1.1. General Introduction

Under normal circumstances foodstuffs are broken down into fat, protein and the carbohydrate glucose, from which the body’s supply of energy is produced through a series of reactions primarily involving metabolism with oxygen (figure 1.1.).

Figure 1.1. : Outline of the conversion of foodstuffs to energy in the body.

As its primary energy source, constant supplies of glucose and oxygen are critical to brain function, a fact that is highlighted by findings of cognitive impairments associated with situations where the ability to regulate the supply of the brain’s energy sources are decreased. Examples of such situations include ageing, high altitude and the hypoglycaemic phase of diabetes. Conversely, a number of newly developed nootropics or "smart drugs" are believed to have their cognitive enhancing effect through targeting cerebral blood flow, glucose utilisation or oxygenation.

It is a commonly held belief that the brain has evolved to function optimally in healthy individuals. However there is now increasing evidence that enhancing the brains potential for metabolic activity is reflected by an augmentation of cognitive performance. This phenomenon has been extensively investigated in Benton’s laboratory with respect to glucose. The general finding is that cognitive performance over a number of tasks correlates with blood glucose levels, irrespective of resting, basal level. One possible explanation for the enhancing effects of glucose administration on cognition is that it leads to increased levels of acetylcholine (ACh) synthesis (Figure 1.2.), a neurotransmitter that has long been associated with attention and memory.

Figure 1.2. : Outline of the relationship between glucose metabolism, acetylcholine synthesis and energy production.

However it may be the case that the increase in fuel supply leads to an upgrade in adenosine triphosphate (ATP) production at times of high demand. ATP is the "cellular energy currency" and increased production may enable improvements to be made in information processing during cognitive task performance. Such improvements would be manifest as cognitive enhancement.

It is the purpose of this thesis to investigate the possible positive influences of oxygen administration on cognitive performance and any concomitant physiological responses, following our initial work indicating improvements in memory recall following transient oxygen administration (Moss and Scholey 1996). Indications of the mode of influence of oxygen in educing any such effects may also be found through the use of a range of tasks that are believed to tap into differing neural subsystems.

As a nutrient oxygen has no substitute – unlike fat, carbohydrate and protein which are, for the most part metabolically interchangeable. Although higher animals use molecular oxygen in the synthesis of a great variety of important chemical compounds that act as regulators and constituents of cellular metabolism, e.g. catecholamines and serotonin (Gibson et al. 1981), the amount of oxygen used for such purposes is minor compared to that consumed for energy production (Forster and Eastabrook 1993).

The brain is disproportionately metabolically active for its size, accounting for up to 30% of an organism’s total basal energy expenditure, whilst comprising only around 2–3% of total body mass (Siebert et al. 1986; Krassner 1986). The brain is remarkable in its dependence on the blood for its immediate and constant supply of oxygen and other essential energy substrates (e.g. glucose). Any interruption in their delivery leads within seconds to unconsciousness and within minutes to irreversible changes resulting in cell death. By comparison to the rest of the viscera it may be seen as very vulnerable organ, sensitive to small and transient fluctuations in the supply mechanisms on which it relies (Bradford 1985). Despite this there are, paradoxically, low levels of essential metabolic resources stored within the brain. Glycogen storage levels in liver, muscles and brain are in the ratio of 100/10/1, with brain levels being in the region of 2-4 m mol/g of tissue, an amount capable of sustaining function for up to 10 minutes (Marks and Rose 1981). By comparison there is no storage capacity for oxygen with a disruption of supply having an almost instantaneous effect (Yamatoto et al. 1993). This means that oxygen delivery must be adjusted within seconds in response to changes in metabolic rate. Under normal conditions metabolic activity is limited by the rate of oxygen delivery (Forster and Eastabrook 1993).

A considerable body of evidence has accumulated addressing the effects of variations in glucose availability on cognitive function. Mild hypoglycaemia has been demonstrated to reduce memorial performance (Lapp 1981; Benton 1989; 1990), and a large amount of interest has been directed at investigating the possible beneficial effects of increased glucose availability through glucose administration, both injected directly into the brain (Lee et al. 1988), and through ingestion and delivery through the cerebral blood flow. Animal studies have shown that raised blood glucose levels are associated with improved memory performance (Gold 1986; 1991; 1992), and these results have been mirrored by those from human studies on the healthy elderly (Hall et al. 1989), patients with senile dementia of the Alzheimer type, (Manning et al. 1993), and healthy young adults (Benton and Owens 1993; Benton et al. 1994).

The effects of ischemic oxygen deprivation on cognitive function have also been widely documented. Mnemonic deficits in humans have been described by Volpe and Hirst (1983), and Graf et al. (1985); and in animals by Zola-Morgan et al. (1992), and Wood et al. (1993). There is also indirect evidence that even fleeting fluctuations in cerebral oxygen delivery within normal physiological limits can impact on cognitive performance, (Sandman et al. 1977). To date however, few authors have examined the effects of specifically enhancing oxygen availability through oxygen administration. Edwards and Hart (1974) examined the effects of hyperbaric oxygen administration on healthy elderly outpatients and found substantial improvements in performance on tests of short term memory and visual organisation, but their conclusions are tentative due to the lack of a comparative control group.

It is the primary objective of this thesis to investigate the possible beneficial effects of oxygen inhalation on a range of cognitive performance measures in the healthy young and aged. Further to this physiological responses to oxygen administration are examined in order to identify any physiological correlates of oxygen breathing and cognitive task performance.

Chapter two is a partial replication of our first study in this area (Moss and Scholey 1996). Performance on a long term verbal recall task is compared between oxygen and air breathing participants, with particular attention being paid to serial order effects in recall. Following our demonstration that oxygen administration at time of learning increased subsequent recall it was considered logical to determine where the improved performance stemmed from in terms of individual item recall. The results indicate that the middle order items from a word list are more readily recalled under hyperoxic conditions.

Chapter three investigates and compares the effect of a range of oxygen administration regimes on a battery of tasks identified as measuring the performance of attentional, working memory and long term memory systems. Any subjective mood response is also assessed using visual analogue scales for alertness, contentedness and calmness (Bond and Lader 1974). It is deemed important to compare different durations of oxygen breathing on performance as the duration used in our first studies had been arbitrarily decided upon, and there was no reason to assume that optimum delivery for enhanced performance had been achieved. The battery of tasks employed here is able to identify more clearly where (in terms of cognitive components) enhancement may be achieved It also allows comparison with experimental group performance to population norms, and to the effects of other clinical interventions on the tasks which have been widely documented. Significant improvements following oxygen administration are reported for tests of attention and long term memory recall, with no effects found for tests of working memory, or mood. Furthermore, the size of the observed improvements were found to be related to the duration of oxygen administration in a task specific manner.

Chapter four addresses the question of the temporal kinetics of oxygen administration in terms of physiological response (blood oxygen saturation) and task performance (word recall, and forward and backward digit span). This study is designed to indicate how long it takes for haemoglobin-bound oxygen levels to increase whilst breathing oxygen and how long these levels remain high subsequent to the return to ambient air breathing, and during cognitive task performance. In addition the possible proactive and retroactive effects of induced hyperoxia are assessed. This is achieved by virtue of the fact that performance is compared, within subjects, across gas delivery times up to 10 minutes prior to and after stimulus presentation (for word recall), and up to 20 minutes prior to the digit span tests. The results obtained indicate the existence of a ‘window’ of hyperoxia during which time encoding of target material can be significantly enhanced. No significant effect is apparent for the digit span tests.

Chapter five follows this by systematically determining the changes in blood oxygen saturation during task performance, specifically word recall and simple reaction time measures both of which had been shown previously to be sensitive to oxygen administration. This is done in order to compare how differences in performance may relate to differences in available blood oxygen and its consumption during task performance. From the theoretical standpoint of this thesis increased availability of oxygen at the time of encoding the target material, and performance of the reaction time task would be expected to be associated with enhanced performance and a concomittant reduction of oxygen levels during the tasks. The results demonstrate that improved performance is associated with elevated blood oxygen saturation, which rapidly declines during task performance. Heartrate is also monitored throughout the experimental sessions, and is found to increase during task performance independent of oxygen administration. It may prove to be the case that heartrate reactivity and oxygen carrying capacity are important individual differences in determining the degree of effects found.

Chapter six attempts to clarify if a task that may be non cholinergic in mediation is susceptible to oxygen intervention. The rationale behind this study is based on the widely posited hypothesis that glucose may enhance performance by virtue of a possible increase in acetylcholine synthesis (e.g. Messier et al. 1990; Stone et al. 1988; Parsons and Gold 1992b). The task employed in this study is considered to be one that taps into implicit memory processes, a subsystem that has been proposed to be non-cholinergic in nature. If performance on this task is also enhanced by oxygen administration then it could be argued that oxygen does not only influence cholinergic systems, but may be available to produce an increment in the available energy required by the brain for a wider range of neural pathways, and general neuronal functioning at times of cognitive load. The results show a positive effect on reaction time, but no significantly enhanced implicit learning effect. A possible alternative explanation for these findings is considered.

Chapter seven makes a comparison of performance under normal and hyperoxic conditions on two different tests of aspects of attention, viz the embedded figures task (a measure of focussed attention), and the water jars task (a measure of broadened attention). This study is designed to provide an indication of the level or mechanism at which oxygen exerts its cognitive enhancing influence. The evidence suggests that focused attention is increased by cholinergic agonists but broadened attention is impaired by such agents. A comparison is made here of the effects of nicotine, (established as a cholinergic agonist) and oxygen in order to identify differences or similarities in their action, and hence provide more information on oxygen’s mode of influence. If oxygen exerts its influence through cholinergic mechanisms, it would be predicted that performance on the embedded figures task would be improved, but that on the water jars task it would be impaired. Conversely if our outline hypothesis of a potential global or regional increment in metabolic output under conditions of hyperoxia is accurate, then both focussed and broadened attention may be facilitated; which indeed is supported by the results.

Chapter eight returns to the issues of physiological responses in terms of cognitive load and performance. Heartrate and blood oxygen saturation are constantly monitored during the performance of cognitively demanding, (serial sevens) and simple, (counting upwards) tasks. Carroll et al. (1986a) compared heartrate responses for easy, hard and impossible cognitive tasks and found that the increase in heartrate under conditions of psychological challenge was substantially greater than would be predicted by participants’ HR-VO2 regression, (the relationship between heartrate and oxygen consumption) during isotonic exercise. It is argued here that this may reflect a situation where demand may outstrip supply of neural fuels, leading to an exaggerated physiological response in an attempt to redress the imbalance. If this is the case then an upgrade in available resources, (in this instance oxygen) may compensate for this to some degree and lead to a reduction in the exaggerated heartrate response. However, the results obtained here indicate higher heartrate increases in the oxygen condition, which is also associated with significantly better performance.

Chapter nine takes the logical step of combining oxygen and glucose administration in an attempt to establish if a synergistic response to increased availability of both fuels may be possible. Combinations of treatments and placebos are utilised and the same cognitive test battery employed as in chapter two. It is hypothesised that if, as has been demonstrated previously, either intervention has a beneficial effect, then a combination will produce a combined effect greater than either in isolation. This is based on the premise that both components are inextricably linked in terms of energy production, and if both are available at supra-baseline levels then metabolism may be able to proceed at a faster rate than if only one is present at high levels. Contrary to the predictions no significant effects were found for any of the experimental interventions. Methodological considerations are discussed in relation to these findings.

Up to this point all the studies in this thesis have focused on the healthy young as candidates for cognitive enhancement through oxygen administration. Chapter ten addresses this issue by examining the effect of oxygen inhalation on a group of healthy elderly volunteers. This study essentially replicates chapter two in methodology and is designed to assess if a similar profile of enhancement is available to the elderly. Research on glucose administration has shown beneficial effects in the elderly, both healthy (e.g. Gonder-Frederick et al. 1987), and those suffering from SDAT (e.g. Craft et al. 1992; Manning et al. 1993; Craft et al. 1996). Consequently it is considered important to establish if oxygen administration can provide similar benefits to the aged as have been observed in the young. Analysis of the data indicates that in broad terms young and old participants respond in a similar manner under conditions of hyperoxia, although the enhancements in the elderly are of a lesser magnitude.

Chapter eleven details a study which records heartrate, blood oxygen saturation, and also employs a technique for analysing exhaled gas fractions, in order to establish further how oxygen delivery is related to oxygen utilisation and metabolism. This is measured in terms of the levels of exhaled oxygen and carbon dioxide during gas administration and task performance. Comparisons are made between young and old participants under conditions of both air and oxygen administration. The tasks employed are simple reaction time, number vigilance, verbal fluency and the Stroop, in an attempt to get a profile of physiological responses for a number of different tasks. Oxygen induced enhancement was found for all the cognitive tests, and the physiological profiles indicate somewhat different responses for the young and old, with those of the young being more pronounced.

Finally chapter twelve provides a report that outlines a possible therapeutic use of oxygen administration. A considerable amount of research has been carried out to attempt to objectively quantify the nature and extent of the cognitive problems that are so regularly reported by individuals with Myalgic Encephalomyelitis (ME) / Chronic Fatigue Syndrome (CFS), (Moss-Morris et al. 1996). Costa (1994) provided evidence of decreased regional blood flow through the brain stem of ME patients causing a reduction of oxygen levels in this area. Following the reported evidence that oxygen can enhance performance on a range of cognitive measures it was therefore hypothesised that oxygen administration in ME patients may reverse the cognitive impairments experienced by re-establishing oxygen levels. The results show that some of the performance measures do indeed respond in a significantly positive manner to oxygen administration as hypothesised. However, performance is not returned to normal levels, and the possible reasons for this are discussed.

1.2. The Energy Requirements, Production and Utilisation in the Brain.

Most organs in the body are able to utilise many substrates present in the blood. They are able to absorb and metabolise a wide range of amino, keto and fatty acids for example, in addition to glucose, and the supplies of all these substances are fully adequate to maintain normal function. Such is not the case for the brain which relies solely on the oxidative metabolism of glucose for its energy requirements (Siesjo 1978). At rest the brain consumes 17 calories per 100 grams of brain tissue per minute (Siebert et al. 1986). Kadekaro et al. (1985) demonstrated that electrical stimulation of the sciatic nerve produced increases of up to 150% in metabolic rate where the afferent terminals made synapses with dendrites. This indicates that local activation leads to large scale changes in local metabolism, and by virtue in glucose and oxygen utilisation. The normal arterial concentration of glucose is 5.5mM/L, and the normal level of oxygen is equivalent to 0.12mM/L. As 6 molecules of oxygen are required to oxidise 1 molecule of glucose, then from the standpoint of supplying these metabolic needs, the concentration of glucose is 275 times greater than that of oxygen in the extracellular fluid at the surface of the cell. Thus oxygen turnover is the highest amongst the essential nutrients (Forster and Eastabrook (1993). Such times of high cellular demand for energy as mentioned above, (and more importantly in terms of this thesis, during cognitive processing) may outstrip the supply of oxygen and the cells may have to fall back (to some degree) on anaerobic metabolism. This provides less energy and leads to the accumulation of toxic end products, but allows a level of baseline cellular metabolism until physiological responses can restore supply to the required levels (Rose 1966).


1.2.1. How is the Energy For Neural Function Produced ? Glucose

In the normal brain energy is almost exclusively derived from the oxidative metabolism of glucose. No other significant identifiable source of energy has been isolated. The brain is able to obtain the required glucose from two sources; the breakdown of glycogen (a large molecule made up of glucose units) that is stored in astrocytes, and from glucose carried in blood serum. Synthesis and degradation of glycogen appears to be linked generally to the level of membrane activity, with most metabolism occuring in the grey rather than the white matter; and specifically to synaptic transmission, synaptic excitation and inhibition, transmitter synthesis and protein phosphorylation as all these processes require energy to continue (McCasland and Woolsey 1988; Hof et al. 1988). However glycogen provides only a fraction of the glucose required by the brain, the amount stored in the human brain is not known exactly, although it is higher than that found in laboratory animals (Clarke et al. 1989), nor is the length of time that the brain can survive using glycogen as an exclusive energy source. The brain is therefore dependent on a constant supply of glucose from the blood, being transported across the blood brain barrier via a saturable carrier mechanism. Blood capillary endothelial cells contain specific carrier molecules which transport glucose into the extracellular space of the brain. The rate of this transport is intrinsically linked to neuronal activity, in so much as the capacity for transport increases as a function of increasing capillary surface. The capillary surface area is proportional to regional metabolic activity so that capillaries dilate when metabolic activity increases (Roland 1993). Once inside the extracellular space glucose is carried into neurones and glia by specific membrane-bound transport systems. Neither of these glucose transport systems are energy consuming, being driven by concentration gradients. Interestingly the specific transport systems located in the nerve terminals have a capacity 30 times that of the mechanisms located in other parts of the neuronal membrane. These transport mechanisms are rate limiting under normal circumstances (Lund-Andersen 1979), with trans-membrane glucose trafficking increasing locally during periods of higher neuronal activity.

Once glucose has entered cells it undergoes the process of glycolysis in the cytosol, thereafter pyruvate, the main product of glycolysis, enters the tricarboxylic cycle in mitochondria. It is through these complex series of reactions that ATP the ‘universal energy currency of nature’ is produced. Glycolysis

Firstly glucose is phosphorylated into glucose-6- phosphate by the enzyme hexokinase, a reaction that consumes one molecule of ATP. The rest of the breakdown of glucose via the glycolytic pathway is regulated by the activity of hexokinase under normal conditions (Lund-Andersen 1979). This regulation takes the form of increased hexokinase activity driven by increased inorganic phosphate concentration, or increased ADP/ATP ratio, and decreased activity when glucose-6-phosphate concentration increases. Glucose-6-phosphate so produced is available to three possible processes: 1) as the substrate for glycogen synthesis (little is actually channelled to this path); 2) as a substrate for glucose-6-phosphate dehydrogenase which initiates the pentose shunt pathway (estimates of the amount of glucose entering this path vary between 1 and 8 per cent in primates (Sacks 1965; Gaitonde et al. 1983)), or 3) it can be further metabolised along the glycolytic pathway.

The remainder of the reactions involved in glycolysis result in the production of pyruvate Figure 1.3.

Figure 1.3 : The key reactions involved in glycolysis (Http://www.wiley).

The rate of glycolysis is regulated at three points. The regulation of hexokinase activity (see above). The regulation of the activity of the enzyme phosphofructokinase, which is enhanced by, amongst other things increased concentrations of ADP, AMP and inorganic phosphate and is inhibited by increased concentrations of ATP. Lastly by the activity of the enzyme pyruvate kinase which is also enhanced by high ADP concentrations and inhibited by high ATP concentrations. It is apparent from this that any energy consuming process (i.e. those which convert ATP to ADP) will lead to increases in the rate at which glycolysis proceeds. The Tricarboxylic Acid Cycle

The enzymes that catalyze the reactions of the trycarboxylic acid (TCA) cycle are located in the mitochondria. The membrane of the mitochondria is not permeable to pyruvate which is therefore transported across the membrane by a special carrier system. Once inside the mitochondrion pyruvate is decarboxylated and combines with coenzyme A to produce acetylcoenzyme A (Acetyl Co A), which carries a two-carbon unit and two molecules of CO2. The rest of the metabolism of glucose is made up of the conversion of acetyl Co A into CO2, NADH and FADH2, which can be described by:

CH3CO~SCoA + 3NAD+ + FAD + GDP + Pi + H2O ® CoASH + 2CO2 + 3NADH + FADH2 + GTP +2H+

Where NAD +/ NADH = Nicotinamide Adenine Dinucleotide ; FAD/FADH2 = Flavin Adenine Dinucleotide ; GDP = Guanosine 5-Diphosphate, and GTP = Guanosine 5-Triphosphate.

The tricarboxylic acid cycle is connected to a number of side paths, including the GABA shunt, and the synthesis of acetylcholine - one neurotransmitter involved in memory formation and attention. The TCA cycle and all its associated side paths behave as one interconnected series of reactions into which the pyruvate enters. As a result both pyruvate and acetyl Co A can become trapped for undetermined periods of time as one of the intermediaries or products of one of these side paths, rather than being processed directly into the end products outlined above.

The most important purpose of the TCA cycle however is the production of NADH and FADH2, which then feed electrons into the electron transfer chain to produce energy in the form of ATP. Oxidative Phosphorylation

The phosphorylation of ADP to ATP is the key to this sysytem, and can be defined by the equation :

ADP3- + Pi2- + H+ ® ATP4- + H2O

Where ADP = adenosine di phosphate; Pi = inorganic phosphate, and H+ = proton.

Under normal physiological conditions about 95% of ATP is produced by this mitochondrial oxidative phosphorylation, while 0-5% is derived from lactate production (Kintner et al. 1984 ; Hawkins et al. 1974).

The electron transfer chain in oxidative phosphorylation is in reality a series of enzymes which are, by virtue of their molecular constitution, able to accept electrons. The complete system is quite complex (Figure 1.4), but the electron transfer chain has two main functions :

1) To pump H+ ions across the inner mitochondrial membrane. This leads to a H+ gradient which acts as the driving force for the conversion (phosphorylation) of ADP to ATP.

2) The completion of the oxidation of glucose through the transfer of electrons to molecular oxygen, the most powerful electron acceptor.

The final reaction of the electron transfer chain is the movement of an electron to cytochrome aa3 and then to oxygen to form O2 which is then able to react with 2H+ (from within the mitochondrial space to form H2O. Under resting conditions the rate of this chain of reactions is limited by the availability of reduced cytochrome aa3 (which is usually only partly oxidised (Kreisman et al. 1981 ; Piantadosi et al. 1986)), as oxygen diffuses readily accross the mitochondrial membrane (Roland 1993). However under times of cognitive demand it has been suggested that oxygen may be rate limiting, and indeed metabolism may be transiently forced into the anaerobic route leading to increased levels of lactate production followed by a recoupling phase during which lactate would be oxidised by the neurons (Magestretti and Pellerin 1997). Magnetic resonance spectroscopy studies in humans have revealed that during physiological activation of the visual system, a transient lactate peak is observed in the primary visual cortex (Prichard et al. 1991; Sappey-Marinier et al. 1992).

Figure 1.4 : The key reactions in the Tricarboxylic Acid (TCA) or Krebs Cycle (Http://www.wiley). Oxygen

To maintain the oxidative metabolism of glucose then, the brain needs a constant supply of oxygen. Certain metabolic intermediates e.g. lactate and pyruvate can substitute for glucose as alternative substrates for metabolism (Sokoloff 1989); however there is no such alternative for oxygen, and as the brain does not store oxygen, even a transient disruption of supply can have deleterious consequences. Glucose utilisation by the brain proceeds at a rate of 31m mol/100gm/min, and oxygen consumption at 160m mol/100gm/min (Sokoloff 1960). With a global brain blood flow of 57ml/100gm/min, the brain extracts approximately 50% of available oxygen and 10% of glucose from arterial blood under resting conditions. It should be noted that a limited proportion of the oxygen supply is consumed for other neural processes than the production of energy, including interactions with oxydases and hydroxylases, which are key regulatory enzymes in the metabolic pathways of a number of neuroactive pathways, and the recently discovered nitric oxide (NO) synthase pathway also consumes oxygen.

Currently it is not known exactly how much oxygen is consumed during neural activation. Fox et al. 1988 employed positron emission tomography (PET) and identified that the brain resorts to glycolysis, at least initially, to meet the increased energy demands during heightened activation. Other data from PET and MRS studies (Marrett et al. 1995; Hyder et al. 1996) support the notion of a significant increase in oxygen consumption during functional activation. The debate is still ongoing but Magistretti and Pellerin (1997) propose a model that is consistent with an initial glycolytic processing of glucose occurring in astrocytes during activation, resulting in a transient lactate overproduction, followed by a recoupling phase with increased oxygen consumption. Recent observations made in vivo in the rat hippocampus suggest this is the case. It is hypothesised here that, at such times a supplemental oxygen supply (achieved through the inhalation of 100% oxygen) may augment energy production and consequently enhance neural performance at times of cognitive demand.

1.3. Where is the Energy Consumed?

In vivo and in vitro experiments have led researchers to the conclusion that most of the ATP consumption in the resting brain is linked to the sodium/potassium (Na+/K+) pump. Astrup et al. (1981) administered barbiturates (which elevate the action of GABA on chloride channels leading to neural membrane hyperpolarisation) to a dog until no electrical activity could be recorded from the brain, and found that this reduced the oxygen and glucose consumption by 30% compared to the resting awake state. Furthermore, the additional administration of lidocaine (which blocks sodium channels) and ouabain (which blocks the sodium/potassium pump) reduced metabolic rate by an additional 35%.

Ion pumps are responsible for the establishment and maintenance of ionic gradients across neural cell membranes that allow for the passage of action potentials. The most important is the sodium pump or Na+/K+ ATP-ase which transports two K+ ions into the cell and three Na+ ions out of the cell for each ATP molecule consumed. This results in the inside of the neurons and glia being more negatively charged than the extracellular space.

The exact proportion of energy consumed by the sodium pump during brain activation is not known, but it is estimated that the ATP consumption during excitatory post synaptic potentials (EPSPs) and inhibitory post synaptic potentials (IPSPs) is greater than that during the passage of action potentials. Mata et al. (1981) employed an in vitro technique in order to estimate how much of the increase in energy production was due to ATP consumption by the sodium pump during heightened activity. Her results indicated that the metabolic increase during activation is effectively all due to the increased activity of the sodium pump. However it can be argued that the in vitro technique used did not account for ATP usage by second messenger cascades, activity of the calcium pump, and the synthesis of neurotransmitters.

1.4. How is Energy Production Linked to Neuronal Activity?

As it appears that sodium pump activity may be the key factor in energy consumption during neuronal activity, it would be of great functional value for the production of ATP to be regulated in order to ensure the continuous efficacy of the pump, and such a situation would appear to exist. Neuronal activity starts with depolarisation which leads to the opening of the sodium and other voltage-gated channels. This results in increased work for the sodium pump to re-establish the ionic gradient. The re-uptake of neurotransmitters will increase its activity further. These events result in increased hydrolysis of ATP by the pump, leading to a decrease in the ratio of [ ATP] / [ ADP] [ Pi] which acts as the stimulus for oxidative phosphorylation (Ericinska and Wilson 1982), and as a consequence an increase in ATP production. A combination of the effect of the activation of rate limiting enzymes in glycolysis and the TCA cycle leads to an upgrade in TCA cycle activity and consequently an increase in NADH production which in turn stimulates the electron transfer chain. Through this mechanism ATP production is maintained at a high level during a high rate of sodium pump activity. Once the level of sodium pump activity reduces, the level of available ATP rises and the above regulatory controls reduce oxidative phosphorylation, and the TCA cycle and glycolytic rate are slowed.

A number of in vitro and in vivo studies provide evidence in support of the link between neuronal activity and metabolic rate. Hill (1926) demonstrated that an isolated nerve cell increased its oxygen consumption when it was electrically stimulated. Larrabee (1958) found that neuronal glucose consumption and oxidative metabolism increased during stimulation and that the increase in metabolic rate was dependent upon the frequency of stimulation. Sokolof et al. (1977) first used the autoradiographic method for the measurement of glucose metabolism in vivo and subsequently a great many papers have shown a close relationship between increased glucose metabolism and increased neural activity.

1.5. What Evidence Suggests that Brain Activation Increases the Regional Metabolic Rate?

Metabolic rate is not uniform across the brain, or even within single neurons. Research has demonstrated that changes in the metabolic rate associated with neuronal activity are localised to regions that have a large concentration of synapses, at axon terminals and dendrites, and to the axonal processes but not the cell bodies (Hand et al. 1978; Juliano et al. 1981; 1983a; Kadekero et al. 1985; Schwartz et al. 1979). Prolonged increases in neuronal activity can also increase the number of mitochondria in active neurons (Ericenska and Wilson 1982). It is a logical conclusion therefore that the density of mitochondria, and so the capacity for metabolism, reflects the long term activity level of the cell. In vitro studies, particularly those using the cytochrome oxidase staining technique, and in vivo studies on laboratory animals have all indicated a large variation in the regional and laminar metabolic rates in the resting brain, and differences in the capacity for an increment in metabolic rate during activation (Wong-Riley 1989; Livingstone and Hubel 1984; Braun et al. 1985; Durham and Woolsey 1984).


1.6. Regulation of Metabolism by Regional Cerebral Blood Flow

The heart pumps blood to the main cerebral arteries which subdivide into smaller arterioles and capillaries. The pressure waves created by the heart’s pumping, i.e. phasic cardiac output are changed into a steady state arterial blood pressure by elasticity of the blood vessels. The brain receives 15% of the resting cardiac output (700ml/min in the adult) and accounts for 20% of basal oxygen consumption. Mean resting cerebral blood flow in young adults is about 50ml/100g brain per minute. This mean value represents two very different categories of flow: 70 and 20ml/100g per min for grey and white matter respectively (Menon 1995). Blood supply to the brain is provided by two internal carotid arteries and the basilar artery, which divides into the two posterior cerebral arteries. Importantly, the brain’s blood pressure is independent of the rest of the body. The cerebral circulation is protected from systemic blood pressure surges by a specially designed branching system and resistance elements in the two types of blood vessels. The arteries and arterioles are innervated with nerve fibres which regulate their degree of contraction and hence blood pressure. For neurons and glia, the blood pressure and flow is not relevant. The important factor is whether the cells can get more glucose and oxygen at times of high demand; a factor referred to as regional cerebral blood flow (rCBF).

There are two ways in which rCBF can be increased: either by allowing more blood to pass through at the same velocity or by allowing the same volume of blood to pass through at a higher velocity. The former is the most important (Roland 1993). Dunning and Wolff (1937) found that the number of capillaries in any localised region of the brain significantly correlated with the number of synapses in the region but not with the number of cell bodies. Additionally, the density of capillaries in the brain is closely related to the density of the mitochondrial enzyme cytochrome oxidase, with more capillaries in areas rich in cytochrome oxidase (Borowsky et al. 1989; Zheng et al. 1991). The concentration of tissue oxygen varies locally in such a way that it indicates that capillaries must open and close frequently (Jobsis et al. 1975; Lubbers 1975). This opening and closing occurs in order to distribute glucose and oxygen evenly to local tissue. At times of high demand the capillaries must respond in such a way as to match supply with demand. Tyson et al. (1987) and Kushinsky et al. (1987) found that the density of open capillaries was a linear function of rCBF, and that rCBF was thus also a linear function of capillary volume. The rCBF and capillary density are also linear functions of regional glucose metabolism (Gross et al. 1987). Effectively rCBF, capillary volume and regional metabolic rate interact in such a way that more capillaries are recruited when there is a high metabolic rate, and so the rCBF increases to supply the increased demand for glucose and oxygen. There are several theories relating to the mechanism responsible for the opening of capillaries in response to increased metabolic demand. Nitric oxide (NO) relaxes blood vessels and is produced by endothelial cells in response to a range of substances including acetylcholine, adenosine mono-phosphate (AMP), ADP and ATP (Bredt et al. 1990). It is an ideal candidate for regulating rCBF, having a half life of seven seconds and an effect that disappears as soon as production ceases. However, little is known about the distribution of NO in the brain and it remains to be seen if rCBF matches NO concentration. A second group of potential mediators of rCBF are the purines: adenosine, AMP, ADP and ATP, all potent vasodilators (Forrester et al. 1979). It is suggested that these substances (in particular adenosine) are released into the extracellular space during times of increased activity. Increased sodium pump activity consumes ATP and results in increased levels of AMP and ADP. These are in turn converted to release adenosine which in turn causes an increase in rCBF. It has yet to be demonstrated however that rCBF is linearly related to concentrations of adenosine near to endothelial cells. A parsimonious hypothesis is that carbon dioxide production is involved in linking metabolic rate and rCBF. Certainly carbon dioxide is a potent vasodilator as well as the end product of metabolism. rCBF changes linearly with the arterial and precapillary partial pressure of carbon dioxide (pCO2), (although this relationship may be non-linear when there are large deviations from the normal partial pressure of carbon dioxide (Olesen 1974)). However the fact that rCBF is more highly correlated with arterial pCO2 than with tissue pCO2 does not support the conclusion that metabolically produced carbon dioxide is the key to regulation (Severinghaus and Lassen 1967).

At present there is no single substance that can be held responsible for regulating variations in rCBF at the tissue level. It is clear however a close relationship exists between changes in rCBF and changes in regional metabolism, and that these changes can be coupled to neuronal activity. rCBF and regional cerebral glucose consumption (rCMRgl) are perfectly correlated in all cerebral structures in awake rats (Reivich et al. 1975). Indeed this coupling is so strong that it can be observed at the the microscopic level (Ginsberg et al. 1987a).

It is possible that several factors interact to mediate the relationship between neuronal activity, neuronal metabolism, and tissue blood flow. It appears that no single compound can be said to regulate rCBF under all conditions.


1.7. Brain Oxygen Consumption and Cognitive Functioning


1.7.1. Brain Imaging Studies

Signals detected using functional brain imaging techniques are based on the coupling between neuronal activity and energy metabolism. Positron emission tomography (PET) detects blood flow, oxygen consumption and glucose utilisation associated with localised neuronal activity. Functional magnetic resonance imaging (fMRI) is thought to detect the blood oxygen level as at least part of its signal, whereas magnetic resonance spectroscopy (MRS) identifies the spatiotemporal pattern of glucose or lactate levels. Although these offer a higher degree of sophistication than earlier imaging techniques, the exact mechanisms and cell types involved in coupling and generating metabolic signals are still debated. Magistretti and Pellerin (1997) suggest that a current assumption is that neuronal signals (e.g. adenosine, pH, and NO) produced by synaptic activity act directly on brain capillaries to increase the local delivery of energy substrates.

Recent research has suggested that there may be a degree of uncoupling of supply and demand in the early stages of neuronal activation. MRS in humans has revealed that during physiological stimulation of the activation of the visual system, a transient lactate peak is observed in the primary visual cortex (Prichard et al. 1991; Sappey-Marinier et al. 1992). These MRS data would support the proposition that there is transient anaerobic glycolytic processing of glucose during neuronal activation. PET analyses by Raichle and Fox (1988) have indicated that oxygen consumption in activated brain areas does not increase in tandem with blood flow and glucose utilisation, suggesting an activity-dependent glycolytic processing of glucose in the early period of brain activation. However this issue is has been the subject of intense debate due to other researchers finding that the degree of uncoupling between glucose metabolism and oxygen consumption during activation may actually vary, and may even not occur, depending on the type of stimulation used (Marrett et al. 1995). To add to the debate, Hyder et al. (1996) used 13C-glucose MRS and found evidence for an increase in oxygen utilisation during activation.

At present, the critical question of how much oxygen is consumed during brain activation remains unresolved. However a model proposed by Pellerin and Magistretti (1994), based on studies at the cellular level (figure 1.5.) would be consistent with an initial burst of glycolytic metabolism of glucose occurring in astrocytes, resulting in a transient lactate overproduction, followed immediately by a recoupling phase during which the lactate would be oxidised by neurons.

Figure 1.5. : Schematic of the mechanism for glutamate-induced glycolysis in astrocytes durind physiological activation. From Pellerin and Magistretti (1994).


The spatiotemporal ‘window’ during which the lactate peak could be detected by MRS would depend on the speed of the recoupling process, and the sensitivity and resolution of the measuring technique employed. Such a model would support the hypothesis that during the processing of information in cognitive tasks, supplemental oxygen supply may compensate for a transient shortfall and augment energy production at a time of high demand, thereby leading to more efficient processing and hence improved performance.


1.8. Compromised Oxygen Delivery and Cognitive Dysfunction


1.8.1. Ischemia

Ischemia may be defined as an inadequate supply of oxygen supply in relation to demand, and in general terms is caused by an interruption in blood supply. Cerebral ischemia associated with systemic hypotension classically produces maximal lesions in areas where the zones of blood supply from two vessels meet, resulting in ‘watershed’ infarctions. However anatomical variations lead to a wide range of possible consequences (Menon 1995) In addition to the interruption in oxygen supply ischemia also depletes the citric acid cycle of its intermediates, especially succinate (Taegtmeyer 1978), and it is proposed that there will be a subsequent increase in demand for glucose and/or lactate in order to anaerobically replenish the energy lost from the disruption of the citric acid cycle (Schwaiger et al. 1985, 1989; Czernin et al. 1993). The cognitive consequences of ischemic insult are gross, but reversible if the break in blood supply does not exceed a few seconds (Delatorre et al. 1993). Global anterograde amnesia following hypoxic ischemia has been thoroughly documented. Mnemonic deficits in humans have been described by Volpe and Hirst (1983) and Graf et al. (1985), and are believed to result from hypoxic damage to the medial temporal lobe and its thalamic projections as measured by regional cerebral blood flow in human amnesics (Kuwert et al. 1993). Experimental hypoxic ischemia in animals has been shown to lead to focal hippocampal damage (Zola-Morgan et al. 1992; Wood et al. 1993), and even brief and transient oxygen deprivation have been associated with reversible functional cognitive deficits (Yamatoto et al. 1993).


1.8.2. Altitude and Hypoxia

Disturbances of psychological functioning after exposure to altitude have been recognised for many years (Dunlap 1918; Heber 1921; Paton 1918; Wilmer and Berens 1918). However there have been few quantitative investigations of the effect of hypoxia on physical proficiency, cognitive functioning and subjective symptomatology. McFarland (1937b) performed an early behavioural study of the effects of exposure to high altitude, and found decrements in performance on a number of cognitive measures. Fowler et al. (1985) attributed impaired performance to a combination of hypoxia, exercise and hypoventilation because of breathing resistance. Fowler and Porlier (1987) showed that response time on a serial choice reaction time task was increased in a dose dependent manner which reached significance at an arterial oxyhaemoglobin saturation (SaO2) of 82% (equivalent to 10000 ft. altitude). This study provided a threshold estimate for cognitive performance decrements and implicated disruption of vision as a key factor in these decrements. However other factors such as smoking, alcohol, medication and exercise may interact with reduced oxygen supply to influence this threshold value (Collins et al. 1987; Collins and Mertens 1988; Fowles and Loeb 1992).

In an investigation comparing fatigue and reduced oxygen availability on colour naming, Bills (1937) found support for the theory that the physiological basis of mental fatigue is, in part at least, accounted for by a reduction in the available oxygen supply to the brain. Russell (1948) studied the effects of mild hypoxia (18000 ft.) on 3 tasks (finger dexterity, arm-hand co-ordination and simple addition). He found that impairments of performance appeared immediately after the introduction of mild hypoxia, that rapid adjustment occurred as the duration of hypoxia increased and that continued practice under hypoxic conditions led to further improvement. Evans and Witt (1966) reported a cognitive performance decrement at 14000 ft. on Weschler’s Digit Symbol Substitution Test, and Gill et al. (1964) found decreased card sorting ability at 19000 ft.

Vigilance performance on a 2 hour brightness discrimination task was tested by Cahoon (1970) under four levels of hypoxia : 21% oxygen (control), 12.8% oxygen (13000 ft.), 11.8% oxygen (15000 ft.) and 10.9% oxygen (17000 ft.). The results indicated that a significant reduction in signal detection efficiency could be seen as a function of severity of hypoxia and task duration. Kramer et al. (1993) studied the effects of altitude on a group of experienced climbers. A series of perceptual, cognitive and sensory-motor tasks were performed before, during and on completion of a 20000 ft. climb. Relative to a matched group of controls who performed the tasks at sea level, the climbers showed deficits of learning and retention in perceptual and memory tasks, as well as taking a longer time to complete the tasks.

The possibility of reversing altitude induced impairments through the administration of supplemental oxygen was investigated by Crowley and colleagues (1992). They demonstrated that transient (less than 1 day) impairments of aspects of memory, grammatical reasoning and the Stroop test occurred at an altitude of 15000 ft. More importantly for this thesis they report that oxygen administration significantly enhanced previously impaired performance on code substitution, serial addition/subtraction, and elevated the activity index on a mood scale on the first day at altitude (but not on subsequent days).

In summary it is generally accepted that altitudes above 10000 ft., lead to profound effects on human cognitive performance, and that these effects result from hypoxia induced by the low levels of available oxygen. Limited evidence also suggests that such decrements in performance may be reversed through oxygen administration.


1.8.3. The Elderly

It is well known that cognitive decline goes hand in hand with advancing age (albeit not inevitably). Kuhl et al. (1984) and Reige et al. (1985) reported that human ageing is also associated with decreased glucose metabolism, and it is possible that the two are inextricably linked. As has been stated above, glucose metabolism is reliant on a sufficient and continuous supply of oxygen, and any compromise in this delivery system may be responsible, at least in part, for any resultant cognitive decline.

The major factor that is influential in compromising the delivery of oxygen to the brain in the elderly is that of regional cerebral blood flow (rCBF). rCBF has been studied extensively in a variety of pathological and physiological conditions and reductions in rCBF and cerebral oxygen consumption (CMRO2) have been shown to be generally proportional to the clinical neurologic and psychiatric symptomatology (Lassen and Ingvar 1980).

It has been a commonly held belief that the cognitive consequences of normal ageing, as well as many types of abnormal ageing are caused by an insufficient blood supply to the brain. Several studies have shown a decline in rCBF in the healthy elderly (Scheinberg et al. 1953; Fazekas et al. 1955; Kety 1956; Dekorninck et al. 1977). Indeed, Kety (1956) proposed that progressive CBF reduction occurs throughout adolescence, adulthood and senescence. The main cause of the reduction in flow is generally assumed to be arteriosclerosis of the brain’s blood vessels. According to this view, the reduced function of the central nervous system, including symptoms of failing intellectual functions observed in elderly people, is due to ischemia, which leads to a successive reduction of brain metabolism and a reduction in the number of neurons. This also implies that ageing of the brain might be counteracted if oxygen delivery through increased blood flow or other means is augmented by cerebral vasodilation or by hyperbaric oxygen, respectively.

By contrast to this view others have not found significant differences in CBF between healthy young and old participants (Lassen et al. 1960; Dastur et al. 1963). Reasons for these discrepancies have been given as the invasive and traumatic nature of the techniques traditionally used to determine rCBF in man, and the lack of data from age-matched controls. The development of non-invasive, atraumatic techniques permitted new approaches to this problem.

Melamed et al. (1980) employed the 133Xenon inhalation technique to study normal participants aged 19 to 79 years and found that normal ageing is associated with rCBF reduction. These decreases were observed in mean brain, and both mean left and mean right hemispheric blood flows as well as in regional flow values. This supports what has been termed the ischemic theory of ageing.

Conversely Lassen and Ingvar (1980) argue that the reductions found in CBF and CMRO2 (Dastur et al. 1963; Lassen et al. 1960) using the 85Krypton technique are minimal and can not be held responsible for the decreases recorded in cognitive performance. Indeed they argue that humans living at altitude have a cerebral venous oxygen tension of less than that found in the normal elderly (32 mm Hg versus 35.9 mm Hg) without showing signs of cerebral dysfunction. They add that voluntary hyperventilation in normal participants may substantially decrease the cerebral venous oxygen tension without producing cerebral symptoms.

Lenzi and Jones (1980) claim that the most unresolved question in ageing research is still the relationship between eventual functional changes of brain metabolic activity and cognitive decline, and that the few data that are available are mainly concerned with the overall metabolic activity. Eventual regional impairments of the brain’s metabolism is, they claim, as yet unknown. More recently, Reige et al. (1985) reported that the elderly can be distinguished from the young on two factors. Firstly the reduction in long term memory for verbal material, which was closely associated with glucose metabolism in Broca’s area, and secondly the performance on organisation and planning tasks that was associated with the metabolic rate in the thalamic area. However, not all research has supported such findings (Haxby et al. 1986; Duara et al. 1984).

It is important to note that all clinical and many laboratory methods of measuring CBF or rCBF are indirect and may not produce directly comparable measurements. It is also essential to treat results from any one method with caution, and attribute any observed phenomena to physiological effects only when demonstrated by two or more independent techniques (Menon 1995).

The data then lead to only tentative conclusions, but whether oxygen delivery via regional cerebral blood flow is compromised or not in the elderly, the hypothesis of this thesis would suggest that an upgrade in available metabolites, in this case oxygen, may still be capable of leading to enhanced cognitive performance through a global or regional increase in metabolic rate, providing more energy for neural processing.

1.9. Supplemental Oxygen Administration and Cognitive Functioning

Despite the fact that hyperbaric oxygen therapy has been (at times controversially) linked to the successful treatment of a range of physical conditions from sport induced muscle damage to multiple sclerosis (Fischer et al. 1983; Barnes et al. 1987), there has been very little research in terms of oxygen administration and cognitive function.

Raskin et al. (1978) studied the effects of increased blood oxygen levels on cognitive impairment in elderly patients. Patients with significant cognitive impairment were treated with either normobaric (atmospheric pressure) or hyperbaric (greater than atmospheric pressure) oxygen for two 90 minute sessions per day for 15 consecutive days. They were then evaluated on measures of memory and intellectual capacity, as well as on psychiatric symptom rating scales. The authors concluded that the results immediately after treatment and at one, two, three, and eight weeks following the treatment did not provide evidence of enhanced cognitive functioning, or significantly greater symptom reduction compared to controls.

In a study of healthy elderly outpatients suffering from memory lapses, Edwards et al. (1974) treated the participants with 100% oxygen at two atmospheres pressure for 15 daily sessions of two hours each. Subsequent comparison of the pre- and post-treatment results revealed substantial improvement, particularly in tests concerned with short term memory and visual organisation. The authors also stated that there was no reason to conclude that improvement had reached a plateau after 15 sessions, though the authors do not posit a process through which oxygen produces such marked effects.

The author knows of no published research regarding oxygen administration and cognitive function in the healthy young prior to the commencement of this thesis, however following the publication of our first papers, work has been reported from one other laboratory. Winder and Borrill (1998) performed a study comparing the possible enhancing effects of both oxygen and glucose on a number of everyday memory tasks. They report a significant effect for oxygen administration but not for glucose on delayed recall. These results provide support for our previous findings, and those described here.


1.10. The Pharmacology of Nootropics or "Smart Drugs"

The elucidation and understanding of the mechanisms that underlie memory is one of the major goals of modern brain research. To this end, and in order to discover ways of enhancing memory and treat clinical dysfunctions researchers have studied countless neuroactive compounds for signs of potential pharmocological effects or therapeutic properties. The available findings on the mode of action of such compounds can be grouped into four main categories : (1) effects on energy metabolism; (2) effects on cholinergic mechanisms; (3) effects on excitatory amino-acid-receptor-mediated functions; and (4) steroid sensitivity. The absence of effects in traditional (transmitter-sensitive) psychopharmacological tests caused the search for the underlying mechanism to be shifted primarily in the direction of energy metabolism, (Mondadori 1993), and it is this area that shall be considered here.

Cerebral metabolism can be impaired for many reasons including hypoxia, (Giurgea et al. 1971; Grau et al. 1987; Groo et al. 1989). Additionally, hypoxia has been suggested to induce changes in the turnover and/or release of a range of neurotransmitters including acetylcholine, (Groo et al. 1989). Together these effects are seen as being responsible for the behavioural effects, e.g. reduced cognitive performance, observed under hypoxic conditions. As a result, a great deal of research has been performed in order to find drugs that will reverse these effects under hypoxic conditions and enhance such mechanisms under normoxic conditions (Zupan et al. 1994).

Piracetam and oxiracetam have been found to enhance cerebral metabolism, (Schindler et al. 1984) by accelerating ATP turnover and affecting glucose metabolism in the cerebral cortex. In addition they have been found to selectively reverse the impairments produced by the anticholinergic scopolamine (Cumin et al. 1982; Pepeu et al. 1989; Piercey et al. 1987; Spignoli et al. 1986) and hypoxia (Chleide et al. 1991; Giurgea et al. 1971; Giurgea and Salama 1977; Piercey et al. 1987; Sara and Lefevre 1972).

Post-mortem studies of brains of demented and healthy aged populations indicate that a number of mitochondrial abnormalities may be present. As mitochondria are the site of metabolism these abnormalities have been linked to inefficient metabolism and cognitive decline, (Mizuno et al. 1995; Hoch 1992; Okayasu 1985). Treatment with the nootropic Acetyl-L-carnitine, (ALC) in animal models has demonstrated that some of the abnormalities can be restored to "youthful" levels (Paradies et al. 1992; 1994; Okayasu 1985). In particular, ALC has been shown to restore overall respiratory activity (oxygen energy conversion) of aged rat mitochondria to normal levels, (Paradies et al. 1994).

The effectiveness of nootropics for treating the effects of craniocerebral trauma, where oxidative phosphorylation in the brain mitochondria is compromised, has also been assessed. The results indicate that several compounds, including piracetam, picamilon and nooglutyl exert a protective effect on the mitochondria, and in particular the effectiveness of oxidative phosphorylation (Novikov and Kovaleva 1998).

In terms of impacting on the metabolic system in the brain the above evidence indicates that nootropics or "smart drugs" are effective at times of compromised function. In terms of their effects on the cognitive performance under normal conditions, numerous studies have reported direct positive effects of nootropics on learning and memory. Aniracetam and piracetam, (Wolthuis 1971; Yamada et al. 1985) etiracetam, (Sara 1980) and oxiracetam, (Mondadori et al. 1986; 1992) were found to exert direct effects on the acquisition and retention performance of rats and mice in both passive and active avoidance tasks. Positive effects have also been found for radial maze, place navigation, object recognition and matching to sample tasks (Mondadori 1993).

With regard to human participants, Reidel et al. (1998) describe the effects of four weeks of treatment with piracetam on the driving performance of a group of healthy elderly as "disappointing" although there was a trend towards improvement. By comparison, DeVreese et al. (1996) assessed the influence of pramiracetam and memory training, each alone and in combination on the performance of a group of healthy aged participants. Their results indicated significantly better memory performance for the drug, and drug combined with training groups compared to training alone and a control group.

The evidence cited here is only a small sample of the vast quantity of research into putative cognitive enhancers. It is important to the basis of this thesis however that many of the compounds under investigation, and certainly many of those that have demonstrated positive effects, influence the cerebral metabolism, whether through increased blood flow, glucose metabolism or other indirect routes, and that these metabolic effects are believed to be responsible for the cognitive improvements that have been demonstrated. Indeed, many of the putative cognitive enhancers currently available claim modes of influence that would fall in line with the main hypothesis of this thesis (see Table 1.1.).

It is proposed here that the provision of supplemental fuels, specifically here oxygen, can allow for greater metabolism to occur under conditions of cognitive demand in healthy individuals, and therefore improve performance.





Improved cerebral microcirculation.

Increased ATP production.


Increased cerebral metabolism.

Increased cerebral oxygen delivery.


Improved cerebral microcirculation.

Increased ATP synthesis.

Increased utilisation of oxygen and glucose.


Increased glucose metabolism.

Increased ATP production.


Promotion of vasodilation and increased blood flow.


Increased glucose metabolism.


Increased cerebral blood flow.

Table 1.1 : Proposed mode of influence of a range of putative cognition enhancing compounds.


1.11. A Metabolic Resource Model of Cognitive Enhancement

It is hypothesised here that as cognitive demand increases so do the requirements for metabolic resources, (glucose and oxygen) in order to fuel cognitive processes. These requirements are then reflected in physiological responses such as increased heartrate (Carroll et al. 1986a) and increased regional cerebral blood flow (Roland 1993) in order to supply the additional metabolic reactants. It is therefore further suggested that increasing the supply of these reactants above normal levels will allow for increased metabolism, with the resultant increment in available energy being utilised for cognitive performance. This would therefore raise the ceiling for cognitive performance levels, effectively producing an enhancement effect. A schematic representation of this model is presented in figure 1.6. As can be seen, up to a point baseline levels of metabolism perform cognitive operations without significant physiological adjustments. Increasing mental effort is then associated with declining cognitive resources and physiological responses are required to enable the processing to be fuelled effectively. An additional supply of resources, (glucose or oxygen) may then enable even more efficient processing above and beyond normal limits. This would then be manifest as enhanced performance.

Figure 1.6. : Proposed metabolic resource model of cognitive enhancement.

1.12. Aims and Objectives

The purpose of the studies reported in this thesis is to examine the relationship between elevated levels of blood oxygen saturation and cognitive performance in the healthy young and elderly, with particular attention being paid to the possibilities of cognitive enhancement and it’s underlying mechanisms. The four main aims of the present thesis are :

    1. To open a new avenue of psychobiological research, given the lack of associated investigation in the literature.
    2. To investigate the possible neural and physiological substrates of any observed enhancements.
    3. To establish the relationship between blood oxygen availability, cognitive performance and physiological responses in the healthy young and elderly.
    4. To empirically investigate a metabolic resource model of cognitive functioning and enhancement.