that rapid, acute hypoxic exposures have negative consequences on cognitive processing and psychomotor function within seconds to minutes of exposure. The mechanisms underlying such rapid effects are unclear, but likely reflect the direct effects of hypoxia on neurotransmitter function, which can result in glutamate-driven excessive flow of sodium and calcium ions into postsynaptic neurons, damaging the cell-signaling processes (Virués-Ortega et al. 2004). In 1973, Ernsting reported that pilots experienced an impairment in their ability to recall a learned sequence of operations eight to 10 seconds after being rapidly exposed (∼2 seconds) to a simulated altitude of 12,195 m (Ernsting et al. 1973), and similar findings have been reported in a trove of investigations fueled by the aviation industry, demonstrating that during rapid exposure to extreme simulated altitudes, tracking tasks (Temme et al. 2010), working memory (Malle et al. 2013), attention (Bustamante-Sánchez et al. 2018), and learning (Nation et al. 2017) are all impaired.

At moderate altitudes, the neurocognitive effects of acute hypoxia are less clear, although a recent meta-analysis of 22 studies reported a moderate correlation between estimated P_aO₂ and cognitive performance (R² = 0.45, P<0.001), with no effect of normobaric versus hypobaric hypoxia (McMorris et al. 2017). The duration of hypoxic exposure was not included in this analysis; however, numerous chamber and rapid ascent studies have yielded support for an altitude-dependent decline in cognitive function during acute exposures.

Cognitive functions appear to be preserved during exposure to low levels of hypoxia (Balldin et al. 2007; Legg et al. 2018; Zhang et al. 2011), although a threshold of approximately 4000 m has been proposed (Dykiert et al. 2010; Kida and Imai 1993; Nelson 1982), above which progressive impairments in executive functions and psychomotor abilities may be acutely observed (Figure 12.4). During a 20-minute normobaric hypoxic exposure simulating ∼4200 m, Nakata et al. (2017) observed signs of impaired neural activity from EEG signals in areas of motor executive and inhibitory processing. Using a similar level of hypoxia, Seo et al. (2015). found that performance on a running memory continuous performance task was impaired after 40 minutes; however, no change in reaction time was reported (Seo et al. 2015). In contrast, a group was passively transported by helicopter to an altitude of 5260 m, and reductions on measures of reaction time and five out of nine tests of various domains of cognitive function were observed when tested immediately after arrival at altitude (Subudhi et al. 2014). Evidence for a progressive reduction in cognitive functions with increasing levels of hypoxia is further supported by Shukitt-Hale et al. (1998), who observed that four out of 10 military-specific performance measures were impaired after four hours in a chamber simulating 4200 m, and seven out of 10 measures were impaired at 4700 m. After 50 minutes at a simulated altitude of 6000 m, Turner et al. (2015) reported large reductions in verbal memory (–34%), processing speed (–36%), reaction time (–10%), and cognitive flexibility (–18%). However, it is also important to consider that observations of impairments to neurocognitive function are not universal. During two hours at a simulated altitude of 4500 m, for example, Pavlicek et al. (2005) reported no change in any domain of cognitive function, including word fluency, word association, and decision-making, and tests of longer-duration exposures have routinely shown conflicting results.

Chronic hypoxia and cognitive function

Despite the changes seen with acute exposures, the effect of hypoxia becomes less apparent when high altitude exposures are extended to days and months. A summary of investigations into cognitive decline during high altitude exposures lasting more than four hours can be found in Figure 12.5. Factors that appear to influence the magnitude of cognitive dysfunction experienced at high altitude include: 1) the magnitude of the hypoxic stimulus; 2) the extent of ventilatory and cardiovascular acclimatization, mediated by the total time spent at high altitude; and 3) the sensitivity of the tests and functions being tested, as complex tests of executive function appear to be more sensitive to changes than simple tests of reactions or timing. The relationships between these factors, paired with a lack of uniformity across testing conditions, limit the ability to define clear thresholds for maintaining cognitive and psychomotor function at high altitude. As a result, findings are frequently limited to the unique circumstances of each experiment. Changes in personality and mood have often been described at high altitude (Bonnon et al. 1999; Cavaletti 1993; De Aquino Lemos et al. 2012; Gerard et al. 2000; Legg et al. 2018; Nelson et al. 1990), yet such measures are largely subjective and can often be a consequence of the conditions of the expedition itself, such as changes in sleep, diet, fatigue, living conditions, and living in close quarters with others. More robust tests of cognitive function, mental processing, and psychomotor speed have been developed; however, large changes in scores (and sometimes even improvements) at high altitude are observed independently, often as a product of proficiency gained through the process of learning.

During a 40-day gradual decompression experiment, using an ascent profile designed to simulate the climbing of Mount Everest, researchers found that cognitive function became progressively impaired with increasing elevation. Scores for psychomotor ability and processing speed were stable until relatively high altitudes, but importantly, decompression was intentionally slow and participants were well-acclimatized to their conditions. In a similar study conducted in the field, it was found that there was marked deterioration in cognitive abilities at altitudes above 4000 m, but no changes were observed at altitudes tested below that threshold (Nelson et al. 1990; Dykiert et al. 2010). While many climbers report feeling cognitively “dull” at high altitudes, these reports often come from altitudes >7000 m, where the extent of cardiovascular and cerebrovascular acclimatization may be limited, and likely confounded by fatigue and symptoms of altitude sickness (reviewed in: Ainslie et al. 2014).

The role of acclimatization on maintenance of cognitive function at high altitude has been supported by several experiments and is illustrated in Figure 12.6. In contrast to rapid ascent or decompression studies, which show marked impairments in cognitive function at high altitude or during periods of reduced oxygen availability, a majority of studies where participants are tested after a period of acclimatization have failed to show significant changes in most domains of cognitive function (Figure 12.6). In participants rapidly transported to 5260 m, a reduction of 5–15% in domains of simple reaction time and executive functioning was immediately observed; however, this impairment was completely restored when retested on the 16th day of sojourn (Subudhi et al. 2014). Similar findings are reported by Pagani et al. (1998) who observed that mountaineers performed significantly better on a memory task after spending 15 days climbing between 5350 m and 7300 m, compared to their initial arrival at 5350 m. Furthermore, while a rapid decompression to a simulated altitude of 4300 m reduced multitask performance by 4.7% in healthy soldiers, a six-day stay at only 2200 m prior to decompression, referred to as staged ascent, abolished this reduction (Adam et al. 2008). Alternatively, reducing the initial rate of ascent also appears to limit the potential for cognitive decline. During an intentionally slow 18-day ascent to 5100 m, healthy trekkers demonstrated no impairment in cognitive or motor function at any time point (Issa et al. 2016), as was the case with cognitive function during a slow (18-day) ascent to 5400 m (Bonnon et al. 1999). Even at more extreme altitudes, “well-acclimatized” climbers as high as 6265 m (Merz et al. 2013) and 6500 m (Nelson et al. 1990) displayed preserved executive functions and memory retrieval. As humans are generally unable to support basic life processes for a prolonged period at extreme altitudes (i.e., the 8000 m “death zone”), it is quite likely that a ceiling also exists for the ability of our central nervous system to “acclimatize” to declines in cognitive function with acutely increasing altitude. However, it appears that with ample preparation and acclimatization, these effects can be attenuated even at altitudes >6000 m. It is important to note, however, that all tests of cognitive performance do not respond to high altitude equally. Scores on many tests of higher cognitive and executive functions are often maintained at moderate altitudes, yet the ability to learn new tasks is frequently impaired. Furthermore, on many test scores, group variability increases at high altitude, suggesting that cognitive effects of high altitude may show significant interindividual variability (Figure 12.6). Despite this, the protective benefits of a slow ascent and careful acclimatization are nearly universal.

Structural changes in long-term residents at high altitude

Table 12.1 summarizes the MRI-based studies to date that have investigated mostly structural brain changes either in migrants to the Qinghai-Tibet Plateau (2300–4400 m) or in lowlanders following trekking or climbing to high altitude. At least following migration to high altitude, evidence of adult brain resilience of spontaneous neural activity after long-term high altitude exposure without inherited and developmental effects has been reported (Chen et al. 2016a; Chen et al. 2016b). These latter findings generally contrast with others when Tibetan natives are born and raised at high altitude. Here, for example, a number of studies outlined in Table 12.1 have reported general reductions in cortical thickness and increased cortical folding associated with increased altitude—changes that were predominantly in left hemisphere (superior/middle temporal gyrus, lingual gyrus, rostral middle frontal cortex, insular cortex) (Wei et al. 2017). Although there is some evidence of compensatory mechanisms to maintain cognitive/behavioral performance via local increases in activation (Yan et al. 2011a), this is not a universal finding (Yan et al. 2011b, c).

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