Category Archives: Physiology

Homeostasis And The Constancy Principle – We Are All Creatures Of Comfort Even When We Go Out Of Our Comfort Zone

It is autumn in our part of the world, and the first chills are in the air in the late evening and early morning, and the family discussed last night the need to get out our warm clothes from storage in readiness for the approaching winter, in order to be well prepared for its arrival. After sharing in the fun of Easter Sunday yesterday and eating some chocolate eggs with the children, a persistent voice in my head this morning instructed me to eat less than normal today to ‘make up’ for this out of the normal chocolate eating yesterday. It is a beautiful sunny day outside as I write this, and I feel a strong ‘urge’ to stop writing and go out on a long cycle ride because of it, and have to ‘will’ these thoughts away and continue writing, which is my routine activity at this time of morning. After a recent health scare I have been checking on my own physical parameters with more care than normal, and found it interesting when checking what ‘normal’ values for healthy folk are, that most healthy folk have fairly similar values for things like blood glucose, blood pressure, cholesterol concentrations and other such parameters, and that there are fairly tight ranges of values of each of these which are considered normal and a sign of ‘health’, and if one’s values are outside of these, it is a sign of something wrong in the working of your body that needs to be treated and brought back into the normal range either by lifestyle changes, medication, or surgical procedures. All of these got me thinking about the regulatory processes that ensure that the body maintains its working ‘parts’ in a similar range in all folk, and the concept of homeostasis, which as a regulatory principle explains and underpins the maintenance of this ‘safe zone’ for our body’s multiple activities, including the sensing of any external or internal changes which could be associated with the potential for one of the variables to go out of the ‘safe zone’, and initiates changes either behaviourally or physiologically which attempt to bring the variable at risk back into the ‘safe zone’ either pre-emptively or reactively.

Homeostasis is defined scientifically as the tendency towards a relatively stable equilibrium between inter-dependent elements. The word was generated from the Greek concepts of ‘homiois’ (similar) and ‘stasis’ (standing still), creating the concept of ‘staying the same’. Put simply, homeostasis is the property of a system whereby it attempts to maintain itself in a stable, constant condition, and resists any changes or actions on the system which may change or destabilize the stable state. It’s origins as a concept were from the ancient Greeks, with Empedocles in around 400 BC suggesting that all matter consisted of elements which were in ‘dynamic opposition’ or ‘alliance’ with each other, and that balance or ‘harmony’ of all these elements was necessary for the survival of the individual or organism. Around the same time, Hippocrates suggested that health was a result of the ‘harmonious’ balance of the body’s elements, and illness due to ‘disharmony’ of the elements which it was made up of. Modern development of this concept was initiated by Claude Bernard in the 1870’s, who suggested that the stability of the body’s internal environment was ‘necessary for a free and independent life’ and that ‘external variations are at every instant compensated for and brought into balance’, and Walter Cannon in the 1920’s first formally called this concept of ‘staying the same’ homeostasis. Claude Bernard actually initially used the word ‘constancy’ rather than homeostasis to describe the concept, and interestingly, a lot of Sigmund Freud’s basic work on human psychology was based on the need for ‘constancy’ (though he did not cross-reference this more physiological / physical work and concepts), and that everyone’s basic needs were for psychological constancy or ‘peace’, and when one had an ‘itch to scratch’ one would do anything possible to remove the ‘itch’ (whether it be a new partner, a better house, an improved social status, or greater social dominance, amongst other potentially unrequited desires), and further that one’s ‘muscles are the conduit through which the ego imposes its will upon the world’. He and other psychologists of his era suggested that if an ‘itch’, urge or desire was not assuaged (and what causes these urges, whether a feeling of inadequacy, or previous trauma, or a desire for ‘wholeness’, is still controversial and still not clearly elicited even today), the individual would remain out of their required ‘zone of constancy’, and would feel negative emotions such as anxiety, irritation or anger until the urge or desire was relieved. If it was not relieved for a prolonged period this unrequited ‘itch’ could lead to the development of a complex, projection or psychological breakdown (such as depression, mania, anxiety, personality disorder or frank psychosis). Therefore, as much as there are physical homeostasis related requirements, there are potentially also similarly psychological homeostasis related requirements which are being reacted to by the brain and body on a continuous basis.

Any system operating using homeostatic principles (and all our body systems do so) has setpoint levels for whatever substance or process is being regulated in the system, and boundary conditions for the substance or process which are rigidly maintained and cannot be exceeded without a response occurring which would attempt to bring the activity or changes to the substance or process back to the predetermined setpoint levels or within the boundary conditions for them. The reasons for having these set boundary conditions are protective, in that if they were exceeded, the expectation would be the system would be damaged if the substance or process being regulated (for example, oxygen, glucose, sodium, temperature, cholesterol, or blood pressure, amongst a whole host of others) was used up too quickly or worked too hard, or was allowed to build up to toxic / extremely high levels or not used enough to produce life-supporting substrates or useable fuels, which would endanger the life and potential for continued activity of the system being monitored. For example, oxygen shortage results in death fairly quickly, as would glucose shortage, while glucose excess (known as diabetes) can also result in cellular and organ damage, and ultimately death if it is not controlled properly. In order for any system to maintain the substance or process within homeostasis-related acceptable limits, three regulatory factors (which are all components of what is known as a negative feedback loop) are required to be components of the system. The first is the presence of a sensory apparatus that can detect either changes in whatever substance or process is being monitored, or changes in the internal or external environment or other systems which interact with or impact on the substance or process being monitored. The second is a control structure or process which would be sent the information from the sensory apparatus, and would be able to make a decision regarding whether to respond to the information or to ignore it as not relevant. The third is an ‘effector’ mechanism or process which would receive commands from the control structure after it had made a decision to initiate a response in response to the sensed perturbation potentially affecting the system it controls, and make the changes to the system decided upon by the control structure in order to maintain or return the perturbed system to its setpoint value range.

The example of temperature regulation demonstrates both the complexity and beauty of homeostasis in regulating activity and protecting us on a continuous basis from harm. Physiological systems in most species of animals are particularly sensitive to changes in temperature and operate best in a relatively narrow ranges of temperature, although in some species a wider range of temperatures is tolerated. There are two broad mechanisms used by different organisms to control their internal temperature, namely ectothermic and endothermic regulation. Ectothermic temperature regulators (also known as ‘cold-blooded’ species), such as the frog, snake, and lizard, do not use many internal body processes to maintain temperature in the range which is acceptable for their survival, but rather use external, environmental heat sources to regulate their body temperature. If the temperature is colder, they will use the sun to heat themselves up, and if warm, they will look for shadier conditions. Ectotherms therefore have energy efficient mechanisms of maintaining temperature homeostasis, but are more susceptible to vagaries in environmental conditions compared to endotherms. In contrast, endotherms (also known as ‘warm-blooded’ species), into which classification humans fall, use internal body activity and functions to either generate heat in cold environments or reduce heat in warm conditions. In endotherms, if the external environment is too cold, and if the cold environment impacts on body temperature, temperature receptors measuring either surface skin temperature or core body temperature will send signals to the brain, which subsequently initiates a shiver response in the muscles, which increases metabolic rate and provides greater body warmth as a by-product of fuel / energy breakdown and use. If environmental temperature is too warm, of if skin or core temperature is too high, receptors will send signals to brain areas which initiates a chain of events involving different nerve and blood-related control processes which result in increased blood flow to the skin by vasodilatation, thereby increasing blood cooling capacity and sweat rate from the skin, thus producing cooling by water evaporation. All these endotherm associated heating and cooling processes utilize a large amount of energy, so from an energy perspective are not as efficient as that of ectotherms, but they do allow a greater independence from environmental fluctuations in temperature. It must be noted that endotherms also use similar behavioural techniques to ectotherms, such as moving into shady or cool environments if excessively hot, but as described above, can tolerate a greater range of environmental temperatures and conditions. Furthermore, humans are capable of ‘high level’ behavioural changes such as putting on or taking off clothes, in either a reactive or anticipatory way. It is evident therefore that for each variable being homeostatically monitored and managed (on a continuous basis) there are a complex array of responsive (and ‘higher-level’ pre-emptive) options available with which to counteract the potential or actual ‘movement’ of the variable beyond its ‘allowed’ metabolic setpoints and ranges.

There are a number of questions still to be answered regarding how homeostasis ‘works’ and how ‘decisions’ related to homeostasis occur. It is not clear how the regulatory mechanisms know which variable they ‘choose’ to defend as a priority. Brain oxygen would surely be the most important variable to ‘defend’, as would perhaps blood glucose levels, but how decisions are made and responses initiated for these variables preferentially, which may impact negatively on other systems with their own homeostatic requirements, is not clear. Furthermore, there is the capacity for ‘conflict’ between physical and psychological homeostatic mechanisms when homeostatic-related decisions are required to be made. For example, one’s ego may require one to run a marathon to fulfill a need to ‘show’ one’s peers that one is ‘tough’ by completing such a challenging goal, but doing so (running the marathon) creates major physical stress for and on the physical body. Indeed, some folk push themselves so hard during marathons that they collapse, even if they ‘feel’ warning signs of impending collapse, or of an impending heart attack, and choose to keep running despite these symptoms. To these folk, the psychological need to complete the event must be greater than the physical need to protect themselves from harm, and their regulatory decision-making processes clearly valences psychological homeostasis to be of greater importance than physiological homeostasis when deciding to continue exercising in the presence of such warning symptoms. However, running a marathon, while increasing physical risk of catastrophic physical events during the running of it, if done on a repetitive basis has positive physical benefits, such as weight loss and increased metabolic efficiency of the heart, lungs, muscles and other organ structures, along with enhanced psychological well-being which would be derived from achieving the set athletic performance-related goals. Therefore, ‘decision-making’ on an issue such as running a marathon is complex from a homeostasis perspective, with both short and long term potential benefits and harmful consequences. How these contradictory requirements and factors are ‘decided upon’ by the brain when attempting to maintain both psychological and physical homeostasis is still not clear.

A further challenge to homeostatic regulation is evident in the examples of when one has a fever, where a high temperature may paradoxically be beneficial, and after a heart attack, where an altered heart rate and blood pressure setpoint may be part of compensatory mechanisms to ensure the optimal function of a failing heart. While these altered values are potentially ‘outside’ of the ‘healthy’ setpoint level range, they may have utilitarian value and would be metabolically appropriate in relation to either a fever or failing heart. How the regulatory homeostatic control mechanisms ‘know’ that these altered metabolic setpoints are beneficial rather than harmful, and ‘accepts’ them as temporary or permanent new setpoints, or whether these altered values are associated with routine homeostatic corrective responses which are part of the body’s ongoing attempt to induce healing in the presence of fever or heart failure (amongst other homeostatically paradoxical examples), is still not clear. Whether homeostasis as a principle extends beyond merely controlling our body’s activity and behaviour, to more general societal or environmental control, is also still controversial. For example, James Lovelock, with his Gaia hypothesis, has suggested that the world in its entirety is regulated by homeostatic principles, and global temperature increases result in compensatory changes on the earth and in the atmosphere that lead to eventual cooling of the earth, and this warming and cooling continues in a cyclical manner – and most folk who believe in global warming as a contemporary unique catastrophic event don’t like this theory, even if it is difficult to support or refute without measuring temperature changes accurately over millennia.

Homeostatic control mechanisms can fail, and indeed our deaths are sometimes suggested to be the result of a failure of homeostasis. For example, cancer cells overwhelm cellular homeostatic protective mechanisms, or develop rapidly due to uncontrolled cellular proliferation of abnormal cells which are not inhibited by the regular cellular homeostatic negative feedback control mechanisms, which lead to physical damage to the body and ultimately our death, for these or other reasons that we are still not aware of. In contrast, Sigmund Freud, in his always contrary view of life, suggested as part of his Thanatos theory that death in the ultimate form of ‘rest’ and is our ‘baseline’ constancy-related resting state which we ‘go back to’ when dying (with suicide being a direct ‘mechanism’ of reaching this state in those whose psyche are operating too far away from their psychological setpoints, whatever these are), although again this is a difficult theory to either prove or disprove. Finally, what is challenging to a lot of folk about homeostasis from a control / regulatory perspective is that it is a conceptual ‘entity’ rather than a physical process that one can ‘show’ to be ‘real’, much like Plato’s Universals (to Plato the physical cow itself was less relevant than the ‘concept’ of a cow, and he suggested that one can only have ‘mere opinions’ of the former, while one has absolute knowledge of the latter, given the physical cow changes as it grows, ages, and dies, while the ‘concept’ of a cow is immutable and eternal). It is always difficult scientifically to provide categorical evidence which either refutes or support concepts such as universals and non-physical general control theories, even if they are concepts which appear to underpin all life as we know it, and without which function we could not exist in our current physical form and living environment.

As I look out the window at the falling autumn leaves and wonder whether we will have a very cold winter this year and whether we have prepared adequately for it clothes-wise (pre-emptive long-term homeostatic planning at its best, even if perhaps a bit ‘over-the-top’), while taking off my jersey as I write this given that the temperature has increased as the day has changed from morning to afternoon (surely a reactive homeostatic response), and as I ponder my health-related parameters, and work out how I am going to get those that need improvement as close to ‘normal’ as possible (surely as part of behavioural homeostatic / health-optimization planning), I look forward to that bike ride now I have managed to delay gratification of doing so until I have completed writing this (and feel a sense of well-being both from doing so and by realizing I am now ‘free’ to go on the ride and by doing so can remove the psychological ‘itch’ that makes me want to do it and therefore return to a state of psychological ‘constancy’ / homeostasis). Contemplating all of these, it is astonishing to think that all of what I, and pretty much all folk, do is underpinned by a desire to be, and maintain life, in a ‘comfort zone’ which feels right for me, and which is best for my bodily functions and psychological state. Given that all folk in the world have similar physical parameters when we measure them clinically, it is likely that our ‘comfort zones’ both physically and psychologically are not that different in the end. Perhaps the relative weighting which each of us assigns to our psychological or physical ‘needs’ create minor differences between us (and occasionally major differences such as in folk with psychopathology or with those who have significant lifestyle related physical disorders), though at the ‘heart of it all’, both psychologically and physically, is surely the over-arching principle of homeostasis. While on the bike this afternoon, I’ll ponder on the big questions related to homeostasis which still need to be answered, such as how homeostasis-related decisions are made, how the same principle can regulate not just our body, but also our behaviour, and perhaps that of societal and even planetary function, and how ‘universals’ originated and which came first, the physical entity or the universal. Sadly I think it will need a very long ride to solve these unanswered questions, and remove the ‘itch that needs scratching’ which arises from thinking of these concepts as a scientist who wants to solve them – and I don’t like to spend too long out of my comfort zone, which is multi-factorial and not purely bike-focused, but rather is part bike, part desk, part comfy chair, the latter of which will surely become more attractive after a few hours of cycling, and will ‘call me home’ to my next ‘comfort zone’, probably long before I can solve any of these complex issues while out on the ride watching the autumn leaves fall under a beautiful warm blue sky, with my winter cycling jacket unused but packed in my bike’s carrier bag in case of a change in the weather.


Consistency Of Task Outcome And The Degrees Of Freedom Problem-The Brain Is Potentially Not A Micro-Manager When Providing Solutions To Complex Problems

Part of the reason I enjoy cycling as my chosen sport now I am older is not just because it is beneficial from a health perspective, but because the apparent regularity of the rhythmical circular movement required for pedalling creates a sense of peace in me and paradoxically allows my mind to wander a bit away from its routine and usually work-focussed and life task orientated thoughts. I enjoy watching competitive darts, from the perspective of marvelling at how the folk participating in the competitions seem to so often hit the small area of the board they are aiming for with such precision, after fairly rapidly throwing their darts when it is their turn to do so. This week an old colleague and friend from University of Cape Town days, Dr Angus Hunter, published some interesting work on how the brain controls muscle activity during different experimental conditions, a field of which he is a world expert in, and it was great to read about his new research and innovative ideas as always. Some of the most fun times of my research career were spent in the laboratory working with Angus measuring muscle activity during movement related tasks, where one of our most challenging issues to deal with was the variability of the signal our testing devices recorded when measuring either the power output from, or electrical activity in, muscle fibres each time they contracted when a trial participant was asked to do the same task. A large part of the issue we had to solve then was whether this was signal ‘noise’ and an artefact of our testing procedures, or if it was part of the actual recruitment strategy the brain used to control the power output from the muscles. All of these got me thinking about motor control mechanisms, and how movement and activity is regulated in a way that gets tasks done in a seemingly smooth and co-ordinated way, often without us having to think about what we are doing, while when one measures individual muscle function it is actually very ‘noisy’ and variable, even during tasks which are performed with a high degree of accuracy, and how the brain either creates or ‘manages’ this variability and ‘noise’ to generate smooth and accurate rhythmical or target-focussed activity, as that which occurs when cycling and throwing darts respectively.

Some of the most interesting scientific work that I have ever read about was done by Nikolai Bernstein, a Russian neurophysiologist, who when working in the 1920’s at the somewhat euphemistically named Moscow Central Institute of Labour, examined motor control mechanisms during movement. As part of the communist government of the times centrally driven plans to improve worker productivity and output, Bernstein did research on manual labour tasks such as hammering and cutting, in order to try and understand how to optimise it. Using novel ‘cyclogram’ photography techniques, where multiple pictures were taken of a worker using a hammer or chisel to which a light source had been attached, he was able to produce the astonishing observation that each time the worker hit a nail or cut through metal, their arm movements were not identical each time they performed the action, and rather that there was a great degree of variability each time the similar action was performed, even though usually this variability in action produced an outcome which had a high degree of accuracy. He realized that each complete movement, such as moving the arm towards the target, is made up of a number of smaller movements of muscles around the shoulder, elbow and wrist joints, which together synergistically create the overall movement. Given how many muscles there are in the arm, working around three joints (and potentially more when one thinks of the finger joints and muscles controlling them), he suggested that were a very large number of potential combinations of muscle actions and joint positions that could be used for the same required action, and a different combination of these appeared to be ‘chosen’ by the brain each time it performed a repetitive task. From a motor control perspective, Bernstein deduced that this could potentially cause a problem for the brain, and whatever decision-making process decided on which movement pattern it would use to complete a task, given that it created a requirement for choosing a particular set of muscle synergies from a huge number of different options available, or in contrast not choosing all the other muscle synergistic options, each time the individual was required to perform a single task or continue performing a repetitive task. This would require a great amount of calculation and decision-making capacity on a repetitive basis by the brain / control processes, and he called this the motor redundancy, or degrees of freedom, problem.

Like a lot of work performed in the Stalin era in Russia, his fascinating work and observations did not become known to Western scientists until the 1960’s, when he published a text-book of his career in science, which was subsequently translated and taken forward by excellent contemporary movement control scientists like Mark Latash of the University of Pennsylvania State in the USA. Further studies have supported Bernstein’s earlier work, and it is astonishing how much variability there is in each movement trajectory of a complex action that is goal orientated. Mark has suggested that this is not a redundancy problem, but rather one of abundancy, with the multiple choices available being of benefit to the body of any individual performing repetitive tasks, potentially from a fatigue resistance and injury prevention perspective, which may occur if the same muscle fibres in the same muscle are used in the same way in a repetitive manner. Interestingly, when a person suffers a stroke or a traumatic limb injury, the quantity of movement variability appears to paradoxically reduce rather than increase after the stroke or injury, and this reduced variability of motor function is associated with a decrement in task performance accuracy and completion. Therefore, the high variability of movement patterns in healthy folk appears to paradoxically make task performance more accurate and not just more efficient.

How control processes choose a specific ‘pattern’ of muscle activity for a specific task is still not well known. A number of theories have been proposed (generally as a rule in science, the more theories there are about something, the more the likelihood there is that there is no clarity about it) with some quaint names, such as the equilibrium point hypothesis, which suggests that choice at the motor neuron level is controlled as part of the force-length relationship of the muscle; the uncontrolled manifold hypothesis, which suggests that the central nervous system focuses on the variables needed to control a task and ignores the rest (the uncontrolled manifold being those variables that do not affect task required activity); and the force control hypothesis, which suggests that the central nervous systems compares the required movement for the task against internal models, and then uses calculations and feedforward and feedback control mechanisms to direct activity against that set by the internal model; amongst others. All these are interesting and intellectually rigorous theories, but don’t tell us very much about exactly how the brain chooses a particular group of muscles to perform a task, and then subsequently a different group of muscles, which use a different flight trajectory, to perform the task again when it is repeated. It has been suggested that there are ‘synergistic sets’ of muscles which are chosen in their entirety for a single movement, and that the primitive reflexes or central pattern generators in the spinal cord may be involved. But the bottom line is that we just do not currently know exactly what control mechanism chooses a specific set of muscles to perform one movement of a repetitive task, why different muscles are chosen each time the same task is performed sequentially, or how this variable use of muscles for the same task is managed and controlled.

We have previously suggested that a number of other activities in the body beyond that of muscle control have similar redundancy (or abundancy) in how they are regulated, or at least in respect of which mechanisms are used to control them. For example, blood glucose concentrations can be controlled not only by changes in insulin concentrations, but also by that of glucagon, and can also be altered by changes in catecholamine (adrenaline or noradrenaline) or cortisol levels, and indeed by behavioural factors such as resisting the urge to eat. Each time blood glucose concentrations are measured, the concentrations of all these other regulatory hormones and chemicals will be different ratio-wise to each other, yet their particular synergistic levels at any one point in time maintains the level of blood glucose concentrations at homeostatically safe setpoint levels. The blood glucose level is maintained whatever the variability in the regulatory factor concentration ratios, and even though this variability in choice of control mechanisms similarly creates a potential for high computational load when managing blood glucose concentrations from a control perspective. Similarly, perception of mood state or emotions are thought to have redundancy in what factors ‘creates’ them. For example we can fairly accurately rate when we feel slightly, moderately or very fatigued, but underpinning the ‘feeling’ of fatigue at the physiological level can be changes in blood glucose, heart rate, ventilation rate, and a host of other metabolites and substrates in the body, each of which can be altered in a variable ratio way to make up the sensation of fatigue we rate as slightly, moderately or very high levels of fatigue. Furthermore, fatigue is a complex sensation made up of individual sensations such as breathlessness, pounding chest, sweating, pain, and occasionally confusion, dizziness, headache and pins and needles, amongst others, a combination of which can also be differently valenced to provide a similar general fatigue rating by whoever is perceiving the sensation of fatigue. To make it even more complex, the sensation of fatigue is related to inner voices which either rate the sensation of fatigue (the ‘I’ voice) or make a judgement on it related to social circumstances or family and environmental background (the ‘Me’ voice), and it is through the final combination of these that an individual finally rates their level of fatigue, which adds another level of redundancy, or abundancy, to the factors underpinning how the ‘gestalt’ sensation of fatigue is both created and perceived. There are therefore three potential ‘levels’ of redundancy / abundancy in the signals and factors which either individually or collectively make up the ‘gestalt’ sensation of fatigue, and a corresponding increased level of computational requirements potentially associated with its final genesis, and how this perceptual redundancy / abundancy is managed by the control mechanisms which generate them is still not well known.

In summary, therefore, the presence of variability during activities of daily living across a number of different body systems is not only ‘noise’ / artefacts of testing conditions which are challenges for us researchers to have to deal with, it also appears to be part of some very complex control mechanisms which must have some teleological benefit both for optimizing movement and activity, and ensuring the capacity to sustain it without fatigue or injury to the components of the mechanism which produces it. Each time I cycle on my bike and my legs move up and down to push the wheels forward, different muscles are being used in a different way during each rotation of the wheel. Each time a darts player throws a dart, different muscle synergies are used to paradoxically create the accuracy of their throw. There is real ‘noise’ that a researcher has to remove from their recorded traces after a testing session in a laboratory, such as that caused by the study participant sweating during the trial, which can affect electrophysiological signals, and there is always a degree of measurement error, and therefore some degree of ‘noise’ is present in the variability of the recorded output for any laboratory technique that measures human function. But, equally, Bernstein’s brilliant work and observations all those years ago helped us understand that variability is inherent in living systems, and after understanding this, each time I observe data, particularly that generated during electrophysiological work such as I have used for a number of experiments in my own research career, including electromyography (EMG), electroencephalography (EEG) or transcranial magnetic stimulation (TMS), which has low standard deviations in the results sections of published research articles, I do wonder at the validity of the data and whether it has been ‘paintbrushed’ by the researchers who describe it, as my old Russian neurophysiology research colleague Mikhail Lomarev used to describe it, when he or we thought data was ‘suspect’. The inherent variability in brain and motor control systems makes finding statistical significance in results generated using routine neurophysiological techniques more difficult. It also seems to create a huge increase in the requisite control-related calculations and planning for even a simple movement, though as Mark Latash suggested, the brain is likely to not be a micro-manager, but rather some effective parsing mechanism which can both generate and utilize a large number of synergistic movement patterns in a variable manner for any task, while not utilizing much decision making power using some sort of heuristic-based decision-making mechanism. Most importantly though, it fills one with a sense of awe at the ‘magic’ of our own body, and for the level of complexity involved in both its creation and operative management, when even a simple movement like striking an object with a hammer, or cutting a piece of metal, can be underpinned by such complex control mechanisms that our brains cannot currently comprehend or make sense of.

In a laboratory in the middle of Russia nearly a century ago, Nikolai Bernstein made some astonishing observations by doing exceptional research on basic motor control, while trying to increase the productivity of soviet-era industrial work. A century later we are still scratching our heads trying to understand what his findings mean from a motor control perspective. As I type these final sentences, I reflect on this, and wonder which synergistic composition of muscle activity in my fingers are responsible for creating the actions which lead to these words being generated, and realize that each time I do so, because of the concepts of variability, redundancy and abundancy, I will probably never use an identical muscle sequence when typing other ideas into words at another future point in time. But then again, I guess the words I will be writing in the future will also be different, and daily life, like motor control programs, will always vary, always change, even though the nail on the wall on which the picture hangs becomes a permanent ‘item’, as will this article become permanent when I hit the ‘send’ button to publish it. What is never to be seen again though are the traces in the ‘ether’ of the hammer blow which embedded the nail in the wall, and the exact movement of the individual muscles in the labourers arms and hands, and in my fingers as I typed which created these words. Like magic their variability was created, and like magic their pattern has dispersed, never to recur again in the same way or place, unless some brilliant modern day Bernstein can solve their magic and mystery, reproduce them in their original form using some as yet to be invented laboratory device, and publish them in a monograph. Let’s hope that if they do so, their great work does not languish unseen for forty years before being discovered by the rest of the world’s scientists, as was Bernstein’s wonderful observations of all those years ago!


Testosterone And Its Androgenic Anabolic Derivatives – One Small Drop Of Liquid Hormone That Can A Man Make And Can A Man Break

I watched a great FA Cup football final last night, and was amused as always when players confronted each other after tackles with aggressive postures and pouting anger-filled stares – all occurring in front of a huge crowd looking on and under the eyes of the referee to protect them. On Twitter yesterday and this morning I was engaged in a fun scientific debate with some male colleagues and noted that each time the arguments became ‘ad hominem’ the protagonists became aggressive and challenging in their responses, and only calmed down and became civil again when they realized it is banter. I have over many years watched my wonderful son grow up daily, and now he is ten have observed some changes occurring in him that are related to increasing development of ‘maleness’ which occurs in all young men of his age. In my twenties while completing my medical and PhD training, I worked part time as a bouncer, and it was always fascinating to see the behaviour of males in the bars and clubs I worked in then change when around females ‘dressed to kill’ and out for the evening. With the addition of alcohol this became a dangerous ‘cocktail’ late in the evenings, with often violence breaking out as the young men tried to establish their dominance and ‘turf’, or as a result of perceived negative slights which ‘honour’ demanded they respond to, and which resulted in a lot of work for me in the bouncer role to sort out. All this got me thinking of the male hormone testosterone and its effect on males through their lifetime, both good and bad.

Testosterone is the principal male sex hormone that ‘creates’ the male body and mind from the genetic chromosomal template supplied at conception. It is mostly secreted by the testicles in men, and to a lesser degree from the ovaries in women, with some secretion also from the adrenal glands. There is approximately 7-8 times higher concentration of testosterone in males than females, but it is present also in females, and females are susceptible to (and may even be more sensitive to) its actions. Testosterone is a steroid type hormone, derived originally from cholesterol related chemical substances which are turned into testosterone through a complex pathway of intermediate substances. Its output from the testes (or ovaries) is stimulated by a complex cascade of neuro-hormonal signals that arise from brain structures (gonadotrophin release hormone is released by the hypothalamus structure in the brain and travels to the pituitary gland, which in turn releases luteinizing hormone and follicle stimulating hormone, which travels in the blood to the testicles and in turn cause the release of testosterone into the bloodstream) in response to a variety of external and internal stimuli (though what controls testosterone’s release, and how it is controlled, in this cyclical manner over many years is almost completely unknown). The nature of ‘maleness’ has been debated as a concept since antiquity, but it was in the 1800’s that real breakthroughs in the understanding that there was a biological basis to ‘maleness’ occurred, with hormones being identified as chemical substances in the blood, and several scientist folk such as Charles Brown-Sequard doing astonishing things like crushing up testicles and injecting the resultant product into their own bodies to demonstrate the ‘rejuvenating’ effect of the ‘male elixir’. Eventually in the late 1800’s testosterone was isolated as the male hormone – it was named as a conglomerate derivative of the words testicle, sterol and ketone – and in the 1930’s, the ‘golden age’ of steroid chemistry, its structure was identified, and synthetic versions of testosterone were produced as medical treatment analogues for folk suffering from low testosterone production due to hypogonadism (reduced production of testosterone due to testicular function abnormality) or hypogonadotropism (reduced production of testosterone due to dysfunction of the ‘higher’ level testosterone release control pathways in the brain described above).

Testosterone acts in both an anabolic (muscle and other body tissue building) and androgenic (male sex characteristic development) manner, and one of the most fascinating things about it is that it acts in a ‘pulsatile’ manner during life – increasing dramatically at very specific times in a person’s life to effect changes that are absolutely essential for both the development and maintenance of ‘maleness’. For example, in the first few weeks after conception in males there is a spike in testosterone concentration in the foetus that results in the development of genitals and prostate gland. Again, in the first few weeks after birth testosterone concentrations rise dramatically, before attenuating in childhood, after which a further increase in the pre-puberty and the pubertal phases occurs, when it is responsible for increases in muscle and bone mass, the appearance of pubic and axillary hair, adult-type body odour and oily skin, increased facial hair, deepening of the voice, and all of the other features associated with (but not all exclusive to) ‘maleness’. If one of these phases are ‘missed’, normal male development does not occur. As males age, the effects of continuously raised testosterone associated with adulthood become evident as loss of scalp hair (male pattern baldness) and increased body hair, amongst other changes. From around the age of 55 testosterone levels decrease significantly, and remain low in old age. Raised testosterone levels have been related to a number of clinical conditions that in the past have been higher in males than females, such as heart attacks, strokes and lipid profile abnormalities, along with increased risk of prostate (of course it’s not surprising that this is a male specific disorder) and other cancers, although not all studies support these findings, and the differences in the gender-specific risk of cardiovascular disorders in particular is decreasing as society has ‘equalized’ and women’s work and social lives have become more similar to those of males in comparison to the more patriarchal societies of the past.

More interesting than the perhaps ‘obvious’ physical effects are the psychological effects of testosterone on ‘male type’ behaviour, though of course the ‘borders’ between what is male or female type behaviour are difficult to clearly delineate. Across most species testosterone levels have been shown to be strongly correlated with sexual arousal, and in animal studies when an ‘in heat’ female is introduced to a group of males, their testosterone levels and sex ‘drive’ increases dramatically. Testosterone has also been correlated with ‘dominance’ behaviour. One of the most interesting studies I have ever read about was one where the effect of testosterone on monkey troop behaviour was examined, in which there are strict social hierarchies, with a dominant male who leads the troop, submissive males who do not challenge the male, and females which are ‘serviced’ only by the dominant male and do not challenge his authority. When synthetic testosterone was injected into the males, it was found that the dominant male become increasingly ‘dominant’ and aggressive, and showed ‘challenge’ behaviour (standing tall with taught muscles in a ‘fight’ posture, angry facial expressions, and angry calls, amongst others) more often than usual, but in contrast, there was no effect or change of the testosterone injections on non-dominant male monkeys. When the females were injected with testosterone, most of them became aggressive, and challenged the dominant male and fought with him. In some cases the females beat the dominant male in fighting challenges, and became the leader of the troop. Most interestingly, these ‘became dominant’ females, when the testosterone injections were discontinued, did not revert back to their prior submissive status, but remained the troop leader and maintained their dominant behaviour even with ‘usual’ female levels of testosterone. This fascinating study showed that there is not only a biological effect of testosterone in social dominance and hierarchy structures, but that there is also ‘learned’ behaviour, and when one’s role in society is established, it is not challenged whatever the testosterone level.

Raised testosterone levels have also been linked with level of aggression, alcoholism, and criminality (being higher in all of these conditions) though this is controversial, and not all studies support these links, and it is not clear from the ‘chicken and egg’ perspective if increased aggression and antisocial behaviour is a cause of increased testosterone levels, or is a result of it. It is also been found that athletes have higher levels of testosterone (both males and females) during sport participation, as have folk watching sporting events. In contrast, both being ‘in love’ and fatherhood appears to decrease levels of testosterone in males, and this may be a ‘protective’ mechanism to attenuate the chance of a male ‘turning against’ or being aggressive towards their own partners or children. Whether this is true or not requires further work, but clearly there is a large psychological and sociological component to both the functionality and requirements of testosterone, beyond its biological effects. One of the most interesting research projects I have been involved with was at the University of Cape Town in the 1990’s, where along with Professor Mike Lambert and Mike Hislop, we studied the effect of testosterone ingestion (and reduction of testosterone / medical castration) on male and female study participants. We found not only changes in muscle size and mass in those taking testosterone supplements, but also that participants ingesting or injecting testosterone had to control their aggression levels and be ‘careful’ of their behaviour in social situations, while women participants described that their sex drive increased dramatically when ingesting synthetic testosterone. In contrast, men who were medically castrated described that their libido was decreased during the study time period when their testosterone levels were reduced by testosterone antagonist drugs to very low levels (interestingly they only realized this ‘absence’ of libido after being asked about it). All these study results confirm that testosterone concentration changes induce both psychological and social outcomes and not just physical effects.

Given in particular its anabolic effects, testosterone and its synthetic chemical derivatives, known commonly as anabolic steroids, became attractive as a performance enhancing drug by athletes in the late 1950’s and 1960’s as a result of it being massed produced synthetically from the 1930’s, and as athletes became aware of its muscle and therefore strength building capacity after its use in clinical populations. Until the 1980’s, when testing for it as a banned substance meant it became risky to use it, anabolic steroids were used by a large number of athletes, particularly in the strength and speed based sporting disciplines. Most folk over 40 years old will remember Ben Johnson, the 1988 Olympic 100m sprint champion, being stripped of his winner’s medal for testing positive for an anabolic steroid hormone during a routine within-competition drug test. Testosterone is still routinely used by body-builders, and worryingly, a growing number of school level athletes are being suggested to be using anabolic steroids, as well as a growth of its use as a ‘designer drug’ in gyms to increase muscle mass in those that have body image concerns. An interesting study / article pointed out that boy’s toys have grown much more ‘muscular’ since the 1950’s, and that this is perhaps a sign that society places more ‘value’ on increased muscle development and size in contemporary males, and this in a circular manner probably puts more pressure on adolescent males to increase their muscle size and strength due to perceived societal demands, and thereby increases the pressure on them to take anabolic steroids. There is also suggested to be an increase in the psychological disorder known as ‘muscle dysmorphia’ or ‘reverse anorexia’ in males, where (mostly) young men believe that no matter how big they are muscle size wise, they are actually thin and ‘weedy’, and they ‘see’ their body shape incorrectly when looking in the mirror. This muscle dysmorphia population is obviously highly prone to the use of (perhaps one should say abuse) anabolic steroids as a group. There appears to be also an increase in anabolic steroid use in the older male population group, perhaps due to a combination of concerns about diminishing ‘male’ function with increasing age, a desire to maintain sporting prowess and dominance, and a perception that a muscular ‘body beautiful’ is still desirable by society even in old age – which is a concern due to the increased cardiovascular and prostate cancer risks taking anabolic steroids can create in an already at-risk population group. There is also a growth in the number of women taking anabolic steroid / synthetic testosterone, both due to its anabolic effects and its (generally) positive effects on sex drive, and a number of women body builders use anabolic steroids for competitive reasons due to its anabolic effect on muscles, despite the risk of the development of clitoral enlargement, deepening voice, and male type hair growth, amongst other side effects, which potentially can result from females using anabolic steroids. Anabolic steroid use therefore remains an ongoing societal issue that needs addressing and further research, to understand both its incidence and prevalence, and to determine why specific population groups choose to use them.

It has always been amazing to me that a tiny biological molecule / hormone, which testosterone is, can have such major effects not only on developing male physical characteristics, but also on behavioural and social activity and interactions with other folk, and in potentially setting hierarchal structures in society, though surely this ‘overt’ effect has been attenuated in modern society where there are checks and balances on male aggression and dominance, and females now have equal chances to men in both the workplace and leadership role selection. Testosterone clearly has a hugely important role in creating a successfully functioning male both personally and from a societal perspective, but testosterone can also be every males ‘worst enemy’ without social and personal ‘higher level’ restraints on its potential unfettered actions and ways of working. It has a magic in its function when its effects are seen on my young son as he approaches puberty and suddenly his body and way of thinking changes, or when its effects are seen (from its diminishment) in the changes of a man in love or in a new father. Perhaps there is magic also in the reduction of testosterone that occurs in old age, as this is likely to be important in allowing the ‘regeneration’ of social structures, by allowing new younger leaders to take over from previously dominant males, by this attenuation of testosterone levels perhaps making older males ‘realize’ / more easily accept that their physical and other capacities are diminished enough to ‘walk away’ gracefully from their life roles without the surges of competitive and aggressive ‘feelings’ and desires a continuously high level of testosterone may engender in them if it continued to be high into old age. But testosterone has an ugliness in its actions too, which was evident in my time working as a bouncer in bars and clubs, when young men became violent with other young men as a way of demonstrating their ‘maleness’ to the young females who happened to be in the same club and were the (usually) unwitting co-actors in this male mating ritual drama which enacted itself routinely on most Friday and Saturday nights, usually fuelled by too much alcohol. Its ugliness is also evident on the sporting field when males kick other men lying helpless on the ground in a surge of anger due to losing the game or for a previous slight, despite doing so within the view of a referee, spectators and TV cameras. Its ugliness is also evident in the violence that one sees in fans after a soccer game preying on rival fans due to their testosterone levels being high due to watching the game, and in a myriad of other social situations where males try to become dominant to lever the best possible situation or to attract the best possible mate for themselves, at the expense of all those around them – whether in a social or work situation, or a Twitter discussion, or even a political or an academic debate – the ‘male posturing’ is evident for all to see in each situation, whether it is physical or psychological. Perhaps it was not for the sake of a horseshoe that the battle was lost, but rather because of too little, or too much, testosterone coursing around the veins of those directing it. There are few examples as compelling as that of the function of the hormone testosterone in making male behaviour what it is which demonstrates how complex, exquisite and essential the relationship between biological factors and psychological behaviour and social interplay is. What truly ‘makes up’ a man and what represents ‘maleness’ though, is of course another story, and for another debate!


Anxiety, Stress And The Highly Sensitive Person – Too Much Of Something Always Becomes A Bad Thing That Damages One In The End

I am one of those people that worries all the time. If there is an issue at work or at home that is of concern, I will up at 2.00 am in the morning wondering how best to solve it and worrying about it until I am sure it is solved. When all is as well as it can be I will find something to worry about – the plans for the future, pension funds (or lack of them), my kids health, anything and everything. In many ways this has been a good thing, as it has helped me always plan ahead, find solutions to problems and be aware of challenging situations as they develop, or even before they do. In many ways this has been a bad thing, as it means I get irritable and stressed when things are not working out well, and I am at the age when this continued mental ‘strain’ has the potential after many years of being the ‘status quo’ to cause cumulative physical damage to my body resulting potentially in such clinical conditions as migraines, high blood pressure, heart attacks, and strokes amongst others. There is clearly a genetic or physical environment component to this ‘worry’ state, as my father was very similar, and always seem to be worried when he was not almost overly exuberant and happy (there never was a middle ground with him, which made life as a child both fun and challenging), and for most of his adult life until he suffered a series of heart attacks in his early fifties, he smoked ninety cigarettes a day (and was in his early years ‘proud’ of this fact and his capacity to smoke prodigiously, given that in his era it was the ‘done thing’ to smoke) and was never to be seen without a cigarette in his hand, surely as an antidote for and a mechanism to assist him to cope with the stress he felt on a daily basis and which he surely worried about continuously. I have noticed since the advent of the mobile phone, during meetings I sit in at work, or when I go out for a social evening, folk around me check their phone for text messages or emails on a regular basis, with some folk doing so seemingly every few minutes, which is also surely a pathological sign of something ‘worrying’ these folk, or of a ‘worry’ type of personality in these folk who seem to need to check on information coming to them on an almost continuous basis. All these got me thinking about ‘worry’ – known clinically as anxiety – and what causes it to occur, and why some folk appear to feel it more than others and seem to be ‘highly sensitive’ to stressful situations.

Anxiety is defined as a worry about future events before they occur, and is different, though related, to the concept of fear, which is defined as a psychological reaction to current events. Related to both concepts are those of stress, homeostasis and allostasis. The theory of homeostasis suggests that our natural preferred state of existence is one where we are in ‘equilibrium’ with the environment in which we live, and our body and mind are in a ‘steady state’, free of requirements, needs and challenges. When this steady state we exist in is challenged, for example by low energy levels in the body, we notice this as a stressor to our steady state existence (‘hunger’ is the mechanism by which we ‘notice’ this particular stress factor), and this stress induces us to respond to it, by in this example generating actions and plans that will allow us to source and eat food, thereby increasing our body’s energy ‘levels’ back to the state in which we are comfortable and ‘happy’ with. Similarly if we become hot, we move to a place where cooler conditions exist. In more complex examples, if our social or community life changes in a way we feel uncomfortable with, we make plans and enact changes that will attenuate this social stress by either moving to a new place or environment, or taking steps to remove whatever or whoever is causing us discomfort if it is in our power to do so. The process of achieving stability, or homeostasis, using behavioural and psychological changes, has recently been described as allostasis (though some of us believe this is an unnecessary definition as the definition of homeostasis incorporates what is now described as allostasis). These allostatic responses attenuate stressful changes, or changes which are at least perceived as stressful by us, by means of releasing stress hormones in the body (for example cortisol) via the hypothalamic-pituitary-adrenal gland pathway in the body, or by activating the autonomic nervous system (for example the sympathetic nerves which are responsible for initiating ‘fight or flight’ responses in the body), or by releasing cytokines (which are humoral blood-borne ‘signallers’ which also induce a number of physical body responses to stress), or other systems which are generally adaptive in the short term. These pathways all induce a number of ‘general alarm’ or ‘specific response’ changes in the physiological systems and different organs in the body, such as increasing the concentration of glucose in the blood and re-distributing it to areas of the body that need it most as a result of the induced stress, increasing cardiac output, blood pressure and blood flow to specific organs in the body such as the muscles while reducing blood flow to the digestive and reproductive system, and altering the immune system response, amongst others – which all in turn lead to symptoms one ‘feels’ such as dry mouth, rapidly beating heat, increased breathing rate, shaking muscles, nausea, diarrhoea, and even dizziness and confusion in extreme conditions. Like all things, some stress and occasional activation of this stress response ‘allostatic’ system is beneficial to one both for reducing the targeted stress and for making the response systems more efficient by ‘practice’. But, like all things, if the stressor is not removed, or if multiple different stressors occur at once, and these responsive systems remain ‘wide open’, this can result in a status of ‘chronic response fatigue’ in these systems, and ultimately cause damage to the body by the very mechanisms which are designed to protect (for example a raised blood pressure allows blood to pumped quickly to targeted organs requiring increased blood flow for their optimal function, but chronically raised blood pressure causes ‘backflow’ problems to the heart which leads to heart failure eventually, or ‘forward flow’ problems to other organs such as the kidneys, which are eventually damaged by continuously increased blood pressure over a period of time). What is defined as the ‘allostatic load’ is the ‘wear and tear’ of the body (and mind) which increases over time when someone is exposed to repeated or chronic stress, and represents the physiological consequences of chronic exposure to the hormonal and neural responses described above which are ultimately damaging to the person who is ‘feeling’ the stress and whose body is continuously trying to react to it.

All of these allostatic responses are reactive to an already occurring, or perceived to be occurring, stressful situation or environment, and the sensation of fear would be the psychological accompanying emotion associated with perceiving such already occurring situations. But as described above, anxiety is somewhat different, in that it is a worry about future, rather than already occurring events. When one is anxious, one is thinking about all the potential, rather than actual, implications of possible scenarios that could occur based on ones ‘reading’ of current situations or events occurring around one that may, rather than will, occur and potentially impinge on one and possibly cause stressful situations at some time point in the future. Interestingly, anxiety ‘uses’, or is at least associated with, a number of the physical allostatic ‘response’ systems described above, such as the hypothalamic-pituitary-adrenal system, autonomic and interleukin systems, and a number of the symptoms of anxiety are associated with activity of these ‘fight or flight’ response systems and the physiological perturbations they induce. In episodes of acute anxiety (also known as panic attacks), symptoms including trembling, shaking, confusion, dizziness, nausea and difficulty breathing occur, all of which are induced by the allostatic stress-related pathways described above. While some anticipation of the future and resultant planning for it can only be good for one from a long term safety and security perspective, and therefore occasional anxiety can also be beneficial in ‘encouraging’ the planning of and ‘making ready’ future reactive plans for potential stressors one is concerned about after ‘reading the runes’ of one’s current life, generalized anxiety disorder is a clinical condition that is characterized by excessive, uncontrollable and often irrational worry about future events that occurs in between three and five percent of the population word-wide, where folk have a high level of anxiety about everyday problems such as health issues, finances, death, family / social / work problems, or anticipated catastrophic situations which are not commensurate with their actual level of probability of occurring. Individuals with chronic anxiety disorder have a wide variety of ‘psychosomatic’ (body and mind) symptoms, including fatigue, headaches, nausea, muscle aches and tension, numbness in their hands and feet, fast breathing, stomach pain, vomiting, diarrhoea, sweating, irritability, agitation, restlessness, sleep disorders and an inability to either control the anxiety and / or its physical symptoms. If not adequately controlled, generalized anxiety disorder can result in a number of what are known as chronic ‘lifestyle’ disorders, such as high blood pressure, diabetes, migraines, heart attacks and strokes, as well as depression or irritable bowel syndrome, as well as a host of what are defined as ‘psychosomatic’ disorders’. What causes an individual to develop a generalized anxiety disorder is currently not well understood (it occurs more often in folk who have a family history of it), but it most often begins to manifest itself between the ages of 30-35, but can also occur in childhood or late adulthood, and appears to ‘tap in’ and chronically activate the allostatic physiological response mechanisms described above.

Another interesting ‘relative’ of anxiety disorders is what has become known as the Highly Sensitive Person (HSP) ‘disorder’. Folk who are highly sensitive people have a high degree of what is known as sensory processing sensitivity, or in other words they appear to respond to, or be aware of physical body symptoms of stress and anxiety, or to social or environmental situations, to a greater degree than folk who do not ‘suffer’ from this disorder. Folk who have HSP ‘feel’ all these body allostatic responses in an extremely sensitive way, via mechanisms that are still currently not well understood. Because of this, they are also ‘hyper-aware’ of social situations or environments that may trigger the ‘release’ of these physiological anxiety / stress-related response pathways in their bodies (or vice versa and they may be hyper-aware of these social situations because of their natural ‘up-regulated’ physical sensory state). This HSP state is either a curse or a blessing (or both), as it makes folk who ‘suffer’ from it prefer low stimulation environments and try to construct their lives to avoid over-stimulation, and predisposes them potentially to higher risk of chronic stress / anxiety related disorders, but it also make them ‘feel’ life more, have more insight into and early awareness of developing social situations that others may not even be aware of, and make them more ‘intuitive’ to what is going on around them. Whether HSP folk have higher levels of anxiety or greater incidence of a generalized anxiety disorder is currently not well known, but given both ‘tap into’ the same allostatic physical body systems and mechanisms make it more likely that this is indeed so. It must be noted that the concept of a highly sensitive person has been differentiated from that of a hypersensitive person, who are defined as folk who over-react to any stimuli or slight. Folk with HSP may simply be quiet, appear introverted or ‘shy’, or are able to ‘hide’ their HSP ‘condition’, while hypersensitive folk are typically very challenging to deal with socially, but they also may have underlying anxiety as a cause of their over-reactions, ‘temper-tantrums’ and rages. The treatment of all of these different anxiety related disorders is challenging, and requires lifestyle change, psychological intervention (such as cognitive behavioural therapy) and / or medication, but there is always a relatively poor cure rate and a high degree of recidivism, and folk with anxiety and stress related disorders need to themselves understand, acknowledge and work on their underlying condition, though the problem for doing so is that a hyper-sensitivity responsive ‘state’ or condition is very difficult to understand, let alone treat. A number of folk use smoking, alcohol consumption, or avoidance behaviour, as methods of ‘dealing’ with their anxiety or high level of sensitivity, but these short term ’emollients’ create their own specific problems and may themselves paradoxically increase anxiety and stress in those that use them as a stress / anxiety reducing mechanism.

Worry, therefore, can be a useful thing to prepare one to enact future potential responses to what one is ‘picking up’ in one’s current circumstances that causes one to worry, if it continues for a short period of time only and if it is about a specific issue. Worry, if chronic or if it is a clinical disorder, through the allostatic pathways and circuits it uses to initiate and mediate ‘fight or flight’ body changes, can cause a wide array of unpleasant symptoms and diminish one’s quality of life, and can ultimately cause major physical damage to one’s body if one does not manage it carefully, or treat it as something that needs to be ‘cured’. The ‘trappings’ of modern society such as mobile phones and increased work and social connectivity and immediate communication capacity have many benefits, but these can also ‘tap into’ and reinforce these anxiety-related allostatic pathways and create continuous stress of their own making – it is likely that those folk who compulsively reach for their phones to check their messages every few minutes almost certainly have an anxiety disorder, or are prone to developing one, and future research is surely needed to ascertain the veracity of this possibility. I myself am a ‘worrier’, and almost certainly am a highly sensitive person, as was my father before me. This has created blessings and challenges both for us and those around us – life can be beautiful, but life can also be challenging, on a daily basis, with most of it ‘raging’ around in our own minds rather than in the ‘real’ life around us per se. At twenty five, I would have said the benefits of being and living such as a highly sensitive person and ‘worrier’ surely outweighed the challenges – the rose surely smelt better, the rain surely felt softer, the love was deeper, the anger stronger, the passion for life greater to and for us compared to how most folk around us probably experienced their less ‘perceived’ life. However, now I am about to reach the age of fifty, and am reaching the ‘tiger territory’ period of life for high blood pressure, heart attacks and other ‘diseases of a lived life’, I am not so sure, and the thought of a calm life, without worry, without stress, lived in soft colour and tranquil shades and hues, seems to be perhaps the better one, and one that should have been chosen as preferential way of living all those years ago, or at least changed to now I am more aware both of my own highly sensitive ‘condition’ and the potential negative effects such a life can have on one’s physical response mechanisms and body organs and physiological systems. But, at the end of the day, can one ever really ‘choose’ one’s own ‘sensitivity to stimuli’ levels? Perhaps our own anxiety and stress levels, or at least our own perception of them, were set in our ancestors body’s thousands of years ago and passed down to us, even if they are redundant as a ‘need’ in our modern life, and are therefore almost impossible to materially change despite our wishes and best efforts to do so. More research is needed to better understand if sensitivity to stimuli levels, and indeed those of anxiety itself, can ever be permanently attenuated, or rather if they stay permanently ‘as is’, and one merely learns rather how to cope and ‘deal with’ them better with the passing of time or with enhanced understanding, treatment or therapy.

One’s life will surely happen to oneself, as it does for each of us as we move through life and its challenges, whether one worries about it or not, or whether one ‘feels it’ more or less, I guess, but in many ways it surely ‘feels’ more like it is ‘happening to one’ when one worries about it than when one does not – though doing so appears to damage one’s physical survival mechanisms by over-use as part of the process. It must be wonderful to live a life in the always warm, always comfortable environment which is the one in which has no worries. But, equally, one can never maintain a hot fire without some internal combustion occurring which creates the heat, or even more so, put out a fire once it has been burning for a long time and has created the ‘heat’ which is manifestly evident in the life lived with maximal sensitivity to stimuli and responsivity to all around it. Would one choose to put this ‘fire’ out and reduce the ‘heat’ in oneself if one could do so? How one answers that question will perhaps ascertain for oneself where on the spectrum of anxiety and sensitivity to stimuli scale one is, or at least where one would like to be (without the need to reach for one’s mobile phone to get the answer to it as we do these days, or lighting up a cigarette in order to help one reflect on it like they did in my old man’s days). I’ll ponder this question myself as I listen with delight to the sound of the birds chirping in the garden outside that ‘feels’ as if they ‘pierce’ my ears, as I sip my coffee and go through what I have written this morning wondering if it has been a good or bad writing session, as I bang the table in frustration when I discover that my printer has run out of ink and I can’t print it out for my records, and as at the same time I worry if I have all my ‘ducks in a row’ ahead of those important meetings I have at work on Tuesday after the public holiday Monday. Reflect, reflect, reflect. Worry, worry, worry. For some there is no peace, even on the quietest of days!


Chronic Fatigue Syndrome – Is This Contemporary Neurasthenia An Organic Neurological Or Psychiatric Disorder Associated With Childhood Trauma Related Chronic Anxiety And Resultant Ego Depletion

I was watching the Two Oceans running marathon in Cape Town yesterday on the square box, and marvelled not only at the aesthetic beauty of Cape Town, but also at how many folk of all ages ran the iconic race, and at their visible efforts to resist the sensations of fatigue they were clearly all feeling as the race reached its endpoint and as they laboured valiantly to reach the finish line in the fastest time possible for each of their abilities. Some recently published top-notch research articles on the mechanisms of fatigue by Roger Enoka, Romain Mueusen and Markus Amman, amongst others (surely with Simon Gandevia the scientists who have shaped our contemporary view of fatigue more than anyone else) have been doing the ’rounds’ amongst us science folk on research discussion groups the last while, and has ‘reignited’ an interest in the field in me. A large period of my research life was involved in trying to understand the mechanism behind the symptoms of fatigue, mainly in athletes, but also in those suffering from the clinical disorder known as chronic fatigue syndrome. As I come up quickly to the big age of 50 later this year, I notice that the daily physical and mental activity which I used to do with ease in my youth fatigue me more easily now. Because of this I have to ‘pace’ myself more carefully in all aspects of life to ‘preserve’ energy to ‘fight the good fight’ another day, in order to not run the risk of collapsing completely in the manner I witnessed in those folk with chronic fatigue syndrome I tried to assist both as a clinician and scientist during my earlier career, who pushed too hard and subsequently became moribund because of it. All of these recent observations have got me thinking of chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis (ME), what causes it, and why it manifests in some folk and not others.

Fatigue is a complex emotion which is felt by all folk on a daily basis, but paradoxically is very difficult to define. It has mental and physical symptoms and signs, and is often increased by and related to exertion of any kind. Fatigue can be either acute, where there is a direct correlation of the symptoms of fatigue to a specific task or activity and the symptoms attenuate when the activity ends, or can be chronic, when the symptoms of fatigue remain for a prolonged period and are not attenuated by a period of rest, and the reasons for these chronic symptoms remaining are very difficult to understand. In the sporting world, chronic fatigue is caused by pushing oneself too long and too hard in training and racing, and is known as over-training syndrome, and has a symptom complex which includes apart from the symptom of extreme fatigue also those of ‘heavy legs’, increased waking pulse rate, sleep disorders, weight loss (or weight gain), lack of motivation, depression and decreased libido, which do not improve unless there is a prolonged period of rest with no physical training. Working at the University of Cape Town with great scientists Mike Lambert, Liesl Grobler, Malcolm Collins, Karen Sharwood, Wayne Derman, and others, for my medical doctorate in the late 1990’s we examined athletes who were moribund from over-training, and found that a number of them had pushed themselves so hard and so long that they had developed skeletal muscle pathology (damaged mitochondria in particular) to go with all these chronic fatigue symptoms, and we called this symptom complex the fatigued athlete myopathic syndrome, and later acquired training intolerance. The words the athletes we examined used to describe their symptoms were classic and perhaps ‘explained’ the issues better than scientific or medical terms – with one sufferer declaring that they had ‘no spring in the legs’, another that ‘one kilometre now feels what equalled 100 km previously’, and another that ‘at its peak, the fatigue left me halfway between sleeping and waking most of the time’. Although there was perhaps a degree of hubris in these self-reported symptoms of fatigue, all these folk felt that the symptoms profoundly affected their exercise performance and lifestyle. Significantly, the majority of folk had evidence of suffering from depression, and also did not want to stop training and racing, and indeed found it almost impossible to stop training and racing despite these profound symptoms of chronic fatigue.

I carried on my interest in this field when moving to Northumbria University in the UK in 2006, and assisted Paula Robson Ansley and her PhD student Chris Toms, who did some great work examining causation, clinical testing of and exercise prescription for folk with classical chronic fatigue syndrome, as opposed to those with acquired training intolerance (though there is surely a relationship between these syndromes). Folk with CFS have symptoms of chronic and extreme fatigue which is persistent or relapsing, present for six months or longer, not resulting from ongoing exertion, not attenuated substantially by rest and causing impairment of activities which were previously easy to perform. They also have four or more ‘other’ diagnostic criteria, including impaired memory or concentration, sore throat, tender cervical / axillary lymph nodes, muscle pain, multi-joint pain, headaches, unrefreshing sleep or post-exercise malaise. It is importantly a diagnosis of exclusion of other medical causes of fatigue such as cancer, TB, endocrine or hormonal imbalances, or psychiatric or neurological disorders, and a clinician must always be careful to exclude these specific organic medical causes before diagnosing someone with CFS. The cause of CFS is unknown and hotly debated – it is usually precipitated by a viral infection such as Ebstein Barr Virus infection (glandular fever), and viral or infective causes, immune function issues, toxic pathogens or chemicals have all been suggested to be the cause of CFS, but not all folk who have CFS have any or all of these potential triggers or causal agents as part of their presenting history. It is notoriously difficult to treat, and some folk are left moribund and with significantly impaired lives for decades, although in some folk the syndrome seems to ‘burn out’ and they improve with time or learn to live with their symptoms by managing them carefully. Unfortunately there is a high level of suicide in folk suffering from CFS, though it is not clear if this is related to the underlying causation of the disorder or due to its long-term effect on lifestyle and physical capacity.

What is interesting (and of concern) for those folk studying CFS and trying to understand its aetiology and how to treat it, is the controversy and level of emotion attached to its diagnosis and treatment. Chronic fatigue syndrome used to be more well known as myalgic encephalomyelitis (ME), first diagnosed in the 1950’s after a group of doctors and nurses in a specific hospital developed post-viral syndrome with symptoms including chronic fatigue and with some neurological muscle and central nervous system related symptoms (hence the name ME) and it was first thought to be a neurological disorder. But with time, and as it was found that more folk who were diagnosed with ME did not have classic ‘organic’ neurological signs, it became thought of more as a psychiatric disorder and became more often described as CFS, due to the predominant symptomatology of fatigue as being the major ‘descriptor’ of the disorder. What is astonishing is that, as well described in a fascinating article by Wotjek Wojcic and colleagues at Kings College, London, in a survey of neurologist specialist members of the British Neurologist Association, 84% of respondents did not view CFS as a neurological disorder but rather as a psychiatric disorder. But, paradoxically, a number of patients with CFS would prefer it to be described as a neurological rather than a psychiatric disorder (and would prefer it to be still called ME), because of the social stigma of the label of having a psychiatric disorder. Somewhat astonishingly, as described by Michal Sharpe of the University of Edinburgh, there was even a negative response to a study of his which found that cognitive behavioural therapy and graded exercise therapy (the PACE trial) helped improved the symptoms of sufferers of CFS/ME, with several major patient organizations apparently dismissing the trial findings and being critical of them, because the findings could suggest that the syndrome was psychiatric in origin if cognitive behavioural therapy worked, rather than what would be the case if it was an organic neurological disorder, in which case such therapy should not work. As Sharpe concluded, in his own words it is a ‘funny old world’ when a study shows that a therapy works, but patients are angry because they didn’t want it to work, because of the stigma it would potentially create by it working.

Wojcic and colleagues also made the point that the majority of symptoms of CFS are almost identical to that of neurasthenia, a psychiatric disorder which was prominent in the 1800’s and early 1900’s, but has become almost unheard of as a diagnosis in contemporary times. Neurasthenia was described as a ‘weakness of nerves’ by George Beard in 1869, and as having symptoms of fatigue, anxiety, headache, heart palpitations, high blood pressure, neuralgia (pain along the course of a specific nerve) and depressed mood associated with it. The ICD-10 definition of neurasthenia is that of having fatigue or body weakness and exhaustion after minimal effort, which is persistent and distressing, along with depressive symptoms and two of the symptoms of either muscle aches and pains, dizziness, tension headaches, sleep disturbances, inability to relax, irritability and dyspepsia (indigestion). William James referred to neurasthenia as ‘Americanitis’ (he suffered from neurasthenia himself) as so many Americans in the 1800’s were diagnosed with it, particularly women, and it was a ‘popular’ diagnosis whose treatment was either a rest cure or electrotherapy. In world war one neurasthenia was a common diagnosis for and of ‘shell shock’, and folk with shell shock related neurasthenia were treated with prolonged rest. In the 20th century neurasthenia was increasingly thought of as a behavioural rather than a physical condition, and eventually it ‘fell out of favour’ and was ‘abandoned’ as a medical diagnosis. As Wojcic and colleagues suggest, not just the symptoms, but the ‘trajectory’ of the classification of the disorder have and follow a strikingly similar pattern to that of CFS/ME, which also started off as being diagnosed as an organic / neurological disorder and is now thought of a psychiatric disorder, which is (sadly) increasingly stigmatized by lay folk and indeed even some clinicians.

Neurasthenia was thought by Beard to being caused by ‘exhaustion’ of the central nervous system’s energy reserves, which he attributed to the (even in those days) stresses of urbanization, increasingly competitive business environment and social requirements – it was thought that neurasthenia was mostly associated with ‘upper class’ folk and with professionals working in stressful environments. Sigmund Freud thought there was a strong relationship to anxiety and to the basic ‘drives’, and as he almost always did, related neurasthenia to ‘insufficient libidinal discharge (ie not enough sex) that had a poisonous effect on the organism’. Both Freud and Carl Jung believed that drives were the result of the ‘ego’ state, and that disorders such as neurasthenia were a result of imbalances in this ego state. In their model, the ‘id’ was the basic component of the subconscious psyche which encompassed all our primitive needs and desires. The ‘ego’ was the portion of the psyche which maintains the sense of self, and recognizes and tests reality. A well-functioning ego perceives reality and differentiates the outer world from inner images and desires generated by the id, and ‘controls’ these. The ego develops in the first part of life, and is associated with a history of object cathexes. Cathexes are attachments of mental or emotional energy upon an idea or object. Object cathexes are generated by the id, which ‘feels’ erotic and other ‘trends’ as needs. The ego, which to begin with is feeble, becomes aware of these object cathexes, and either acquiesces or understands these needs and manages them (and thus becomes ‘strong’) or is disturbed by them and ‘fends’ them off by the process of repression (and becomes weak and ‘conflicted’). If weak, the ego deals with its inadequacy by either repressing unwanted thoughts (thrusting back by the ego from the conscious to the unconscious any ideas of a disagreeable nature) or developing a complex (a group of associated, partially or wholly represented ideas that can evoke emotional forces which influences an individual’s behaviour, usually ‘outside’ of their awareness). As a result of these complex developments, folk either use projection, which is a mental mechanism by which a repressed complex is disguised by being thought to be belonging to the external world or to someone else, or transference, which is the ‘shifting’ of an affect from one person to another or from one idea to another, either affection or hostility, based on unconscious identification, in order to deal with them at a subconscious level. Albert Adler described the inferiority complex as such – that a combination of emotionally charged feelings of inferiority operates in the unconscious to produce either timidity, or as a compensation, exaggerated aggression or paradoxical perception of superiority, and ones drives were a result of, or compensation for, feelings of inferiority derived from previous unpleasant experiences. For example, competing in extreme sport would be a compensation for being bullied in the past, or being abused as a child, or being ignored by a parent when young. Signs of such complexes included for Freud and Jung disturbing dreams and ‘slips of the tongue’, nervous tics and involuntary tremors, fanatical attachment to projects and goals, envy and dislike of individuals who are successful, falling apart when failing to successfully complete a challenge, desire for public acknowledgement and seeking of title and awards, compulsive exercising, and the development of neuroses and psychoses, all of which can be used to diagnosed the presence of ‘unsolved’ complexes, projections and transferences. Importantly for the development of neurasthenia (and chronic fatigue), Jung and Freud thought that there was an ‘energy cost’ to maintaining repressions and their associated complexes – Freud defined drives as the ‘psychical representative of the stimuli originating within the organism and reaching the mind, as a measure of the demand made for work in consequence of its connection to the body’ – and this energy cost eventually leads to the ‘breaking down of the will’ by the constant ‘fighting’ to maintain what was ‘hidden’ that was painful and not wanting to ‘come out’, and this breakdown of the will / ‘mental exhaustion’ lead to the signs and symptoms described above, which could in a circular way be used to diagnosed the presence of the underlying disorders. In a positive final observation, both Jung and Adler thought that the psyche was self-regulating, and that the development of these symptoms was purposive, and an attempt to ‘self-cure’ by compensation, and by bringing the destructive repressions, which exist at a subconscious level so are not directly perceived by the folk who have them, to their attention, or at least to that of their clinician or therapist, it would eventually lead to cure or at least ‘individuation’ and acknowledgement of the underlying issues, which to therapist of that era was the start of the cure.

Therefore, in this ‘id and ego’ model developed by Freud, Jung and their colleagues all those years ago, symptoms of chronic fatigue and burnout may be the psyche’s way of creating knowledge of and thereby attempting to cure latent psychic drives which lead to obsessive work or sporting goals and activity, created by past psychological trauma and a resultant ‘weak ego’, which results in chronic fatigue when the psyche cannot ‘cope’ with ‘fighting’ these often unperceived issues for a long period of time / for the life period up to the point when they collapse. Interestingly, while these theories have been mostly long forgotten or have fallen into disfavour, there has recently been an increase again in interest in the concept that mental and physical ‘energy’ is a finite commodity, with psychologist Roy Baumeister’s theory of ‘ego depletion’ gaining much traction recently, which suggests that a number of disorders of ‘self-regulation’, such as alcohol addiction, eating disorders and obesity, lack of exercise or excessive exercise, gambling problems and inability to save money and personal debt, may be related to one using up one’s ‘store of energy’ resisting the ‘deep’ urges which lead to these life imbalances, and eventually willpower decreases to a level where one cannot resist ‘doing’ them, or cannot raise the effort to continue resisting the desire to act out one’s wishes. In Baumeisters own words a tempting impulse may have some degree of strength, and so, to overcome it, the self must have a greater amount of strength, which can eventually be worn out or overcome, leading to adverse lifestyle choices in this ‘impaired mental energy state’. All lifestyle diseases and disorders may in his model therefore be related to an insufficiency of self-regulatory capacity, and there is an energy cost to resisting the ‘urges’ that lead to poor lifestyle choices, that may with time lead to either acute mental or physical fatigue, or in extreme cases to the development of chronic fatigue. Like with most contemporary psychology, the underlying reasons for such potential eventual failure of self-regulation were not deeply examined by Baumeister to the level that it was by Freud, Jung and colleagues, perhaps because so much of Freud, Jung and Adler’s theories are difficult to prove or disprove and therefore psychology and psychiatry have in the last few decades ‘turned against’ their theories and embraced neuroscience as having the best chance of understanding how the mechanisms underpinning self-regulation or the lack of it ‘work’, but neuroscience is currently far too ‘weak’ a discipline methodologically wise to be able to do such. Having said this, it is surely important that folk like Roy Baumeister are re-breaking such ground, and our understanding of such complex disorders such as CFS, and others such as fibromyalgia, which are also complex diagnostic dilemmas, is enhanced by the insight that mental energy ‘ego’ depletion may play a part in them. Sadly, there is evidence (described by Tracie Afifie and colleagues at Manitoba and MacMaster Universities) that folks who suffered physical or sexual abuse in childhood, or were exposed to between-parent physical violence at a young age, have an increased association with a number of chronic physical conditions (including arthritis, back problems, high blood pressure, migraine headaches, cancer, stroke, bowel disease, and significantly also CFS), and also a reduced self-perceived general health in adulthood, all of which would support the ‘ego and id’ psychopathology development theories of Freud and Jung to a degree, though of course surely not all folk who develop CFS have such childhood trauma issues.

Like the definition of neurasthenia and CFS, perhaps our understanding of their ‘deep causes’ is also moving in a ‘full circle’, and our knowledge of the underlying causes of CFS, if it does not have a specific organic or viral / toxic cause, needs to reconsider these basic concepts proposed by Jung, Freud and Adler more than one hundred years ago, and currently appears to be potentially re-occurring in a ‘repackaged’ version as suggested by Baumeister and his contemporaries theories in recent times. Perhaps the drive to keep on exercising that we found in all those athletes we examined in our studies at the University of Cape Town all those years ago was the key factor in the cause of their chronic fatigue, and was an ‘external’ manifestation of issues that they were not even aware of. We did not know enough about the subject back then to even ask them about it when we were trying to understand the causation of their symptoms. Perhaps a major component of CFS is mental exhaustion associated with continuously ‘fighting’ underlying past psychological trauma that the folk suffering from it are not even aware of, or at least this is part of the cause of the symptom complex along with other more organic or infective causes. Of course describing a disorder as either neurological or psychiatric is reductive, and indeed dualistic, and surely similar physical brain neural mechanisms underpin both ‘neurologic’ and ‘psychological’ disorders which we just cannot currently comprehend with the research techniques currently available. One has try to understand the reasons why one is ‘driven’ to do anything, particularly as one gets older and one’s physical (and perhaps mental) resources diminish and need to be ‘husbanded’ more carefully, though paradoxically CFS is a disorder which afflicts folk most often initially in their early twenties, and often ‘burns out’ / attenuates with increasing age, perhaps because part of growing older is often about understanding one’s issues to a greater degree, dealing with them, and living more ‘within one’s means’ all of materially, socially, physically, mentally and spiritually (although for some folk such learning never occurs). Aging may therefore be curative or protective from a CFS perspective (or one may die of ‘corollary damage’ such as heart attacks rather than developing CFS as a result of chronic stress related to unfulfilled drives).

Fatigue as a symptom is surely the body and mind ‘telling us’ that something is not ‘right’ and we need to rest – either acutely when we are doing sport, or chronically when we are ‘fighting’ something we do not understand or are aware of. The challenge is for us not just to rest, but to try and understand why we so often resist resting (well, those of us with complexes rather than those of us who are completely self-actuated and do not have stress or drives), and why life balance is so hard for many folk to find. The need (or unwanted requirement) for a prolonged rest / period of avoidance of one’s routine life / a ‘long sleep’ is often perhaps the last resort of those who are chronically fatigued and is nature’s way of ‘telling’ folk that they have ‘run out’ of responsive resources, and healing will not happen without it, though the healing may paradoxically be not of the fatigue itself, but of its underlying ‘deep’ causes. Now I am finished this its time to rest, and ponder what caused the need to write it in the first place, and why I have spent my holiday Easter period preparing for its writing, and ‘stoking the creative demon’ which never rests and which surely eventually damages one even as it creates, rather than just sitting in a coffee shop watching the world go by and thinking of nothing but how nice the next sip of coffee is sure to be. Demons of the past, away with you, before you lead to permanent mental and even physical damage, and tire folk out in the process!


Information Processing In The Brain And Body – Are We Managed By And Do We Regulate Our Lives Using Discrete Units Of Information Rather Than A Continuous Flow Of Knowledge

I have been spending quite a bit of time at work since I started my current role as a Head of a Medical School two years ago trying to get data ‘dashboards’ together of all aspects of our business profile, so I can better understand our strengths and weaknesses, and make informed decisions on how to strategically improve what we do and how we do it. On the home front we are making some plans to change our living environment, and are gathering data to make the best possible decision before doing so with the information we have available to us. Most of my life I have been a research scientist, and generating and understanding data has been the ‘trademark’ of my working life. One of the major challenges left for science and us scientists to solve is the understanding of basic brain function and the brain’s capacity for dynamic regulation of the body’s activity. A major component of this endeavour is understanding how the brain responds to information flow from the body, how it analyses this information it receives, how it comes to a decision to act (or not act) based on this information analysis, and how it generates information flow back to the body in order in order for it to respond to and / or make changes as a consequences of these decisions. Most of the time life ‘feels’ as if it occurs in an ‘always happening’, linear, continuous manner, and there are no apparent ‘gaps’ in our conscious awareness of activities occurring either around us or in which we are ourselves functioning and required to make decisions about. But, us scientists when examining brain and body function, ‘break up’ the information we record from a research participant we are observing into discrete data units, using a variety of physiological laboratory assessment equipment, which are recorded and stored as such, and we later print these data out or put these recordings into spreadsheets as numerical data, and create line or bar graphs in order to understand and explain what we have observed. The question therefore arises if as part of the inherent brain and body regulatory mechanisms which manage our daily life activity, do we similarly understand and assimilate an understanding of activity occurring in and around us in such an information processing / discrete data based way?

One of the most pivotal moments of my research life was working with the peerless Neurologist Dr Bernhard Voller as a Research Fellow at the National Institutes of Health in Washington DC, fifteen years ago, when he showed me how to perform the technique of fine wire invasive recording of skeletal muscle activity (known as electromyography). When we had placed the electrode in a muscle (we examined the nerve firing in eye muscles for the particular experiment), and the subject blinked, one heard the firing of the nerves controlling the muscle via a speaker attached to the electrode recording device, and the rate of firing increased rapidly each time the subject blinked with greater force. What was such a ‘wow factor’ for me, was that what we were listening to was the information ‘code’ going down from the brain to the specific muscle we were studying, in order to make it contract with the required force. If you put a similar electrode into any nerve in the brain or travelling from the brain to the body, you will see or hear a similar firing rate change happening, which is the ‘code’ used by the brain to generate commands and induce changes in function of any organ the nerves target. One of the most interesting studies I have ever read looked at single neuron firing in the motor cortex of a monkey’s brain when its arm was being moved in different directions around its elbow joint. Each movement created a different ‘code’ of firing which was unique to each specific movement, and if one looked at the graph plots of the generated data after learning the different ‘codes’ for each movement, one could predict with a high degree of certainty which arm movement had occurred to produce each specific trace. So certainly at the physical nerve firing level, information is generated, and function regulated, by discrete coded information that was evident and could be ‘decoded’ when examining a particular nerve’s firing rate.

This numerical coding of information is also evident across a variety of body systems. For example, heart rate is a measure of how fast the heart beats, and we know that when the heart beats faster it is working harder in response to a greater need for blood flow around the body, such as when doing exercise, or during a hot day, or when one is sick and has a fever. So if we examine a heart rate trace collected during a 24 hour period of time from someone, without being told what the person whose heart rate we were retrospectively examining had been doing, we could make a good guess of what activities the person had been involved with at different stages of the time period their heart rate was assessed. For example, if the heart rate is very high for an hour or two in the early morning or evening period, one can assume with a high degree of certainty that this is probably caused by the performance of a bout of exercise. In contrast, if heart rate is very low for an extended period of several hours in the evening time, one can guess that this would be associated with a period of time when the participant was sleeping. Another very interesting study for me was one that examined the output of neurotransmitters (a chemical substance) when a varying change in firing rate was artificially induced in a neuron ‘upstream’ of the synapse where the neurotransmitter was released, and it was found that the release of neurotransmitter occurred in a discrete pulsatile manner that was directly correlated with the ‘upstream’ induced firing rate. This indicates that the ‘fidelity’ of the rate coded neural message was maintained even by chemical substances, and that regulatory information is not confined in complexity or content only to neuronal firing mechanisms, but occurs also in blood borne / neurochemical substrates.

In order for this ‘rate coded’ information to be created and interpreted, some yet unidentified algorithmic processes in the brain needs to break it up into ‘useable’ bits or chunks of information of a certain length or period of time, and the interpreting algorithm needs to have a ‘pause’ in order to both make sense of this information and respond to it, before ‘receiving’ and responding to further information from the same source. If information arrived in a continuous stream that was not ‘broken up’ into ‘bits’ of information, no interpretative sense could be made of it, and no logical response based to the information encoded in it could be initiated. We have previously suggested that information must occur as, or be broken up by the brain into, ‘quantal packets’ of information, and each ‘quantal packet’ of information is used by the brain to make sense of what is required by whatever initiated the perturbation that lead to the generation of the information flow, and how the brain needs to respond to the information. There is surely always alternating periods of ‘certainty’ and ‘uncertainty’ occurring related to the flow of information in the brain and body – certainty when a coherent quantal packet of information is received and ‘understood’, and uncertainty in the periods prior to the full required quantal packet of information being received, or during the period after the full quantal packet of information was received and a response to it enacted, during which time and after which further information from the original source will be required to assess whether the response was satisfactory and / or fulfilled the need that caused the original information to be generated. So the passing of time is a fundamental requirement of information flow and the understanding of it, and there will always be alternating time periods of certainty and uncertainty related to the information flow. What length of period of time or quantity of information is required to create a period of certainty in any brain or body system is likely to be a product of the type of substance which creates the information (ie shorter in nerve tissue and longer in humoral / blood substance), what purpose the information is created for, and the complexity of the issue the information is associated with.

Clearly from the above examples, a strong case can be made that information coding underpins the regulation of physical brain and body function. However, it is more difficult to understand how cognitive (mental) information we receive from the external world is ‘managed’, and if and how we ‘break it up’ into useable ‘bits’ of discrete information that can be made sense of by our algorithmic information processing functions of the brain. Most data would suggest that we do indeed break up information of social or environmental situations into at least categorical (for example need to respond / not respond) information. My esteemed colleague at the University of Worcester, Andy Renfree, has looked at decision making theory in relation to physical activity and shown that we make cognitive decisions on future levels of activity or plan for future activity based on either rational (taking all factors into account) or heuristic (using past experience to attenuate the complexity of decision making requirements) information and cognitive decision making, using differentiated information about one’s own current physical capacity and performance level, environmental factors, and the capacity of other individuals one is competing against, amongst a number of other factors. Knowledge of all possible behavioural outcomes, and an assessment of the potential risks to oneself of all the potential outcomes, as well as their potential rewards, are surely also individually assessed as part of any action related decision making process. However, cognitively and consciously it never ‘feels’ that all such factors are so individually and discretely assessed, but rather that life occurs as a ‘smooth’, continuous activity, with no perceptual ‘gaps’ occurring when decisions are being made or when cognitive uncertainty must be occurring. This ‘smooth’ conscious perception of life with no ‘gaps’ in it may occur because we do not focus on a specific thought, activity or sensation for any extended period of time, and rather ‘switch’ our attention continuously between different issues we are ‘working through’. Therefore, as a number of different thoughts related to different issues ‘intrude’ sequentially on our consciousness, this may ‘fill the cognitive gaps’ which would occur as a necessity when making cognitive decisions on any one specific issue or requirement, in the time periods of uncertainty before a cognitive ‘decision’ is made about any one ‘issue’ one is dealing with. It is obviously very difficult to research this area of cognitive information processing, given our lack of knowledge of core brain function, and the difficulty of being able to objectively assess one’s continuous real-time thought processes with the current laboratory research techniques available to us, which are still very crude and retrospective / mostly qualitative in nature.

While life as we know it may thus appear to occur as a continuous flow of activity and events which we respond and react to, how we interpret these activities and events and regulate our responses to them may indeed occur in a discrete information based numerical manner, replete with information ‘gaps’ and periods of uncertainty interspersed with ‘quantal packets’ of information rich certainty time periods, that each vary in length dependent on the complexity of the situation being assessed, the processes being used to assess it, and the physical substances in the brain and body used to assimilate and understand them. Information processing and decision making underpins all regulation of our brain and body functions and our successful interaction with the socially and environmentally challenging external world in which we exist. Our successful reaction to changes in either external environments or our internal physiological milieu depends on the successful generation of information describing these changes, the successful interpretation of this information, and the successful generation of actions in response to this information. At the neuronal level simple firing rate and rate coding underpins all information flow, and our physical responses are related to changes in this ‘code’ and the information encoded by these firing rate changes. To better understand the manner in which this information processing occurs in more complex issues is a lifetime of work in the time ahead for us neuroscience and information science folk. But, perhaps us scientists use discrete numbers and data to makes sense of how things work, because at the level of brain and body regulation and control, information flow and discrete data generation and assessment are the conceptual requirements underpinning all successful life activity, and us scientist folk are merely copying the ‘instruments and methods’ of the master designer who created us in the way we have been created when we do such work, whatever that master designer is or was. Time will tell if this is true or not, but, pertaining to our domestic decision-making requirements relating to whether we should stay in our current environment or move to another – brain neurons, was that one click or two I heard when you fired as I was thinking on this issue a moment ago!


Cell Function And Metabolic Flux Control – The Puzzle of Regulation of Massive Numbers Of Continually Occurring Processes In A Spatially Challenged Environment

In the early years of my medical training, many years ago, it was hugely exciting to learn the basic science of how the body functioned, before we learnt about the pathological processes affecting body function, and how to treat these. Two visual memories have always stuck in my mind from the lectures I attended back then. These were both of some brilliant diagrams drawn on the blackboard during these basic physiology and anatomy lectures by two charismatic teachers. The first was of the neural pathways flowing to and from the brain, and these complex but organized information directing structures were drawn with such clarity that they entranced me, to the extent that they perhaps in part led to me becoming an integrative neuroscience and system regulation researcher for much of my career. The second blackboard drawing I remember was of the metabolic pathways of a cell, which made me feel a sense of awe regarding the complexity and sheer volume of processes and structures present in a cell when I saw them for the first time as line drawings on the blackboard way back then. Being throughout my life more of a systems and processes, rather than a specifics and detail, type of thinker and person, these cell pathway pictures made me feel a touch ‘queasy’, no matter how beautiful they were drawn, and this ‘queasiness’ I felt then perhaps moved me ‘away’ from molecular or cellular biology as a career choice, because intuitively I knew even then I would never have the capacity, or interest, to learn each different enzyme or DNA or protein structure in the cell, and how each of these ‘worked’ to provide the basic energy needed to sustain life as we know it. A couple of days ago, Professor Craig Sale, one of the UK’s foremost Physiology and Exercise Science researchers, and surely one of the nicest persons on the planet, posted a fascinating review article on Twitter examining basic cellular metabolism changes related to exercise to rest transitions, and reading about the associated changes in ATP, NADH, and CrP, amongst other cellular substrates and enzymes described in this review article, reminded me of those flow diagrams of my medical training days, and got me thinking about the basic function of the cell, and how the flux of all these basic cellular substrates is managed in the microscopic cellular environment.

The cell is the basic structural and functional unit of any organism, including us humans. One’s entire body is made up of cells, and it is thought that each person consists of around 10 trillion cells (a number so vast I can’t get my head around it). While the cells making up different structures in the body like skin, muscle, bone have some differences in their structure and function, the basic ‘makeup’ of all cells is almost identical, and fascinatingly from an evolutionary perspective works similarly across all species and indeed most living structures. Each cell is surrounded by a cell membrane, and has a number of organelles in it that are important for its survival and optimal function, including a nucleus (where the cell’s DNA is stored which is important for replication), mitochondria (the energy creating ‘powerhouses’ of the cell), and several storage and structure creating entities known as the Golgi apparatus and endoplasmic reticulum, amongst others. The cell membrane is important not just for structural integrity, but also for controlling the movement of substrates, fuels, metabolites and signalling molecules into the cell, using enzyme related receptor mechanisms. The cell’s interior consists of a fluid substance known as cytoplasm, in which enzymes and cofactors either break down carbohydrates, fats and proteins into basic energy products (the basic energy molecule in the cell is adenosine triphosphate – ATP) in a process known as catabolism (this process also occurs at a rapid, energetically efficient process in the mitochondria), or builds up structural components required to repair damage in the cell, or to create a second cell when the cell replicates, in a process known as anabolism.

In either the cytoplasm of the cell, or the mitochondria, are the numerous metabolic ‘pathways’ which were so elegantly drawn for us in our student days, and as a ‘cascade’ through numerous sequential intermediary products in a process managed by sequential enzymes and co-enzymes, fuels such as carbohydrates and fats are catabolised into basic energy products such as ATP. For example in the cytoplasm of the cell, the ‘glycolytic’ pathway occurs, while in the mitochondria the ‘Krebs cycle’ and ‘citric acid cycle’ are different catabolic pathways. Oxygen is a necessary requirement of the mitochondrial basic energy producing processes which are therefore defined as ‘aerobic’ pathways, while the cytoplasmic glycolytic processes do not require oxygen, and are defined as ‘anaerobic’ pathways. The anaerobic glycolytic pathways are not as efficient in producing basic energy as the aerobic pathways, and produce metabolic by-products which need to be removed from the system, such as lactic acid. Because lactic acid builds up during high intensity exercise like sprints or other ballistic / maximal activity, it is thought that during high intensity exercise the cells become oxygen deprived or ‘anaerobic’, and the glycolytic pathways are use preferentially and as a final energy ‘reserve’, though whether cells are ever completely oxygen deprived and therefore rely on ‘anaerobic’ mechanisms to produce fuel during activities of daily living or during exercise is still controversial. There are an enormous amount of different pathways in a cell, and seemingly each month, a new enzyme, co-factor, intermediate product, or metabolic by-product is discovered, which creates an even more complicated ‘picture’ of the working environment in each cell.

The regulation of these complex cellular activities and structures has focussed principally on metabolic flux and enzyme kinetic processes. Metabolic flux is defined as the rate of turnover of molecules through a specific metabolic pathway, and describes the ‘movement’ of substrates or intermediary products ‘through’ a specific pathway. Metabolic flux is related to the ‘need’ of both the general body and specific cell environment for energy, and is increased when there is greater need (for example when one exercises), or when there is greater substrate present (for example after a meal). One of the most amazing things in science is how each of the different ‘steps’ of each pathway increases sequentially and in a temporally co-ordinated way when increased need or increased substrate availability occurs, to ensure that the pathways work correctly and are not ‘overwhelmed’ whenever there is the need for increased activity in all its component parts. This coordinated increase in activity in an entire metabolic pathway is thought to be controlled by increased and optimized enzyme function at each step of the specific pathways processes. Enzymes are protein molecules that can ‘manipulate’ and therefore control other molecules and substrates, and enzyme kinetics is defined as the study of the chemical reactions that are regulated by enzymes. When there is increased energy requirements, the function of the pathway’s enzymes is up-regulated, in order to ‘deal with’ the increased demand. The function of an enzyme can be plotted (for those technically minded folk an example of this is the Michaelis-Menten function equation) as substrate concentration increases, and generally at the start of a period of increased ‘need’, enzyme activity at each different step of a metabolic pathway is rapidly increased to compensate for the increased requirement. Subsequent to this initial rapid increase in enzyme activity, enzyme activity ‘levels out’ as the absolutely maximal activity capacity of the enzyme is reached. The enzyme kinetic / cell regulation researcher folk suggest that the rate limiting capacity of any pathway (and therefore the energy creating ‘controller’) is that of the enzyme with the ‘lowest’ functional capacity – in other words, the enzyme in a pathway that can least up-regulate its function in a time of increased energy demand or increased energy fuel supply, is the factor that controls the metabolic properties and activity of that particular cell. In this paradigm, therefore, the human body’s physical functional capacity is related to these cellular-level rate limiting enzymes, together with the quantity of energy fuels available that can be used by the enzymes.

All this knowledge of basic cell structure and function, that is still increasing incrementally (perhaps even exponentially) as yet another cellular regulatory molecule, enzyme or membrane signalling / transduction regulatory protein is discovered, still fills me with as much awe today as it did nigh on thirty years ago when I first learnt about it as a first year medical student. But, I do believe that a lot more research is needed in the field of cellular metabolic regulation for us to have a clearer understanding of its regulatory processes. Indeed, the wonderful ‘pictures’ drawn of the metabolic pathways may, in a paradoxical way given that they are so complex, be describing cellular regulatory mechanism in a too simplistic manner, and we perhaps have a long way to go still to fully understand regulatory control mechanisms at the cellular level. For example, hundreds, if not thousands of different metabolic pathways are actively catabolizing substrate fuels, or synthesizing new structural molecules, at any one point in time. Likewise, thousands, if not millions of different individual molecules are being acted upon, or are acting upon other molecules, in any one cell at any single point in time. How the integrity and fidelity of each metabolic pathway is maintained in the face of all this co-existing ‘other’ metabolic activity has still not been determined. How each molecule ‘knows’ where it ‘has to go’, and where in the cell it will be acted upon, at a single point in time, let alone in the required temporally appropriate manner, is still pretty much unknown. Equally, how the function of individual cells is harmoniously regulated as a component of the gestalt millions and billions of cells in a specific organ, which all must be similarly up-regulated in time of need or increased substrate concentration, and then down-regulated at time of work-rest transition, is not understood at all. Whether different specific cells have different efficiencies and metabolic milieus compared to that of their neighbours, has also not been determined, and for us to have knowledge of this conundrum will need spectacular new laboratory techniques to be developed. How the afferent ‘messages’ from each cell become a gestalt ‘message’ to the brain which ‘suggest’ a requirement for an initiation of behavioural change, when for example fuel supplies are depleting, is also completely unknown, as is how each different cell receives similar efferent information to either increase anabolic or catabolic need as it is required. Furthermore, the relationship between the ‘physical’ control processes such as enzyme kinetic control process or metabolic flux determinants, and electrical / electromagnetic energy, is not clear. All active metabolic control mechanisms are underpinned by electrical activity changes, or at least electrical activity can be detected in cells whenever physical chemical changes occur in the cell. One of the most interesting research papers I have ever read described a study of NADPH activity in macrophage cells. When interleukin-6, a humoral (blood / fluid related) signalling / regulatory molecule was added to the cells, the concentrations of NADPH increased. When an electrical current was supplied to the cells along with interleukin-6, the concentration of NADPH increased even more than when just the interleukin-6 was added. How this ‘piezo-electric’ electrical / chemical interaction works at the cellular level is still not clear, as is whether electrical, or electromagnetic activity, are subsidiary or integral components of cells and their metabolic regulation.

A beautiful picture or line drawing of a particular metabolic pathway of a cell gives us therefore a ‘snapshot’ of the processes involved in that particular pathway, but does not give us the full picture of what must be ‘dizzying’ real life / real time activity occurring as a hugely complex, interactive, always changing, process and environment in any one cell, let alone in an aggregation of cells. How control processes occurs in not just one cell but similarly in many cells is another problem of an order of magnitude greater than we can perhaps currently understand with our available research techniques and conceptual frameworks we use to understand such function, which usually involve breaking down such dynamic processes into its composite parts to allow easier explanation. By reducing the complexity such in order to do so, we perhaps lose our capacity to understand the ‘gestalt’ control processes and mechanisms in the cell. A good scientist will always be humbled by the awareness of how much activity, and how much regulatory control, is required for even a single, ‘simple’ cell, which is the basic building block of all physical life processes and structures we know of and are made of. An integrative systems scientist like myself will always admire and respect the work done by the scientist folk who work at solving the ‘detail’ that exists in each cell and its individual component. But the big questions of cellular function and metabolic regulation are still surely ahead of us to be answered, and beautiful flow diagrams of cellular metabolic regulatory pathways, as those which will always be engraved in my mind from those seminal days of my academic youth were, will never be sufficient to allow understanding of the ‘place’ of the regulatory processes in the cell in the bigger picture of the regulation of life as we know it.

Perhaps using a three dimensional high-tech video clip of real time cellular activity, some charismatic lecturer, way in the future, will be able to explain to some young medical students how it really does all work, when I have long been resting in my pine box, and my cells are of the earth and being used as energy for another generation of cells in another future scientists body. Time will tell. But, for now, I will have to be satisfied with the memory of those beautiful drawn cellular pathways, and keep trying to remember the names of each substrate, enzyme and intermediate metabolite associated with them. And if I could go back in time, I would tell those two great lecturers that their drawing skills and passion for their subject matter were still remembered thirty years down the line, and inspired a career choice for me!


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