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SECTION SIX

Limitations of theory

Limitation is an understatement, to say the least. Biological theories are inevitably examples of inductive generalisations made from observed phenomena; medical theories are, at a further remove, inferences upon them. As inferences are made upon inferences and the chain grows longer, the links inevitably become weaker. While Medicine has, since the Classical Period, relied to some extent upon empirical observations, Evidence Based Medicine is a very recent approach to decision- and policy-making. As part of a mission to make money go further and with the laudable aim of analysing treatments so that futile and ineffective measures are abandoned, EBM attempts to reduce the cognitive biases under which we all operate. It is applied to therapeutic and diagnostic decisions and is narrower in its scope than a model or theory and, it might be argued, is more truthful in accepting this limitation.

Personalised medicine cannot by definition be subjected to statistical evaluation though it would be a worthwhile enterprise, if not an imperative, if we were to conduct and systematise clinical audit of our practices. By this and other means of evaluation, we might lessen our inevitable cognitive bias and reduce the inferential generalisations made by theory. EBM attempts to minimise the subjective in clinical decision–making, admirable for public policy, yet illness itself is a subjective phenomenon for which biological theory attempts to make cohesive inferences. Theories like contracts are inherently incomplete⁸⁹ and cannot preconfigure every possible circumstance.

It might therefore seem perverse to extend a theory in a section expressing its Limitations. I do so because there is at least good scientific work on the deep influence of our physical world on biological rhythms, and these oscillations are at the centre of Poise. The absence from EBM of any such theory leads to a fragmented empiricism, which is adequate only for emergency medicine.

Escape from limitations

Constraints form the springboard of life and creativity. We cannot escape the limitations of the model, but we can use them to our advantage as I hope to do in the rest of this section, morphing into Potential Applications towards the end of this section.

How medicinal plants can help a person maintain Poise is the focus of Part Three, but as we are here considering the strengths as well as the limits of theory, it may be helpful to outline those systems that need stabilising. A summary of clinical indicators is made in Sections 10, 11 and 12.

Time and drive

Awareness depends upon the maintenance of an adequate perfusion of oxygenated blood to the brain and vital organs. From moment to moment, survival and consciousness depends upon the maintenance of blood glucose and reserves of substrate. In the slightly longer term, water and salt balance must be regulated. Reserves of substrate can be maintained by antagonising systems that catabolise them and enforcing systems that conserve them. The relationship between the corticosteroids with muscles, liver and pancreas concerning glycogen, amino acids and lipids is the primary contender. It is therefore towards those organs and to the HPA axis that therapeutic support can be directed. Blood viscosity permits and limits all these drivers.

Rheology

Perhaps the greatest limitation to any concept of health comes from an unseen state: the flow characteristics of blood in vital tissues. In the limbs, obstructions soon show up as pain and other inflammatory signs, but those in deeper structures will do so only in hindsight, and the longer the flow of lifetime, the greater the potential for perturbations in the river bed ahead and the accumulation of impedance in vessel walls. When blood ceases to flow, time ceases to flow.

At the other end of life, without a clear flow of blood, the blastocyst could not have been implanted. Flow depends upon the smoothness of an unbroken vessel wall and is characterised by the proteins, solutes and cellular constituents of blood as it courses along. Almost certainly, a diet rich in the many nutraceutical compounds from plants⁹⁰ will maintain vessel integrity, but probably only upon a state afforded by a fortunate early life, relieved of a chronic infectious and inflammatory load. If medicine and culture would only direct their resources into the care and protection of pre–conceptual, pregnant and nursing mothers, good health would attend without the need for much medication, herbal or otherwise, and many of the discussions in this book would be glad to be rendered redundant.

Patterns and drivers

Mindedness is developed from micro to macro, from the binary choices facing the cell to the dense skein of S–O–R loops that constitute the multicellular organism (to be revisited in Section 22). Yet it is the macro, by the tidal forces generated by the sun, moon and earth, that generates the micro. As discussed in Section 3, the nervous system provides immediate responsiveness, mostly musculoskeletal while the endocrine system enables capacitance. A neurotransmitter is effectively paracrine: a local hormone, delivered as it were by a pipette, so the distinction is more of degree than kind.

Even though ultradian rhythms like heart-rate and blood pressure respond inherently to demand, as walking briskly upstairs will demonstrate, they do so against an inherent rhythmicity in heart cells, and there appears to be a background circadian influence on patterns of this cardiovascular reactivity.

The coupling of these circadian drives and their organisation within the human body can be systematised into the following four regional elements (all of which are underpinned by the flow characteristics of the blood):

1. The Hypothalamic–Pituitary Driver

2. Cholinergic and Aminergic referees/regulators

3. Hypothalamic–Posterior Pituitary Intensifiers

4. Organ responders and pacemakers.

1. The hypothalamic–pituitary driver

The pituitary stalk leads to five cell types in the order of the usual number of secretory cells:

1. Somatotrophes mainly secreting Growth Hormone

2. Lactotrophes secreting Prolactin

3. Gonadotrophes secreting FSH and LH

4. Corticotrophes mainly secreting ACTH

5. Thyrotrophes secreting TSH.

It seems that the relative populations of each cell type can vary to accommodate changes in environmental patterns and that there are even cells within the pituitary that behave like stem cells, conferring great adaptive capacity. This correlates well with the horizontal relationship between hormonal axes that is fundamental to Endobiogenic theory, though it falls short of substantiating the theory of the double loop (see footnote 48).

The diurnal patterns within the endocrine system are well known and documented, notably in thyroid and adrenal axes in which cortisol figures strongly. These phases of dominance divide the light/dark cycle into a series of time–segments, as follows:

Hour	Phases of hormonal feedback loops	Phase length
22	cortisol* decreases to its lowest value and remains low	for 6 hours
22–	maximal influence of insulin–like growth factors but with an obligate dependent on sleep states, for next 6 hours
3	pacemakers in the liver increase amplitude in preparation for next phase	1 hour
4	cortisol* abruptly released and rises steeply (most births and deaths occur here)	4 hours
8	cortisol peaks and its rise flattens off
8	levels* of thyroid hormones rise steeply	3 hours
11	thyroid hormones peak and their rise flattens off
14–16	trough in levels* of thyroid hormones	2 hours
16–18	steep pre–crepuscular rise* in cortisol and thyroid hormones; peak in body temperature	2 hours
18–20	slow and modest crepuscular ascent	2 hours
20–22	descent of cortisol*	2 hours
*I am using the single hormone as shorthand to stand in for the axis within which it operates. Although these hormones can be measured in blood, they stand not for themselves alone but for a web of relations and so it would be more accurate to characterise these as modifications of feedback loop sensitivity in the axes (induced in part by other co–factors, such as ADH) rather than serum levels of the hormones themselves, but the outcome is effectively the same. Even the whole axis operates in tandem with others so that endocrine life is always coaxial. More crucially and impossible to measure directly, hormonal levels exist in proportion to the population of their receptors on the membranes and in the cytosol of responsive cells.

As can be seen from the table above, these phases are not symmetrical either side of noon, and unpredictable events must inevitably modify these episodic fluctuations in the daily rhythm. Social and cultural events tend to follow a normative pattern that respects local conditions and the diurnal phases. As everybody connected to a theatrical production, at least in the Western tradition knows, a matinée performance is very different from the one given a few hours later. Although we do not allocate function rigidly to a time of day, cultural timings are far from arbitrary. A fixed rhythm must be stable and short enough to provide a regular background. There could be many candidates for pulses that might influence human attentiveness and stamina and surely they vary between individuals. Pulses are not simply of arithmetic length but are complex waveforms that are stable yet available for recalibration according to circumstances.

Even so, the question for physiology is whether any of these phases is divisible into shorter rhythms. The question for health asks whether a greater responsiveness to episodic time would confer benefit. The first rather obvious observation notes that the phases are of different length and range from one or two to five or six hours (but see the caveat in the preceding paragraph). For circadian rhythms to be effective for survival and reproduction, they need a range of values that allows for the opposite needs of precision and approximation, allowing for the capacity to anticipate with a responsiveness to variation. In humans, attention and focus depend upon personal and cultural motives and expectations and cannot be generalised even though recent research has tried to explore the range which finds values as short as eight seconds while there seems to be some convergence on maxima of 20 minutes. This is the approximate length of time taken for each cell division during embryogenesis and has much the same period as the pulse generated by the discharge of CRH from the hypothalamus to the pituitary, and possibly also that of Gn–RH. Regular rhythmic pulsation thus drives the adrenal and reproductive axes in human metabolism. Even if such regularities do exist, cultural divisions of time do not seem to follow them, taking other cues and markers. Nevertheless, lectures and talks on a single theme rarely exceed the hour without exciting comment or protest.

Even if this short period is real, circumstance easily extends it as enforced waiting has an effect on human performance and expectation. Those who are used to episodic work will recognise this change in stamina over time and an up-regulation of endurance; by contrast, the performance of those whose work is inflexibly timetabled will be reduced. The watched clock on the wall perhaps defines regularised boredom. Boredom is not of course confined to periods of 20 minutes but rather the period in which time is watched. Absorption in a task rather suspends anticipatory drive for other tasks. A requirement for or an aversion to stimulation are markers of personality that we will consider in Part Two, but in most cases Poise will depend upon capacities to manage phases of time which are not symmetrical through the course of the day and night.

In the tropics day and night are only roughly equal but there are other asymmetries: rest and activity, parasympathetic and orthosympathetic are not of equal duration. Like the alternation between systole and diastole of the cardiac cycle, there must be room for adaptation to events but this variance must play upon a stable ground. The set points are calibrated by the individual terrain in utero and at developmental and later life stages. In my beginning is my end.91 These initiating settings are shifted at times of stress and do not easily shift again when the stress is continuous and chronic.

2. Cholinergic and aminergic referees/regulators

The branches of the autonomic nervous system are the peripheral agents of cerebral circuits based upon these neurotransmitters that are widely distributed in networks within the brain:

1. Acetylcholine

2. Histamine

3. Noradrenaline and adrenaline

4. Dopamine

5. Serotonin.

The alternation between parasympathetic and orthosympathetic mimics that between the high energy state of day with the conserved and maintenance mode of night. Acetylcholine interpenetrates these two states.

Histamine is associated with central arousal though in some ways it may limit drive, because in the autonomic cycle its action as an autocoid attenuates the alpha–sympathetic period, priming the person for action. Caught in the priming mode may delay and even frustrate action. The central circuits have consonant centres throughout the body, especially in skin and the mucosae of the digestive and respiratory tracts and so are sites of the expression of many symptoms and obvious candidates for therapy. Histamine converges less towards gratification than dopamine so the associated drive may be one that is less resolved, though perhaps we should hesitate before dubbing it the hormone of irresolution. Serotonin provides us with a notion of our capacity and may act as some kind of internal index, while noradrenaline braces us for the discharge of adrenaline.

3. Hypothalamic–posterior pituitary Intensifiers

These have been discussed in the segment entitled Organisational Structure in Section 4c. While oxytocin may be reactive to circumstances and occasion, ADH is strongly yoked to ACTH and thus is linked with its anterior pituitary circadian drive. Much of the ADH secretion is pulsatile and independent of the posterior pituitary, though even here its setting for volume regulation of the circulation alters between day and night, conserving both water and sleep.

Anterior and Posterior Pituitary hormones are systems that have more in contrast than in common which reflects the fact that they have different embryological origins.

4. Organ responders and pacemakers

Most organs respond to demand yet there are pacemakers in the liver that prime the principal pacemaker in the SCN in the hypothalamus. The kidney's involvement with the calcitropic hormones⁹² is linked to the pacemakers by aldosterone and angiotensin as well as by ADH. Although the natriuretic economy monitored by the heart⁹³ is more reactive, there exists a background circadian drag on the cardiac response. The small intestine responds of course to the food it receives yet the perception of hunger and the drive to assuage it comes as much from the digestive tract as from the hypothalamus and central regulators. The tube is replete with paracrine and endocrine cells especially with effects in the somatotrophic axis. Many of these are more resonant with seasonal and even annual rhythms than they are with the diurnal pace.

Potential applications of theory

Dark	Light
If ACTH is generated early, middle insomnia, especially at 3am is almost certain	ACTH dominant at the end of night and has many receptors in the caecum and rectum at the beginning and end of the colon, hence early waking may be accompanied by digestive disturbance. Focus of treatment on the Corticotrophic axis should be considered
Parasympathetic and central cholinergic circuits dominate.	To launch the Beta–sympathetic, the Parasympathetic should paradoxically be maintained if good digestion of breakfast and utilisation of Serotonin is to be enhanced; however, diminution of the alpha–sympathetic will speed the day
If hypertonic, congestion and respiratory distress likely
Prolactin and Growth Hormone will permit growth and repair. Pulse of TRH will disturb sleep	Use the morning to optimise Thyroid axis which will require good pancreatic function
Reduction in both Alpha– and Beta–sympathetic with reciprocal Parasympathetic response necessary to initiate sleep	Adequate generation of serotonin in the retinae and in the digestive tract and its movement to the pineal needed for melatonin formation
Melatonin needed to maintain sleep
Late eating will tax duodenum and gallbladder and rouse typically at 2am	Optimal thyroid management by diet and activity in the morning and less of both in the afternoon will set a person up for a good night
Overburdened liver will disturb sleep pattern and rouse typically at 3am
If histamine and noradrenaline do not sleep then neither will the patient	Diurnal expression of histamine is best managed through liver and gallbladder; noradrenaline can be best managed by the Corticotrophic axis
Serotonin and Dopamine need to be well expressed by day to provide adequate rest and effective dreaming by night	Prolactin needs (but according to circumstances) to liberate Dopamine by day to provide adequate drive and motivation
	Excessive dopamine and inadequate Prolactin may tend to disorganisation
	Excessive Prolactin and inadequate dopamine may tend towards an obsession with organisation and a failure of imagination, or one that is confined to detail and impending catastrophe

Configuration of the terrain within the human body

We tend naturally to see the wholeness of the physical body in front of us, but in medical practice it is helpful to switch perspectives and focus rather like the flip of a multidimensional Necker cube.

We need also to see that we are the built environment for the biome in our guts and on our skin. We may be one pinnacle of evolution but we sit upon an enormous pyramidal base of evolutionary experiment. Our survival as individuals or as a species is ineluctably dependent upon this relationship with species of microorganisms which have learnt the lessons before we have to. Our physical environments have their own state and as we move through them we have to adapt to them and to what they have adapted to. In these senses, the interactions outside the body are almost as multifarious as those within. In human interaction, whether in the clinic or the street, more than one sphere is operating and emphasis shifts from here to there from moment to moment. The following table extracts a summary of the bulleted text in Human Drives as a function of time in 3/5 Life as Trajectory in Section 3.

The Proprioceptive or “Thalamic Mind”	contained largely in the Musculoskeletal System and its spinal and central connections
The “Hypothalamic Mind”	responding and ordering
Analogue Consciousness
The Terrain	the archivist of the above relationships
The engines of response	Heart, Blood vessels, Spleen and Brain
The organs of first resort	Adrenal Cortex and Medulla Thyroid gland
The organs of last resort	Liver and Kidney

The order of these elements is a deliberate reversal of the Cartesian tendency in the opposite direction. The miracle of Consciousness allows us to be bystanders to the life miraculous, but this vision is an emergent product. The really intelligent machine is the thinking of moving and deciding, whether by a cat, a mouse or a person.

Moravec's paradox

The work of Hans Moravec and others in Artificial Intelligence demonstrates the paradox that, despite appearances to the contrary (and the word “appearance” is telling) abstract reasoning makes a relatively small computational demand upon our resources whereas, by contrast, the everyday pottering about, as well as the cooking, sewing and cleaning that make up the texture of our physical lives requires enormous computational resources. As Moravec writes:

Encoded in the large, highly evolved sensory and motor portions of the human brain is a billion years of experience about the nature of the world and how to survive in it. The deliberate process we call reasoning is, I believe, the thinnest veneer of human thought, effective only because it is supported by this much older and much powerful, though usually unconscious, sensorimotor knowledge. We are all prodigious olympians in perceptual and motor areas, so good that we make the difficult look easy. Abstract thought, though, is a new trick, perhaps less than 100 thousand years old. We have not yet mastered it. It is not all that intrinsically difficult; it just seems so when we do it.

(Mind Children, 1988, Harvard University Press, pp. 15–16)

An older co–worker in the field, Marvin Minsky says, in The Society of Mind (see Bibliography):

What magical trick makes us intelligent? The trick is that there is no trick. The power of intelligence stems from our vast diversity, not from any single, perfect principle.

The cognitive and linguist scientist Steven Pinker puts it succinctly in The Language Instinct:

The main lesson of AI [and Robotic] research is that the hard problems are easy and the easy problems are hard. The mental abilities of a four-year-old that we take for granted—recognising a face, lifting a pencil, walking across a room, answering a question—in fact solve some of the hardest engineering problems ever conceived…gardeners, receptionists, and cooks are secure in their jobs for decades to come.

Likewise, whether a bird thinks is a less useful question than how it learns not to stall when flying. As Leonardo and Gerard Manley Hopkins observed and wondered at the magnificence of their flight, in doing so, they used up less intelligence than in their sitting and walking. Their artefacts enlarged the size of our cultural potential, shared and expanded by millions on another order of existence, to which we may all belong. As a footnote I would add that while sitting and thinking and writing a book, looking at a computer screen all the while, may be tiring after a concentrated stretch, it is not just the demands made upon blood glucose by focused cerebration that takes its toll, but that the proprioceptive mind has all the while been underused. It is this uncoupling of the needs of the physical with the mental that is the source of deep fatigue. Poise at its height implies deep physical comfort but it is as life is in continuous inner movement; besides, sociality will inevitably recruit some emotional discomforts. That is what it is there for, to remind us that:

No man is an island entire of itself; every man is a piece of the continent, a part of the main. If a clod be washed away by the sea, Europe is the less, as well as if a promontory were, as if a manor of thy friend's or of thine own were. Any man's death diminishes me, because I am involved in mankind. And therefore never send to know for whom the bell tolls: it tolls for thee.

(From A Selection from the Prose of John Donne—London: The Folio Society, 1997)

The materialist defence

The defence is needed against the spiritualist claims of superiority which lead to all manner of dualist absurdities. When I write my signature, I do not claim that my hand wrote it while I merely supervised from on high. Our patients often say that their current state probably comes from their hormones as if somehow these are separate agents over whom they have little control. I respond usually by pointing out that we are our hormones as much as we are our hands, mouths, eyes and feet. In politics, we may speak of a body being an agent of the state, but in biological systems, which cannot be other than integrated, our parts are our whole.

Just as the subconscious is an upsurge from the parts we cannot see, so spirituality is a down-surge from the totality of our being, reminding us of the extensiveness of our conscious minds. Materialism is not a denial of religion or religiosity (see—Reflexive Collectivism in Section 17—the unconscious).

Intelligence is an index of capability. The early IQ tests suggested that narrow computational skills were the only predictive and useful ones and displayed an equally narrow hierarchical version of capability. They seemed to suggest that animal intelligence is somehow lower, but being intelligent enough to be a dog or a fish is no more or less than is needed. There are of course a multitude of capabilities and most of them are temperamental. Intellect, for example, is not an index of intelligence, just a particular disposition and attitude to the world. Children suffer if their parents have little emotional intelligence.

For the concept of intelligence to be comprehensive and distributed rather than hierarchical, it must be integrated at all levels with praxis. Matter matters this much.

Choice without constraint presents an enormous burden, almost more than an entire absence of choice: dilemmas become multiplied, meaning extinguished. In ideal political and social systems, every voice should be heard and considered but commitment to action or inaction must exclude someone's wishes. The patient leaves our dispensary with a package of medicinal products, not with a sheaf of immense possibilities or pregnant ideas. Not all of these medicaments will prove to be the ablest runners at that moment. There is always the future with its possibility of change and adaptation, but the present has momentum on its hands. In an ideal democracy, though current exclusion might be inevitable, if mobility were infinitely fluid (or at least no more than viscous) no elite could prevail for long though prevail for the present it must.

There is, however, a philosophical narrowness in scientific materialism in that not all events are locatable, except transiently. A thought may be located in a single human brain but when transmitted to another it will almost certainly undergo some change. Here, the distinction between process and event is difficult to maintain with any coherence. When a thought is written down it is an abstraction from the original thought; indeed, every time the original thought is repeated it will have undergone metamorphosis of some kind. In that sense, if a process is a continuity of events, all events are immediately lost by the passing of time. We retrieve them only partially. Our minds are embodied, our multiple identities perceptual, figured in the ground we feel as we walk upon it.

______________

⁸⁹ Cf. Oliver Hart's work on the contracts that underpin societies for which he jointly won the Nobel Prize for Economics in 2016.

⁹⁰ For a discussion, see Etkin and Johns in Prendergast, HDV 1998.

⁹¹ Line 1, East Coker, Four Quartets, T.S. Eliot.

⁹² Parathyroid Hormone (PTH), calcitonin and Vitamin D₃.

⁹³ Via Atrial Natriuretic Factor (ANF).