Central nervous system


The central nervous system is exquisitely sensitive to hypoxia, so it is not surprising that changes in neuropsychological function might occur at high altitude. Brain oxygenation is a function of both the arterial PO2 and cerebral blood flow. The latter is regulated in part by the arterial blood gases, as hypoxemia causes cerebral vasodilatation while hypocapnia results in cerebral vasoconstriction. Although the delivery of oxygen to the brain is generally maintained at altitude, there are still notable reductions in centrally mediated fatigue as well as selected aspects of neuropsychological function. At higher altitude, many aspects of higher cognitive function have been shown to be impaired including reaction time, hand-eye coordination, and higher functions such as memory and language expression. Surprisingly, however, there seems to be no clear relationship between the magnitude of high altitude and the degree of impairment in higher cognitive function. The mechanisms driving changes in fatigue and neuropsychological function at high altitude are unclear but are likely related to the direct effects of oxygen tension on ionic channels and/or neurotransmitter activity. Several neuroimaging-based studies have documented residual alterations in cerebral structure and function both at altitude and following ascents to very high altitude. Oxygen enrichment of room air improves some aspects of neuropsychological function at high altitude and therefore holds promise for improving performance in people who commute to work in mines and telescopes. Since neuropsychological function of school-age children is reduced when compared to similar children at low altitude, oxygenation in this context might be of particular importance to improve learning outcomes. These topics are reviewed in this chapter.


Changes in mood and behavior at high altitude have been recognized from the early days of climbing high mountains. However, the most extreme effects of hypoxia on the central nervous system (CNS) were seen by the early balloonists where partial paralysis, difficulties with vision, mood changes, and even loss of consciousness are well documented. For example, during the famous flight of the balloon Zenith by Tissandier (1875) and his two companions, we read

This lack of appreciation of the dangers of acute hypoxia is well known to aircraft pilots and is the reason why there are stringent regulations on using oxygen above certain altitudes in spite of the fact that pilots may not feel they need it.

Some balloonists developed paralysis as described during the balloon ascent by Glaisher and Coxwell in 1862 (Glaisher et al. 1871). At the highest altitude, Glaisher collapsed unconscious in the basket, and it was left to Coxwell to vent the hydrogen from the balloon to bring it down. However, Coxwell had apparently lost the use of his hands and instead had to seize the cord that controlled the valve with his teeth and dip his head two or three times. Incidentally, this flight also underscored the rapid recovery from severe acute hypoxia. When the balloon landed, Glaisher stated that he felt “no inconvenience,” and they both walked between seven and eight miles to the nearest village because they had come down in a remote country area. Despite this description, paralysis is not frequently seen in acute hypoxia and, alternatively, it has been suggested that Coxwell may have been suffering from decompression sickness (Doherty 2003).

When climbers began to reach very high altitudes, neuropsychological disturbances were frequently reported. For example, there were several descriptions of bizarre changes in perception and mood on the early expeditions to Mount Everest. During the 1933 Everest expedition, there were dramatic descriptions of hallucinations (Ruttledge 1934), while on other occasions, the changes in CNS function suggestive of transient cerebral ischemia were noted. For example, the very experienced mountaineer Shipton (1943) had a remarkable period of aphasia at an altitude of about 7000 m on the same expedition, which he described in the following manner:

Early clinical observations by the Polish climber and psychiatrist Ryn reported a range of psychiatric disturbances in mountaineers who had ascended to over 5500 m (Ryn 1971). He also reported that symptoms similar to an organic brain syndrome persisted for several weeks after the expedition. Some climbers had electroencephalogram abnormalities after climbs to great altitudes. Studies made during the war between China and India in the early 1960s, when Indian troops were rapidly airlifted to high altitude, showed residual changes in psychomotor function on return to sea level (Sharma et al. 1975; Sharma and Malhotra 1976). Townes et al. (1984) made measurements on members of the American Medical Research Expedition to Everest (AMREE) after they had returned to sea level following about three months at altitudes of 5400 m to 8848 m and found residual abnormalities of neuropsychological performance. Similar results were found on Operation Everest II, including the additional interesting observation that climbers with the highest hypoxic ventilatory response were more severely affected (Horbein et al. 1989). The authors postulated that in spite of the less severe hypoxemia in the individuals with the higher ventilatory responses, the resultant more profound hypocapnia may have caused relatively greater vasoconstriction and decreased cerebral blood flow and brain oxygen delivery. The findings in the more controlled Operation Everest II chamber study were similar to those in AMREE, and the results were combined for the Horbein et al. (1989) publication. Subsequent improvements in neuropsychological testing techniques have increased our understanding of the neuropsychological effects of acute severe hypoxia, information which will be summarized later in this chapter.

Central Consequences of Hypoxemia

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+ (KATP) channels (Trapp and Ballanyi 1995). At normal cellular ATP levels, the KATP 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 (Km) 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 (FIO2 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.

Visual Evoked Potentials

Visual processing capability is commonly measured by using visual evoked potentials (VEP). Acute exposure to a simulated altitude of 4572 m did not decrease visual cognitive function, although participants occasionally reported reduced attentiveness and ability to concentrate (Tsarouchas et al. 2008) and the component of the VEP associated with elementary spatial-selective feature was reduced in amplitude (Di Russo et al. 2001). However, the remaining components of the VEP associated with visual categorization and recognition systems (Curran et al. 2002) were larger. Overall, the hypoxic stress had no effect on the final identification and response choice for targets.

Sustained residence at high altitude marginally affects the VEP. Initial arrival at altitudes of 4300 m and 5200 m may induce increased latency of the VEP, with no significant decrease in VEP amplitude (Forster et al. 1975; Singh et al. 2004; Wohns et al. 1987). With acclimatization (even to altitudes above 5200 m, VEP latency was reported to return to sea-level values (Wohns et al. 1987). However, there may be considerable individual variability, as shown in a study Forster et al. (1975), in which four participants had reduced VEP amplitude, while three reported increased VEP amplitude after sojourning nine to 12 days at 4300 m.

Auditory Evoked Potentials

The effect of high altitude exposure on auditory capabilities has been measured by means of auditory sensitivity, auditory evoked potentials (AEP), and auditory brainstem responses (ABR). When acutely exposed to simulated altitude of 3700 m through hypobaric hypoxia, the auditory threshold showed a small but significant reduction across a range of frequencies from 1 to 16 kHz (McAnally et al. 2003). This may be due to a loss in sensitivity from a change in the endocochlear potential, or to central auditory or general cognitive deficits. Interestingly, across the same frequency range, the auditory threshold was unaffected when normobaric hypoxia, instead of hypobaric hypoxia, was used (Watson et al. 2000). At simulated altitudes of 4000 mto 5000 m, the latency of key components of the AEP (considered as index of stimulus evaluation, discrimination, and categorization) were increased but normalized with administration of oxygen (Hayashi et al. 2005). These features suggest decreased sensitivity of the brainstem neurons to auditory input and a decrease in the related signal to the auditory cortex or decreased cognitive processing speed (Hayashi et al. 2005). With acute exposure to altitudes above 5000 m, reaction time in a go/no-go auditory cognitive task increases, in association with increased latency of the AEP (Kida and Imai 1993). In addition, slow components of the AEP were evident and associated with increased cognitive effort and further processing (Kida and Imai 1993).

Chronic exposure to high altitude has been reported to increase latency of both AEP and ABR. With stays of two to 21 days at altitudes of 3500 m to 4300 m, the last positive peak of the AEP and the first component of the ABR were found to increase latency (Mukhopadhyay et al. 2000; Singh et al. 2004), which the authors ascribed to impaired sensory discrimination and delay in evaluation processing (Singh et al. 2004), and impaired conduction at the cochlear level (Mukhopadhyay et al. 2000). During longer residence at high altitude, the latency of the last positive peak of the AEP was delayed after one month at 4115 m, with greater delays after six months at the same altitude (Thakur et al. 2011). However, the earlier components of the AEP were not affected. Thus, according to the authors, this may represent unaffected attention capacity and stimulus detection, but slowed stimulus evaluation and categorization (Thakur et al. 2011). Interestingly, the latency of the ABR components was greater in children (5–15 years) living in Andean villages between 2800 m and 3000 m, compared to a sea-level age-matched control. Whether this has functional significance is still unknown, and studies investigating causative mechanisms are lacking.

Central fatigue during exercise at high altitude

A realistic and important consequence of hypoxemia on the CNS is how it might accelerate fatigue. Exercise-induced fatigue can be defined as a reversible decrease in maximal voluntary force or power produced by a muscle (Bigland-Ritchie et al. 1983). Fatigue is determined by central and peripheral components, with central fatigue representing a reduction in voluntary drive resulting in decreased voluntary muscle activation during exercise from central mechanisms (i.e., above the neuromuscular junction, Figure 12.1) (Gandevia 2001). Acute exposure to simulated high altitude is accompanied by impaired performance (Goodall et al. 2014a; Jubeau et al. 2017; Ruggiero et al. 2018) and greater central fatigue than in normoxia. Specifically, this exacerbated decrease in central drive in acute hypoxia occurs mainly due to factors at or above the motor cortex (Goodall et al. 2014a, 2014b; Ruggiero et al. 2018), also known as supraspinal fatigue (Figure 12.1) (Gandevia 2001). Two main factors have been deemed responsible for increased supraspinal fatigue during exercise with acute exposure to severe hypoxia: direct effect of lower tissue PO2 on neuronal function and reduced cerebral oxygenation compared to normoxia, especially during high-intensity exercise when hyperventilation-induced hypocapnia causes cerebral vasoconstriction (Goodall et al. 2014a, 2014b; Subudhi et al. 2009).

Figure 12.1

Figure 12.1Division of muscle fatigue into central and peripheral components. Central fatigue represents a reduction in voluntary drive, resulting in decreased voluntary muscle activation during exercise (Gandevia 2001), and is due to mechanisms located above the neuromuscular junction. Supraspinal fatigue is a subset of central fatigue, and is defined as a decline in voluntary drive from the motor cortex. Supraspinal fatigue is exacerbated in acute hypoxia compared to normoxia, and recovers to normoxic standards in chronic hypoxia (Goodall et al. 2014b; Nicol and Komi 2011; Ruggiero et al. 2018). (Adapted from Taylor et al. 2008.)

Exercise after subacute exposure to hypoxia (i.e., one to two weeks at >5000 m) is associated with comparable central and supraspinal fatigue, as observed during exercise in normoxia (Amann et al. 2013; Goodall et al. 2014b; Ruggiero et al. 2018). This recovery of supraspinal fatigue to normoxic standards can be partially ascribed to increased PaO2, arterial oxygen content (CaO2), and increased cerebral oxygen delivery (CDO2) during the performance (Goodall et al. 2014a). Interestingly, the period of measurements of the above-mentioned studies in chronic hypoxia corresponds with the window (sixth to 18th day) of maximal sympathetic norepinephrine concentration following exposure to high altitude (Barnholt et al. 2006), suggesting norepinephrine acts as a neuromodulator, triggering increased motoneuron excitability at altitude (Ruggiero et al. 2018). In turn, this can diminish the supraspinal neural effort, decrease fatigability, and improve successful completion of the task. Importantly, the recovery of supraspinal fatigue to normoxic standard with chronic hypoxia has notable positive implications for performance.

Cerebral Blood Flow and Oxygen Delivery

Cerebral blood flow under normal physiologic conditions

Under normal conditions, the cerebral vasculature is sensitive to changes in CaO2. This sensitivity occurs below a PaO2 of ∼55 mmHg, whereby further reductions in PaO2 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 PaO2 and CaO2. The cerebrovascular response to changes in CaO2 is dependent on the prevailing PaCO2; hypercapnia increases and hypocapnia decreases cerebrovascular sensitivity to hypoxia (Mardimae et al. 2012). The cerebral vasculature is also highly sensitive to small changes in PaCO2. 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 PaCO2 above and below eupneic PaCO2, 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).

Figure 12.2

Figure 12.2Blood flow (Q) through the internal carotid (ICA) and vertebral arteries (VA) during steady-state changes in arterial CO2 (left) and oxygen (right) in humans. Cerebrovascular reactivity to changes in CO2 and to hypoxia (%ΔCBF / mmHg CO2 and %ΔCBF / %SaO2) was found to be similar between vessels in the hypercapnic range, ∼10% greater for the VA than the ICA in the hypocapnic range, and 50% greater for the VA with extreme hypoxia. Note that in the hypoxia trial (right), the arterial PCO2 was maintained normal. (Adapted from Willie et al. 2012.)

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 PaCO2, 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 PaCO2 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 CaO2 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 CaO2, 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).

Figure 12.3

Figure 12.3Changes in cerebral blood flow and oxygen delivery following ascent to altitude. Following initial exposure to high altitude, arterial oxygen content (CaO2) is reduced and cerebral blood flow (CBF) is commensurately increased. Increases and decreases in CaO2 and CBF, respectively, then mirror each other throughout acclimatization and maintain cerebral oxygen delivery (CDO2) constant. Alternating vertical bars represent individual days at altitude. Data are labeled based on their corresponding study. 1: Severinghaus et al. (1966), 2: Huang et al. (1987), 3: Jensen et al. (1990), 4: Baumgartner et al. (1994), 5: Lucas et al. (2011), 6: Willie et al. (2014a), 7: Willie et al. (2014b), 8: Subudhi et al. (2013).

While hyperventilation mitigates the drop in CaO2 at high altitude, it leads to concomitant reductions in PaCO2 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 PaCO2 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 CaO2 and PaCO2 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 (FIO2 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 CaO2 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 CaO2 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 PaCO2 and underscore the net vasodilatory stimulus and maintained CDO2 observed upon exposure to high altitude. Collectively, global CBF at high altitude mirrors changes in CaO2 and although PaCO2 is a very potent regulator of tone, following initial exposure to altitude, arterial pH is minimally altered. Therefore, it appears CaO2 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.

Cerebral Venous Blood Flow

Although the focus in this chapter has been on inflow to the cerebral circulation, it should be noted that a mismatch between cerebral inflow and venous outflow may play a role in the pathophysiology of AMS (Chapter 20) (Wilson and Imray 2015) and potentially cerebral edema (Sagoo et al. 2016). In the latter landmark study, it was reported that CDO2 was maintained via increased arterial inflow (i.e., CBF) and this preceded the development of cerebral edema, thus implicating venous outflow restriction as a key mechanism (Sagoo et al. 2016).

Central Nervous System Function at High Altitude

Many professions rely on a thorough understanding of the effects of hypoxia on neurological function, as job performance and workplace safety are tightly linked to the oxygen availability of the local environment. In areas considered to have a high risk or consequence of fire, for example, oxygen concentration is often reduced in order to minimize the potential for fire outbreak. In specific areas of many nuclear plants, the ambient oxygen concentration is reduced to 15%, as this amount is thought to be a threshold for maintenance workers and inspectors to safely carry out their work unhindered by the cerebral effects of hypoxia (Küpper et al. 2011). If airplanes travelling at cruising altitude were not pressurized, pilots and passengers would certainly endure a rapid loss of consciousness, as was the case in the fatal Helios Airways Flight 522, where cabin pressure was lost at 10,365 m and all crew and passengers were rendered unconscious for almost three hours before the plane eventually ran out of fuel. While this is an extreme example, shorter unpressurized flights at lower altitudes would almost certainly have cognitive consequences; therefore, most commercial airlines are pressurized to simulate an “acceptable” altitude of <2574 m (Hampson et al. 2013). Typically, cabin altitude tends to be lower (70–1863 m) with flights of shorter duration (<200 miles) when compared to flights of longer duration (1252-3654 km) where cabin altitude ranges between 433 m and 2574 m (Hampson et al. 2013). Although cabin altitude data are not currently available, it is noteworthy that nonstop ∼14,480 km flights have recently (2018) begun from Perth (Australia) to London (UK).

The US Army provides specific regulations to its pilots (Department of the Army 2014), requiring the use of supplemental oxygen if operating 1) above 3040 m for more than one hour; 2) above 3650 m for longer than 30 minutes; or 3) above 4260 m for any amount of time. High altitude mountaineers are often exposed to altitudes much greater than these minimums without the use of supplemental oxygen, opening the possibility of critical judgement errors in high-risk situations, although exposure to such altitudes is not nearly as acute as that experienced by the pilots. The extent of cognitive dysfunction during high altitude travel has been the topic of dozens of scientific investigations, building on the early anecdotal accounts, described earlier, of high altitude “stupor” documented during many historical mountaineering expeditions.

All cognitive functioning processes require oxygen and may be susceptible to the effects of severe hypoxia at high altitude. Furthermore, many cognitive tests involve the overlap of several different processes, making it difficult to determine if a change in score is of motor or processing origin. Broadly, the cognitive decline at high altitude has frequently been tested at three main levels: 1) executive functions, which can include tests of shifting attention, visuospatial processing, selection and inhibition, and integration of working, short-term, and long-term memory; 2) perception/attentional processing, which requires identifying relevant stimuli and carrying out simple, predetermined responses; and 3) psychomotor ability, which refers to the speed and accuracy of a response to a change in environment.

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 PaO2 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.

Figure 12.4

Figure 12.4Change in performance on tests of higher cognitive function during acute high altitude or hypoxic exposure. Values represent mean change (%) from baseline with calculated 95% confidence limits. Note (1) that although obviously variability was apparent, 21 out of the 25 studies show a reduction in higher cognitive function; and (2) there is no clear relationship between the magnitudes of high altitude and reductions in higher cognitive function. (References: Bartholomew et al. 1999; Bustamante-Sánchez et al. 2018; Caldwell et al. 2017; Gao et al. 2015; Harris et al. 2009; Hu et al. 2016; Issa et al. 2016; Legg et al. 2018; Lemos and Moreira 2012; Petiet et al. 1988; Pelamatti et al. 2003; Rimoldi et al. 2016; Subudhi et al. 2014; Turner et al. 2015; Wang et al. 2013; Zhang et al. 2011; Zhang et al. 2013a.)

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.

Figure 12.5

Figure 12.5Change in performance on tests of psychomotor speed during prolonged high altitude or hypoxic exposure. Values represent mean change (%) from baseline with calculated 95% confidence limits. SRT, simple reaction time; CRT, choice reaction time; TMT, trail making test; FT, finger tapping. Note (1) that although variability was apparent, 10 out of the 14 studies show a reduction in reaction time following four-hour exposure to high altitude; and (2) there is no clear relationship between the magnitude of high altitude and reductions in reaction time. (References: Davranche et al. 2016; Dykiert et al. 2010; Gao et al. 2015; Harris et al. 2009; Kim et al. 2015; Petiet et al. 2011; Pramsohler et al. 2017; Subudhi et al. 2014; Zhang et al. 2011, 2013a.)

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.

Figure 12.6

Figure 12.6Change in performance on tests of higher cognitive function during chronic high altitude or hypoxic exposure. Values represent mean change (%) from baseline with calculated 95% confidence limits. Note: (1) 12 out of the 24 studies show a reduction in higher cognitive function during chronic high altitude or hypoxic exposure, and (2) there is no clear relationship between the magnitude of high altitude and alterations in higher cognitive function. (References: Caldwell et al. 2018; Gao et al. 2015; Harris et al. 2009; Hu et al. 2016; Issa et al. 2016; Petiet et al. 1988; Pelamatti et al. 2003; Subudhi et al. 2014; Wang et al. 2013; Zhang et al. 2011.)

Residual Effects of Exposure to High Altitude

While it appears that the central nervous system shows some resiliency and ability to adapt to changing conditions of reduced oxygen availability, the effects of long-term hypoxic exposure are less clear. The use of MRI imaging techniques has allowed for more in-depth investigation of structural and functional changes that occur as a result of prolonged hypoxic exposure, whether it be after repeated extreme-altitude hypoxic challenges (e.g. mountaineers), in migrants to high altitude, or in those whose residence at high altitude can be traced back over hundreds of generations. A discussion of these topics follows next.

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).

Table 12.1 MRI-based studies investigating brain changes after high altitude exposure



Type of and duration of hypoxic exposure


Main findings

Chen et al. (2016a)

16 high altitude (age: 20.5 ± 0.7) + 16 controls (age: 19.91.5); all males

Migrants to high altitude (2 years)

2300–4400 m

Regional homogeneity in right inferolateral sensorimotor (visual) cortex significantly increased, suggesting functional resilience against high altitude exposure.

Chen et al. (2016b)

16 high altitude (age: 20.5 ± 0.7) + 16 controls (age: 19.9 ± 1.5); all males

Migrants to high altitude (2 years)

2300–4400 m

In the high altitude group, voxel-mirrored homotopic connectivity in visual cortex significantly enhanced and length of white matter fibers connecting homotopic visual areas was increased. Evidence of interhemispheric structural and functional connectivity resilience.

Chen et al. (2017a)

29 (13f), age: 20 ± 0.8 years

Travelers to high altitude (4 weeks)

4200 m

Increase in iron in gray matter, more pronounced in right hemisphere and in females. Evidence for intracellular edema after acclimatization.

Chen et al. (2017b)

49 (17f), age: 18.2 ± 0.3 years

Students studying at high altitude (2 years)

3658 m

Decreased gray matter volume and regional homogeneity in left putamen, related to cognitive dysfunction.

Fan et al. (2016)

31 (15f), age: 19.7 ± 0.7 years

Travelers to high altitude (30 days)

4300 m

Gray and white matter volumes increased (indicating edema, without neurological signs), and cortical surface area in areas of cardiovascular and respiratory regulation increased after 30 days, but all returned to baseline levels after two months.

Fayed et al. (2006)

35 climbers, age: 33.8 ± 4.1 years; 20 controls

Postclimbing expedition

4810 m, 5895 m, 6959 m, or 8848 m

Abnormalities in 12 of 13 climbers who returned from attempting Everest, and all 8 climbers returning from Aconcagua. Cortical atrophy and enlargement in perivascular Virchow-Robin spaces in most climbers. Subcortical lesions in climbers who were not properly acclimatized.

Foster et al. (2015)

6 (1f), age: 31.8 ± 3.7 years

Travelers to high altitude (3 weeks)

5050 m

Reduction in brain volume attributed to gray matter atrophy. Brain regions of negative cerebrovascular reactivity increased functionality.

Garrido et al. (1993)

26 climbers (4f), age: 35 ± 5 years; 21 age and sex-matched controls

Climbers with a history of ascents >7000 m

>7300 m, no supplemental O2

MRI abnormalities in 46% of climbers. 19% showed hyperintensities, 19% demonstrated cortical atrophy.

Garrido et al. (1996)

7 elite Sherpa climbers, 21 elite lowland climbers, 21 elite controls

World class climbers (Sherpa and lowlanders), all with history of climbs >8000 m

>8000 m

MRI abnormalities (cortical atrophy, white matter hyperintensities) were present in 13 of 21 lowland climbers (66%), but only found in 1 of 7 Sherpa climbers (14%). No abnormalities were observed in the controls.

Hackett et al. (2019)

8 patients with severe HACE

Evacuated from Colorado mountain communities

2700–3000 m

HACE characterized by cytotoxic and vasogenic edema, which progresses to microvascular disruption and microbleeds.

Paola et al. (2008)

Mountaineers (9) and controls (19), age: 37.9 ± 7.2 years; all male

High altitude mountaineering, pre/post expedition

Recently >7500 m; >15 days over 6500 m; plus history of high altitude exposure

Extreme high altitude exposure causes gray and white matter changes (reductions in volume/density) in areas involved in motor activity.

Wei et al. (2017)

77 Tibetan natives (43f), age: 16 ± 1.2 years; 80 lowlander controls (46f), age: 16 ± 1.3 years

Adolescents born and raised at high altitude

2300–5300 m

Reduced cortical thickness and increased cortical folding associated with increased altitude, predominantly in left hemisphere (superior/middle temporal gyrus, lingual gyrus, rostral middle frontal cortex, insular cortex).

Yan et al. (2011a)

28 (16f) raised at high altitude, age: 20.4 ± 1.4 years; 28 lowland controls (16f), age: 20.9 ± 1.5 years

Students born and raised at high altitude (>18 years), relocated to sea level for 1 year

2616–4200 m

Common activation patterns during spatial working memory, increased activation in superior temporal gyrus and pyramid in high altitude, indicating increased attention levels as compensatory mechanism to maintain cognitive/behavioral performance.

Yan et al. (2011b)

10 high altitude, 9 age-matched lowland controls

Students born and raised at high altitude (>20 years), relocated to sea level for 1 year

2616–4200 m

In high altitude group, decreased activation in neural circuit for food craving, decreased activation in regions for cognitive control, increased activation in regions for emotional processing.

Yan et al. (2011c)

28 high altitude, 30 age-matched lowland controls

Students born and raised at high altitude (>18 years), relocated to sea level for 1 year

2616–4200 m

Impaired in reaction time and accuracy, verbal working memory in high altitude residents, and reduced activation in inferior and middle frontal gyrus, middle occipital lingual gyrus, pyramid of vermis, and thalamus.

Zhang et al. (2012)

14 (6f), age: 21 ± 1.9 years

Single short-term climbing, no prior high altitude exposure (26 days)

6206 m

No changes in global or regional gray matter, white matter, or cerebral spinal fluid volumes. Compromised white mater fiber microstructural integrity.

Zhang et al. (2013a)

16 male soldiers, 16 age-matched controls (age: 21 ± 0.7 years)

Lowlanders garrisoned at high altitude for 2 years

2300–4400 m

Broad regional differences in cortical thickness, including decreased thickness in right superior frontal gyrus. No difference in total gray matter volume, but high altitude immigrants showed reduced gray matter volumes in right middle frontal gyrus, right parahippocampal gyrus, right inferior middle temporal gyri, bilateral inferior ventral pons, and right cerebellum crus.

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Jul 25, 2021 | Posted by in RESPIRATORY | Comments Off on Central nervous system
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