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Neuropsychology Review, Vol. 14, No. 4, December 2004 (
C
2004)
DOI: 10.1007/s11065-004-8159-4
Neuropsychological Functioning Associated
with High-Altitude Exposure
Javier Viru
´
es-Ortega,
1,2,6
Gualberto Buela-Casal,
1
Eduardo Garrido,
3,4
and Bernardino Alc
´
azar
5
This article focuses on neuropsychological functioning at moderate, high, and extreme altitude. This
article summarizes the available literature on respiratory, circulatory, and brain determinants on
adaptation to hypoxia that are hypothesized to be responsible for neuropsychological impairment
due to altitude. Effects on sleep are also described. At central level, periventricular focal damages
(leuko-araiosis) and cortical atrophy have been observed. Frontal lobe and middle temporal lobe
alterations are also presumed. A review is provided regarding the effects on psychomotor performance,
perception, learning, memory, language, cognitive flexibility, and metamemory. Increase of reaction
time and latency of P300 are observed. Reduced thresholds of tact, smell, pain, and taste, together
with somesthetic illusions and visual hallucinations have been reported. Impairment in codification
and short-term memory are especially noticeable above 6,000 m. Alterations in accuracy and motor
speed are identified at lower altitudes. Deficits in verbal fluency, language production, cognitive
fluency, and metamemory are also detected. The moderating effects of personality variables over the
above-mentioned processes are discussed. Finally, methodological flaws found in the literature are
detailed and some applied proposals are suggested.
KEY WORDS: altitude; acute hypoxia; hypocapnia; brain dysfunction; mild neuropsychological impairment.
This article reviews current developments in research
on neuropsychological functioning in altitude with a par-
ticular focus on biological and environmental factors. At-
tention is paid to hypoxia as a responsible stimulus for
the consequences of altitude together with other modulat-
ing factors such as individual differences. Additionally,
methodological shortcomings in this kind of research are
also discussed.
In 403 BC the Chinese traveler Fa Hsein reported
the first documentary record of the effects of altitude on
1
Departamento dePersonalidad, Evaluaci
´
on y Tratamiento Psicol
´
ogicos,
Universidad de Granada, Granada, Spain.
2
Servicio de Salud Mental, Complejo Hospitalario de Ja
´
en, Ja
´
en, Spain.
3
Unitat de Medicina de l’Esport i Fisiologia de l’Exercici, Servei de
Medicina Preventiva, Hospital General de Catalunya, Barcelona, Spain.
4
Departament de Ci
`
encies Fisiol
`
ogiques i de la Nutrici
´
o, Universitat de
Barcelona, Barcelona, Spain.
5
Servicio de Neumolog
´
ıa, Complejo Hospitalario de Ja
´
en, Ja
´
en, Spain.
6
To whom correspondence should be addressed at Departamento de
Personalidad, Evaluaci
´
on y Tratamiento Psicol
´
ogicos, Universidad de
Granada, Facultad de Psicolog
´
ıa, Campus Universitario de Cartuja,
18071 Granada, Spain; e-mail: virues@ugr.es.
human beings, in this case probably lung edema (Gilbert,
1983). In 326 BC Plutarch described several symptoms
of mountain sickness in his chronicles of the march of
Alexander over India (Plutarch, 1912). Fifteen centuries
later, in 1298, Rustinian noted down several malaises
suffered by Marco Polo during his explorations of Tibet
(Castell
´
o-Roca, 1993). Jose de Acosta, a Spanish Jesuit
of the sixteenth century spoke in his book Historia natu-
ral y moral de las Indias (Natural and Moral History of
the West Indies) about his sickness, vomits, and headaches
while on a visit to the Andean mountain range (De Acosta,
1590). Acosta’s seems to have been the first known case
of acute mountain sickness (AMS) although there is no
complete agreement on whether it was AMS or gastroen-
teritis. Yet, the first clinical classification of this disorder
was made by Thomas Ravenhill, a British surgeon who
worked in several mines in the north of Chile (Ravenhill,
1913). The AMS is an acute syndrome associated with
an inadequate adaptation to a hypoxic environment. AMS
is a syndrome with unspecific symptoms, most charac-
teristically headache, insomnia, dizziness, fatigue, and
197
1040-7308/04/1200-0197/0
C
2004 Springer Science+Business Media, Inc.
198 Viru
´
es-Ortega, Buela-Casal, Garrido, and Alc
´
azar
Tabl e 1 . The Lake Louise Consensus Committee Definition of Acute
Mountain Sickness
Diagnostic feature Description
Criteria A recent gain in altitude
At least several hours at the new altitude
Presence of headache
Symptoms Gastrointestinal upset (i.e., lack of appetite,
nausea or vomiting)
Fatigue or weakness
Dizziness or lightheadedness
Difficulty sleeping
Note. In order to diagnose AMS, all criteria 1, 2, and 3 and one of symp-
toms are required. Adapted from “The Lake Louise Acute Mountain
Sickness Scoring System,” by Roach, R., B
¨
artsch, P., and Oelz, O.
(1993). In: Sutton, J., Houston, G., and Coates, G. (eds.), Hypoxia and
Molecular Biology (pp. 272–274), Queen City Printers, Burlington, VT.
gastrointestinal symptoms (lack of appetite, nausea, or
vomiting). AMS is observed in up to 25% of persons
who have recently reached an altitude of 2,000 m or more
(Montgomery et al., 1989). The most widely accepted set
of diagnostic features was established by the Lake Louise
Consensus Committee and is presented in Table 1 (Roach
et al., 1993).
Apart from western references, AMS has always
been identified in populations living at high altitude. In-
digenous Quechua call it soroxchi and Tibetans named it
mundara. AMS drew the attention of members of expedi-
tions to high mountains and has been the object of thor-
ough biomedical research in the last 30 years (Hornbein
et al., 1989; West, 1984). As a result, advances have
been made in the identification of its physiopathological
foundations (Basnyat and Murdoch, 2003; Garrido and
Botella, 1998; Hornbein and Schoene, 2001).
Corporatively, neuropsychological impairment has
been the focus of fewer studies. Neuropsychological im-
pairment in high altitude were sited very early by Janssen
(1890). On an ascent to Mont-Blanc, this author experi-
enced symptoms of AMS when observed that a sudden
weakness prevented him from noting down the symp-
toms of AMS. This was overcome by a quick series of
aspirations. Accordingly, before thinking he made sev-
eral aspirations. Janssen concluded that intellectual ca-
pacity required strength and oxygen so that to preserve
it, the climb had to be made without making any phys-
ical effort (Jansen, 1890). No other precedent is found
until 1911, when Massot i Palmers gave a paper at the I
Catalonian Conference of Excursionists entitled “El ex-
cursionismo como medio del desarrollo f
´
ısico e intelec-
tual en el ni
˜
no” (Physical and intellectual development
of children by means of excursions; Massot i Palmers,
(1911)). There have been numerous anecdotal references
to emotional, cognitive, and perceptive alterations asso-
ciated with altitude in well-known expeditions (Dunlap,
1918; Herzog, 1952; Ruttledge, 1934; Shipton, 1943;
Wilmer and Berens, 1918). Later on, the administration of
neuropsychological tests was intended to obtain indirect
evidence of brain damage by researchers who were not
psychologists and consequently no particular attention
was devoted to the functional pattern of alterations. A
ground-breaking exception in this respect was the work
by McFarland (McFarland, 1932, 1937a, 1937b, 1937c,
1937d, 1941; McFarland and Barach, 1937; McFarland
and Evans, 1939). McFarland investigated the altitude-
related alterations of visual adaptation to darkness, psy-
chomotor coordination, immediate memory, and the influ-
ence of anxiety on oxygen tension. McFarland employed
diverse methods to observe the effects of hypoxia: ex-
tended periods at high altitudes, fast ascents in aircraft,
and hypobaric chambers. Between the 1960s and 1970s,
several interesting attempts were made at establishing pat-
terns of neuropsychological impairment associated with
altitude (Denison et al., 1966; McFarland, 1971; Ryn,
1971). In the last two decades, more thorough and rigorous
studies have related behavior alterations with respiratory
and neurological variables (Garrido et al., 1995; Hornbein
et al., 1989; Regard et al., 1989; West, 1984).
The present article is specifically centered on the
altitude neuropsychological impairment (ANI) in high
mountaineering although related areas will also be men-
tioned including animal models, and chronic hypoxia dis-
orders such as the chronic obstructive pulmonary disease
(COPD) or the obstructive sleep apnea (OSA). Chronic
hypoxia conditions should be distinguished from acute
hypoxia conditions—the duration of acute hypoxia ranges
between some seconds and several weeks while chronic
hypoxia is characteristic of chronic respiratory disorders
or extended permanence in a hypoxic environment. In
this article, we refer almost exclusively to cases of acute
hypoxia studied in laboratory conditions or in real ascents.
Since the work of McFarland, 100 of studies concern-
ing the effects of altitude havebeen published. Their meth-
ods have been highly diverse so a comprehensive assess-
ment is most complex. The following review is intended
to include all relevant evidence with a particular emphasis
on the neuropsychological impairment. This article briefly
reviews the respiratory, vascular, pathological, (i.e., AMS)
and neurological foundations of the neuropsychological
functioning at high and extreme altitude. In addition, the
moderating role of sleep patterns associated with altitude
are also analyzed. Then, we review in more detail the em-
pirical evidence regarding cognitive malfunctioning due
to altitude. In this respect, we discuss the likely dysfunc-
tion of: (a) psychomotor performance (i.e., psychomotor
Neuropsychological Functioning at High Altitude 199
speed, psychomotor accuracy, permanent mild psychomo-
tor dysfunction), (b) perceptive processes (i.e., reaction
time (RT) studies, perceptive discrimination studies, color
perception studies, hallucinatory experiences reports), (c)
memory, learning and attention (e.g., retrieval vs. storage
alteration, spatial memory, short-term memory), (d) func-
tions associated with frontal lobe (i.e., verbal fluency, cog-
nitive flexibility, metacognition). Afterwards, we consider
the moderating role of anxiety and personality factors in
the neuropsychological outcomes of subjects exposed to
hypoxic environment due to altitude. Throughout the text,
we propose a number of theoretical analyses based on the
available evidence. Moreover, we argue about method-
ological shortcomings and challenges addressed by neu-
ropsychological assessment at high altitude. Finally, we
suggest a unified ANI assessment strategy.
RESPIRATORY ADAPTATION AND
NEUROPSYCHOLOGICAL FUNCTIONING
Exposure to high altitude is considered a case of
anoxic (Adams et al., 1999) in which the metabolic deficit
is due to a reduced arterial pressure of oxygen. The effect
is similar to that observed in chronic form in COPD or in
OSA, although, in these cases the environmental pressure
of oxygen is adequate and it is the obstruction of the
respiratory tract that is responsible for hypoxia.
The proportion of oxygen in the air remains con-
stant at 20.9% up to the limits of the troposphere (ap-
proximately 12,000 m). However, pressure decreases
exponentially with altitude. The loss of barometric
pressure (P
B
), and consequently of oxygen pressure due
to altitude is the determining factor of ANI. A pressure
of 101 kPa at sea level is cut down to a half at 5,500 m
(53 kPa), and to a third at 8,848 m (33.5 kPa). Individuals
who ascend high altitudes are subject to a reduction of
oxygen in the air they breathe. This phenomenon is called
hypoxia. Environmental hypoxia determines the reduction
in alveolar pressure of oxygen (PAO
2
) and the reduction
in arterial partial pressure of oxygen (PaO
2
) once this
gas passes through the alveolar–arterial interface by dif-
fusion. Hypoxemia is a reduction in oxygen saturation
in arterial blood (%SaO
2
) associated with hypoxia. For
instance, at an altitude of 4,500 m, PaO
2
is 47 mmHg
and the saturation is 80% (a reduction of 20%), while at
the summit of Mount Everest PAO
2
is 35 mmHg, PaO
2
is
28 mmHg and saturation ranges between 57% and 70%
(Sutton et al., 1988; West, 1983b; West, 1984). Extreme
reductions above 50% can take place during vigorous ex-
ercise at an environmental pressure equivalent to that at
the summit of Mount Everest (Sutton et al.,1988). Table 2
shows an extract of the relationships among altitude, P
B
,
PaO
2
,PAO
2
, and %SaO
2
.
At a high altitude there is a reduction in P
50
that is
the PaO
2
corresponding to a SaO
2
of 50%. This means,
that for the same PaO
2
, hemoglobin carries more oxygen.
This phenomenon is a result of respiratory alkalosis due to
lung hyperventilation produced by high altitude and tends
to displace the hemoglobin dissociation curve progres-
sively to the left. As a result of hyperventilation there is a
reduction in arterial pressure of carbon dioxide (PaCO
2
),
known as hypocapnia. Hypocapnia produces an intense
vasoconstriction in the brain. The result is always positive
Tabl e 2. Respiratory Variables Associated to Oxygen Uptake at Different Altitudes and Barometric Pressures
Altitude P
B
PiO
2
PAO
2
PaO
2
PaCO
2
M Feet Torr kPa Torr kPa Torr kPa torr kPa Torr kPa %SaO
2
0 0 760 101.3 149 19.9 100 13.3 95 12.6 40 5.3 97
152 500 747 99.3 147 19.5 99 13.2 92 12.2 40 5.3 97
1,610 5,280 640 85.1 123 16.4 84 11.2 77 10.2 34 4.5 95
2,300 7,544 582 77.4 118 15.7 74 9.8 72 9.6 32 4.3 95
4,500 13,725 433 57.7 81 10.8 62 8.2 55 7.3 30 4.0 87
5,500 18,050 379 50.5 69 9.2 38 5.2 36 4.8 26.4 3.5 82
6,300 20,664 351 46.7 59 7.9 35 4.6 27 3.51 9 1.2 61
8,848 29,028 253 33.6 43 5.7 35 4.6 28 3.7 7.5 1.0 75
Note. P
B
= barometric pressure, PiO
2
= pressure of inspired oxygen in the trachea, PAO
2
= alveolar pressure of
oxygen, PaO
2
= partial pressure of oxygen in arterial blood, PaCO
2
= partial pressure of carbon dioxide in arterial
blood
,
%SaO
2
= percent saturation of hemoglobin with oxygen in the arterial blood. These data have been obtained
from different investigations with different register situations. Adapted from Martin, L. (1999). All you really need
to know to interpret arterial blood gases. Lippincott Williams and Wilkins, Philadelphia; West, J. (1984). Human
physiology at extreme high altitudes on Mount Everest. Science 323: 784–788; and West, J. B., Hackett, P. H., Maret,
K. H., Milledge, J. S., Peters, R. M., Pizzo, C. J., et al., (1983b). Pulmonary gas exchange on the summit of mount
Everest. J. Appl. Physiol. 55: 678–687.
200 Viru
´
es-Ortega, Buela-Casal, Garrido, and Alc
´
azar
for hypoxemia so that the vasomotor tone favors vasodi-
latation and consequently increases the cerebral blood
flow (CBF).
Human beings rely upon several compensatory
mechanisms for the hypoxic stimulus. The individual ca-
pacity for adaptation to hypoxia by increasing ventilation
is established by the evaluation of the hypoxic ventilatory
response (HVR). This response is measured as VE40,
which means that the volume of exhaled air from nor-
moxic conditions up to conditions of PaO
2
of 40 mmHg
(equivalent to an altitude of 5,500 m at rest). Evaluation
is made at rest in supine position maintaining isocapnia,
that is, constant levels of arterial carbon dioxide (Schoene
et al., 1984). The presence and intensity of this response
runs parallel to the activity of the nucleus of the carotid
body so a causal role has been hypothesized for this struc-
ture (see Lahiri et al., 2001). Agadzhanyan et al. (1972)
found that damages in the carotid body prevent adaptation
to a hypoxia corresponding to 5,000 m and consequently
impair the execution of a sequence of conditioned motor
responses. It has been recently established that the begin-
ning of HVR displays a time pattern with a similar inten-
sity to the firing rate of the nucleus of the carotid body,
whose activation depends on peripheral chemoreceptors
that detect metabolic acidosis and decrease of levels of
PaO
2
(Lahiri et al., 2000). Recent research emphasizes
that extended exposure to high altitude ends up blocking
the activity of this nucleus and the peripheral receptors.
This coincides with a reduction of HVR and the process
of acclimatization (Moore, 2000), and also with the per-
manent reduction of HVR in highlanders (Moore, 2000).
In these communities, this structure shows less sensitivity
to environmental hypoxia and a smaller HVR. Besides
adaptability to altitude (Lahiri, 1984), HVR seems to
have a strong genetic component as suggested by research
with twins (Kawakami et al., 1982) and ethnic differences
(Moore, 2000).
On the one hand, an intense HVR is a protecting
factor against AMS (Hackett et al., 1982) and a predictor
of physical adaptation to altitude (Schoene, 1982). On the
other hand, subjects with an intense HVR display greater
subsequent neuropsychological impairment than subjects
with a reduced response during a simulated ascent in a hy-
pobaric chamber to 8,488 m in a 40-day period (Hornbein
et al., 1989). The effect seems generalized because of
the significant correlations in the said study, which in-
cluded almost the totality of tests where impairment was
found. In particular, significant correlation was reported
(p<.05) in the simulated ascent group between HVR and
Buschke’s selective reminding test (SRT)—sum recall—
paired associate of the Wechsler memory scale (WMS)—
immediate and delayed recall—verbal WMS—immediate
recall—and Aphasia Screening Test. These results were
only replicated in the case of the real-ascent group for
the number of aphasic errors in the Aphasia Screening
Test. This seems to indicate a greater sensitivity of ver-
bal memory and verbal fluency functions to this effect
although this interpretation remains an issue for further
study.
Horbein et al. (1989) hypothesized several likely
causes of such apparently paradoxical impairment. First, it
was thought that subjects showing a high HVR experience
lower levels of oxygenation during exercise or sleep thus
causing the impairment. However, a number of studies
have demonstrated that %SaO
2
of subjects with a weak
HVR during exercise is lower than that of subjects with
an intense HVR. As a consequence, subjects with a weak
HVR should suffer a higher hypoxia triggered by exercise
(Oelz et al., 1986; Schoene et al., 1984). Regarding sleep,
further evidence has shown that subjects with a high HVR
display similar levels of night hypoxia as apposed to those
with a weak HVR (Coote et al., 1993a) in spite of showing
more periodic breathing (PB) or Cheyne–Stokes breath-
ing during sleep (i.e., a pattern of breathing with varying
depth of respiration and brief periods of apnea). As part
of Operation Everest II, Hornbein et al. (1989) point out
that subjects with a smaller mean %SaO
2
spent most of
their sleep time with a smaller saturation compared to the
rest and in turn suffered a greater impairment in delayed
recall of verbal material established by the WMS. These
subjects also showed a greater impairment in the Finger
Tapper Test (FTT). Nevertheless, Hornbein et al. (1989)
did not find any connection between HVR and the degree
of desaturation during the night.
A third explanation of the paradoxical effect
(Hornbein et al., 1989) stresses that in strong physical
exercise, a high HVR allows greater muscle oxygenation
and justifies the better physical performance of these sub-
jects (Masuyama et al.,1986; West, 1984). In addition,
the increase of hypocapnia in periods of physical activ-
ity should be considered. The vasoconstricting effect of
hypocapnia (Gotoh et al., 1965) competes with the in-
crease of CBF and the vasodilating response produced as
adaptations to hypoxia (Adams et al., 1999). According
to this approach, we consider that the following sequence
takes place: first, a high HVR produces high levels of
PaO
2
, which results in better physical performance and
so an elevated hypocapnia. In turn, this results in brain
vasoconstriction with an impairment of circulation and
oxygenation (ischemia and hypoxia). It is hypothesized
that these two factors are responsible for neuropsycho-
logical impairment. It has been already mentioned that
the ratio between hypoxemia and hypocapnia is usually
favorable to hypoxemia in normal subjects as regards to
Neuropsychological Functioning at High Altitude 201
brain vasodilatation. Nevertheless, we believe that sub-
jects with a high HVR have a higher hypocapnia but this
pattern can be reversed at certain times in areas of the
encephalon producing a lesser tissue oxygenation.
Further research is needed to associate HVR, neu-
ropsychological impairment, altitude, and rest/activity, in
order to check the value of the latter hypothesis, which
is supported by indirect evidence. Firstly, subjects with
a high HVR show a greater hypocapnia at rest at alti-
tude, and accordingly more brain vasoconstriction asso-
ciated with it (West et al., 1983a). However, Hornbein
et al. (1989) did not find any correlation between the
speed of mean blood flow in the middle brain artery
during a simulated stay at altitude and HVR or neu-
ropsychological impairment. It should be stressed that
these measures were made at rest and that the dif-
ferences in hypoxemia and hypocapnia between sub-
jects with a high- and low-HVR manifest especially, in
exercise.
Recent evidence in agreement with the previous hy-
pothesis, although not validating it directly, is the evolu-
tion of HVR in increasing workloads between highland
sojourners and adapted subjects. It has been observed
that, despite repeated climbs and extended exposure to the
highest summits, Sherpas living at altitude show minimal
risks of brain damage (Garrido et al., 1996) and the asso-
ciated memory impairment (Bakharev, 1981). Their HVR
is adapted to optimize SaO
2
and minimize hypocapnia
(Santolaya et al., 1989; Rodas et al., 1998). More specif-
ically, Rodas et al. (1998) established that at sea level,
Sherpas hyperventilate more with moderate workloads
and ventilate less with maximum workloads in compar-
ison to European mountain climbers. If this pattern is
maintained at extreme altitude, Sherpas would attain a
greater SaO
2
during the habitual exercise in mountain
climbing thus avoiding brain vasoconstriction and proba-
bly brain dysfunction in intense physical effort. This pos-
sibility was explored by Garrido et al. (1996) who studied
a group of 7 top Sherpas and a group of 21 top mountain
climbers living in lowlands. Both groups did not differ in
age or time of exposure to altitudes above 7,000–8,000 m.
An extended medical record was made of the subjects
about neurological, emotional, perceptive, and neuropsy-
chological symptoms, and they were explored by mag-
netic resonance imaging (MRI). The results indicated that
lowland climbers showed neurological symptoms during
ascents (i.e., headaches, ataxia, insomnia, aphasia, vision
loss, irritability, hallucinations), while half of them re-
ported neuropsychological difficulties after the descent
(i.e., memory impairment, lesser cognitive efficiency, de-
pression). Sixty-one percent of them revealed abnormali-
ties in MRI. Unexpectedly, only one of the Sherpas (14%)
showed alterations in MRI and indicated to have suffered
neurological symptoms. Summing up, the experience of
altitude does not seem to be an important factor in adap-
tation as the biological conditioning. The final section of
this article considers possible training factors. On the other
hand, interaction between effort and altitude is observed
in the levels of hypoxia although such interaction has
not been checked considering ANI a second dependent
variable.
The adaptation of organisms to high altitude should
be approached from a broad perspective. So together with
the relevant respiratory factors one should consider com-
pensatory vascular mechanisms.
VASCULAR AND HEMATOLOGICAL
ADAPTATION ASSOCIATED WITH ALTITUDE
A posterior adaptive process that takes place in
longer stays, more than a week at high altitude is poly-
cythemia. Polycythemia provokes an increase in hema-
tocrit due to erythropoiesis mediated by erythropoietin.
This process rises the arterial oxygen uptake, which re-
duces PaO
2
due to a reduced plasmatic pressure of free
oxygen (Richalet et al., 1994). This facilitates the gas ex-
change in the alveolar–arterial membrane. At brain level,
the reduced cerebral perfusion is balanced by a response
of compensatory vasodilatation that maintains CBF con-
stant. Normality in CBF by means of this strategy can be
kept up to levels of 60 or 70 mmHg PaO
2
(i.e., 3,500 m
approximately). Given the limit of vasodilatation, beyond
this point, the organism compensated the oxygen deficit
by increasing CBF (Baumgartner et al., 1999; Jensen et al.,
1990). For instance, the reduction of PaO
2
to 25 mmHg
produces an increase of 400% in CBF, although obviously
at these levels the increase of CBF, obviously, loses capac-
ity to keep constant the oxygenation of the neural tissue
(Adams et al., 1999).
On the other hand, the drop in PAO
2
produces a lung
vasoconstriction mediated by endotelin 1 produced by
endotelian cells (Morganti et al.,1994). Lung arterial hy-
pertension generates a hemodynamic overload in the right
ventricule with a clear effect in the increase of electroen-
cephalographic activity (Karliner et al., 1985; Milledge,
1963; Pe
˜
nazola and Echevarr
´
ıa, 1957). This sequence of
events may lead in, extreme cases, to lung edema (West
and Mathieu-Costello, 1992). As Moore et al. (1992) have
pointed out, this process, observed in Andean commu-
nities, does not appear among Sherpas and Butanese,
perhaps because these populations have inhabited their
regions for 25,000 years. On the contrary, Andean com-
munities were established 10,000 years ago. That much
202 Viru
´
es-Ortega, Buela-Casal, Garrido, and Alc
´
azar
longer period allows a better adaptation to the hypoxic
environment as postulated by Moore et al. (1992).
SLEEP ALTERATION AND
NEUROPSYCHOLOGICAL FUNCTIONING
The first research to make a record of the physiology
of sleep at altitude was performed by Reite et al. (1975). In
this study, six subjects were taken to an altitude of 4,300 m
where they underwent a polysomnographic record during
4 nonconsecutive nights. Previously, two nights had been
recorded at sea level. It should be stressed that the sub-
jects had not made any special exercise during the stay
at altitude, and that they were taken there by helicopter.
The most remarkable results were the increase in sleep
phases III and IV, and a hardly significant tendency to
reducing rapid eye-movement sleep. In addition, the to-
tal amount of sleep decreased but in a limited proportion
compared with the subjective sensation of not having slept
mentioned by the subjects. Another effect was the increase
in arousals during the night (19.5 in normoxia against
29.2 at altitude). A new finding was the appearance of
PB that was observed in some subjects during most of
the night, especially during sleep phases of slow waves.
The results showed that arousals were more likely during
periods of PB coinciding with the transition from apnea to
the beginning of PB. However, there was no relationship
between the number of arousals and the time spent in PB.
An extreme case was subject 1, who did not show PB at
all but displayed the most outstanding increase in arousals
after exposure to altitude.
Anholm et al. (1992) placed five subjects under a
simulated pressure of 282 mmHg for 6 weeks making
polysomnographic records. His results are similar to those
by Reite et al. (1975) but showed a much clearer re-
duction in rapid-eye-movement (17.9% vs. 4%) and a
more significant reduction in the total amount of sleep
(337 min. vs. 167 min.). Anholm et al. (1992) specified
that at 282 mmHg, the mean SaO
2
during the night was
52%. Subsequent investigations have revealed that both
PB and sleep apnea during exposure to altitude are related
to ventilatory sensitivity to hypoxia (Lahiri et al., 1983;
Lahiri and Data, 1992). Specifically, a higher HVR entails
a more extended PB during the night. Others have put for-
ward the possible explicatory role of PB in the neuropsy-
chological impairment of mountain climbers (Hornbein
et al., 1989; Hornbein, 1992). In this research a more
considerable neuropsychological impairment was found
after a simulated ascent to 8,848 m in subjects who had
displayed a greater HVR, and who paradoxically show
a better physical adaptation to altitude established by
number of symptoms of AMS (Masuyama et al., 1986;
West, 1984). Likewise, subjects who showed a high HVR
maintained their PaO
2
above 30 mmHg (above 8,000 m).
Below this point it has been observed that hypoxia-related
alterations suffer a qualitative change (Schoene, 2001) as
a result of an alteration in the gradient of alveolar pressure
that prevents gas transfer.
As mentioned above, it has been suggested that the
periods of hypoxemia suffered during sleep time with PB
associated with a high HVR were responsible for a greater
cognitive impairment at altitude. This hypothesis, how-
ever, does not hold since more recent evidence has demon-
strated that subjects with a reduced HVR also show peri-
ods of acute hypoxemia during sleep that are not related
to periods of PB (Coote et al., 1993a; Hackett et al., 1987;
Sutton et al., 1987). Matsuzawa et al. (1994) recorded
electroencephalographic and electrooculographic activity,
and SaO
2
of a group of nine subjects during the first night
of sleep at a simulated altitude of 3,700 m. It was ob-
served that saturation fell by a mean of 7% during the
night (p<.01), the symptoms of AMS were stronger
the morning after, and eight of the subjects showed PB
between 0 and 57.8% of the night. No correlation was
found between PB and SaO
2
, PB and the symptoms of
AMS, nor between PB and HVR.
Furthermore, it has been noticed that arousals during
the night protect against severe deprivation of oxygen. In
his pioneering research Reite et al. (1975) did not find con-
nection between apneas or PB during sleep and number
of arousals. More recently, Khoo et al. (1995), in research
with nine subjects inside a hypobaric chamber using a
range of altitudes between 4,500 and 7,500 m noticed a
clear association between number of apneas and number
of arousals. This supplies further evidence that subjects
with a high HVR, and consequently more frequent PB
and apneas during sleep, do not suffer more acute night
hypoxia. In the results obtained by Khoo et al. (1995), the
number of apneas only explained a 20% of the arousals so
that arousals should be taken as an independent protective
mechanism against a hypoxic environment, as suggested
by other authors (Coote et al., 1993a; Coote et al., 1993b;
Selvamurthy et al., 1986).
Another way of elucidating the possibility that night
hypoxia is responsible for the impairment would be to
check whether the administration of O
2
during sleep,
which has a demonstrated effect on PB (Reite et al.,
1975), reverses the pattern of impairment in subjects with
a high/low HVR. Future research should test this hypoth-
esis.
Until new studies shed light on this question, one
can rely on a clinical model of chronic hypoxia such
as OSA, whose pattern of associated neuropsychological
Neuropsychological Functioning at High Altitude 203
impairment is generally similar to that of exposure to al-
titude as explained below (Grant et al., 1987; Kelly et al.,
1990; Telakivi et al., 1993). Nevertheless, it should be re-
membered that this is a case of chronic, not acute, hypoxia.
Findley et al. (1986) found that in subjects with OSA who
suffered associated hypoxemia, the total degree of neu-
ropsychological impairment correlated with the levels of
PaO
2
and SaO
2
both measured during the night or the
daytime. Unfortunately, these results only indicate that
hypoxia related to altitude during sleep could be enough
to explain the associated neuropsychological impairment.
However, at altitude, oxygen desaturation is still present
in the daytime and the periods of hypoxia are shorter than
those suffered by patients with chronic OSA.
In conclusion, during sleep at high altitude there is
a reduction in the later sleep phases of slow waves and
an increase in phase 1, which produces impairment in the
quality of sleep (Matsuzawa et al., 1994; Wickramasinghe
and Anholm, 1999). Rapid eye-movement sleep is reduced
and night arousals increase significantly (Buguet et al.,
1994). Finally, there is a considerable drop in oxygen sat-
uration values during the night, a phenomenon not clearly
associated with AMS, PB, or HVR that can contribute
strongly to neuropsychological impairment. Interestingly,
this pattern of alterations is hardly observed in Andean
communities living at high altitude (Coote et al., 1992;
Coote et al., 1993b).
ACUTE MOUNTAIN SICKNESS: SUFFICIENT
BUT NOT NECESSARY CONDITION FOR
ALTITUDE NEUROPSYCHOLOGICAL
IMPAIRMENT
AMS should be distinguished from concurrent neu-
ropsychological or behavioral alterations. AMS is associ-
ated with too sudden an ascent for the body to perform
compensatory actions, especially ventilatory and vascular,
for a reduced environmental oxygen pressure (PO
2
), while
psychological alterations are related to the consequences
of a reduced PaO
2
in the organism independent of an
adequate or inadequate acclimatization. In other words, it
is not necessary to have AMS to detect neuropsycholog-
ical alterations since compensatory mechanisms do not
neutralize completely the effects of hypoxia on the ner-
vous system and consequently on behavior. For example,
Kramer et al. (1993) did not find any correlation between
the degree of AMS and the increase in latency in RT. Nei-
ther did they connect AMS and the degree of dysfunction
in a battery of perceptive, cognitive, and motor tests. In
this case, subjects were exposed to a moderate rate of as-
cent so that AMS was prevented (none of them surpassed
a score of 3 out of a 6-point scale of AMS). However, this
did not avoid the presence of a set of psychological conse-
quences, despite a mean ascent of 300 m per day favored
an adequate physical adaptation. Also, Krammar et al.
(1983) did not find any relationship between altitude and
AMS at a similar rate of ascent. For this reason, it is nec-
essary that studies not only specify altitude but also rate of
ascent. Above mean values used by Krammar et al. (1983)
there is indeed a positive association between altitude and
symptoms of AMS (Nicolas et al., 1999). Considering that
both altitude and the pace of ascent are associated with
the presence of AMS and neuropsychological impairment
(Hansen et al., 1967; Shukitt and Banderet, 1988), apriori
or a posteriori controls should be made of the symptoms
of AMS in order to determine which effects are the result
of a normal adaptation to altitude and which correspond to
this disorder. Studies made about high rates of ascent have
found that the pattern of effects may differ whether the
subject develops AMS or not. Regard et al. (1991) have
established a double dissociation between subjects who
developed AMS and subjects who did not. A fast ascent
to an altitude of 4,500 m was made inside a hypobaric
chamber. The ascent took 24 hours. This rate avoided the
ground effect that similar investigations have suffered in
trying to associate the symptoms of AMS with the psycho-
logical effects of altitude (Kramer et al., 1993). Subjects
who developed AMS showed little deficit in short-term
memory and a more significant impairment in concep-
tual tasks. On the contrary, those who did not develop
AMS displayed the reverse pattern: a greater impairment
of short-term memory and scarce alteration in conceptual
tasks. Similar findings were obtained by Forster (1985).
It should be stressed that a human being who is
still conscious with a PaO
2
of 30 mmHg (equivalent to
an altitude higher than 8,000 m) after an adequate rate
of ascent must have an enormous capacity of acclima-
tization. A chronic hypoxia model of this phenomenon
can be found in COPD, who live normally around the
threshold of 30 mmHg of PaO
2
(Adams et al., 1999). In
contrast, a nonacclimatized subject exposed to such con-
ditions would die or lose consciousness, as was dramati-
cally observed in balloon ascents in the 19th century (Bert,
1878/1978). The case of Gaston Tissandier in 1,875 made
the scientific community aware of the mortal danger of too
fast ascents. Tissandier and the brothers Croce–Spinelli
ascended together in the balloon Le Z
´
enith to an altitude
of 8,600 m. Above 8,000 m they all lost consciousness.
Tissandier brightened up after the descent. The others
perished (Tissandier, 1875).
After considering the respiratory and vascular ef-
fects associated with acute hypoxia and being aware that
the causal factors of neuropsychological impairment are
204 Viru
´
es-Ortega, Buela-Casal, Garrido, and Alc
´
azar
hypoxia and cerebral ischemia, we are going to analyze
the nature of the brain dysfunction related to altitude.
BRAIN DYSFUNCTION ASSOCIATED WITH
ALTITUDE: STRUCTURAL AND
FUNCTIONAL ALTERATIONS
Despite vasodilatation, polycythemia, and the in-
crease in CBF associated with hypoxia, the human or-
ganism cannot avoid a drop in oxygen saturation in the
central nervous system (CNS) in conditions of high or
extreme altitude. Desaturation is particularly intense if
the subject exercises (Bradwell et al., 1999; Roach et al.,
2000; Saito et al., 1999; Sutton et al., 1988), sleeps at
altitude regardless of the presence of PB (Coote et al.,
1993a; Hackett et al., 1987; Matsuzawa et al., 1994) and
shows a high hypocapnia associated with an intense HVR
(Hornbein et al., 1989; Schoene, 1999). Brain desaturation
resulting from these phenomena may explain reversible
neuropsychological alterations associated with altitude.
Such processes are independent of AMS, whose symp-
toms display a different temporal pattern (Shukitt-Hale
et al., 1991). In addition, the symptoms of AMS are in-
dependent of the occurrence of neuropsychological im-
pairment (Bahrke and Shukitt-Hale, 1993) although AMS
entails qualitative changes in the type of dysfunction, as
discussed above.
Blood hyperviscosity due to the increase of hema-
tocrit (Samaja et al., 1993), alterations in coagulation
(Doughty and Bearmore, 1994), and probably the increase
in intracranial pressure (Roach and Hackett, 2001) aug-
ment the probability of thrombosis during prolonged stays
at high and extreme altitude. These alterations may cor-
respond to focal ischemic infarcts in the CNS (Garrido
et al., 1993; Garrido et al., 1995; Song et al., 1996) that
develop with acute neurological symptoms from mild to
severe. Among others, ataxia (Hacket et al., 1998), apha-
sia (Garrido and Javierre, 1996), blindness (Hackett et al.,
1987), hemianopsia (Garrido et al., 1993), diplopia (Shlim
et al., 1995), hemiparesis (Basnyat, 1997), delirium
(Basnyat, 2002) and global amnesia (Litch and Bishop,
1999), have been described in this context. Ischemic acci-
dents together with a sufficiently extreme and prolonged
desaturation to interrupt the neuronal metabolism and pro-
duce necrosis are probably the most relevant factors to
produce short and long-term ANI after returning to low-
land. The possibility of irreversible brain dysfunction due
to hypoxia in absence of ischemia remains a matter of
debate (Hornbein, 2001; Simon, 1995).
Hypoxia damages all necessary aerobic processes
maintaining Krebs cycle and the electronic transport sys-
tem. When neurons are deprived of oxygen, they catabo-
lize themselves. The resulting accumulation of catabolic
products such as lactic acid causes irreversible damages
that eventually result in the death of the cell (Adams
et al., 1999). Besides this mechanism, in the case of glu-
tamatergic neurons, hypoxia induces an excessive release
of glutamate. Once it is linked to n-methil-
D-aspartatus
(NMDA), this neurotransmitter generates an excessive
flow of sodium ([Na
+
]
e
) and calcium ions ([Ca
2+
]
e
)in
the postsynaptic neuron. This causes cellular death af-
ter the postsynaptic neuron has released its reserves of
glutamate producing a toxic flow that extends to adja-
cent neurons (Schousboe et al., 1997; Pinel, 2001). The
considerable presence of glutamatergic cells in the hip-
pocampus explains partially the enhanced sensitivity of
this structure to conditions of hypobaric hypoxia (Gozal
et al., 2001; Shukitt-Hale et al., 1996). These findings have
not been confirmed in human investigations analyzing
through imaging techniques the damage to the encephalon
after climbs to peaks above 8,000 m without supplemen-
tary oxygen (Garrido et al., 1995; Garrido et al., 1996;
Hacket et al., 1998).
Structures Sensitive To Hypoxia
The direct assessment of brain damage associated
with altitude is limited so we have turned to consider-
ing laboratory findings related to other hypoxic accidents.
Brierley (1976) observed that in hypoxic conditions, the
most damaged structures were the hippocampus, the tha-
lamus, layers 2, 4, and 5 in the cortex, the amygdala, and
the corpus striatum. Pichiule et al. (1996) obtained similar
results. These authors exposed rats to intermittent hypoxia
(4,300 m) during 10 weeks. They observed a reduction in
the agonist ligament (2H)MK-801 of the NMDA receptor
with respect to 36% control in the case of the cortex,
35% in the hippocampus, and 31% in the striatum. Reed
et al. (1999) observed by MRI that four subjects who had
suffered severe hypoxia and showed anterograde amnesia
had a clear damage in the middle temporal lobe compris-
ing all the hippocampus and the parahippocampal areas.
Adams et al. (1999) observed that subjects with hypoxic
encephalopathy of various etiologies showed damages in
inferomesial areas in both temporal lobes, and problems
of memory and anterograde amnesia in accordance with
altitude. Schulze et al. (1990) observed that exposing his
subjects to a SaO
2
between 88% and 90% (equivalent
to an altitude of 2,500 m) produced a metabolic delay
in the hippocampus, hypothalamus, cortex, and striatum.
The reduction in the release of acetilcoline (Ach) in rats
exposed to 5,500 m was studied by Shukitt-Hale et al.
Neuropsychological Functioning at High Altitude 205
(1993). The physiological measurement was more sensi-
tive than the behavioral assessment, in this case the Morris
Water Maze (MWM). This test did not indicate significant
damages up to 5,950 m. This author noticed damages in
area CA3 in the hippocampus after exposing animals to an
altitude of 6,400 m for 4 days (Shukitt-Hale et al., 1996).
Gozal et al. (2001) used immunohistochemistry to record
an increase in apoptosis in area CA1 of the hippocampus
after 2 days of exposure to intermittent hypoxia (10/21%
O
2
). This alteration reverted after 14 days. Intermittent
hypoxia increased latencies and longitude of the paths in
the MWM.
Zola-Morgan et al. (1986) have verified in humans
the special sensitivity to hypoxia of the hippocampus and
the limbic system. In this regard, hypoxia has been sig-
nificantly associated to tests that measure dysfunctions to
the hippocampus such as the MWM (Shukitt-Hale et al.,
1996). Prigatano et al. (1983) and Bedard et al. (1991)
maintain that the frontal lobe is also affected in subjects
who suffer from hypoxia continuously. In support of this
hypothesis, Viapiano et al. (2001), exposed a group of
21 monkeys to hypoxia, found a 30% decrease in maxi-
mal binding capacity in γ -amynobutiric acid (GABA) to
GABA
A
receptor sites. The change was reversible after
returning to normoxia. Adams et al. (1999) point out that
the hippocampus and the deep cerebellar folia are the most
sensitive structures to anoxia.
Specific investigations by Regard et al. (1989) found
that two subjects from a group of eight world-class
mountain climbers who had ascended repeatedly above
8,000 m without supplementary oxygen experienced
chronic anomalies in their temporal and frontal electroen-
cephalographic activity measured months after their last
ascent.
NEUROIMAGING RESEARCH
Using MRI techniques, Anooshiravani et al. (1999)
did not detect functional nor structural alterations in a
group of climbers after returning from a 6,000 m peak.
On the contrary, Garrido and his team have found on three
occasions structural alterations in the brain through MRI
in subjects who had ascended above 8,000 m without sup-
plementary oxygen (Garrido et al., 1993; Garrido et al.,
1995; Garrido et al., 1996). In the first case, in a sam-
ple of 26 mountaineers who had climbed to peaks above
7,000 m they detected anomalies in MRI with respect to
controls. The authors observed anatomical anomalies in
46% of the subjects, basically signs of cortical atrophy
in five subjects, and leuko-araiosis in five other subjects.
Two other subjects displayed both alterations in MRI. It
should be noted that this research has a transversal design
not a longitudinal one. A control group of nonclimbers
was selected and the neuroimaging records were made up
to 3 years after the ascent. Another study by the same
authors (Garrido et al., 1995) without the said shortcom-
ings obtained similar results. This time, after an ascent,
alterations in the form of high intensity signals were de-
tected in 56% of a sample of nine subjects (five subjects)
in periventricular areas (leuko-araiosis), posterior parietal
cortex, and occipital white matter, thus confirming pre-
vious observations (Griggs and Sutton, 1992). In a third
study, the authors replicated these findings (Garrido et al.,
1996) with a group of 21 lowland elite mountaineers with
an average stay of 445 hours above 7,000 m and 56.5 hours
above 8,000 m. In this case, 61% of the subjects showed
signs of cortical atrophy and high-density signals while
no abnormalities were reported in the controls. Alterations
were mainly found in the atrial zone and the periventricu-
lar regions of the posterior horns of the lateral ventricles.
In this latter study, these results did not appear when a
third group of seven world-class Sherpas was evaluated.
On the other hand, no associations were found between
anomalies obtained by MRI and neuropsychological al-
terations described by medical history and neurological
examination (no formal neuropsychological assessment
was arranged). The number of ascents, time of exposure
to extreme altitude, and time elapsed since previous as-
cents were not correlated with MRI findings. Hackett et al.
(1998) examined nine subjects with High-Altitude Cere-
bral Edema and noted that seven of them showed intense
signals in T2 in different areas of the white matter, espe-
cially the splenium and the corpus callosum.
Leuko-araiosis observed by means of MRI is as-
sociated with cortico-subcortical injury with a widen-
ing of Virchow-Robin spaces that contain the perforat-
ing vessels of the middle cerebral artery. Histologically,
leuko-araiosis shows demyelination, axonal degeneration
and astrogliosis considering a partial infarct of the white
periventricular matter. Leuko-araiosis is a likely conse-
quence of intermittent anoxias due to alterations in the
regulation of the cerebral flow in long and thin vessels
with no anastomosis (Garrido, 1997). In the absence of
ventricular enlargement, leuko-araiosis is associated with
a slow-down in complex mental processes (Junqu
´
e et al.,
1990) that can be similar to that frequently suffered by
climbers at extreme altitude and identified by Ryn (1988)
as acute organic brain syndrome. A significant associa-
tion has been reported between leuko-araiosis and reduced
speed in complex information processing and with initial
dementia in elderly people (Steingart et al., 1987; Junqu
´
e
et al., 1990). However, the long-term evolution of such
neuroimaging findings observed in world-class Caucasian
climbers is not known (Garrido et al., 1996).
206 Viru
´
es-Ortega, Buela-Casal, Garrido, and Alc
´
azar
In this context, considering the oxygen uptake
previous to 8,000 m, the negative result obtained by
Anooshiravani et al. (1999) seems logical, rather than con-
tradictory, since their subjects did not go above 6,000 m
and were exposed to a shorter stay at altitude than those
studied by Garrido and his team. However, Garrido et al.
(1995) stress that 80% of their subjects who showed al-
terations in neuroimaging before the ascent had never
climbed higher than 6,800 m before the studied expedi-
tion. This contradicts Anooshiravani’s results as long as it
is assumed that the dysfunctions observed in these subjects
were due to hypoxia suffered in previous expeditions.
Recent techniques to record brain metabolism in vivo
have shed light into this issue. Hochachka et al. (1999)
evaluated the regional metabolism of the brain glucose
in six subjects by means of Positron Emission Tomog-
raphy (PET) before and after training during 63 days at
an altitude between 3,181 and 6,157 m. These authors
found a reduction in the brain activity in three frontal
areas, the left occipital lobe, and the right thalamus. A
bilateral increase in the cerebellum activity was also ob-
served. The effects were intense with oscillations between
10% and 18% of the absolute metabolism compared with
the first measurement. These striking results were not be
replicated by Moller et al. (2002). These researchers es-
tablished global brain metabolic rates for oxygen and glu-
cose, oxygen delivery, and CBF before and after a stay
at altitude of a group of nine lowlanders, without finding
differences between both conditions neither in exercise
nor at rest. The difference with findings by Hochachka
et al. (1999) is due to their global, not regional, mea-
surements, their different techniques (Kety-Schmidt vs.
PET), a shorter exposure (21 vs. 65 days), and a lower
maximum altitude (5,260 m vs. 6,157 m). The alterations
observed by Hochachka et al. (1999) are not found among
Sherpas, who have a brain metabolism at altitude similar
to that of lowlanders in normal conditions, as measured by
PET (Hochachka et al., 1996). Unfortunately, these stud-
ies did not include measurements of neuropsychological
functioning.
Extreme desaturation, together with the presence of
focal ischemic processes provoked by hypoxia produce
neuronal death in mountaineers exposed to high and ex-
treme altitude extendedly or repeatedly. MRI has shown
focal ischemic damages in periventricular areas and corti-
cal atrophy in climbers exposed to extreme altitude. These
findings have not been replicated in exposure to moderate
and high altitude. It is hypothesized that a mild damage can
happen in structures sensitive to hypoxia, such as the hip-
pocampus, due to a high desaturation. This has been tested
in animals but not in humans. The new application of
functional neuroimaging techniques has demonstrated the
regional, but not global, reduction of the CBF especially
in frontal areas. Because most of the neuropsychological
impairment associated with altitude is reversible, and the
circumstance that no neuropsychological measurements
have accompanied functional records of brain activity, it
is not possible to reach conclusions about physiological
correlates at CNS of ANI. Future research using PET
or functional MRI, together with an extensive neuropsy-
chological record will improve the knowledge of brain
function underlying ANI.
PSYCHOMOTOR EFFECTS OF ALTITUDE
A most debated effect of altitude has been the im-
pairment of motor performance. It was already pointed out
by McFarland (1937a, 1937c), and has been measured by
most recent investigations on this issue. The effect man-
ifests as a lesser motor speed and precision as compared
to subjects’ sea level performance (Berry et al., 1989;
Bolmont et al., 2000; Hornbein et al., 1989; Sharma et al.,
1975; West, 1984). Differences in RT cannot be attributed
to this effect, as argued below.
The most widespread test to detect motor speed im-
pairment is the FTT from the Halstead-Retain Neuropsy-
chological Battery. This test has proved its efficiency to
discover slight motor dysfunctions (e.g., Pe
˜
na-Casanova
et al., 1997). Other motor tests have obtained similar ef-
fects, for instance the Purdue Pegboard Test, sensitive to
speed, motor coordination and precision (Bolmont et al.,
2000; Lezak, 1995).
It is debatable whether motor effects are the direct
result of hypoxia or due to related factors. In this re-
spect, investigations have highlighted the modulating role
of anxiety and fatigue in connection with motor perfor-
mance in experiments of exposure to simulated altitude.
Several reports from Operation Everest II and Everest-
Comex 97 supply some relevant results. We argue that the
hypothesis that psychomotor effects are an indirect result
of exposure to altitude is supported by three types of ob-
servations. First, experimental data indicate the absence of
neuromuscular alterations at simulated altitude up to 8,848
m. This is consistent with the possible effect that fatigue
is a central, rather than peripheral symptom (Garner et al.,
1990). These authors measured 3 torques during a 40-day
simulated ascent to 8,848 m in a hypobaric chamber (Op-
eration Everest II Project), muscle twitch torque, titanic
torque and maximal voluntary contraction torque. Al-
though the amplitude of muscle activity was not affected
at 6,500 m and 8,848 m conditions, they found evidence
of fatigability of the twitch in a test interpolating a 20
Hz stimulus into the muscle. This result accords with the
Neuropsychological Functioning at High Altitude 207
emergence of central fatigue (Garner et al., 1990). Second,
psychophysical findings demonstrate that alterations in
RT do not obey motor commitments (Abraini et al.,
1998; Bouquet et al., 1999). These studies have shown
that performance in psychomotor activity in an altitude-
dependent manner considering altitudes above 6,000 m
(Everest-Comex 97 Project), while RT remains at basal
levels in all altitude conditions. These data shows that ba-
sic motor processes remain unaffected. Third, it has been
noted that fatigue established by the Profile of Mood States
is significantly associated with performance in the Purdue
Pegboard Test, but not with RT, assigning new value to
the central mediation hypothesis (Bolmont et al., 2000).
Conversely, Hornbein et al. (1989) as part of Operation
Everest II Project reported that the poorer performance in
the FTT was not significant in a group of simulated ascent
to 8,848 m, whereas in a group that climbed to Mount
Everest there was a significant impairment (p<.001).
These paradoxical results as compared with the Everest-
Comex 97 data call for further investigation in order
to properly establish the particular conditions in which
psychomotor impairment can be replicated in vivo and
in vitro.
Possible Permanent Dysfunctions
On the contrary, a second group of observations indi-
cates that motor impairment is a genuine effect of altitude.
The long-term permanence of motor impairment after
returning to sea level supports the hypothesis that this
alteration cannot be an indirect consequence of altitude
by the effect of anxiety or fatigue. During the American
Medical Research Everest Expedition (AMREE-1981),
Townes et al. (1984) and West (1984) noticed that 15 out
of 16 mountaineers showed a significant impairment in
the FTT right after the expedition and that 13 of them
still showed it a year later. This expedition did not use
supplementary oxygen. West (1986) confirmed that im-
pairment was still significant 2 years later. These re-
sults should be taken cautiously because this investiga-
tion did not take into account whether the climbers were
exposed again to extreme altitude. Then again, Regard
et al. (1989) gave the same test (FTT) to world-class
climbers who had not been exposed again to altitudes
above 5,000 m during an average period of 7 months. Their
results showed that the motor impairment was significant
in two out of the eight subjects examined with respect to
controls.
Neither hypothesis is conclusive if one considers that
both hypoxia and fatigue are modulated by the workload.
A higher degree of fatigue is likely to increase the levels
of hypoxia and produce long-term effects, though this
remains an object for future investigations.
The finding of permanent effects of altitude depends
on three factors, only one of which is irreversible and ac-
tually permanent. (a) There may be a diffuse brain dam-
age in areas especially sensitive to hypoxia through re-
peated and prolonged exposure to altitudes above 8,000 m.
(b) Subjects may have been repeatedly exposed to alti-
tude during the posttest period. (c) The posttest may be
performed during a period of 45 days after the descent.
This means that subjects have an increased HVR and ac-
cordingly one cannot be sure that they have returned to
normoxia (Forster et al., 1971; Masuyama et al., 1986).
Factors (b) and (c) should be taken into account because
the available evidence indicates that, although effects can
be long-lasting, they tend to disappear in less than 2 years
(Townes et al., 1984; West, 1986). Alternatively, when
no such long-lasting effects have been found the reasons
seem to be the types of tests used, durations of exposure
(i.e., shorter durations), maximum altitude reached (i.e.,
lesser altitude), the use of supplementary oxygen, or an
inadequate timing of the posttest measurement (i.e., sev-
eral days or weeks after the descent). These factors partly
explain the negative results of some investigations (e.g.,
Clark et al., 1983; Jason et al., 1989; Milne and Gray,
1983).
In order to justify the genuine effects of altitude on
motor performance we can observe the convergence of
results among clinical models of chronic hypoxia. Bedard
et al. (1991) noticed that in subjects with OSA, a poorer
performance in the Purdue Pegboard Test was associated
with higher levels of apnea. McSweeney et al. (1985) ob-
tained similar findings among subjects with COPD using
the FTT. However, results in this area are inconclusive
(Grant et al., 1987; Stuss et al., 1997). A third element
that supports the genuine effect of altitude is the finding
of psychomotor impairment in laboratory experiments for
controlling fatigue and anxiety effects (e.g., Berry et al.,
1989). In addition, experimental research has shown that
a poorer performance in the FTT is strongly related to
the reduction in oxygen saturation in a higher propor-
tion than its correlation with anxiety. Berry et al. (1989)
detected a linear tendency between oxygen saturation (be-
tween 100% and 80% SaO
2
) and the number of tappings
(p = .009). In a laboratory study, Hornbein et al. (1989)
established a correlation of -0.98 (p<.05) with PaO
2
,
and 0.85 (p<.05) with SaO
2
using the same test. Ad-
ditional evidence for this hypothesis is supplied by the
permanence of effects after prolonged exposure to alti-
tude. Sharma et al. (1975) recorded motor speed and effi-
ciency at different moments in a community that stayed at
4,000 m for 2 years. Psychomotor efficiency suffered an
208 Viru
´
es-Ortega, Buela-Casal, Garrido, and Alc
´
azar
initial impairment and disappeared several months after
the beginning of the stay. The speed variable, strongly
associated with the task of the FTT, remained altered
throughout the stay at altitude, too long to be considered
an effect of anxiety, fatigue, or novelty.
At etiological level, psychomotor impairment seems
to be the result of a reduction in oxygen saturation since
hypocapnia associated with acute hypoxia does not al-
ter the pattern of motor effects when the levels of CO
2
(isocapnia) are stable, as observed by Berry et al. (1989).
Unfortunately, these authors did not apply sufficient oxy-
gen saturation to establish the vasoconstrictor effect of
hypocapnia. The sensitivity to conditions of hypoxia of
motor structures such as the basal ganglia or the cere-
bellum (Adams et al., 1999) can be a decisive factor to
display such effects.
The minimum height that produces motor impair-
ment varies among investigations between 2,500 m and
6,000 m. Some consensus will necessarily be reached
when similar tasks are used. For instance, Bolmont et al.
(2000) has not found significant dysfunctions below
8,000 m using the Purdue Pegboard Test, while Berry
et al. (1989) observed them at a mean altitude of 3,500 m
using the FTT.
Performances in the FTT and HVR level were not
correlated, detaching psychomotor impairment from other
cognitive processes whose levels were significantly cor-
related with HVR in the report (Hornbein et al., 1989).
Psychomotor impairment process may follow a specific
temporal pattern of development or simply indicate a flaw
of this investigation to detect a significant connection.
In this respect, FTT results show a high correlation with
SaO
2
(r = .85; p<.05) for a simulated altitude of 8,100
m and 8,848 m, respectively. Furthermore, the effect of
HVR on the %SaO
2
takes only a few seconds of latency
(Khoo et al., 1995).
Regarding clinical models of chronic hypoxia, alter-
ations are not convergent. In the case of COPD, simple
psychomotor skills, and psychomotor speed are resilient
to hypoxia. Motor alterations are only detected in subjects
suffering from severe hypoxia (Grant et al., 1987).
We have argued that psychomotor effects seem a
direct consequence of hypoxia, as suggested by its asso-
ciation with biological markers of hypoxia and its perma-
nence after return to lowlands. The effect is modulated by
anxiety and fatigue. In the case of fatigue, it is presumed
to have an indirect effect increasing the degree of hypoxia.
In contrast, impaired speed is detected at lower altitudes
than impaired precision. It is advisable for future research
that speed and precision tests are applied concurrently. For
instance, using both the FTT and the Grooved Pegboard
Test, a test more focused on precision and coordination.
EFFECTS OF ALTITUDE ON PERCEPTION
Basic Processes: Reaction Time
The effect that meets most acceptance in the litera-
ture on the effects of altitude is the increase in complex
reaction time (CRT). It has been found both in laboratory
conditions (Bolmont et al., 2001; Fowler et al., 1987) and
real expeditions (Kramer et al., 1993), and both with and
without AMS (Mackintosh et al., 1988), although AMS
triggers a greater CRT increase compared to baseline lev-
els (i.e., low-altitude, sea level P
B
). CRT is a sensitive
index of exposure to altitude although most effects do
not appear up to 6,000 m and after prolonged exposure
(Hornbein et al., 1989; West, 1984), significant increase
of CRT can be found above 2,500 m. Denison et al. (1996)
found increases in CRT at such low altitude as 1,500 m.
Fowler et al. (1987) demonstrated that increase in CRT
in their subjects was significant from 2,438 m upwards,
considering altitude by means of induced %SaO
2
.
A better understanding of the factors that affect this
process has been gained by using event-related potentials
(ERP). Wesensten et al. (1993) recorded the auditory CRT
of their subjects using a hypobaric chamber to induce a
hypoxia corresponding to 4,300 m. They observed that
the increase in CRT due to hypobaric environment corre-
sponded to increases in latency of component P300. P300
also suffered a reduction following a temporal pattern
that differed from the increase in latency and CTR, which
suggests two different mechanisms. In contrast, no effects
of altitude were found in components N100, P200, and
N200. Considering the amplitude of P300, Fowler and
Prlic (1995) observed that it displayed an inverted-u rela-
tionship with the degree of hypoxia, while the increase in
CRT and P300 latency showed a linear co-variation. This
provided additional evidence of the existence of two dif-
ferent mechanisms. More recent research has confirmed
the findings related to P300 and demonstrated increases
in latency of N200 (Kida, 1997).
Fowler and Lindeis (1992) applied the oddball
paradigm (Carreti
´
e and Iglesias, 1995) to the auditory
ERP and also found an increase in latency of the com-
ponent P300. These authors obtained the same results in
visual ERP. The literature on the topic coincides in the
attribution of the increase in CRT to the rise in latency
of P300 setting aside motor factors in this case (Fowler
and Adams, 1993). This evidence can be interpreted as
a slowing in the identification of stimuli, given the in-
crease of P300 latency typically related to this function
(e.g., Johnson, 1988), which results in an increased CRT.
Fowler and Prlic (1995) measured auditory CRT and ERP
at different levels of saturation between 86% and 77%
Neuropsychological Functioning at High Altitude 209
SaO
2
observing equivalent linear relations between de-
saturation and CRT increase, and between desaturation
and P300 latency. However, Fowler and Adams (1993)
found that previous levels of processing can also be af-
fected. According to their results using the method of
additive factors, below a level of oxygen desaturation be-
tween 63% and 64% they found a high interaction between
degree of hypoxia and stimulus intensity, and CRT. The
effect of the increased stimulus intensity is considered to
be associated with a preprocessing stage rather than with
a stimulus identification stage.
Takagi and Watanabe (1999) applied the paradigm
of contingent negative variation, where a subject has to
choose between two answers, whether the stimulus shown
was the same as, or different from, another shown a second
earlier. This is related to motor programming, attention,
motivation, and memory (e.g., McCallum, 1988). The said
study found a reduction in contingent negative variation as
an effect of a 6,000 m hypoxia especially in earlier com-
ponents to the detriment of later components. Conversely,
up to 3,000 m the amplitude of later contingent negative
variation was negatively correlated with CRT while above
3,000 m it was the amplitude of the early component that
correlated with CRT negatively.
Basic Processes: Perceptive Discrimination
Watson et al. (2000) observed that ERP and increase
of CRT were not associated with a rise in the absolute
threshold for auditory stimuli up to 16 kHz at a hy-
poxia equivalent to altitudes of 1,200, 2,400, and 3,700 m.
Fowler and Grant (2000) obtained similar results. Burkett
and Perrin (1976) noticed that at 6,600 m altitude had
no effect on the discrimination of speech sounds. Finally,
in an analogous investigation, Martin et al. (2000) found
no effects on the localization of stimuli at an altitude of
3,700 m.
The findings in discrimination of auditory stimuli
cannot be extended to other sensory modalities. Typical
findings in exposure to altitude include reductions in the
absolute threshold for tact, detection of CO
2
, smell, light,
and taste (Fleisch and Von Murant, 1944, 1948; Kobrick,
1983). The same alteration in threshold was observed
in the sensation of breathing (N
¨
oel-Jorand and Burnet,
1996). These reductions vary between 25% and 40%,
and are clearly associated with acute effects of hypoxia,
since administration of oxygen reverts the effects quickly.
N
¨
oel-Jorand et al. (1996) applied a method of constant
stimuli with nociceptive stimuli. They made evaluations
before an expedition, during the expedition at 3,500 m and
5,600 m and after the expedition. Clark’s Situational Pain
Questionnaire was used. The climbers showed a greater
subjective tolerance to pain especially above 5,000 m.
Nevertheless, the absolute threshold was reduced coin-
ciding with findings by Fleisch and Von Morant (1944,
1948) for other sensory modalities, that is, climbers had a
greater subjective tolerance to pain but perceived painful
stimuli of lesser intensity. This effect cannot be attributed
to a tendency of response or the consequence of cold,
which was also suffered by control subjects and is known
to have the reverse effect (Plaghki et al., 1994). In ad-
dition, the presumed stoicism of mountaineers should be
distinguished from sport induced analgesia (Padawer and
Levine, 1992) since no analgesia is produced but only
an increase in the subjective representation of tolerance to
pain (no direct test of pain tolerance was carried out). This
result is attributed to adaptation to a situation of precarious
survival. Similar results have been obtained in Sherpas and
Tuaregs (Clark and Clark, 1980). N
¨
oel-Jorand and Burnet
(1996) consider that these sensory changes follow a broad
response of adaptation to altitude; however, the relation-
ship between these changes and the degree of adaptation
to altitude has not been sufficiently evaluated.
Experiments on adaptation to darkness under hy-
poxia revealed a rise in the threshold of detection of vi-
sual stimuli (Kobrick and Appleton, 1971; McFarland and
Evans, 1939). In contrast, the threshold of detection of
visual contrast under conditions of severe and prolonged
hypoxia was not affected, according to the results of the
Ginsburg Vistech Test (Kobrick et al., 1988). Alterations
in the perception of progressively greater brightness have
been observed in simulated altitudes of 3,962 m, 4,572 m,
and 5,186 m (Cahoon, 1970). Another effect of altitude on
perception is the alteration in color vision although little
research has been done in field conditions. By studying
curves of adaptation to darkness during exposure to an
altitude of 4,300 m for 2 weeks, Kobrick et al. (1984)
observed a rise in the absolute threshold of green that re-
mained throughout the whole function of adaptation and
the whole stay. With similar conclusions, Richalet et al.
(1988) observed alterations in the green–red axis in a
field research. In particular, a reduced sensitivity to green
in relation to red was recorded in the measures obtained
by a portable analoscope up to al altitude of 4,350 m. The
same authors (Richalet et al., 1988) replicated success-
fully these results at 4,800 m during an expedition to the
Annapurna (8,091 m). Laboratory research performed in
a hypobaric environment obtained similar results (Smith
et al., 1976; Vingrys and Garner, 1987). Recently, Leid
and Campagne (2001) have criticized those initial re-
sults. They argue that by using a technique that primarily
evaluates long wave longitude the shades of red can ob-
tain a lower perception due to the measuring procedure.
210 Viru
´
es-Ortega, Buela-Casal, Garrido, and Alc
´
azar
Using the Lanthony Test of Desaturation D15, Leid and
Campagne (2001), took measurements up to 7,000 m dur-
ing two expeditions to mountains Cho Oyu (8,201 m) and
Gasherbrum (8,068 m) checking meteorology, age, phys-
iological state, AMS, fatigue, and time. This study found
a subtle impairment of the yellow–blue axis in two out of
five subjects, while the rest of the subjects were not im-
paired. However, the D15 exhibited a weak sensitivity in
the red–green axis so that the results obtained by Richalet
et al. (1988) cannot be discarded. Using a discrimination
task that is not biased towards any color, Bouquet et al.
(2000) obtained intermediate results. The subjects em-
ployed by Bouquet et al. (2000) in a simulated ascent of
31 days to 8,848 m performed a discrimination task with
different hues in the red, blue, and green ranges. They
observed slight impairment that was specially significant
in red and blue.
Hallucinatory Experiences
In the list of perceptive alterations due to exposi-
tion to altitude, we should take into account hallucina-
tory experiences. In the history of mountain climbing,
plenty of anecdotes have been recorded. Rutledge (1934)
reported how the mountaineers climbing Mount Everest
in 1933 talked about hallucinations or perceptive alter-
ations such as the feeling of being accompanied to the
extent of dividing the food supplies with an inexistent
companion. McFarland and Barach (1937) observed the
frequent appearance of hallucinations in psychoneurotic
patients subjected to hypoxia. Ryn (1988) describes a case
of complex visual hallucination at 6,900 m. A subject was
reported to have seen red snowflakes falling around him.
This hallucination lasted 2 days with a variable intensity
and only stopped when the subject descended to 5,000 m.
More recently, Brugger et al. (1999) interviewed a group
of world-class mountaineers to find out that 88.9 % had
experienced some kind of hallucination. Most frequent
cases were somesthetic illusions, and visual and auditory
pseudo-hallucinations. Garrido et al. (2000) interviewed
33 mountaineers who had climbed above 7,500 m at least
once. This time, 32.3% declared having experienced hal-
lucinations: somesthetic illusions (especially the sensa-
tion of having an imaginary companion behind), visual
and auditory hallucinations. With two exceptions, all the
episodes occurred above 6,000 m and their duration lasted
between two seconds and several hours. In these cases, it
is difficult to dissociate the effects of hypoxia or altitude
from those associated with stress, sensory deprivation,
social deprivation or the experience of danger that have
been associated with somesthetic illusions. These per-
ceptive alterations have not been connected with poste-
rior neuropsychological dysfunction or MRI abnormali-
ties (Brugger et al., 1999; Garrido et al., 2000).
Summing up, it can be said that exposure to altitude
produces consistent increases in CRT around 3,000 m
which can be attributed to a slow-down in the process of
identification of the stimulus, apart from extreme cases
where the intensity of the stimulus can increase the CRT.
This is consistent with occasional findings of increases
in latency of N200 associated with the initial process-
ing of stimuli (Carreti
´
e and Iglesias, 1995; Kida, 1997).
These findings have been obtained at visual and auditory
modalities. In contrast, changes in ERP and CRT can-
not be attributed to motor problems since the increase in
simple RT can be very slight or inexistent in exposure to
altitude (Fowler and Lindeis, 1992). In this respect, we
notice that recording the preparation potential associated
with the temporal pattern of motor responses will sup-
ply relevant information, but we have not found related
investigations. Additionally, the reduction in the ampli-
tude of P300 seems to indicate some adaptive process
independent of the increase of CRT since it displays a
linear and temporal pattern unrelated to changes in RT.
Also, discrimination and localization should be discarded
as factors in the previous findings. Reductions have been
observed in the thresholds of detection of smell, light,
taste and pain stimuli. A reduced response is detected in
adaptation to darkness. Finally, hallucinatory experiences,
especially somesthetic, have been reported in subjects as-
cending above 6,000 m without supplementary oxygen.
MEMORY, LEARNING AND
ATTENTION IMPAIRMENT
The high sensitivity to hypoxia of structures such
as the hippocampus and the limbic system (Shukitt-Hale
et al., 1996; Zola-Morgan et al., 1986) makes it predictable
that exposure to altitude will bring about dysfunctions
to learning and memory. The effects on memory have
been noticed by numerous studies using diverse methods
(Bakharev, 1981; Bedard et al., 1991; Kramer et al., 1993;
Prigatano et al., 1983; West, 1986). Certain evidence indi-
cates that these memory difficulties depends on a reduced
capacity to learn new information rather than its retrieval
(Cavaletti et al., 1987; Kennedy et al., 1989; Oelz et al.,
1986; Townes et al., 1984).
Retrieval Vs. Storage Deficits
Initially, Shock (1942) demonstrated that a 10% re-
duction in oxygen concentration (90% SaO
2
) interfered
Neuropsychological Functioning at High Altitude 211
with the learning of a visual discrimination task in rats
inside a maze. This time, hypoxia had a stronger effect
in acquisition than in retrieval. Using Facretrieval2, a test
to dissociate memory problems in humans due to diffi-
culties in information retrieval or storage, Nelson et al.
(1990) found that up to 6,000 m altitude played no effect
on retrieval but learning new information was impaired.
However, as suggested by animal research, severe hypoxia
is likely to dysfunction the retrieval of known, and even
automatized, tasks. In a study with rats, Chleide et al.
(1991) found dysfunctions in the retrieval of a learned task
after inducing hypoxia for 4 days and allowing 6 days for
rest before testing an instrumental conditioning task. The
performance of the test on successive days showed that
the effects on retrieval were reversible. At any rate, these
results should be taken cautiously because researchers
used food as reinforcement ignoring the reduction in food
craving and consumption in rats under hypoxia (Ettinger
and Sttadon, 1982). In humans, Kramer et al. (1993) ob-
tained a similar result by observing the effects of altitude
(6,100 m) on an actual expedition performing a task that
required controlled processing (targets and distractors ex-
changed their roles during the task), and a second task
demanding automatic processing (every stimulus evoked
a constant response throughout the experiment). The per-
centage of transfer between sessions for the RT showed
that the automatized task was more impaired than the
controlled task in comparison with the control pattern.
Control and experimental subjects displayed 80% transfer
against 25.5% for the automatic task, and 95.6% against
80% for the controlled task, respectively. The authors ob-
served that dysfunction affected other learning tasks (both
with perceptual and semantic material) even 2 days after
descending to sea level. In another study, Koller et al.
(1991), observed dysfunctions in the execution of a well-
learned task (mental calculation) that demands controlled
processing during exposure to an altitude of 6,000 m. The
effect was stronger if subjects were not acclimatized (20%
vs. 7% error).
Nicholson and Wright (1975) observed that under
moderate hypoxia (4,572 m, 50 mmHg of PaO
2
)theex-
ecution of a matching task was improved in monkeys.
The discrimination task used probably required controlled
processing since the relationship between stimuli and re-
sponses varied during the task. We have found only one
case in the literature where performance improved be-
cause of slight hypoxia. In an inter-group study, Kelman
and Crow (1969) subjects exposed to a simulated altitude
of 2,438 m performed a card sorting test faster.
Alterations in long-term memory, specifically
episodic memory, have rarely been observed, and always
as an acute effect, never as long-term effect. Garrido
et al. (1995) discuss a case of transitory global amne-
sia strongly related to the symptoms of AMS and High-
Altitude Cerebral Edema during the ascent to a summit
above 8,000 m. Litch and Bishop (1999) describe two
cases with the same alteration, both at moderate altitude
(4,400 m and 3,750 m). Their subjects were disoriented at
spatial and personal level, and unable to remember auto-
biographic episodes. In both cases, the disorder occurred
without severe AMS and ceased with relative quickness
when subjects descended 450 m and 760 m, respectively.
Spatial Memory, Short-Term Memory and Attention
The effects of hypoxia on rats have also been eval-
uated with respect to localization and spatial memory.
Using the MWM, Shukitt-Hale et al. (1994) found that
acute exposure to a variable altitude between 5,500 m and
6,400 m produced an altitude-dependant dysfunction to
spatial memory. The effects were observed in the speed,
distance covered, and time taken to reach a hidden plat-
form. It should be highlighted that it was learning, rather
than retrieval, that was impaired. The task was learned
under hypoxia and retrieved under normoxia. The effect
was only noticeable beyond 5,500 m so this seems to
be the lower threshold for dysfunction in rats. In general,
results were less significant when evaluated after exposure
than during exposure. Significance was also greater when
performance was evaluated after 6 hours of exposure than
after 2 hours. In contrast, there was a more significant
impairment in the execution of the first trial as compared
with the second, which suggests a greater dysfunction
to the learning of new abilities than to the retrieval or
execution as observed above. Gozal et al. (2001) have
observed similar results with the MWM applying inter-
mittent hypoxia. Nelson (1982) evaluated spatial mem-
ory in 20 mountaineers during a 35-day climb to Mount
McKinley (6,193 m). At 3,800 m no impairment was no-
ticed but at 5,000 m results were significantly inferior.
In a short-term memory task, Crow and Kelman
(1971) had 86 subjects learn lists of numbers at different
simulated altitudes. Indications of dysfunction (p = .07)
were only found at the highest altitude (3,658 m). In a
later study, these authors obtained identical results using
a free recall task (Crow and Kelman, 1973). Bartholomew
et al. (1999) had 72 aircraft pilots make radio calls at
606 m, 3,788 m, and 4,545 m. Half of them required a
high memory capacity (4–5 bits). Significant deficit was
only observed at 4,545 m in those trials that required a
high capacity of memory. Viru
´
es et al. (2002) observed a
slight but significant reduction in short-term memory es-
tablished through Weschler’s Digit Span associated with
212 Viru
´
es-Ortega, Buela-Casal, Garrido, and Alc
´
azar
climbs to 4,800 m and 4,600 m. Apparently the lower
threshold of altitude to produce memory dysfunction is
above 3,500 m, in agreement with observations in animals
(Shukitt-Hale et al., 1994).
The effects of altitude on attention capacity have
rarely been described. Evans and Witt (1966) found im-
pairment in their subjects with the Digit Symbol test from
the Weschler Adult Intelligence Scale at 4,200 m. Berry
et al. (1989) also report the finding of impairment in the
Digit Symbol test after exposure to simulated altitudes
between 3,000 m and 5,000 m. Two recent studies have
produced convergent results. Stivalet et al. (2000) noted
that the results in a task of visual search (detecting a
target among a group of distractors) were reduced after
8 hours of moderate hypoxia. Specifically, the authors
concluded that hypoxia delayed the serial-attentional pro-
cessing while the parallel-preattentional remained unaf-
fected. In a field research, Bonnon et al. (2000) monitored
the attention performance of one expedition that remained
16 days between 2,000 m and 5,600 m and took 2 more
days to climb to 6,440 m and another that stayed 21 days
at 6,542 m. They employed a modified version of the Fort
Test with two levels of complexity. Attention impairment
was only observed in the second expedition. The more
difficult the task was, the greater the differences with the
control group.
Theoretical Issues
There has been disagreement over the permanence
of cognitive impairment induced by exposure to extreme
altitude. In this respect, the effects on memory and mo-
tor capacity have been discussed. Kramer et al. (1993)
recorded a reduced learning rate compared with controls
2 weeks after an ascent to Mount Denali (6,194 m). Sim-
ilar results were obtained in COPD patients (Grant et al.
1987). Cavaletti et al. (1987) made records 75 days after
returning from Mount Satopanth (7,075 m) and noticed
that a memory reduction of 19% right after the ascent
was then 14% lower than the pretest levels. Unfortunately,
these authors do not specify the memory test they used nor
the significance of their results. Furthermore, 12 months
after an ascent to Mount Everest (8,848 m) Townes et al.
(1984) found that the difference in number of attempts
to reach the criterion in the WMS was still significant
(p<.05). This effect ceased when measures were ob-
tained 24 months later. It is noticeable that this research
was performed in an ascent without supplementary oxy-
gen. Eight world-class mountain climbers were subjected
to a multitude of neuropsychological tests by Regard et al.
(1989). These authors used as memory tests, the Digit
Span and Histories from the Weschler Adult Intelligence
Scale, an audio-verbal test, a visual learning test, and the
reproduction of the Rey Complex Figure. Their results
showed that two subjects displayed two standard devia-
tions (SD) in verbal memory below a control group of
low-altitude climbers whereas the other three were one
SD below the control group. With respect to spatial mem-
ory, five subjects were two SD below the control group
and one subject was one SD below the control group.
This research is often referred to in order to support the
existence of permanent damages. Nevertheless, the com-
parison with the control group is difficult to assess. In ad-
dition, we have observed that the mean time elapsed since
the last exposure to an altitude above 5,000 m was only
7 months for all subjects, and in any case never more than
11 months.
Clinical models of chronic hypoxia can help to ad-
just future research on the effects of altitude as well as to
obtain indirect evidence from highly controlled studies.
For example, correlations between 0.75 and 0.82 have
been found between memory capacity and hypoxia in
COPD patients (Huppert, 1982). More recently and in a
highly controlled investigation, Stuss et al. (1997) have
found correlations in these patients above 0.7 between
PaCO
2
and every index in the WMS with the exception
of immediate logical memory. The same applies to the
correlations with the Benton Visual Retention Test or the
free recall with either short or long retention interval,
and the total recall from list A in the California Verbal
Learning Test (CVLT). Not so with the Digit Span task
or the Brown-Peterson task. Associations in the case of
PaO
2
lead to similar conclusions with a lesser statisti-
cal significance. Likewise, in the case of OSA, similar
dysfunctions to memory and learning of new information
have been found with the WMS (Kales et al., 1985; Kelly
et al., 1990; Lezak, 1995) and the CVLT (Salorio et al.,
2002).
At this stage, laboratory research should establish
the interaction between hypocapnia and hypoxia in the
account of the effect of altitude on memory. For this pur-
pose, Berry et al. (1989) induced a hypoxia equivalent
to 5,000 m in several subjects maintaining PaCO
2
(iso-
capnia) constant. No memory dysfunctions were found
using SRT, a test sensitive to long-term verbal memory,
whereas investigations made without controlling isocap-
nia did find significant differences in memory tests con-
ducted in laboratory (Crow and Kelman, 1969; Shephard,
1956). Memory dysfunctions can be the specific result
of hypocapnia although one can object (a) that hypocap-
nia does not result in an increased brain hypoxia below
8,000 m or a PaO
2
equivalent to 30 mmHg (West, 1984);
and (b) that the SRT is a long-term memory test not used in
other research incapable of distinguishing hypoxia from
Neuropsychological Functioning at High Altitude 213
hypocapnia. Additionally, the study by Berry et al. (1989)
used %SaO
2
as independent variable (IV) with four con-
ditions: 100%, 90%, 85%, and 80%. If we consider that
80% SaO
2
is equivalent to an altitude of 4,500 m the
conclusion is that only one field investigation has found
effects on memory at this or a lower altitude (McFarland,
1971). In this respect, Phillips and Pace (1966) did not
find differences in short-term memory in their subjects
compared with pretest levels either during or after a short
exposure to 3,800 m, Sharma et al. (1975) performed
immediate memory measurements 1, 10, and 13 months
after ascending to an altitude of 4,000 m without finding
significant differences with the pretest at any of these
moments. The same can be concluded from the cited
studies by Crow and Kelman (Crow and Kelman, 1971,
1973).
Against the hypothesis that memory dysfunctions are
only observed after stays above 4,500 m we can object that
these designs frequently ignore the interaction between al-
titude and task difficulty, so that similar results are found
at lower altitudes if tasks are harder (Bartholomew et al.,
1999; Bonnon et al., 2000; Cahoon, 1972; Cudaback,
1984).
Measurements of a simulated ascent to 8,848 m for
40 days inside a hypobaric chamber (Hornbein et al.,
1989) taken in laboratory conditions showed that the SRT
detects significant damages when the altitude is above
4,500 m. In this investigation the neuropsychological im-
pairment was compared between two groups, one ex-
posed to extreme altitude inside a hypobaric chamber
and another belonging to an expedition to Mount Ever-
est (8,848 m). The results of the SRT were not convergent
since damage was only found in the laboratory group. The
results of the WMS indicated damages in long-term vi-
sual memory. Again we face the problem of IV. Although
the barometric altitude in both cases was equivalent, no
direct measurements of blood gases were made (PaCO
2
,
PaO
2
, and %SaO
2
) thus ignoring the fact that subjects
with a low HVR suffer a greater hypoxia under an intense
workload. This factor may be a source of confusion in
the results because no comparison can be made between
the physical activity of a group confined inside a chamber
with another climbing to a peak of 8,000 m. It is unlikely
that such results can be attributed to differences in stress
or confinement factors (Farrace et al., 1999). With respect
to differential hypoxia according to workload, Bakharev
(1981) noted that his subjects displayed greater memory
damages in the days of intense workload. This author did
not take direct measurements of %SaO
2
although pre-
sumably the key factor for the greater alteration was an
increased hypoxia due to intense workloads (Roach et al.,
2000) especially considering that his subjects were work-
ers taken to 3,600 m. So they did not have such a high
mean HVR as can be found in mountain climbers (Johnson
and Rock, 1988).
Memory alterations due to high and extreme altitude
have been replicated for decades. The effect becomes con-
sistent in exposure to altitudes above 4,500 m although
some conditions such as the workload or the level of
HVR modulate hypoxemia. The effect is more solid in
laboratory conditions. A group of investigations with ac-
tual ascents above 5,000 m found no conclusive results
(Clark et al., 1983; Jason et al., 1989; Milne and Gray,
1983). Animal research has observed deficits in spatial
memory due to hypoxia. This has been related to dam-
ages to the hippocampus resulting from hypoxia. This
point has not been correctly replicated in humans. In most
cases, researchers have administered immediate memory,
and short and long-term verbal and visual memory tests.
Isolated cases of global amnesia without posterior sequels
have been observed. Impairment seems to affect specifi-
cally codification rather than retrieval. Motor factors do
not seem to be involved in such deterioration. Several
studies demonstrate that dysfunctions have an average
duration after returning to lowland if exposure surpassed
7,000 m. The previous evidence is not enough to conclude
that hypoxia due to extreme altitude triggers permanent
memory impairment.
FUNCTIONS ASSOCIATED WITH FRONTAL
LOBE: LANGUAGE, COGNITIVE FLEXIBILITY
AND METAMEMORY
Several studies have identified frontal alterations af-
ter exposure to extreme altitude. Such alterations are re-
lated to the sensitivity of the frontal lobe and to slight
hypoxia. Impairment in language and verbal fluency have
been repeatedly reported. In an actual expedition that
reached 6,800 m, Petiet (1988) verified alterations in ab-
stract reasoning and verbal fluency by means of the Word
Finding Ability Test both during and right after the ascent.
Kennedy et al. (1989) registered significant reductions in
grammatical reasoning and the Digit Symbol test in sub-
jects after a simulated ascent to 8,400 m. Cavaletti et al.
(1987) give details of alterations in verbal fluency after
an ascent to the Himalayas that persisted 2 months af-
ter returning to lowland. Regard et al. (1989) used two
fluency tests based on the production of words and fig-
ures corresponding to a category in a limited time. They
found a considerable impairment in world-class climbers
as compared with a control group after the former had
spent an average of 7 months without climbing above
5,000 m. Using the Aphasia Screening Test, both West
214 Viru
´
es-Ortega, Buela-Casal, Garrido, and Alc
´
azar
(1984) and Hornbein et al. (1989) have observed alter-
ations in language production and an increase in aphasic
errors.
In the study by West (1984), records were collected
a year later showing that impairment had reverted to
baseline levels. Shipton (1943), and Garrido and Javierre
(1996) have reported cases of transitory aphasia due to
exposure to extreme altitude. Garrido and Javierre (1996)
observed slight signals of high intensity in a subject’s
posterior lobe in an MRI carried out 40 days after the de-
scent. Analyzing radio calls during an actual expedition to
Mount Everest, Lieberman et al. (1995) found an altitude-
dependant effect regarding articulatory alterations along
with increased time to understand sentences. Similar re-
sults have been published in other cases of hypoxia not
related to altitude. Fox et al. (1989) observed alterations in
resonance, articulation, and phonation in 74% of patients
with OSA and 53% of patients with COPD as compared
with a 7% in normal cases. Discrimination analyses iden-
tified 96.3% of patients without apnea and 63% of patients
with apnea. Kazora et al. (1999) found out a lower verbal
fluency in patients with COPD by means of Letterfluency.
Salorio et al. (2002) has obtained the same results in OSA
patients with this test.
With respect to cognitive flexibility, Regard et al.
(1989) noticed clear impairment in their subjects (world-
class mountain climbers evaluated months after their latest
ascent) through inference tasks of the Stroop Color and
Word Test or the Wisconsin Card Sorting Test. These
authors averaged the results in the Stroop Color and Word
Test, the Wisconsin Card Sorting Test, and two other ver-
bal fluency tasks in a variable called cognitive flexibility.
This variable presented the most impaired results in the
group studied compared with the other cognitive processes
assessed. Two subjects showed a performance one SD
below the controls while the remaining six subjects per-
formed two SD below. Recently, Van Diest et al. (2000)
have found similar results concerning the Stroop Color
and Word Test under slight hypoxia in laboratory con-
ditions. In this case, brain hypoxia was induced through
hyperventilation, as a result of brain vasoconstriction de-
pendent on hypocapnia. It should be noted that results
were obtained at 90 %SaO
2
, equivalent to 2,500 m. Such
effect contradicts the apparently lesser vulnerability of
the frontal lobe but in any case the presence of a strong
hypocapnia predicts an intense central vasoconstriction
that would increase the levels of increased tissue hypoxia
in the brain above the degree of SaO
2
at peripheral level.
Deficient performance in the Wisconsin Card Sorting Test
has also been observed in patients with COPD (Crews
et al., 2001), but not in patients with OSA (Salorio et al.,
2002).
Metacognition or metamemory may also be impaired
under hypoxia (Janowsky et al., 1989). An interesting
study in this respect was conducted by Nelson et al.
(1990). In an expedition to the Himalayas above 6,400 m,
subjects took repeatedly the Facretrieval2, a test which
measures the retrieval capacity of short-term memory to-
gether with metacognitive aspects of the retrieved con-
tent (feeling of knowing what has been retrieved). Results
showed that although no damages in the retrieval capacity
of long-term memory were observed, a reduction took
place in the feeling of knowing that remained a week after
returning from the expedition. Clark et al. (1983) obtained
similar results after a prolonged stay at 5,300 m Subjects
rated their own performance in several tasks as poorer
than before the climb without an actual damage in the
execution. Something similar has been noted in the case
of insomnia associated with altitude. Great differences
are observed between the hours subjects think they sleep,
few or none, and the duration of actual sleep (Reite et al.,
1975).
Higher processes such as language, cognitive flexi-
bility, and metacognition may be impaired due to hypoxia.
Regarding language, clear damages are noticed in verbal
fluency and aphasic errors. In addition, several studies
have reported reduced abstract reasoning, understanding
and articulation. Difficulties in articulation and verbal flu-
ency converge with impairments observed in chronic hy-
poxia disorders (OSA and COPD). Published studies have
confirmed such deterioration above 6,400 m. Although
no long-term language impairment occurred after return-
ing to lowland. Reductions in cognitive flexibility and
in resistance to interference have been replicated several
times above 2,500 m Alterations in various metacognitive
processes have also been verified, and there is a general
feeling of reduced confidence in performance in cognitive
and memory tasks.
PERSONALITY, ANXIETY, AND HYPOXIA
Three aspects have been considered regarding the
connections among personality, anxiety, and hypoxia:
(a) which personality traits distinguish mountaineers from
normal subjects; (b) which alterations in emotional states
are associated with altitude; and (c) the influence of per-
sonality factors in adaptation to altitude.
Several investigations have highlighted that moun-
taineers display special personality traits. Magni et al.
(1985) compared the results of the 16 personality
factor questionnaire (16PF) of 22 mountain climbers
from an expedition to the Himalayas with a control
group. Significant differences were obtained in factors A
Neuropsychological Functioning at High Altitude 215
(reserved-outgoing), G (expedient-conscientious), and Q
(relaxed-tense). Their results showed that mountaineers
exhibit less anxiety, less social control, and greater emo-
tional stability. Freixanet (1991) observed lower levels
of neuroticism as measured by the Eysenck Personality
Questionnaire when he compared subjects practicing risk
sports with a control group. Other personality traits differ-
ing in mountaineers and subjects involved in risk activities
is a higher total score in sensation seeking and a lower
score in social conformity established by Zuckerman’s
Sensation Seeking Scale (Bushov et al., 1994; Freixanet,
1991; Jack and Ronan, 1998). Using the Zuckerman’s Sen-
sation Seeking Scale, Zarewski et al. (1998) noticed that
the subscales of experience seeking and adventure seek-
ing predicted involvement in high-risk sports and were
significant in a posterior discriminating analysis between
high-risk and low-risk sportsmen. Also, N
¨
oel-Jorand et al.
(2001) argue that mountaineers are more stoical and in-
troverted in comparison with other subjects.
Regarding the connection between emotional states
and altitude, Ryn (1971, 1988) concluded, after observ-
ing 80 mountaineers, that at low altitude (below 2,500 m)
emotional excitation or indifference were dominant while
at high altitude (up to 5,500 m) euphoric-impulsive or
depressive syndromes took place. Later, more systematic
reports have tested that the level of anxiety established by
the State-Trait Anxiety Inventory (STAI) increases with
altitude and such increase correlates highly with impair-
ment in the mood state (Bolmont and Abraini, 2001). Us-
ing the Profile of Mood States with a group of subjects that
stayed at 3,630 m for a week, Shukitt-Hale et al. (1990) no-
ticed how the scores in mood state became reduced. This
author remarked that alterations occurred in an elevation-
dependent fashion up to an altitude of 4,700 m (Shukitt-
Hale et al., 1998) and that such impairment followed a dif-
ferent temporal pattern from that of the AMS (Shukitt and
Banderet, 1988). However, a subsequent study Shukitt-
Hale et al., 1991) demonstrated that after 7 hours at
4,700 m, 13 measures of the mood state correlated highly
(r = .77) with the brain factor (AMS-C), measured by
the Environmental Symptoms Questionnaire, a scale that
quantifies the degree of AMS.
One important related issue is the influence of per-
sonality and mood state in adaptation to altitude. Early
studies (Finesinger et al., 1947; McFarland and Barach,
1937; Waldfogel et al., 1950) showed that subjects di-
agnosed with psychoneurosis display a lower PAO
2
and
more serious breathing problems in comparison with con-
trol subjects during adaptation to conditions of acute
hypoxia. Missoum et al. (1992) studied a group of 100
climbers from an expedition to the Himalayas. After the
expedition, subjects were divided between susceptible
and nonsusceptible to AMS. It was demonstrated that
susceptible subjects had a higher level of anxiety-trait
in the STAI before the expedition and a higher level of
anxiety-state after the latest ascent. Bushov et al. (1994)
exposed their subjects to a simulated altitude equivalent
to 3,500 m to distinguish between normals and moun-
taineers. It was observed that the level of neuroticism,
whose group levels were lower in mountaineers, moder-
ated the physical adaptation to altitude. Reduced levels of
neuroticism correlated with reduced levels in the symp-
toms of AMS. Nicolas et al. (2000) obtained negative
correlations between fatigue, a symptom of AMS, and
emotional stability as measured by 16PF (factor C), in the
experiment Everest-Comex 97 (Operation Everest III), in
which volunteers remained inside a hypobaric chamber
for 31 days exposed to altitudes up to 8,848 m. In an-
other study based on this project, Bolmont et al. (2001)
found high and positive correlations between anxiety-trait
established by STAI before the ascent, and CRT during
hypoxia. Negative correlations were obtained regarding
Factor A (reserved-outgoing), and Factor G (expedient-
conscientious) from the 16PF with the CRT. No similar
connections could be found with more complex cogni-
tive or motor activities. These authors conclude that the
influence of anxiety under hypoxia is only exerted on
stimulus-response tasks but not on more complex cogni-
tive or psychomotor tasks.
According to this information, it is advisable to in-
clude mountaineers in control groups since this difference
between groups could produce mixed results. It is also de-
sirable to make a posteriori controls of the influence of the
neuroticism variable, emotional stability or anxiety-trait,
depending on the test used. A second methodological con-
sideration relates to the association between anxiety-trait
and memory processes. Specifically, positive correlations
have been established between anxiety and an increase in
implicit memory (McLeod and McLaughlin, 1995), while
negative correlation has been found between anxiety and
working memory (Hopko et al., 1998; Ikeda et al., 1996).
For this reason, this variable should be considered in in-
vestigations of relationships between altitude and mem-
ory, which is usually disregarded in follow-up analyses.
Similar effects of anxiety have been found in RT and
motor tasks (Bolmont et al., 2000).
With the caveat of the limited research available, we
observe a remarkable impact of personality traits asso-
ciated with anxiety (emotional stability, anxiety-trait, or
neuroticism) and differences in HVR as individual dif-
ferences moderating the effects of exposure to altitude.
As noted above, emotional stability is associated with a
greater physical adaptation to altitude as long as fatigue
and AMS symptoms are concerned. This variable may
216 Viru
´
es-Ortega, Buela-Casal, Garrido, and Alc
´
azar
regulate a different pattern of effects although the results
published by Bolmont et al. (2001) suggest that the impact
of anxiety is limited to simple stimulus-response tasks.
METHODOLOGICAL ISSUES: THE
INDEPENDENT VARIABLE
The effects of hypoxia have been considered in dif-
ferent scientific contexts. Since the beginning of the 20th
century, the performance of human beings at extreme al-
titude has been taken into account in studies involving the
aeronautical domain, hypobaric chambers and mountain
ascents. Likewise, there are various clinical models of
chronic hypoxia whose effects resemble acute hypoxia
(COPD and OSA). Slightly different results have arisen
from every model but they share a general pattern of
impairment. Investigations on the effects of altitude in
flights differ from those in mountains in the exposure to
higher altitudes, much greater rates of ascent, and use of
supplementary oxygen. Neither the physical fatigue nor
the stress associated with mountain climbing is present
in flights. In this respect, methodological concerns might
be arising in comparing laboratory studies—in vitro- and
real-ascent studies—in vivo-. In vivo studies sometimes
confuse the altitude variable with other factors that sys-
tematically covariate with altitude (Table 3). However, as
shown above, there is a general tendency to obtain con-
verging results. With some exceptions that have already
been discussed (Hornbein et al., 1989) there are no inves-
tigations that make the two types of studies readily and
reliably comparable.
The most frequent IV in this field is altitude in me-
ters above sea level. The correct manipulation of this
IV is an added difficulty in these studies. What we call
altitude is a set of factors with unknown specific effects
on ANI in particular. For example, low environmental
temperatures covariate with altitude exposition in real-
ascent studies. Low temperature induces peripheral va-
sodilatation and thyroid gland hyperfunctioning, but the
impact of these factors has not been measured. Similarly,
inadequate nourishment, anorexia, and weight loss are
associated to prolonged hypoxia in high altitude (Hackett
and Rennie, 1976; Milledge, 2002; Timiras et al., 1957).
They are error variables of unknown influence on ANI.
A revision is made of such factors in Table 3. Possible
ways of controlling this sort of variability are also pointed
out.
Geographic altitude is a variable that should be di-
vided into an array of factors in order to assess its influ-
ence on the human organism. Its main effects are hypoxia,
hypoxemia, and hypocapnia. Other environmental and in-
dividual variables that appear inadvertently in the IV—
imprecisely called altitude-–may have an influence too.
Ignoring such factors impinges seriously on the finding
of differences given the reduced number of subjects in
these investigations and the minimal degree of impair-
ment (Clark et al., 1983; Jason et al., 1989). Whenever
Tabl e 3. Possible Confounding Variables in ANI Research
Studies affected
Confounding variable Setting Design Possible way of control
Environmental variables
Variability
a
in the reduction of P
B
IV IG, WS Consider P
B
as independent variable
Reduction of gravity IV IG, WS —
Environmental temperature IV IG Simulate temperature conditions in a nonascent CC
Over-stimulation IV IG Simulate stimulation conditions in a nonascent CC
Alterations in the circadian rhythm IV IG Simulate bio-rhythmic conditions in a nonascent CC
Confinement in simulated ascents IVT IG Consider a nonconfinement control group
Physiological variables
Variability
a
in the reduction of PaO
2
IV, IVT IG Consider %SaO
2
as independent variable in IVT research
Variability
a
in the reduction of %SaO
2
IV, IVT IG Consider %SaO
2
as independent variable in IVT research
Variability
a
in the reduction of PaCO
2
IV, IVT IG Constancy control or co-variance analyses in IVT research
Variability
a
in HVR IV, IVT IG Constancy control or co-variance analyses
Variability in exercise IV IG Simulate exercise conditions in a nonreal-ascent CC
Weight reduction related to altitude IV IG, WS Co-variance analyses in WS research
Psychological variables
Personality traits IV, IVT IG Match relevant personality traits in control subjects
Notes. CC = control group; IV = in vivo (i.e., real ascent studies); IVT = in vitro (i.e., hypobaric chamber studies); IG = inter-groups;
WS = within-subjects.
a
Variability related to the same altitude.
Neuropsychological Functioning at High Altitude 217
these measures have not been controlled, associated im-
pairment has been found at lower altitudes (Fowler et al.,
1987).
Other Methodological Shortcomings
The use of within-subject designs makes it impos-
sible to determine potential effects of practice and the
passing of time. This could be overcome by including
control groups whose dependent measures were regis-
tered at the same time that actual expeditions, or in the
case of moderate altitude, repeating climbs at low alti-
tude to check whether damages occur in successive as-
cents. Viru
´
es et al. (2002) exposed subjects to climbs to
altitudes around 4,500 m and repeated the experiment
after a week. Results showed that impairment reverted
during the rest period and reappeared in the second as-
cent, discarding the effect of practice or the passing of
time.
Other difficulties are derived from the setting in
which tests are recorded. Evaluations made days before
climbing a peak are likely to be biased by the high levels
of anxiety and reduced attention. Few studies have at-
tempted to dissociate the effects of attention from others
(Van Diest et al., 2000; Viru
´
es et al., 2002). In addition,
in High Mountain, tests are often done by nonspecialists
so that the reliability of results can be reduced. Experi-
menters can also affect negatively the results, especially
through emotional variables. Barach (1944) exposed a
group of students to an atmosphere of 13 %O
2
(3,660 m)
for 3 hours. The subjects were asked about their euphoric
and depressive tendencies during the experience. Such
tendencies appeared with a greater frequency when the
experimenter was an attractive woman than when a man
carried out the test. Other psychosocial factors such as
result expectations, social deprivation or leadership have
not been considered in research on the effects of alti-
tude. Several methodological limitations in this respect
are summarized in Table 4.
FUTURE DEMANDS OF EVALUATION OF
ALTITUDE NEUROPSYCHOLOGICAL
IMPAIRMENT AND A FEW USEFUL
GUIDELINES
The present study has revised 70 years of investiga-
tions on the balance between mind and brain during expo-
sure to altitude in a broad sense. Throughout this article,
methodological shortcomings and difficulties of compar-
ison have been observed in many studies. However, there
is an unquestionable impairment of motor, perceptive,
memory, and executive functions as an acute effect and
at least with middle-term duration. Future research will
benefit from more accurate tests since the effects of ANI
are slight. Improvement in control groups and a better
definition of the IV are further issues to consider.
Another aspect that has been overlooked is the pos-
sible set of psychological strategies to reduce hypoxia,
and eventually ANI. Savourey et al. (1995) reported that
AMS symptoms were associated with breathing pattern
more often than with HVR. Conversely, Saul et al. (2002)
demonstrated that voluntary hyperventilation can relapse
hypoxia in subjects that do not present this response spon-
taneously. In this respect we claim that biofeedback pro-
cedures can help in learning protective breathing patterns
at sea level. As a result, useful training programs could
be developed to lessen the damaging effects of hypoxia.
This idea has been put into effect for other respiratory
diseases. Fried (1995) has successfully used biofeedback
from a capnometer, an oxymeter and occasionally elec-
tromiographic biofeedback from the thorax in order to
control respiratory alkalosis in patients with chronic hy-
perventilation. The interest of the data supplied by the cap-
nometer is obvious since it allows to produce a voluntary
ventilatory response before reaching the damaging effects
of hypocapnia. Hillsman (1996a) developed a protocol of
visual biofeedback to teach breathing patterns. According
to Hillsman’s procedure, the tidal volume is shown on
axis Y and the respiratory rate on axis X on a screen. The
patient’s real time breathing is displayed and at the same
Tabl e 4. Frequent Methodological Difficulties in Research on ANI
Methodological issues
Effect of practice and passing of time in within-subject investigations.
Effect of anxiety in pretest registers.
Posttest measurements too close to descent to evaluate lasting effects or too distant to evaluate acute effects.
Control group does not perform a similar amount of physical exercise.
Control group is made up of nonclimbers.
Ceiling effect due to inadequate tests, insufficient maximum altitude, and inadequate stay.
Most investigations referred to adult western males with a high socioeconomic level and high physical fitness.
No dissociation between the effects of hypoxia and hypocapnia.
218 Viru
´
es-Ortega, Buela-Casal, Garrido, and Alc
´
azar
Tabl e 5. Suggested Battery to Evaluate ANI
Assessment goal Assessment instruments
ANI Aphasia screening test
Burchle’s selective reminding test
Computerized measures of reaction
time
Digit span test
Finger tapping test
Perdue pegboard Test
Stroop color-word test
Symbol digit modalities test
Trail making test
Verbal fluency test
Visual cancellation tasks
Wechsler memory scale
Acute mountain Environmental symptoms checklist
sickness symptoms
Lake Louise AMS scoring system
Note. The instrumentswere gathered in regardsto fourcriteria: (a)known
psychometric properties, (b) being affected by altitude in at least to stud-
ies, (c) low practice and ceiling effects, and (d) suitability of administra-
tion by nonexperts. Partially adapted from Echemendia, R. J., and Julian,
L. J. (2001). Mild traumatic brain injury in sports: Neuropsychology’s
contribution to a developing field. Neuropsychol. Rev. 11: 69–88.
time the prescribed breathing pattern is shown. Through
successive approximations the patient finally adopts the
ideal pattern. Similar procedures have been employed in
COPD (Hillsman, 1996b), asthma (Dahmea, 1996), and
other respiratory diseases. The efficiency of these methods
in altitude-related hypoxia will have consequences in the
prevention of AMS and ANI, at least at moderate and high
altitude.
Up to now, the neuropsychological tests applied to in-
vestigations on ANI have been diverse. Some tests with in-
adequately established psychometric properties have been
applied. This circumstance limits an appropriate descrip-
tion of the sample and the variability of the measure in
within-subject investigations, which are most frequent in
the field. We partially subscribe to the core battery pro-
posal by Echemendia and Julian (2001) for the evaluation
of sports-related mild traumatic brain injury. The tests in-
cluded by these authors in their battery have been widely
applied to neuropsychological damages related to sports
and have well-known psychometric parameters. These
tests also meet the practical requirements that increase the
effectiveness in the sports environment: little ceiling and
practice effects, could be administered by nonexperts
and could be administered in a short time (Echemendia
and Julian, 2001). However, given that the mild trau-
matic brain injury can be due to very different brain
dysfunctions, we strongly advocate specific tests for re-
search on altitude. These tests meet the conditions of hav-
ing been affected by altitude on at least two occasions, of
having known psychometric properties, and meeting the
above-mentioned practical requirements of Echemendia
and Julian (2001). Table 5 shows a proposal for such a
battery.
The construction and generalization of a standard-
ized protocol will facilitate an ever difficult comparison
among investigations. Moreover, the addition of neu-
ropsychological criteria to those of structural and func-
tional brain damage may allow advanced assessment of
patterns of functional impairment due to altitude. Neu-
ropsychological assessment at high and extreme altitude
may extend the knowledge on the theoretical relations
among hypoxia, brain, behavior and cognition.
ACKNOWLEDGMENTS
Special thanks go to Dr. Miguel-Angel Mart
´
ınez-
Cabeza for the translation of this manuscript. Authors
would like to thank Dr. Miguel P
´
erez-Garc
´
ıa for his
comments on a previous version of this article. We also
acknowledge the support provided by the Expedici
´
on
Andaluc
´
ıa K2 2003–2004 (Andalusian K2 Expedition
2002–2003) and the Federaci
´
on Andaluza de Monta
˜
nismo
(Andalusian Mountaineering Federation).
REFERENCES
Abraini, J. H., Bouquet, C., Joulia, F., Nicolas, M., and Kriem, B. (1998).
Cognitive performance during a simulated climb of Mount Everest:
Implications of brain function and central adaptive processes under
chronic hypoxia stress. Eur. J. Physiol. 436: 553–559.
Adams, R. A., Victor, M., and Ropper, A. H. (1999). Trastornos
metab
´
olicos adquiridos del sistema nervioso [Acquired metabolic
nervous system disorders]. Principios de Neurolog
´
ıa (7th ed.)
(pp. 961–967), McGraw Hill, Mexico DF.
Agadzhanyan, N. A., Doronin, G. P., and Elfimov, A. I. (1972). Influence
of pressure chamber training on conditioned chain motor reflexes.
Zh. Vyssh. Nerv. Deyat. 22: 27–45.
Anholm, J. D., Powles, A. C., Downey, R., Houston, C. S., Sutton, J. R.,
Bonnet, M. H., et al. (1992). Operation Everest II: Arterial oxygen
saturation and sleep at extreme simulated altitude. Am. Rev. Respir.
Dis. 145: 817–826.
Anooshiravani, M., Dumont, L., Mardirosoff, C., and Soto-Debeuz, G.
(1999). Brain magnetic resonance imaging (MRI) and neurological
changes after a single high altitude climb. Med. Sci. Sports Exerc.
31: 969–972.
Bahrke, M. S., and Shukitt-Hale, B. (1993). Effect of altitude on mood,
behavior and cognitive functioning. Sports Med. 16: 97–125.
Bakharev, V. D. (1981). Investigation of memory during adaptation to
high mountain conditions. Hum. Physiol. 7: 409–414.
Barach, A. L. (1944). Impairment in emotional control producing in both
by lowering and raising the oxygen pressure in the atmosphere.
Med. Clin. North Am. 28: 704–718.
Bartholomew, C. J., Jensen, W., Petros, T. V., Ferraro, F. R., Fire, K. M.,
Biberdorf, D., et al. (1999). The effect of moderate levels of sim-
ulated altitude on sustained cognitive performance.Int.J.Aviat.
Psychol. 9: 351–359.
Neuropsychological Functioning at High Altitude 219
Basnyat, B. (1997). Seizure and hemiparesis at high-altitude outside the
setting of acute mountain sickness. Wilderness Environ. Med. 8:
221–222.
Basnyat, B. (2002). Case report: Delirium at high altitude. High Alt.
Med. Biol. 3: 69–71.
Basnyat, B., and Murdoch, D. R. (2003). High-altitude illness. Lancet.
361: 1967–1974.
Baumgartner, R. W., Spyridopoulus, I., B
¨
artsch, P., Maggiorini, M., and
Oelz, O. (1999). Acute mountain sickness is not related to cerebral
blood flow: A decompression chamber study. J. Appl. Physiol. 86:
1578–1582.
Bedard, M., Montplaisir, J., Richer, F., Rouleau, I., and Malo, J. (1991).
Obstructive sleep apnea syndrome: pathogenesis of neuropsycho-
logical deficits. J. Clin. Exp. Neuropsychol. 13: 950–964.
Berry, D., McConnel, J. W., Phillips, B. A., Carswell, C. M., Lamb, D.
G., and Prine, B. C. (1989). Isocapnic hypoxemia and neuropsy-
chological functioning. J. Clin. Exp. Neuropsychol. 11: 241–251.
Bert, P. (1978). La Pression Barometrique [The barometric pressure].
In: Hichcock, M. A., Hichcock, F. A., and Colombus, O. H. (eds.
and trans.), Undersea Medical Society, Bethesda, MD. (Original
document published 1878)
Bolmont, B., and Abraini, J. H. (2001). State-anxiety and low moods:
Evidence for a single concept. Physiol. Behav. 74: 421–424.
Bolmont, B., Bouquet, C., and Thullier, F. (2001). Relationship of per-
sonality traits with performance in RT, psychomotor ability, and
mental efficiency during a 31-day simulated climb of Mount Ever-
est in a hypobaric chamber. Percept. Mot. Skills 92: 1022–1030.
Bolmont, B., Thullier, F., and Abraini, J. H. (2000). Relationship be-
tween mood states and performances in RT, psychomotor ability,
and mental efficiency during 31-day gradual decompression in a
hypobaric chamber from sea level to 8848 m equivalent altitude.
Physiol. Behav. 71: 469–476.
Bonnon, M., N
¨
oel-Jorand, M. C., and Therme, P. (2000). Effects of dif-
ferent stay duration in attentional performance during two mountain
expeditions. Aviat. Space Environ. Med. 71: 678–684.
Bouquet, C., Gardette, B., Gortan, C., and Abraini, J. H. (1999). Psy-
chomotor skills learning under chronic hypoxia. Neuroreport 10:
3093–3099.
Bouquet, C., Gardette, B., Gortan, C., Therme, P., and Abraini, J. H.
(2000). Color discrimination under chronic hypoxia conditions
(simulated climb “Everest-Comex 97”). Percept. Mot. Skills 90:
169–179.
Bradwell, A. R., Williams, D., Beazley, M., and Imray, C. H. E. (1999).
Can acute mountain sickness be induced by exercise? In: Roach,
R. C., Wagner, P. D., and Hackett, P. H. (eds.),Hypoxia: Into the
Next Millennium (p. 368), Plenum/Kluwer Academic Publishing,
New York.
Brierley, J. B. (1976). Cerebral Hypoxia (Chapter II). In: Blackwood, W.,
and Corsellis, J. A. (eds.), Greenfield’s Neuropathology, Arnold,
London.
Brugger, P., Regard, M., Landis, T., and Oelz, O. (1999). Hallucinatory
experiences in extreme altitude clambers. Neuropsychiatry Neu-
ropsychol. Behav. Neurol. 12: 67–71.
Buguet, A., Pivot, A., Montmayeur, A., and Tapie, P. (1994). Ambulatory
sleep-wake recording in an acclimatized mountaineer over 8 days
at high altitude. J. Wilderness Med. 5: 399–404.
Burkett, P. R., and Perrin, W. F. (1976). Hypoxia and auditory thresholds.
Aviat. Space Environ. Med. 47: 649–651.
Bushov, Y. V., Makhnaham, A. V., and Protasov, K .T. (1994). Analysis of
individualdifferencesin humanpsychological reactionto combined
hypoxic effect. Human Physiol. 19: 302–306.
Cahoon, R. L. (1970). Vigilance performance under hypoxia. J. Appl.
Psychol. 54: 479–483.
Cahoon, R. L. (1972). Simple decision making at high altitude. Er-
gonomics 15: 157–164.
Carreti
´
e, L., and Iglesias, J. (1995). Estudio electrofisiol
´
ogico de la ac-
tividad cerebral relacionada con acontecimientos discretos [Elec-
trophysiological study of brain activity related to enviromental
events]. In: Carreti
´
e, L., and Iglesias, J. (eds.), Psicofisiolog
´
ıa:
Fundamentos Metodol
´
ogicos (pp. 120–121), Pir
´
amide, Madrid,
Spain.
Castell
´
o-Roca, A. (1993). Hombre, Monta
˜
na y Medicina (p. 22), [Man,
Mountains and Medicine]. Editor Service, Barcelona, Spain.
Cavaletti, G., Moroni, R., Garavaglia, P., and Tredici, G. (1987). Brain
damage after high-altitude climbs without oxygen. Lancet 10: 101.
Clark, C. F., Heaton, R. K., and Weins, A. N. (1983).Neuropsychological
functioning after prolonged high altitude exposure in mountaineer-
ing. Aviat. Space Environ. Med. 54: 202–207.
Clark, W. C., and Clark, S. B. (1980). Pain responses in Nepalese porters.
Science 209: 410–412.
Coote, J. H., Stone, B. M., and Tsang, G. (1992). Sleep of Andean high
altitude natives. Eur. J. Appl. Physiol. 64: 178–181.
Coote, J. H., Tsang, B., and Baker, A. (1993a). Respiratory changes and
quality sleep in young high altitude dwellers in the Andes of Peru.
Eur. J. Appl. Physiol. 66: 249–253.
Coote, J. H., Tsang, B., and Baker, A. (1993b). Polycythemia and central
sleep apnea in high altitude residents of the Andes. J. Physiol. 459:
749.
Crews, W. D., Jeffreson, A. L., Bolduc, T., Elliott, J. B., Ferro, N. M.,
Broshek, D. K., et al. (2001). Neuropsychological dysfunction in
patients suffering from end-stage chronic obstructive pulmonary
disease. Arch. Clin. Neuropsychol. 16: 643–652.
Crow, T. J., and Kelman, G. R. (1969). Physiological effects of mild
hypoxia. J. Physiol. 24: 204.
Crow, T., and Kelman, G. (1971). Effect of mild acute hypoxia on human
short-term. Br.J.Anesth.43: 548–552.
Crow, T., and Kelman, G. (1973). Psychological effects of mild acute
hypoxia. Br.J.Anesth.43: 335–337.
Cudaback, D. D. (1984). Four-km altitude effects on performance and
health. Publ. Astronomical Soc. Pac. 96: 463–477.
Chleide, E., Bruhwyler, J., and Mercier, M. (1991). Effect of chronic
hypoxic treatment in the retention of fixed -interval responding.
Physiol. Behav. 49: 465–470.
Dahmea, B. (1996). Interoception of airway resistance in healthy and
asthmatic subjects. Biol. Psychol. 43: 247–248.
De Acosta, J. (1590). Historia Natural Y Moral de Las Indias, Libro
III [Natural and morale history of America: Vol. 3]. Juan de Le
´
on,
Sevilla, Spain.
Denison, D. M., Ledwith, F., Poulton, E. C. (1966). Complex reac-
tion times at simulated cabin altitudes at 5000 feet and 8000 feet.
Aerospace Med. 37: 1010–1013.
Doughty, H. A., and Bearmore, C. (1994). Bleeding time at altitude.J.
R. Soc. Med. 87: 317–319.
Dunlap, K. (1918). Medical studies in aviation: IV. Psychologic obser-
vations and methods. J.Am.Med.Assoc.71: 1392–1393.
Echemendia, R. J., and Julian, L. J. (2001). Mild traumatic brain injury
in sports: Neuropsychology’s contribution to a developing field.
Neuropsychol. Rev. 11: 69–88.
Ettinger, R. H., and Sttadon, J. E. (1982). Decreased feeding associated
with acute hypoxia in rats. Physiol. Behav. 29: 455–458.
Evans, W., and Wit, N. F. (1966). The interaction of high altitude and
psychotropic drug action. Psychopharmacologua 10: 184–188.
Farrace, S., Cenni, P., Tuozzi, G., Casagrande, M., Barbarito, B., and
Peri, A. (1999). Endocrine and psychophysiological aspects of hu-
man adaptation to the extreme. Physiol. Behav. 66: 613–620.
Findley, L., Barth, J., Powers, D., Wilhoit, S., Boyd, D., and Suratt, P.
(1986). Cognitive impairments in patients with obstructive sleep
apnea and associated hypoxemia. Chest 90: 696–690.
Finesinger, J. E., Lindermann, E., Brazier, M. A. B., and Chapple, E. D.
(1947). The effect of anoxia as measured by the electroencephalo-
gram and the interaction chronogram of psychoneurotics patients.
Am.J.Psychiatry.103: 738–748.
Fleisch, A., and Von Murant, A. (1944). Klimaphysiologische Unter-
suchungen in der Schweiz, Part I [Environmental physiology re-
search in Switzerland, Part I].Bemo Schwabe, Basel, Switzerland.
Fleisch, A., and Von Murant, A. (1948). Klimaphysiologische Unter-
suchungen in Der Schweiz, Part II [Environmental physiology re-
search in Switzerland, Part II]. Bemo Schwabe, Basel, Switzerland.
220 Viru
´
es-Ortega, Buela-Casal, Garrido, and Alc
´
azar
Forster, H. V., Dempsey, J. A., Birnbaum, M. L., Reddan, W. G.,
Thoden, J. S., Grover, R. F., et al. (1971). Effect of chronic exposure
to hypoxia on ventilatory response to CO
2
and hypoxia. J. Appl.
Physiol. 31: 586–592.
Forster, P. J. (1985). Effects of different ascent profiles on performance
at 4200 m elevation. Aviat. Space Environ. Med. 56: 758–764.
Fowler, B., and Adams, J. (1993). Dissociation of the effects of alcohol
and amphetamine on inert gas narcosis using reaction time and
P300 latency. Aviat. Space Environ. Med. 64: 493–499.
Fowler, B., Elcombe, D. D., Kelso, B., and Porlier, G. (1987). The
threshold for hypoxia effects on perceptual-motor performance.
Hum. Factors 29: 61–66.
Fowler, B., and Grant, A. (2000). Hearing thresholds acute hypoxia
and relationship to slowing in the auditory modality. Aviat. Space
Environ. Med. 71: 946–949.
Fowler, B., and Lindeis, A. E. (1992). The effect of hypoxia on auditory
RT and P300 latency. Aviat. Space Environ. Med. 63: 976–981.
Fowler, B., and Prlic, H. (1995). A comparison of visual and auditory RT
and P300 latency thresholds to acute hypoxia. Aviat. Space Environ.
Med. 66: 645–650.
Fowler, B., Prlic, H., and Brabant, M. (1994). Acute hypoxia fails to
influence two aspects of short-term memory: implications for the
source of cognitive deficits. Aviat. Space Environ. Med. 65: 641–
645.
Fox, A. W., Monoson, P. K., and Morgan, C. D. (1989). Speech dys-
function of obstructive sleep apnea: A discriminant analysis of its
descriptors. Chest 96: 589–585.
Freixanet, M. (1991). Personality profile of subject engaged in high
physical risk sports participants. Pers. Individual Differences 12:
1087–1093.
Fried, R. (1995). The capnometer and oximeter in the biofeedback treat-
ment of asthma and emphysema. Biol. Psychol. 41: 87.
Garner, S. H., Sutton, J. R., Burse, R. L., McComas, A. J., Cymerman,
A., and Houston, C. S. (1990). Operation Everest II: Neuromuscu-
lar performance under conditions of extreme simulated altitude. J.
Appl. Physiol. 68: 1167–1172.
Garrido, E. (1997). Altitud y Riesgo Neurol
´
ogico: Alpinistas Europeos
vs. Sherpas Del Himalaya [Altitude and neurological risk: Alpinists
vs. HimalayanSherpas]. Unpublisheddoctoral dissertation, Univer-
sity of Barcelona, Barcelona, Spain.
Garrido, E., and Botella, J. (1998). El mal de monta
˜
na [The mountain
sickness]. Med. Cl
´
ın. 110: 462–468.
Garrido, E., and Javierre, C. (1996). Extreme altitude transient aphasia.
Br. J. Sports Med. 30: 364.
Garrido, E., Castell
´
o, A., Ventura, J. L., Capdevilla, A., and Rodriguez,
F. A. (1993). Cortical atrophy and other brain magnetic resonance
imaging (MRI) changes after extremely high altitude climbs with-
out oxigen. Int. J. Sport Med. 14: 232–234.
Garrido, E., Javierre, C., Ventura, J. L., and Segura, R. (2000). Halluci-
natory experiences at high altitude. Neuropsychiatry Neuropsychol.
Beba. Neurol. 13: 148.
Garrido, E., Segura, R., Capdevilla, A., Aldom
´
a, J., Rodriguez, F. A.,
Javierre, C., et al. (1995). New evidence from magnetic resonance
imaging of brain changes after climbs at extreme altitude. Eur. J.
Appl. Physiol. 70: 477–481.
Garrido, E., Segura, R., Capdevilla, A., Pujol, J., Javierre, C., and
Ventura, J. L. (1996). Are Himalayan Sherpas better protected
against brain damage associate with extreme altitude climbs? Clin.
Sci. 90: 81–85.
Gilbert, D. L. (1983). The first documented report of mountain sickness:
The China or headache mountain story. Respir. Physiol. 52: 315–
326.
Gotoh, G., Meyer, J., and Takagi, Y. (1965). Cerebral effects of hyper-
ventilation in man. Arch. Neurol. 12: 410–423.
Gozal, D., Daniel, J. M., and Dohanich, G. P. (2001). Behavioral and
anatomical correlates of chronic episodic hypoxia during sleep in
rat. J. Neurosci. 21: 2442–2450.
Grant, I., Prigatano, G. P., Heaton, R. K., McSweeney, A. J., Wright,
E. C., and Adams, K. M. (1987). Progressive neuropsychologi-
cal impairment and hypoxemia. Arch. Gen. Psychiatry 44: 999–
1006.
Green, R. G., and Morgan, D. R. (1985). The effects of mild hypoxia on a
logical reasoning task. Aviat. Space Environ. Med. 56: 1004–1008.
Griggs, R. C., and Sutton, J. R. (1992). Neurological manifestation
of respiratory diseases. In Asbury, A. K., McKhann, G. M., and
McDonald, W. I. (eds.), Disease of the Nervous System (pp. 1433–
1439), Saunders, Philadelphia.
Hackett, P. H., Hollingsmead, K., Roach, R., Schoene, R., and Mills, W.
(1987). Cortical blindness in high altitude climbers and trekkers.
A report of six cases. In: Sutton, J., Houston, C., and Coates, G.
(eds.), Hypoxia and Cold (pp. 536–550), Praeger Press, New York.
Hackett, P. H., and Rennie, D. (1976). The incidence, importance,
and prophylaxis of acute mountain sickness. Lancet 27: 1149–
1155.
Hackett, P. H., Rennie, D., Hofmeister, S. E., Grover, R. F., and Reeves,
J. T. (1982). Fluid retention and relative hypoventilation in acute
mountain sickness. Respir. Physiol. 43: 321–329.
Hackett, P. H., Roach, R., and Harrison, G. (1987). Respiratory stim-
ulants and sleep periodic breathing at high altitude. Almitrine vs.
acetazolamide. Am.Rev.Respir.Dis.135: 896–898.
Hackett, P. H., Yarnell, P. R., Hill, R., Reynard, K., Heit, J., and
McCormick, J. (1998). High-altitude cerebral edema evaluated with
magnetic resonance imaging. J. Am. Med. Assoc. 280: 1920–1925.
Hansen, J. E., Harris, C. W., and Evans, W. O. (1967). Influence in eleva-
tion on origin, rate of ascent and a physical conditioning program
on symptoms of acute mountain sickness. Mil. Med. 132: 585–592.
Herzog, M. (1952). Annapurna, Premier 8000 [Annapurna, First 8,000].
Arthaud, Paris.
Hillsman, D. (1996a). A visual biofeedback method to define and teach
breathing patterns. Biol. Psychol. 43: 261.
Hillsman, D. (1996b). Clinical experience with a visual method in COPD
rehabilitation. Biol. Psychol. 43: 243–244.
Hochachka, P. W., Clark, C. M., Matheson, G. O., Brown, W. D.,
Stone, C. K., Nicles, R. J., et al. (1999). Effects on regional brain
metabolism of high-altitude hypoxia: A study of six US marines.
Am. J. Physiol. 277: 314–319.
Hochachka, P. W., Clark, C. M., Monge, C., Stanley, C., Brown, W. D.,
Stone, C. K., et al. (1996). Sherpa brain glucose metabolism and
defense adaptations against chronic hypoxia. J. Appl. Physiol. 81:
1355–1361.
Hopko, D. R., Ashcraft, M. H., Gute, J., Ruggiero, K. J., and Lewis, C.
(1998). Mathematics anxiety and working memory: Support for the
existence of a deficient inhibition mechanism. J. Anxiety Disord.
12: 343–355.
Hornbein, T. F. (1992). Long term effects of high altitude on brain
function. Int. J. Sports Med. 13: S43–S45.
Hornbein, T. F., and Schoene, R. B. (2001). High Altitude: An Explo-
ration of Human Adaptation, Marcel Dekker, New York.
Hornbein, T. F., Townes, B. D., Shoene, R. B., Sutton, J. R., and Houston,
C. S. (1989). The cost to the central nervous system of climbing to
high extremely altitude. N. Engl. J. Med. 321: 1714–1719.
Huppert, F. A. (1982). Memory impairment associated with chronic
hypoxia. Thorax 37: 858–860.
Ikeda, M., Iwagana, M., and Seiwa, H. (1996). Test anxiety and working
memory system. Percept. Mot. Skills 82: 1223–1231.
Jack, S. J., and Ronan, K. R. (1998). Sensation seeking among high
and low risk sports participants. Pers. Individual Differences 25:
1063–1083.
Janowsky, J. S., Shimamura, A. P., and Squire, L. R. (1989). Memory
and metamemory: comparisons between patients with frontal lobe
lesions and amnesic patients. Psychobiology 17: 3–11.
Janssen, J. (1890). Club Alpin Francais, Annuaire 1882–1887.
Jason, G., Pajurkova, E., and Lee, R. (1989). High altitude mountaineer-
ing and brain function: Neuropsychological testing of members of a
Mount Everest expedition. Avia. Space Environ. Med. 60: 170–173.
Jensen, J. B., Wright, A. D., Lassen, N. A., Harvey, T. C., Harvey, M.
H., Winterborn, M. H., et al. (1990). Cerebral blood flow in acute
mountain sickness. J. Appl. Phys. 69: 430–433.
Neuropsychological Functioning at High Altitude 221
Johnson, R., Jr. (1988). The amplitude of P300 component of the event-
related potential: Review and synthesis. In: Ackles, P., Jennings,
J.R.,andColes,M.G.H.(eds.),Advances in Psychophysiology
(pp. 69–137, Vol. 3), JAI Press, London.
Johnson, T. S., and Rock, R. B. (1988). Acute mountain sickness. N.
Engl. J. Med. 319: 841–845.
Junqu
´
e, C., Pujol, J., Vendrell, P., Bruna, O., Jodar, M., Ribas, J. C., et al.
(1990). Leuko-araiosis on magnetic resonance imaging and speed
of mental processing. Arch. Neurol. 47: 151–156.
Kales, A., Caldwell, A. B., Cadieux, R. J., Vela-Bueno, A, Ruch, L. G.,
and Mayes, S. D. (1985). Severe obstructive sleep apnea-II: Associ-
ated psychopathology and psychosocial consequences. J. Chronic
Dis. 38: 427–434.
Karliner, J. S., Sarnquist, F. F., Garbers, D. J., Peters, R. N., and West,
J. B. (1985). The electrocardiogram at extreme altitude. Am. Heart
J. 109: 505–513.
Kawakami, I., Yoshikawea, T., Shida, A., Asanuma, Y., and Murao, M.
(1982). Control of breathing in young twins. J. Appl. Physiol. 52:
537–542.
Kazora, E., Filley, C. M., Julian, L. J., and Collum, C. M. (1999). Cog-
nitive functioning in patients with chronic obstructive pulmonary
normal controls. Neuropsychiatry, Neuropsychol. Behav. Neurol.
12: 178–183.
Kelly, D. A., Claypoole, K. H., and Coppel, D. B. (1990). Sleep apnea
syndrome: Symptomatology, associated features, and neurocogni-
tive correlates. Neuropsychol. Rev. 1: 323–342.
Kelman, G. R., Crow, T. J., and Bursill, A. E. (1969). Effect of mild
hypoxia on mental performance assessed by a test of selective
attention. Aerospace Med. 40: 301–303.
Kennedy, R. S., Dunlap, W. P., Banderet, L. E., Smith, M. G., and
Houston, C. S. (1989). Cognitive performance deficits in a simu-
lated ascent climb of Mount Everest: Operation Everest II. Avia.
Space Environ. Med. 60: 99–104.
Khoo, M. C. K., Anholm, J. D., Ko, S., Downey, R., Powles, A. C. P.,
Sutton, J. R., et al. (1995). Dynamics of periodic breathing and
arousal during sleep at extreme altitude. Respir. Physiol. 103: 33–
43.
Kida, M. (1997). Psychophysiological studies under simulated high al-
titude. Jpn. J. of Psychon. Sci. 16: 37–44.
Kobrick, J. (1983). Effects of hypoxia on the luminance thresh-
old for target detection. Avia. Space Environ. Med. 53: 112–
115.
Kobrick, J. L., and Appleton, B. (1971). Effects of extended hypoxia on
visual performance and retinal vascular state. J. Appl. Physiol. 31:
357–362.
Kobrick, J. L., Crohn, E., Shukitt, B., Houston, C. S., and Sutton, J. E.
(1988). Operation Everest II: Lack of an effect of extreme altitude
on visual contrast sensitivity. Avia. Space Environ. Med. 59: 160–
164.
Kobrick, J. L., Zwick, H., Witt, C. E., and Devine, J. A. (1984). Effects
of extended hypoxia on night vision. Avia. Space Environ. Med. 55:
191–195.
Koller, E. A., Bischoff, M., Buhrer, A., Felder, L., and Schopen, M.
(1991). Respiratory, circulatory and neuropsychological responses
to acute hypoxia in acclimatized and non acclimatized subjects.
Eur. J. Appl. Physiol. 62: 67–72.
Kramer, A. F., Coyne, J. T., and Strayer, D. L. (1993). Cognitive function
at high altitude. Hum. Factors 35: 329–344.
Krammar, P., Drinkwater, B., Folins, J., and Bedi, J. (1983). Ocular
functions and incidence of acute mountain sickness in women at
altitude. Avia., Space Environ. Med. 54: 116–120.
Lahiri, S. (1984). Respiratory control in Andean and Hymalayan high
altitude natives. In: West J. B., and Lahiri, S. (eds.), High Altitude
and Man (pp. 147–162), Williams and Wilkins, Baltimore.
Lahiri, S., and Cherniack, N. S. (2001). Cellular and molecular mech-
anisms of O
2
sensing with special reference to the carotid body
(Chapter IV). In: Hornbein T. H., and Schoene, R. B. (eds.),
High Altitude: Exploration of Human Adaptation, Marcel Dekker,
New York.
Lahiri, S., and Data, P. G. (1992). Chemosensivity and regulation of
ventilation during sleep at high altitude. Int. J. Sports Med. 13:
S31–S33.
Lahiri, S., Maret, K., and Sherpa, M. G. (1983). Dependence of high
altitude sleep apnea on ventilatory sensivity to hypoxia. Respir.
Physiol. 52: 281–301.
Lahiri, S., Rozanov, C., and Cherniack, R. (2000). Altered structure
of the carotid body at high altitude and associated chemoreflexes.
High Alt. Med. Biol. 1: 64–74.
Lahiri, S., Razanov, C., Roy, A., Storey, B., and Buerk, D. G, (2001).
Regulation of oxygen sensingin peripheral arterialchemoreceptors.
Int J Biochem. Cell. Biol. 33: 755–774.
Leid, J., and Campagne, J. M. (2001). Color vision at very high altitude.
Color Res. Appl. 26: S281–S283.
Lezak, M. D. (1995). Neuropsychol Assess (3rd ed.), Oxford University
Press, Oxford.
Lieberman, P., Protopapas, A., and Kaniki, B. G. (1995). Speech produc-
tion and cognitive deficit in Mount Everest. Aviat. Space Environ.
Med. 66: 857–864.
Litch, J. A., and Bishop, R. A. (1999). Transient global amnesia at high
altitude. N. Engl. J Med. 318: 1444.
Mackintosh, J. H., Thomas, D. J., Olive, J. E., Chesner, I. M., and Knight,
R. J. E. (1988). The effect of altitude on tests of reaction time and
alertness. Aviat. Space Environ. Med. 59: 246–248.
Magni, G.,Rupolo, G.,Simini, G., DeLeo, D., andRampazzo, M.(1985).
Aspects ofthe psychologyand personality of high altitudemountain
climbers: A study on the members of the 1983 Italian expedition to
K-2 (8,611m Karakorum). Int. J. Sports Psychol. 16: 12–19.
Martin, L. (1999). All You Really Need to Know to Interpret Arterial
Blood Gases, Lippincott Williams and Wilkins, Philadelphia.
Martin, R.L., Watson, D. B., Smith, S. E., McAnally, K. I., and Emonson,
D. L. (2000). Effect of normobaric hypoxia on sound localization.
Aviat. Space Environ. Med. 71: 991–995.
Massot i Palmers, J. (1911). El excursionismo como medio de desar-
rollo f
´
ısico e intelectual en el ni
˜
no [The exclusionism as a way for
physical and intellectual development in the child]. Actas del I Con-
greso Excursionista Catal
´
an, Catalonian Excursionist Association,
Barcelona, Spain.
Masuyama, S., Kimura, H., Sugita, T., Kuriyama, T., Tatsumi, K.,
Kunimoto, F., et al. (1986). Control of ventilation in extreme-
altitude climbers. J. Appl. Physiol. 61: 500–506.
Matsuzawa, Y., Toshio, K., Kesisaku, F., Shinji, Y., Shiro, S., Keishi,
K., et al. (1994). Nocturnal periodic breathing and arterial oxygen
desaturation in acute mountain sickness. J. Wilderness Med. 5:
269–281.
McCallum, W. C. (1988). Potential related to expectancy, preparation
and motor activity. In Picton, T. W. (ed.), Handbook of Elec-
troencephalography and Clinical Electrophysiology (pp. 427–535,
Vol. 3), Elsevier, Amsterdam.
McFarland, R. A. (1932). The psychological effects of oxygen depriva-
tion (anoxemia) on human behavior. Arch. Psychol. 145: 1–135.
McFarland, R. A. (1937a). Psychophysiological studies at high altitude
in the Andes. J. Comp. Physiol. 23: 191–225.
McFarland, R. A. (1937b) Psycho-physiological studies at high altitude
in the Andes: I. The effects of rapid ascents by airplane and train.
Comp. Psychol. 23: 191–225.
McFarland, R. A. (1937c) Psycho-physiological studies at high altitude
in the Andes: II. Sensory and motor responses during acclimatiza-
tion. Comp. Psychol. 23: 227–258.
McFarland, R. A. (1937d) Psycho-physiological studies at high altitude
in the Andes: III. Mental and psycho-somatic responses during
gradual adaptation. Comp. Psychol. 24: 147–187.
McFarland, R. A. (1941). The internal environment and behavior. Am.
J. Psychiatry 97: 868–877.
McFarland, R. A. (1971). Human factors in relation to the development
of pressurized cabins. Aerospace. Med. 12: 1303–1318.
McFarland, R. A., and Barach, A. L. (1937). The response of psycho-
neurotics to variation in oxygen tension. Am.J.Psychiatry93:
1315–1341.
222 Viru
´
es-Ortega, Buela-Casal, Garrido, and Alc
´
azar
McFarland, R. A., and Evans, J. N. (1939). Alterations in dark adapta-
tions under reduced oxygen tensions. Am.J.Physiol.127: 37–50.
McLeod, C., and McLaughlin, K. (1995). Implicit and explicit memory
bias in anxiety. Behav. Res. Ther. 33: 1–14.
McSweeney, A. J., Grant, I., Heaton, R. K., Prigatano, G. P., and Adams,
K. M. (1985). Relationship of neuropsychological status to every-
day functioning in healthy chronically ill persons. J. Clin. Exp.
Neuropsychol. 7: 281–291.
Milne, D., and Gray, D. (1983). Evidence bearing on the generalizability
of the laboratory findings relating to high-altitude mountaineering.
Percept. Mot. Skills 57: 172–174.
Milledge, J. S. (1963). Electrocardiographic changes at high altitude. Br.
Heart J. 25: 291–298.
Milledge, J. S. (2002). Altitude deterioration. In :Viscor G., Ricart A.,
and Leal, C. (eds.), Proceedings of the Fifth World Congress on
Mountain Medicine and High Altitude Physiology, Spain, 173–180.
Missoum, G., Rousnet, E., and Richalet, J. P. (1992). Control of anxiety
and acute mountain sickness in Himalayan mountaineers. Int. J.
Sports Med. 13: S37–S39.
Moller, K., Paulson, O. B., Hornbein, T. F., Colier, W. N., Paulson, A.
S., Roach, R. C., et al. (2002). Unchanged cerebral blood flow
and oxidative metabolism after acclimatization to high altitude.J.
Cereb. Blood Flow 22: 118–126.
Montgomery, A. B., Mills, J., and Luce, J. M. (1989). Incidence of acute
mountain sickness at intermediate altitude. J. Am. Med. Assoc. 261:
732–734.
Moore, L. G. (2000). Comparative human ventilatory adaptation to high
altitude. Respir. Physiol. 121: 257–276.
Moore, L. G., Curran-Everett, L., Droma, T. S., Groves, B. M.,
McCullough, R. E., McCullough, R. G., et al. (1992). Are Tibetans
better adapted? Int. J. Sports Med. 13(Suppl. 1): S86–88.
Morganti, A., Giusani, M., Ghio, F., Pierini, A., Savoia, M. T., and Cogo,
A. (1994). Endotelin releasing stimuli and calcium antagonists in
normal and pathological conditions. J. Hypertens. 12: 27–31.
Nelson, M. (1982). Psychological testing at high altitude. Aviat. Space
Environ. Med. 53: 122–126.
Nelson, T. O., Dunlowsky, J., White, D. M., Steinberg, J., Townes,
B. D., and Anderson, D. (1990). Cognition and metacognition at ex-
treme altitudes on Mount Everest. J. Exp. Psychol. Gen. 119: 367–
374.
Nicolas, M., Thullier, F., Bouquet, C., Gardatte, B., Gortan, C., Joulia,
F., et al. (1999). An anxiety and personality study during a 31-
day period of chronic hypoxia in a hypobaric chamber. J. Environ.
Psychol. 19: 407–414.
Nicolas, M., Thullier, F., Bouquet, C., Gardatte, B., Gortan, C., Joulia, F.,
et al. (2000). A study of mood changes and personality during a 31-
day of chronic hypoxia in a hypobaric chamber (Everest-Comex,
1997). Psychol. Rep. 86: 119–126.
Nicholson, A. N., and Wright, C. M. (1975). Effect of mild hypoxia
on delayed differentiation in the monkey (Macaca mulatta). Exp.
Neurol. 47: 535–543.
N
¨
oel-Jorand, M. C., Baggard, D., and Plaghki, L. (1996). Pain perception
under chronic high-altitude hypoxia. Eur. J. Neurosci. 8: 2075–
2079.
N
¨
oel-Jorand, M. C., and Burnet, H. (1996). The sensation of respiration
in men experiencing high-altitude chronic hypoxia. Biol. Psychol.
43: 1–12.
N
¨
oel-Jorand, M. C., Joulia, F., and Braggard, D. (2001). Personality
factors, stoicism and motivation in subjects under hypoxic stress
in extreme environments. Aviat. Space Environ. Med. 72: 391–
399.
Oelz, O., Howald, H., Di Prampero, P. E., Hoppeler, M., Classen, H.,
Jenni, R., et al. (1986). Physiological profiles of world-class high
altitude climbers. J. Appl. Physiol. 60: 1734–1742.
Padawer, W. J., and Levine, F. N. (1992). Exercise-induce analgesia:
Fact or artifact? Pain 48: 131–135.
Pe
˜
na-Casanova, J., Hernandez, M. T., and Jarne, A. (1997). T
´
ecnicas
neuropsicol
´
ogicas [Neuropsychological techniques]. In Buela-
Casal G., and Sierra, C. (eds.), Manual de Evaluaci
´
on Psicol
´
ogica:
Fundamentos, T
´
ecnicas y Aplicaciones (pp. 421–454), Siglo XXI,
Madrid, Spain.
Pe
˜
naloza, D., and Echeverria, E. (1957). Electrocardiographic observa-
tions on ten subjects at se a level and during one year of residence
at high altitudes. Am. Heart J. 54: 811–822.
Petiet, C. A. (1988). Neurobehavioural and psychosocial functioning
of women exposed to high altitude mountaineering. Percept. Mot.
Skills 67: 443–452.
Phillips, L. M., and Pace, N. (1966). Performance changes at moderated
high altitude: short term memory measured by free recall. Psychol.
Rep. 19: 655–665.
Pichiule, P., Chavez, J. C., Boero, J., and Arregui, A. (1996). Chronic
hypoxia induces modification on the N-methyl-D-aspartate receptor
in rat brain. Neurosci. Lett. 218: 83–86.
Pinel, J. P. (2001). Tratornos cerebrovasculares [Cerebrovascular disor-
ders]. Biopsicolog
´
ıa (pp. 160–162), Petrice Hall, Madrid, Spain.
Plaghki, L., Delisde, D., and Godfraind, J. M. (1994). Heterotopic noci-
ceptive conditioning stimuli and mental task modulate differently
the perceptual and physiological correlates of short CO
2
laser stim-
uli. Pain 57: 181–185.
Plutarch. (1912). Alexander and Caesar, Loeb classics, Heinemann,
London.
Prigatano, G. P., Parson, O., Wright, E., Levin, D. C., and Hawryluk, D.
(1983). Neuropsychological test performance in mildly hipoxemic
patients with chronic obstructive pulmonary disease. J. Consult.
Clin. Psychol. 51: 108–116.
Ravenhill, T. H. (1913). Some experiences of mountain sickness in the
Andes. J. Trop. Med. Hyg. 16: 313–320.
Reed, L. J., Marsden, P., Lasserson, D., Sheldon, N., Lewis, P.,
Stanhope, N., et al. (1999). FDG-PET analysis and findings in
amnesia resulting from hypoxia. Memory 7: 599–612.
Regard, M., Landis, T., Casey, J., Maggiorini, M., Bartsch, P., and Oelz,
O. (1991). Cognitive changes at high altitude on healthy climbers
developing acute mountain sickness. Aviat. Space Environ. Med.
62: 291–295.
Regard, M., Oelz, O., Brugger, and Landis, T. (1989). Persistent cog-
nitive impairment in climbers after repeated exposure to extreme
altitude. Neurology 39: 210–213.
Reite, M., Jackson, D., Cahoon, R. L., and Weil, J. W. (1975). Sleep
physiology at high altitude. Electroencephalogr. Clin. Neurophys-
iol. 38: 463–471.
Richalet, J. P., Duval-Arnould, G., Darnaud, B., Keromes, A., and
Rutgers, V. (1988). Modification of color vision in the green-red
axis in acute and chronic hypoxia explored with a portable analo-
scope. Aviat. Space Environ. Med. 59: 620–623.
Richalet, J. P., Souberbielle, J. C., Antezana, A. M., Dechaux, M., Le
Trong, J. L., Bienvenu, A., et al. (1994). Control of erythropoiesis
in humans during prolonged exposure to the altitude of 6,542 m.
Am. J. Physiol. 266: 756–764.
Roach, R. C., and Hackett, P. H. (2001). Frontiers of hypoxia research:
acute mountain sickness. J. Exp. Biol. 204: 3161–3170.
Roach, R. C., Icenogle, M., Hinghofer-Szalkay, H., Maes, D., Sandoval,
D., Robergs, R., et al. (2000). Exercise exacerbates acute moun-
tain sickness at simulated high altitude. J. Appl. Physiol. 88: 581–
585.
Roach, R., B
¨
artsch, P., and Oelz, O. (1993). The Lake Louise acute
mountain sickness scoring system. In: Sutton, J., Houston, G., and
Coates, G. (eds.), Hypoxia and Molecular Biology (pp. 272–274),
Queen City Printers, Burlington, VT.
Rodas, G., Javierre, C., Garrido, E., Segura, R., and Ventura, J. L.
(1998). Normoxic ventilatory response in lowlander and Sherpa
elite climbers. Respir. Physiol. 113: 57–64.
Ruttledge, H. (1934). Everest 1933: The Unfinished Adventure, (pp. 164–
166), Hodder and Stoughton, London.
Ryn, Z. (1971). Psycopathology in alpinism. Acta. Med. Pol. 12: 453–
467.
Ryn, Z. (1988). Psycopathology in mountaineering: Mental distur-
bance under high-altitude stress. Int. J. Sports Med. 9: 163–
169.
Neuropsychological Functioning at High Altitude 223
Saito, S., Nishihara, F., Takazawa, T., Kanai, M., Aso, C., Shiga, T., et al.
(1999). Exercise-induced cerebral deoxygenation among untrained
trekkers at moderate altitudes. Arch. Environ. Health. 54: 271–
276.
Salorio, C. F., White, D. A., Piccirillo, J., Duntley, S. P., and Uhles, M. L.
(2002). Learning, memory and executive control on individuals
with obstructive sleep apnea syndrome. J. Clin. Exp. Neuropsychol.
24: 93–100.
Samaja, M., Brenna, L., Allibardi, S., and Cerretelli, P. (1993). Human
red blood cell aging at 5050 m altitude: a role during adaptation to
hipoxia. J. Appl. Physiol. 75: 1696–1701.
Santolaya, R. B., Lahiri, S., Alfaro, R. T. Y., Schoene, R. B. (1989). Res-
piratory adaptations in the highest inhabitants and highest Sherpa
mountaineers. Respir. Physiol. 77: 253–262.
Saul, G. D., Lukina, W. J., Brakebush, S. C., Wilmot, D. E., and
Tammelin, B. R. (2002). Voluntary Hyperventilation into a Simple
Mixing Chamber Relieves High Altitude Hypoxia. Aviat. Space.
Environ. Med. 73: 404–407.
Savourey, G., Moirant, C., Eterradossi, E. Y., and Bittel, J. (1995). Acute
mountain sickness relates to sea-level partial pressure oxygen. Eur.
J. Appl. Physiol. 70: 469–476.
Schoene, R. B. (1982). Control of ventilation in climbers to extreme
altitude. J. Appl. Physiol. 53: 886–890.
Schoene, R. B. (1999). The brain at high altitude. Wilderness Environ.
Med. 10: 93–96.
Schoene, R. B. (2001). Limits of human lung function at high altitude.
J. Exp. Biol. 204: 3121–3127.
Schoene, R. B., Lahiri, S., Hackett, R. M., Petters J. R., Milledge, J. S.,
Pizzo, C. J., et al. (1984). Relationship of hypoxic ventilatory re-
sponse to exercise performance in Mount Everest. J. Appl. Physiol.
56: 1478–1483.
Schousboe, A., Belhage, B., and Frandsen, A. (1997). Role of Ca
++
and second messengers in excitatory aminoacid receptors mediated
neurodegeneration. Clin. Neurosci. 4: 191–198.
Schulze, G., Coper, H., and Faehndrich, Ch. (1990). Adaptation capacity
of biogenic amines turnover to hypoxia in different brain areas of
old rats. Neurochem. Int. 17: 281–289.
Selvamurthy, W., Raju, V. R., and Ranganathan, S. (1986). Sleep patterns
at an altitude of 3500 meters. Int. J. Biometereology 30: 123–
135.
Sharma, V., Malhorta, M., and Baskaran, A. (1975). Variations in
psychomotor efficiency during prolonged stay at high altitude.
Ergonomics 18: 511–516.
Shephard, R. J. (1956). Physiological changes and psychomotor
performance during acute hypoxia. J. Appl. Physiol. 9: 343–
351.
Shipton, E. (1943). Upon that Mountain, Hodder and Stoughton,
London, p. 129.
Shlim, D. R., Hackett, P. H., Houston, C., Steele, P., Nelson, D., and
Hultgren, H. N. (1995). Diplopia at high altitude. Wilderness Env-
iron. Med. 6: 341.
Shock, N. W. (1942). The effects on learning of repeated exposures
to lowered oxygen tension of inspired air. J. Comp. Psychol. 34:
55–63.
Shukitt, B., and Banderet, L. E. (1988). Mood states at 1600 and 4300
meters terrestrial altitude. Aviat, Space Environ. Med. 59: 530–
532.
Shukitt-Hale, B.,Banderet, L. E.,and Lieberman, H.R. (1991). Relation-
ships between symptoms, moods, performance, and acute moun-
tain sickness at 4,700 meters. Aviat, Space Environ. Med. 62: 865–
869.
Shukitt-Hale, B., Banderet, L. E., and Lieberman, H. R. (1998).
Elevation-dependent symptom, mood, and performance changes
produced by exposure to hypobaric hypoxia. Int. J. Aviat. Psychol.
8: 319–334.
Shukitt-Hale, B., Kadar, T., Marlowe, B. E., Stillman, M. J., Galli,
R. L., Levy, A., et al. (1996). Morphological alterations in the
hippocampus following hypobaric hypoxia. Hum. Exp. Toxicol. 15:
312–319.
Shukitt-Hale, B., Rauch, T. M., and Foutch, R. (1990). Altitude symp-
tomatology and mood states during a climb to 3600 meters. Aviat,
Space Environ. Med. 61: 225–228.
Shukitt-Hale, B., Stillmann, M. J., Levy, A., Devine, J. A., and
Lieberman, H. R. (1993). Nimodipine prevents the in vivo decrease
in hippocampal extracellular acetylcholine produced by hypobaric
hypoxia. Brain Res. 621: 291–295.
Shukitt-Hale, B., Stillmann, M. J., Welch, D. I., Levy, A., Devine, J. A.,
and Lieberman, H. R. (1994). Hypobaric hypoxia impairs spatial
memory in an elevation-dependent fashion. Behav. Neural. Biol.
62: 244–253.
Simon, R. P. (1995). CNS response to hypoxia. In: Sutton, J. R., Houston,
C. S., and Coates, G. (eds.), Hypoxia and the Brain Proceedings of
the Ninth International Hypoxia Symposium, Queen City Printers,
Burlington, VT.
Smith, V. C., Ernest, J. T., and Pokorny, J. (1976). Effect of hypoxia
on FM-100-hue test performance. Modif. Probl. Ophthalmol. 17:
246–256.
Song, S. Y., Asaji, T., Tanizaki, Y., Fujimaki, T., Matsutani, M., and
Okeda, R. (1986). Cerebral thrombosis at altitude: Its pathogenesis
and the problems of prevention an treatment. Aviat, Space Environ.
Med. 57: 71–76.
Steingart, A., Hachinski, V. C., Lau, C., Fox, A. J., Diaz, F., Cape,
R., et al. (1987). Cognitive and neurological findings in subjects
with diffuse white matter lucencies on computed tomographic scan
(leuko-araiosis). Arch. Neurol. 44: 32–35.
Stivalet, P., Leifflen, D., Poquin, D., Savourey, G., Launay, J., Barraud,
P. A., et al. (2000). Positive expiratory pressure as a method for
preventing the impairment of attentional processes by hypoxia.
Ergonomics 43: 474–485.
Stuss, D. T., Peterkin, D. A., Guzman, D. A., Guzman, C., and Troyer,
A. K. (1997). Chronic obstructive pulmonary disease: effects of
hypoxia on neurological and neuropsychological measures. J. Clin.
Exp. Neurpshychology 19: 515–524.
Sutton, J. R., Houston, C. S., Mansell, A. L., McFadden, M. D., Hackett,
P. H., Rigg, J. R. A., et al. (1987). Effect of acetazolamide in
hypoxemia during sleep at high altitude. N.Engl.J.Med.301:
1329–1331.
Sutton, J. R., Reeves, J. T., Wagner, P. D., Groves, B. M., Cymerman,
A., Malconian, M. K., et al. (1988). Operation Everest II: Oxygen
transport during exercise at extreme simulated altitude. J. Appl.
Physiol. 64: 1309–1321.
Takagi, M., and Watanabe, S. (1999). Two different components of
contingent negative variation (CNV) and their relation to changes
in reaction time under hypobaric hypoxic conditions. Aviat. Space
Environ. Med. 70: 30–34.
Telakivi, T., Kajaste, S., Partinen, M., Brander, P., and Nyholm, A.
(1993). Cognitive function in obstructive sleep apnea. Sleep 16:
S74–S75.
Timiras, P. S., Krum, A. A., and Pace, N. (1957). Body and organ weights
of rats during acclimatization to an altitude of 12470 feet. Am. J.
Physiol. 191: 598–604.
Tissandier, G. (1875). Le Voyage Grande Hauteur du Ballon Le Zenith
[A flight in Le Zenith baloon]. La Nat. 3: 334–337.
Townes,B., Hornbein,T., Schoene,R., Sarnquist, F., and Grant, I. (1984).
Human cerebral function at extreme altitude . In: West, J. B., and
Lahiri, S. (eds.), High Altitude and Man (pp. 31–36), American
Physiological Society, Bethesda.
Van Diest, I., Stegen, K., Woestijne, K. P., Schippers, N., and Bergh,
O. (2000). Hyperventilation and attention: effects of hypocap-
nia on performance in a Stoop task. Biol. Psychol. 53: 233–
252.
Viapiano, M. S., Mitridate de Novara, A. M., Fiszer de Plazas, S., and
Bozzini, C. E. (2001). Prolonged exposure to hypobaric hypoxia
transiently reduces GABA (A) receptor number in mice cerebral
cortex. Brain Res. 894: 31–36.
Vingrys, A. J., and Garner, L. F. (1987). The effect of moderate level
of hypoxia on human color vision. Documents of Ophthalmol. 66:
171–185.
224 Viru
´
es-Ortega, Buela-Casal, Garrido, and Alc
´
azar
Viru
´
es, J., Segui, D., and Buela-Casal, G. (2002). Possible dissociation
between attention and memory impairments related to moderate
high altitude. High Alt. Med. Biol. 3: S35.
Waldfogel, S., Finesinger, J. E., and Verzeano, M. (1950). The effect
of low oxygen on psychological performance tests in psychoneu-
rotic patients and normal controls. Psychosom. Med. 12: 244–
249.
Watson, D.B., Martin, R. L., McAnally, K.I., Smith, S. E., and Emonson,
D. L. (2000). Effect of normobaric hypoxia on auditory sensitiv-
ity.Aviat. Space Environ. Med. 71: 791–797.
Wesensten, N. J., Crowley, J. B., and Thomas, K. G. (1993). Effects
of simulated high altitude exposure on long latency event-related
brain potentials and performance. Aviat. Space Environ. Med. 64:
30–36.
West, J. B. (1984). Human physiology at extreme high altitudes on
Mount Everest. Science 323: 784–788.
West, J. B. (1986). Do climbs to extreme altitude cause brain damage.
Lancet 16: 387–388.
West, J. B., Boyer, S. J., and Graber, D. J. (1983a). Maximal exercise at
extreme altitude on Mount Everest. J. Appl. Physiol. 55: 688–698.
West, J. B., Hackett, P. H., Maret, K. H., Milledge, J. S., Peters, R. M.,
Pizzo, C. J., et al. (1983b). Pulmonary gas exchange on the summit
of mount Everest. J. Appl. Physiol. 55: 678–687.
West, J. B., and Mathieu-Costello, O. (1992). High altitude pulmonary
edema is caused by stress failure of pulmonary capillaries. Int. J.
Sports Med. 13: 54–58.
Wickramasinghe, H., and Anholm, J. D. (1999). Sleep and breathing at
high altitude. Sleep Breath 3: 89–102.
Wilmer, W. H., and Berens, C. (1918). Medical studies in aviation: V.
The effect of altitude on ocular functions. J.Am.Med.Assoc.71:
1394–1398.
Zarewski, P., Marusic, I., Zolotic, S., Bunjevac, T., and Vukosav, Z.
(1998). Contribution of Arnett’s inventory of sensation seeking
ant Zuckerman’s Sensation Seeking Scale to the differentiation
of athletes engaged in high and low risk sports. Pers. Individual
Differences 25: 763–768.
Zola-Morgan, S., Squire, L. R., and Amaral, D. G. (1986). Human
amnesia and the medial temporal region: enduring impairment fol-
lowing a bilateral lesion limited to field CA1 on the hippocampus.
J Neurosci. 6:2950–2967.
