effect of high altitude on cognitive functions

Posted comment on ´Acute and Chronic Altitude-Induced Cognitive Dysfunction in Children and Adolescents` by S.F. Rimoldi, E. Rexhaj, H. Duplain, S. Urben, J. Billieux, Y. Allemann, C. Romero, A. Ayaviri, C. Salinas, M. Villena, U. Scherrer and C. Sartori and published on website Researchgate.net/publication/282245481

SUMMARY

The investigation carried out by Rimoldi and colleagues was to see whether short-term and long-term exposure to high altitude (around 3450m) induces cognitive dysfunction in children and adolescents. They found that short-term hypoxia had a significant negative effect on executive functions (inhibition, shifting and working memory), some memory functions (verbal short-term and verbal episodic memory), but not visuospatial memory and processing speed. The impairments observed were found to be even more severe for those individuals living at high altitudes permanently. A return to lower altitude for one group of study participants gave performance values back in the control range.

Test subjects consisted of 3 groups of healthy European children and adolescents. The control group consisted of 14 children and adolescents (aged between 10 and 17) living at low altitude (less than 800m).The acute, short-term high-altitude group consisted of 48 children and adolescents who were tested 24 hours after arrival at high altitude (Switzerland, 3450m) and 3 months after their return to low altitude (46 living at an altitude less than 800m, 2 at 1100m). The chronic, long-term high altitude group consisted of 21 matched subjects who had lived for longer than 3 years at high altitude (La Paz, Bolivia 3500m). The general cognitive abilities of each subject was assessed before testing using Raven`s Progressive Matrices (a non-verbal reasoning task) and it was found that subjects of all groups performed similarly. The cognitive tests given assessed each subject`s executive function, memory and processing capabilities. Testing of executive functions was carried out using the Attentional Network Task (tested inhibition),   the Trial Making Test Part B (TMT- tested shifting) and the backward Digit Span Task (tested working memory). Memory functions were tested using the  Forward Digit Span Task (tested verbal short term memory), the California Verbal Learning Test (tested verbal episodic memory) and the Corsi Block Tapping Test (tested short-term visuospatial memory).  Speed processing ability was tested using the TMT Part A. Paired student t tests were carried out for all results to indicate statistical significance.

According to Rimoldi and colleagues their study showed that short-term exposure to high altitude produced significant negative effects on all executive and memory performances except for visuospatial memory (tested by the Corsi Block Tapping Test) and processing speed (TMT part A). The value for inhibition was found to be 30% higher (a rise in value from 92 to 129) indicating an increase in reaction time and a decrease in attentional performance. The test of shifting capability (Trial Making Test Part B) showed that the subjects required on average 20% longer (63 to 74) to complete the task demonstrating that cognitive flexibility was reduced and the value of the working memory test (Backward Digit Span Task) was 10% smaller (4.9 to 4.5)indicating that working memory performance had decreased. On return to low altitude the same group of subjects was said to show performances in all of these tests similar to control values, ie. inhibition (Attentional Network Task) demonstrated a shift from 129 to 93 indicating a quicker reaction time and increased performance;  shifting (Trial Making Test Part B) with a shift from 74 to 66 also indicating a quicker reaction time and increased performance;  and working memory (Backward Digit Span Task) with a shift from 4.5 to 4.8 indicating according to the authors an improvement in working memory performance.

In the case of long-term exposure to high altitude, Rimoldi and colleagues said that the detrimental effect on these executive functions were the same or even more severe as those observed for acute exposure compared to the control, ie.  inhibition (Attentional Network Task) had a significantly longer reaction time (92 to 148);  shifting (Trial Making Test Part B) an approx. 20% longer reaction time (63 to 71); and working memory (Backward Digit Span Task) demonstrating an approx. 10% lower capability (4.9 to 4.6).

Rimoldi and colleagues found for the tests of memory capability that both verbal short-term memory and verbal episodic memory were impaired by acute exposure to high altitude. Verbal short term memory tested by the Forward Digit Span Task produced a decrease in length of word series remembered compared to the control from an average of 6.1 to 5.6. In the verbal episodic memory test (California Verbal Learning Test) the number of correct words recalled fell from an average of 12.4 to 11.9 compared to the control. However, in the case of short-term visuospatial memory measured by the Corsi Block Tapping Test, acute short-term exposure to high altitude was said to produce no effect (values recorded of average number of blocks remembered was 6.1 for the control and 6.6 for exposure). The authors concluded that the recall of both numbers and words were significantly impaired with short-term exposure to high altitude, but visuospatial memory capability was not. After return to low altitude the performance of the acute exposure group was said to improve back to the control values (verbal short term memory by a recorded value shift from 5.6 to 5.9 and verbal episodic memory by a recorded value shift from 11.9 to 13.5 and short term visuospatial memory by a recorded shift from 6.6 to 6.8).

In their investigation of the effects of long-term exposure to high altitude, Rimoldi and colleagues  stated that verbal short term memory determined by the Forward Digit Span Task and the verbal episodic memory test determined by the California Verbal Learning Test were no different to those experienced with only short-term exposure. Values recorded were shifts from 6.1to 6.3 in the former and 12.4 to 10.8 for the latter. However, the results of the visuospatial memory test (Corsi Block Tapping Test) was said to show more severe impairment in capability with long-term exposure in comparison to short-term (a recorded negative shift in performance from an average of 6.1 blocks remembered to 5.6) . Therefore, the authors concluded that the recall of words and numbers was not affected by long-term exposure to high altitude compared to short-term, but visuospatial processing impairment was even more severe.

The authors also tested their subjects for speed processing capability using the TMT Part A test. They said that on short-term exposure to high altitude there was no detectable effect on speed of processing, but recorded a shift in average performance time for joining the dots or letters from 25.3 to 27.6. On returning to low altitude, this value was decreased to 26.0. On long-term exposure to high altitude speed processing ability was said to be reduced by more than 25% since the subjects needed longer to complete the task (average recorded values of 25.3 for the control and 32.5 for subjects exposed long-term to high altitude).

Therefore, the authors concluded that changes in some cognitive areas were observed with exposure to high altitude. These changes it was said could not be attributed to acute mountain sickness (AMS) since the neuropsychological changes observed with hypoxia were different to those seen with this condition. In the case of hypoxia, acute short-term exposure to high altitude was found to induce marked cognitive deficiencies in healthy children in the areas of verbal short term memory, episodic memory and executive functions such as inhibition, shifting and working memory. Impairments were said not to be observed in visuospatial memory capability and speed processing for acute exposure, but longer exposure would lead to deficiencies not only in these areas, but also to a more severe level. A return to lower altitude after acute exposure led, according to the authors, to impairments being no longer discernible. The causes of the impairments observed for the executive functions were attributed by the authors to dysfunction of white cerebral matter, perhaps at the level of the prefrontal cortex and anterior cingulate cortex and this dysfunction had been induced by hypoxia. The differences observed between acute- and long-term exposure in the cases of visuospatial memory and processing speed indicated to them that children and adolescents may have a greater resistance to a hypoxia effect at neuronal level in these areas than adults. Since semantic cues were of no help in recall in the verbal episodic memory task the authors hypothesised that the defect in the memory process was at the level of information encoding. This observation was found to contradict the results observed for adults who do not present with episodic deficits with high altitude. Therefore, the authors suggested that the hippocampus which is involved in episodic memory is more sensitive to effects of hypoxia in children than adults. With reference to speed processing problems seen with long-term exposure in children, the authors reported that other research shows that this processing deficit has been reported even at lower altitudes (2500m) for adults and with short-term hypoxia exposure. Hence, they surmised that speed processing capability is better preserved in children than adults.

The authors concluded their article by saying that the results of their investigation into high altitude and executive, memory and processing capabilities were important not only because major tourist destinations are located at high altitudes that would expose tourists to hypoxic conditions that could have effects on their cognitive capabilities, but also that more than 15 million people live permanently at high altitudes and appear to have little or no neurophysiological functional adaptation to living in these conditions.

COMMENT

What makes Rimoldi and colleagues` article interesting is that it indicates an element of influence on cognitive processes that is frequently ignored or forgotten:  that is, the influence of the body`s hormonal system.  Emphasis is often placed on changes to cognitive performance through personal thinking, our attitudes, effects of our experiences and other mental reasons, but this is not the sole explanation for differences in capabilities observed.  The article commented on in this Blog post describes the effect of one example of hormonal influence on cognitive capability. It describes how hormonal changes brought about by low environmental oxygen affects the attentional and memory systems. In this case, low environmental oxygen is achieved by the individuals enduring either a short-term or long-term stay at high altitude (above 3500m). Low oxygen causes the body to experience what is termed ´environmental stress` and researchers have shown that this induces physiological changes that lead to cognitive and emotional effects and they can be different for altitude, duration of stay and age of individual.

Before discussing the cognitive effects observed by Rimoldi and team, we must answer the question as to what influence does high altitude and low environmental oxygen have on cell physiology. One of the most important and obvious is the change in energy production mechanisms. We are all familiar with the processes involved in muscles during intense and prolonged exercise – a situation where cells cannot get enough oxygen. Hence, the normal biochemical mechanisms of energy production cannot continue and other pathways are used instead which leads to the formation of lactate. Continued production means a build-up of lactate in the muscles and a fall in intracellular pH until this inhibits even this energy producing pathway. A similar problem occurs with the energy production in brain cells exposed to high altitude. High altitude is characterised biochemically as ´environmental stress` since the fall in external oxygen leads to a decrease in inhaled oxygen pressure (50% at 3000m of that at sea level) and this results in reduced driving pressure for gas exchange in the lungs. Therefore, the individual has less oxygen intake for each breath and so blood is not fully oxygenated at the alveolar level and ultimately, circulating blood level. Hence, brain cells are unable to obtain enough oxygen for their normal biochemical processes relying on it and as a result cellular adaptation has to occur.

In the case of the energy-producing systems in low oxygen conditions, the normal mechanism of glucose being metabolised by a chain of enzymatic reactions (called glycolysis) to produce pyruvate that occurs in aerobic respiration (ie. in the presence of oxygen) still takes place, but the second stage of the process is altered. This stage is where the pyruvate is converted by another chain of reactions into the energy molecules ATP.  If oxygen is not present at the level required for this aerobic mechanism, then a process called lactic acid fermentation is initiated (anaerobic respiration). Lactic acid fermentation means that pyruvate is then converted to lactate by the enzyme lactate dehydrogenase (LDH). However, this anaerobic process does not produce the same number of ATP molecules as normal aerobic mechanisms, but it does provide some.

The other potential problem is the build-up of lactate which is observed in muscle cells. However, it is likely that in the brain which is dependent on a constant supply of glucose and energy that a safeguarding mechanism is in place called the Cori cycle which transports the lactate out of the cell, back to the liver where it is converted into glucose by a process known as gluconeogenesis. Again the LDH enzyme is involved and this conversion could explain the lack of appetite experienced by some when undergoing rising altitude.

The processes of this energy switch due to the rise in altitude plus the short fall of ATP production are made easier by increasing the production of a cellular factor that influences gene expression. The production of hypoxia-inducible transcription factor (HIF-1) is induced as the oxygen concentration of the blood falls. This transcription factor leads to increased gene expression of many glycolytic enzymes eg. hexokinase, aldolase, phosphoglycerate kinase (ie. those taking part in the first stage of the energy producing cycle), plus LDH (which we have seen converts lactate to ATP) plus the glucose transporter molecules  GLUT1 and GLUT3, which transport glucose across cell membranes. Therefore, the energy producing mechanisms that are required for any metabolic energy changes due to lower oxygen availability have been optimised.

Changes to the blood and circulatory system can also occur to alleviate the absence of oxygen.  This is understandable since oxygen is transported via the blood from the lungs to the brain and the brain has a high need for oxygen and for glucose. Therefore, increased ventilation has been observed from altitudes of 3000m and this response varies with individuals and is not related particularly to performance. There is also an increased level of cardiac output initially leading to normal values with time. However, there is increased heart rate and decreased stroke volume since hypoxia acts as a vasodilator in systemic circulation and a vasoconstrictor in pulmonary areas which can lead to a high risk of pulmonary hypertension and pulmonary oedema. There is also increased viscosity of the blood and increased coagulability which can result in an increased risk of stroke and venous thromboembolism. Blood components can also adapt in travelling to high altitude leading to increased haemoglobin concentrations by the decrease in blood volume due to dehydration. Later on, hypoxia leads to an increased production of erythropoetin and increased haemoglobin production to compensate.

Although clearly the production of energy molecules for the cell is very important, the presence of oxygen in the blood is also required for a number of other biochemical processes that could also influence cognitive function, eg. the degradation of aromatic amino-acids by oxygenases, the formation of steroid hormones by hydroxylation, oxidative phosphorylation, the elongation of unsaturated fatty acids in endoplasmic reticulum of cells, the formation of nitric oxide, the synthesis of plasmologens and the degradation of nucleotides. Systems influenced by low oxygen availability affecting in particular brain cells and cognitive functions are not specifically known, but certain paths could be possible. For example, the degradation of aromatic amino-acids by oxygenases could in the case of the amino acid phenylalanine mean reduced tyrosine levels and tyrosine is used in the brain to form dopamine, a major brain neurotransmitter and instrumental in inducing hypoxic changes as we will describe later. Another example is the elongation of unsaturated fatty acids in the endoplasmic reticulum of cells could influence cell membrane structure ie. affect the formation of membrane lipid rafts and affect the cell surface receptors and other membrane proteins and molecular functioning. Also, an example of an effect on the synthesis of plasmologens could mean that the plasmologen phosphatidal choline which corresponds to the phospholipid, phosphatidyl choline, which is important for cell membrane structure, is not formed.

So we have seen how environmental stress from low oxygen availability causes physical adaptations and these can as with all other influences include effects on brain physiology and because of that, on the functioning of cognitive and emotional systems. For example, increased vigilance and arousal is observed with high altitude exposure and these are associated with increased activity in the ventral tegmentum area (effects linked with increased dopamine availability), raphe nuclei (increased 5HT), locus coeruleus (increased noradrenaline) and other brain stem and basal forebrain areas. The increased neurotransmitter production and increased functioning of these areas in response to high altitude exposure all lead to increased firing of the thalamus and cortical areas which result in changes to the input, processing and storage of information.  High altitude exposure also causes the activation of the autonomic nervous system (ANS) which leads to the production by the adrenal cortex of adrenaline (associated with the ´fight or flight` response) and noradrenaline (associated with the activation of the locus coeruleus and the ´fight or flight` response). Also, there is an observed release of cortisol from the adrenal glands and this has an important role in promoting changes to cognitive capabilities since it leads to the activation of the hypothalamus-pituitary-adrenal axis (HPA). HPA activation from cortisol release leads to increased amygdala responses and decreased hippocampal activity (inhibits corticotropin-releasing hormone CRH release and hippocampal cells can wither and die during chronic stress).  Cortisol can bind to receptors in the cytoplasm of neurons and travel to the nucleus where it stimulates gene transcription. It can also promote calcium ion entry into neuronal cells by either changing ion channel function or by changing energy metabolism in the cell, but independent of method both cause cell depolarisation. The effects on cellular firing and neuronal firing connectivity between brain areas can be linked to performance of attention and memory systems and hence, high altitude exposure can have multiple effects on these dependent cognitive systems.

Rimoldi and colleagues`  investigation looked at certain cognitive functions in relation to exposure to high altitude in European children. We must say at this point that our interpretations of their results were not always in exact agreement with the interpretations by the authors, but in this comment we attempt to understand what is being observed and provide an explanation of the neurochemical mechanisms involved. The first area we will discuss is that of attention. Rimoldi and colleagues say that there is decreased attention capability with exposure to high altitude and with duration of that exposure. We disagree about the interpretation of the level by which this occurs since the authors say acute exposure produces a 30% decrease with chronic exposure greater, but our interpretation gives a greater negative influence at 40% on acute exposure and more severe at chronic (60% decrease in capability). The neurochemical explanation for such a large decrease in capability (whether at the authors´ level or ours) could be that the brain areas associated with attention (ie. of the fear system, the association between the cingulate cortex and ventral tegmentum and the dopamine activation observed) are affected by the physiological changes brought about by hypoxia. Lower levels of firing seen in low-oxygen conditions could result in the level of connectivity between brain areas not being achieved and hence, decreased performance occurs. For example, neuronal cell group connectivity is required as shown by alpha brain waves between that group`s  members to maintain informational items and therefore, if connectivity is disrupted to an extent that the items cannot be held in the working memory, performance on the task (in this case the assessment of arrow direction in relation to a given example) would be reduced.

However, this hypothesis conflicts with the view that increased dopamine would lead to increased attention and processing and increased hippocampal functioning. Therefore, it is possible that the decrease in attention seen with high altitude exposure can be explained by the mechanisms involved being more akin to those observed with increased dopamine seen in individuals with attention-deficit disorder (ADHD). In this case, there is a fear state observed with increased prefrontal cortical and cingulate cortical activities which would lead to an increase in task relevant information and task irrelevant material. The result of this is that the tasks given in Rimoldi and colleagues` study are more difficult to perform since a decision has to be made between whether the arrow points in the same direction as the example or not. If there is an increase in task irrelevant material then it is more likely that errors would increase and reaction time decrease and hence, the overall performance level observed would drop. In Rimoldi and colleagues` attention experiment only correct congruent and incongruent results were measured and the level of errors was not considered. It should be noted however, that decreased blood flow is seen in the frontal lobes of ADHD patients akin to the symptoms observed with high-altitude exposure, but there is also decreased glucose availability and no prefrontal cortex activation of the amygdala, both of which are not observed under hypoxic conditions.

Under chronic environmental stress conditions decreased attention is still measured since there is continued increased dopamine release from the production of cortisol and there is decreased hippocampus functioning via feedback inhibition of the HPA. There is also an increase in amygdala activity because of this continued HPA activation. This could explain why the decrease in attentional capability is more severe with longer duration of high altitude exposure. Long term changes occur at the neuronal level due to over-excitability of the amygdala. Apoptosis of neuronal cells can occur as a result of over-excitability of certain areas and decreased functioning and reduced area size is observed. However, there must be in the areas the capability of readjusting once the stressor is removed since the subject`s return to low altitude is met with a reversion back to control values for certain cognitive functions. Therefore, long-term changes such as the overly large thalamus and decreased size of the hippocampus as seen with full-blown ADHD are not observed in the case of exposure to high altitude. Readjustment of an area`s capability occurs in response to a reduction in HPA activation and cortisol production.

Another cognitive capability investigated by Rimoldi and team was working memory. The authors saw a lower decrease in capability after acute high altitude exposure compared to attention (10% as seen with increased reaction time with our interpretation slightly less at 8%). A greater change was measured (20%) as expected with the Trail Making Test Part B (shifting task) since this task measures a combination of attention and working memory capabilities. Although an association between dopamine and working memory is not definitive (working memory is thought more of a GABA process), an explanation for the negative effect is likely to be decreased hippocampal function (glucocorticoid receptor effects) and increased amygdala function as a result of increased HPA activation and cortisol production. The changes in firing of these areas lead just like with attention to alterations in connectivity of the brain areas involved in the working memory function.  Working memory requires cell group connectivity with theta brain waves (gives temporal order) and alpha (maintains relevant items and keeps non relevant information away) for correct performance and hence, changes in individual brain area functioning could lead to the working memory conditions of binding and presentation of information for the correct completion of the task not possible. Chronic exposure to high altitude appears to bring, according to Rimoldi and team, no change to the level of impairment observed from the acute (although our interpretation is that there is slight improvement with chronic exposure) and therefore, negative influences on the physiology occur on immediate exposure and there is no long-term adaptation to the systems. This is supported by the observation that once the stressor is removed (ie. there is a return to low altitude) the mechanism returns to normal and therefore, any element effected is only temporary and only in the presence of the stressor.

Another capability investigated by Rimoldi and team is the cognitive capability of visuospatial memory. They found that acute exposure to high altitude had no effect on visuospatial memory, but long-term exposure did. Our interpretation is slightly different in that a slight increase (8%) in capability was observed with acute exposure, but chronic exposure led to a slight decrease (8%). An explanation for the observations could be that there is a ´fight or flight` response to acute exposure due to increased amydala activity induced by the activation of the HPA and production of cortisol. The change is amygdala function would lead to both increased levels of task-relevant and task irrelevant material, but the low effect could be due to the task (the Corsi Block Tapping Test) not being complicated enough.  Therefore, what would be observed would be the increased performance from the initial high dopamine concentration which induces ventral tegmentum activity and greater cortex and thalamus activities. Since there is greater activity and greater connectivity, better decision making and higher end-performance would be observed. The effect still remains to some extent (our interpretation 3% increase above control) once the stressor is removed (ie. by returning to low altitude) which implies that some physiological changes are not readily reversed.

However, chronic exposure to high altitude decreases visuospatial capability and this is consistent with the idea that long-term stress causes permanent physiological changes. Other researchers have already shown that there is an age-related decrease in spatial working memory that is exacerbated by increasing HPA activity therefore, it is likely that the chronic effect on the HPA,  downregulation of hippocampal activity, upregulation of amygdala activity and long-term cortisol production leads to decreased capability observed through permanent changes in brain area functioning and connectivity.  In the case of spatial memory, other researchers have said that the dorsal lateral prefrontal cortex is essential (although this is disputed) and this area and the ventral hippocampus and medial prefrontal cortex form a pattern of area connectivity that sets up a theta brain wave for correct functioning. A parieto-temporal circuit is also involved which integrates valuable sensory information. Dopamine receptor stimulation appears to demonstrate an inverted dose activation plot. Therefore, it is assumed that if visuospatial memory capability is decreased with chronic exposure to high altitude then all of these essential areas are affected by long-term administration of the stressor. This also applies to the workings of the visual working memory system where connectivity between the prefrontal cortex, cingulate cortex and hippocampus is involved. Therefore, it is thought that increased dopamine production leads to decreased connectivity patterns resulting in poor visuospatial performance.

Rimoldi and colleagues also looked at the cognitive capability of verbal memory.  They said that exposure to high altitude caused a decrease in capability independent of duration for both verbal working memory and episodic verbal memory. Our interpretation is slightly different with short-term verbal memory demonstrating an 8% decrease in capability, but only 3% after long-term exposure and episodic memory with decreased capability with long-term exposure even more severe (8% to 3% acute).  Researchers have already stated that hypoxic conditions lead to problems with memory encoding, retrieval and retention. In this case, it is likely that there is a decrease in encoding in the acute exposure situation as expected because of decreased working memory and attentional capabilities described above, but there is readjustment with time (long-term exposure leads to a decrease and return to values observed at low altitude albeit that the recovery is not at the same level as control). The decrease in episodic memory capability can be explained by decreased prefrontal cortex functioning as observed and decreased hippocampal activity (through the sustained HPA activation) causing problems with encoding (input and binding), retention and retrieval of information. It has also been reported that glucocorticoid receptors activity associated with hypoxic exposure eliminates newly formed cortical spines and disrupts previously acquired memories. Hence, episodic memory performance would be diminished. Again, hypotheses that cortisol production and HPA activation due to exposure to high altitude would lead to disruption of the brain area connectivity patterns required for memory mechanisms to function normally (ie. adequate and correct cellular connectivity within the groups with theta brain wave patterns required for encoding and gamma brain waves for learning) would apply. This is supported by other research that memory mechanisms under stress when the HPA axis is stimulated are different to those when not.

Although Rimoldi and colleagues provide adequate evidence that physiological changes are induced on exposure to high altitude and these can change according to duration, one factor not investigated by them, but which provides support for their conclusions, is the effect of high altitude exposure on the emotional system and mood. Mood changes are associated with high altitude exposure and duration. Initial environmental stress causes euphoria and arousal, a system which is dopamine dominated and hence, provides support to the observation that there is a rise in dopamine levels on stress exposure.  Corticotrophic releasing factor (CRF) is produced in response to hypoxia and this leads to cortisol production that is known to act on the brain area ventral tegmentum to cause increased dopamine function. As given above, the increased activity of this area leads to firing of axons connected to the frontal cortex and to parts of limbic system such as the nucleus accumbens (known to fire with unpredicted rewards plus known for its role in encoding anticipated rewards) and striatum (increased activity also seen with increased environmental stress). Both systems are thought to be associated to the pleasure system and reward and hence, this supports changes in mood observed. There is also release of other neurotransmitters eg. 5HT and NA recognised as being linked with cortisol and HPA axis activation and both of these can lead to increased dopamine release in the prefrontal cortex by the action of the raphe nuclei.

Continued exposure to stress (ie. high altitude) leads to a change in mood from euphoria to depression. This condition is normally associated with decreased serotonin levels and has symptoms such as a lack of concentration, disinterest, insomnia and loss of appetite. There are two ways of looking at this. The first is that there is decreased serotonin because there is physical acclimatisation to the environmental stress as physiological systems such as the energy production mechanism adjust and therefore, the lack of oxygen is seen as a ´controllable stressor`. This leads to inhibition of the raphe nuclei and decreased ventral medial prefrontal cortical activity which is linked to the System 1 automatic, fast decision-making system and has a role in assessing value. Or, secondly, that there is a down-regulation of the dopamine receptor system in response to its high exposure to its own ligand neurotransmitter as seen in drug addiction for example. Excessive dopamine levels leads to decreased prefrontal cortex activity, decreased numbers of D1, D3 and D4 receptors, decreased glutamate receptors and decreased working memory capability. 5HT follows suit with the down- regulation of its receptors and down- regulation of prefrontal cortical activity leading to the symptoms of depression.  Again, the neurochemical systems readjust to this state and with time will lead to another mood change that of anxiety, irritability and belligerence which are all symptoms normally attributed to increased amygdala activity. This type of mood response supports the documented increase in amygdala activity that HPA axis activation is said to lead to.

Therefore, what can we conclude about the effect of exposure to high altitude on brain functioning? What we have seen is that there are physiological effects at the cellular level due to the low oxygen availability and at the area level because of the activation of the HPA and cortisol production and these translate into effects on cognitive functioning and performance and mood. These effects change in response to duration of exposure and level and naturally, to individual`s own physiological levels.  What makes this topic interesting is that here is another element that has to be considered when we are talking about cognitive capability and bringing about change to cognitive capability. We know about sleep and oestrogen and now we have the HPA system and the action of cortisol and glucocorticoids. It also reinforces the view that changes to physiology and biochemical functioning can have repercussions on how and what we think and even things like environmental stress should not to be underestimated. The results recorded in this investigation with exposure to high altitude shows that individuals should consider it with concern and perhaps for some preventative measures, eg. cognitive training could be advantageous.

Since we`re talking about the topic………

…..can changes in pH in brain cells be observed with exposure to high altitude and do these change with time?

…..would the use of serotonin receptor knock-out mice show definitively that the serotonin system is involved in the effects on working memory and attentional performance caused by exposure to high altitude?

…would administration of serotonin selective uptake inhibitors and other antidepressants lead to a decreased level of anxiety and counteract the depressive mood change observed with longer term exposure to altitude? Would the administration of ketamine also lead to protection from depression as observed with stressed mice?

….what would be the effect of the administration of the ADHD treatment, ritalin? Would there be a shift to normal prefrontal activity as measured by neuroimaging techniques that could accompany the return to normal performance levels for working memory, attention and memory capabilities?

….would there be an increased number of glucocorticoid receptors observed in the hippocampus on acute and chronic exposure to high altitude?

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