The Nervous, Endocrine and Immune Systems and the Principle of Homeostasis - Health Psychology in the Context of Biology, Society and Methodology

Health Psychology: Theory, Research and Practice - David F. Marks 2010

The Nervous, Endocrine and Immune Systems and the Principle of Homeostasis
Health Psychology in the Context of Biology, Society and Methodology

’… almost all aspects of behaviour can be fully understood in terms of the concept of homeostasis.’

Curt Richter (1967)


In this chapter, we outline three interacting biological systems with a primary role in the regulation of health and illness: the nervous system, endocrine system and immune system. These three systems together control and coordinate the body’s responses to changes in the internal and external environment. We outline each system in turn and examine interactions between the nervous system, endocrine system and immune system with examples of recent research on psychoneuroimmunology. We conclude with a description of two kinds of homeostasis, both physiological and psychological.

Biological Systems

Three biological systems of relevance to health psychology are the nervous system (NS), the endocrine system (ES) and the immune system (IS). These three systems communicate within the body using electrical and chemical signals. They activate and de-activate tissues, organs and muscles to control and regulate the body, the emotions and the mind. The principal objective of the three systems is to preserve homeostasis. The three systems and their relationships to the brain and behaviour are illustrated in Figure 2.1.

Figure 2.1 The nervous system (NS), endocrine system (ES) and immune system (IS) and their relationships to brain and behaviour


Constant reciprocated interaction between the three systems — the brain, organs and gut — is required to enable the control and coordination of behaviour. Endocrine substances directly affect the nervous and immune systems. The NS innervates every organ and tissue of the IS with reciprocal connections. The continuous interactions among the nervous, endocrine and immune systems was named ’neuroimmunomodulation’ by Spector and Korneva (1981). Other related terms for these interactions include ’psychoimmunology’, ’psychoneuroimmunology’ (Kiecolt-Glaser et al., 1992), ’immunoendocrinology’, ’behavioural immunology’ and ’mind and immunology’. We review research on psychoneuroimmunology later in the chapter.

The three biological systems provide an essential foundation for the understanding of health and illness. Interest in the NS, however, is more than an academic one; it is also economic. The burden on health care and the economy from neurological disease is massive and rapidly increasing. For example, in the USA nearly 100 million people are ill with neurological disease. The combined annual costs of Alzheimer’s and other dementias, low back pain, stroke, traumatic brain injury, migraine, epilepsy, multiple sclerosis, spinal cord injury and Parkinson’s disease totals nearly $800 billion and this figure is rapidly rising due to the ageing population (Gooch et al., 2017). This huge sum suggests a pressing need to expand knowledge and training in neuroscience. One necessary step is to begin with a basic grounding in the nature and function of the NS, a foundation stone for everything that follows.

The Nervous System

Neurones and Microglia Cells

It has been estimated that the human body consists of 37.2 trillion cells plus or minus around 0.81 trillion (Bianconi et al., 2013) and there are hundreds of different cell types (Mescher, 2016). The cells in one body have identical DNA but carry out a coordinated myriad of functions to enable the maintenance of a near-stable internal environment. Only by communicating with one another can the necessary high level of coordination be possible. The two primary organizations for cell—cell communication are the NS using neurotransmitters such as acetylcholine, and the ES, which transports neuromodulators and hormones (e.g., cortisol) around the entire body. Most cell—cell communication occurs using intracellular enzymes, molecules that speed up chemical reactions (Michael et al., 2017). We outline here the basic structure and functions of the NS.

There are two main cell types in the NS, neurones and glial cells. Both cell types are absolutely necessary for neurological health. Glial cells provide support and nutrition, maintain local homeostasis, produce myelin and participate in signal transmission. The total number of glial cells roughly equals the number of neurons. Of particular importance are microglia cells, a type of glial cell accounting for 10—15% of all cells found within the brain. Microglial cells are highly plastic and act as macrophage (’big eater’) cells, the main form of active immune defence in the central nervous system (CNS).

As both unique immune cells and unique brain cells that constantly change shape and have numerous different functions, microglia cells could stake a claim to being the ’smart’ cells of the body. Microglia travel independently, unattached to any structure, circling a territory with extended arms seeking suboptimal functioning. This constant system of microglial surveillance protects the brain against any microbe invaders, demyelination, trauma and cancerous or defective cells (Lieff, 2013). When glial cells go wrong, all sorts of chaos can break loose, including brain inflammation and neurodegeneration, which can cause chronic pain (McMahon et al., 2005), Alzheimer’s disease (Paresce et al., 1996), Parkinson’s disease (Kim and Joh, 2006) and, according to some research, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) (Morris and Maes, 2014). It can be seen already that intimate connections exist between the immune and nervous systems, and so far we have only mentioned the ’foot soldiers’ of the NS and not the command structures.

Neurones provide the main ’wiring’ of the NS; they are communication devices that connect with other neurones, tissues, organs and muscles. How the neuronal communication works can best be explained by looking at the structure of the neurone (Figure 2.2).

The brain contains around 86 billion neurones, 20% in the cerebral cortex and 80% in the cerebellum (Lent et al., 2012). Each neurone can connect with up to 1—10,000 other neurons so there may be as many as 860 trillion synaptic connections in total. Each neurone consists of a cell body or ’soma’, dendrites and an axon. Dendrites are thin structures that arise from the cell body. They may be hundreds of micrometres in length and branch multiple times to produce a complex ’dendritic tree’. An axon, or ’nerve fibre’ when myelinated, arises from the soma at the axon hillock and travels for a distance which can be as far as one metre in humans (connecting the toe to the spinal column).

Figure 2.2 A schematic neurone and synapse


Source: Yurana’s portfolio, IMG ID:214981837, acquired via Shutterstock

Bartol et al. (2015) explored the memory capacity of a human brain in comparison to computers. Their findings suggest that our brains might hold around one petabyte (PB) of memory, which equals 1,000,000,000,000,000 bytes, which equals 250 bytes or 1,000 terabytes. One petabyte is enough memory to store the DNA of the entire population of the USA — and then clone them, twice. No wonder nobody has yet managed to program a computer to make a decent breakfast or make us laugh like Mr Bean can. Ha!

Most excitatory synapses are formed between the axon of one neuron and a dendritic spine on another. When two neurons on either side of a synapse are active simultaneously, that synapse becomes stronger, a form of memory. The dendritic spine also becomes larger to accommodate the extra molecular machinery needed to support a stronger synapse.

Some axons form two or more synapses with the same dendrite, but on different dendritic spines. Bartol et al. (2015) used a technique called ’serial section electron microscopy’ to create a three-dimensional reconstruction of part of the brain that allowed the sizes of the dendritic spines on which these synapses form to be compared. Measurements in a small cube of brain tissue revealed 26 different dendritic spine sizes, each associated with a distinct synaptic strength. This number translates into a storage capacity of roughly 4.7 bits of information per synapse. This estimate is markedly higher than previous suggestions. It implies that the total memory capacity of the brain — with its many trillions of synapses — may have been underestimated by an order of magnitude. Myelin is a fatty white substance that surrounds the axon of some neurones, providing electrical insulation. Multiple sclerosis (MS) occurs when an abnormal IS response produces chronic inflammation, which damages or destroys myelin.

Synapses and Neurotransmission

One major form of communication in the NS uses neurotransmitters which are ’squirted’ across an inter-cell channel called a ’synapse’ or ’synaptic cleft’. This feature is illustrated in Figure 2.3.

A wave of electrochemical excitation called an action potential travels along the membrane of the presynaptic cell, until it reaches the synapse. Channels that are permeable to calcium ions then open and calcium ions flow through the presynaptic membrane increasing the calcium concentration in the interior. The increased calcium concentration activates a set of calcium-sensitive proteins attached to vesicles which contain a neurotransmitter. These proteins change shape, causing the membranes of some ’docked’ vesicles to fuse with the membrane of the presynaptic cell, thereby opening the vesicles and dumping their neurotransmitter molecules into the synaptic cleft, the narrow space between the membranes of the pre- and postsynaptic cells.

To use an analogy, think of a couple of crazy kids having some fun in the school cafeteria when the teacher is nowhere to be seen. In a mêlée of hundreds of children all waiting for lunch, one kid picks up a bottle of ketchup and squirts it at the other kid’s face. If the ketchup squirt hits the target, and lands squarely in the other kid’s mouth, we have a successful ’transmission’. If he misses, he’ll have to have another go, or another kid from the crowd will need to have a squirt to achieve a successful transmission. This is the kind of thing that goes on in neurotransmission across the synapse. The first kid with the ketchup bottle is the neurone, the bottle is the synaptic vesicle, the ketchup is the neurotransmitter, the first kid’s squeezy hand is the neurotransmitter transporter, and the second kid with ketchup all over his face is the receptor. The more ketchup on the face, the better the communication. Once the ketchup has done its job, it magically returns to the bottle. Job done! Unless, of course, that tomato ketchup is the ’wrong’ kind of neurotransmitter and the receptor kid demands a certain flavour of ice-cream instead! These ’ketchup kid fights’ are going on trillions of times every day in each and everyone of us.

Figure 2.3 The synapse, axon terminal, dendrites and associated processes


Source: Thomas Splettstoesser, Wikipedia Commons, CC 4.0 International license

There are at least 60 different kinds of ketchup — sorry, I mean neurotransmitter — to choose from. To be a neurotransmitter, a molecule must: (1) be red, sticky and taste like ketchup [no cancel that, just checking if you’re concentrating] be produced inside a neurone, be found in the neurone’s terminal button, and be released into the synaptic gap upon the arrival of an action potential; (2) produce an effect on the postsynaptic neurone; (3) be deactivated rapidly, after it has transmitted its signal to this neurone; (4) have the same effect on the postsynaptic neurone when applied experimentally as it does when secreted by a presynaptic neurone. The best-known neurotransmitters are:

· acetylcholine

· serotonin

· catecholamines, including epinephrine, norepinephrine and dopamine

· excitatory amino acids, such as aspartate and glutamate (half of the synapses in the CNS are glutamatergic)

· inhibitory amino acids, such as glycine and gamma-aminobutyric acid (GABA; one-quarter to one-third of the synapses in the CNS are GABAergic)

· histamine

· adenosine

· adenosine triphosphate (ATP)

Peptides form another large family of neurotransmitters, with over 50 known members, including: substance P, beta endorphin, enkephalin, somatostatin, vasopressin, prolactin, angiotensin II, oxytocin, gastrin, cholecystokinin, thyrotropin, neuropeptide Y, insulin, glucagon, calcitonin, neurotensin and bradykinin. However, many peptides act more as neuromodulators than as neurotransmitters. Neuromodulators do not propagate nerve impulses, but instead affect the synthesis, breakdown or reabsorption (reuptake) of neurotransmitters (more on this later). Curiously, certain soluble gases can also act as neurotransmitters, for example nitrogen monoxide (NO, ’laughing gas’). These neurotransmitters have their own distinctive mechanism: they exit the transmitting neurone’s cell membrane by simple diffusion and penetrate the receiving neurone’s membrane in the same way.

Organization of the Nervous System

Having outlined aspects of the ’wiring’ of small clusters of cells in the NS, we need to consider how the 86 or so billion cells of the NS are organized into functional subsystems (Figure 2.4). This diagram divides the highly complex system into a framework of functional domains.

The command and control centre at the ’top’ of the NS is the central nervous system (CNS), consisting of the brain and spinal cord. Decisions made in the CNS are communicated via the peripheral NS, the cranial and spinal nerves, to the motor (effector) division of the NS. Communication back to the CNS is conducted by the sensory (afferent) division. There are two branches of the efferent division, the autonomic nervous system (ANS), which deals with cardiac muscles, smooth muscles and glands, and the somatic nervous system, which deals with skeletal muscular actions (speech and behaviour).

Figure 2.4 Organizational framework of the nervous system


The Brain1

1. Some illustrations and content are from ’The Brain from Top to Bottom’ available at:

The brain and associated structures are shown in Figure 2.5. The cortex controls information input, synthesis and comparison, and output and action. Information input comes through receptors that are sensitive either to variations in the outside world or to variations within the body, such as changes in body position. Before the nerve fibres emerging from a sensory organ reach the primary cortex, where inputs are processed, almost all make at least one connection in subcortical centres such as the thalamic nuclei.

Figure 2.5 The brain, brainstem, medulla, pons and other important brain structures


Source: © Terese Winslow, US Government

Another cortical input consists of fibres from the cortex itself, from either the same hemisphere or the opposite one. Once sensory signals arrive in their primary cortical area, they diverge into various local circuits responsible for information processing. These cortical microcircuits comprise the same types of cell distributed in the same six layers of the cortex. The results of ’computations’ performed by these microcircuits ultimately converge at pyramidal neurons whose axons are the only output pathways from the cortex. A high proportion of axons that leave the cortex return to it, on the same or on the opposite side. Other axons emerging from the cortex terminate in subcortical centres such as the thalamic nuclei, where they come into contact with the sensory fibres that send their axons to the cortex.

’Feedback looping’ is a fundamental characteristic of information processing by the brain. At every stage, some of the fibres and connections loop back to the preceding stage to provide feedback that helps to control it. For instance, feedback loops enable the brain’s motor control centres to correct and adjust their signals to the muscles, right up to the moment these signals are sent. Feedback loops like these let us keep our balance while walking against sudden gusts of wind. Feedback loops are also found in bodily reflexes, such as the leg withdrawal reflex. A complex task, such as playing a piano, involves highly complex connections because it requires the pianist to contract and relax many different muscles simultaneously, which is controlled by the cerebellum.


Neuromodulation occurs when a neurone uses a chemical to regulate diverse populations of neurones. Neuromodulators are secreted by a small group of neurons and diffused through large areas of the NS, instead of into a synaptic gap, affecting multiple neurones at the same time. Just one of these neurones can influence over 100,000 others through the neuromodulators that it secretes into the brain’s extracellular space.

Neuromodulators spend significant amounts of time in the cerebrospinal fluid (CSF), ’modulating’ the activity of several other neurones. Some of the same chemicals that act as neurotransmitters are also neuromodulators, specifically serotonin, acetylcholine, dopamine and norepiniphrene. The neurons of the ’hormonal brain’ differ from those of the ’wired brain’ in several ways. The hormonal neurones are concentrated mainly in the brainstem and the central region of the brain. They form small masses of thousands of cells, but these cells project their axons into large areas of the forebrain and the midbrain. Many drugs and medications, including those prescribed for affective disorders and schizophrenia, act on the neuromodulators of the diffuse projection neurons in the brainstem. For this reason, the function and distribution of the projections of these neurons have been the subject of much research using tracing techniques, because the axons of these neurons are not myelinated and do not form readily identifiable bundles. The results have confirmed how widely diffused these projections are. For example, a single axon from one of these neurons may subdivide and innervate both the cortex and the cerebellum.

The four main neuromodulators are norepinephrine (diffused by the locus coereleus), serotinin (diffused by the Raphe nuclei), acetylcholine (diffused by the basal nucleus of Meynert, pedunculopontine and pontine nuclei) and dopamine (diffused by the substantia nigra and ventral tegmental area). Each of these groups of neurones projects axons into large areas of the CNS and thus modulates numerous behaviours. The diffusion of the four main neuromodulators is illustrated in Figure 2.6.

The Somatic and Autonomic Nervous Systems

The somatic nervous system is the organism’s apparatus for responding to the external environment. It sends information to the brain from the body’s various sensory detectors. The somatic nerves enable us to respond to these stimuli by moving through our environment, taking voluntary action, reacting and speaking. One of the principal roles of the somatic NS is maintaining homeostasis in the external environment, as discussed later in this chapter.

The autonomic nervous system (ANS) maintains homeostasis in the internal environment by regulating vital organs, such as those involved in digestion, respiration, blood circulation, excretion, and the secretion of hormones. The ANS is divided into two subsystems, the sympathetic and parasympathetic systems. The two branches of the ANS generally work in opposite directions, enabling a continuous upward or downward control of the internal organs to maintain homeostasis in the internal environment.

Figure 2.6 Brainstem structures responsible for neuromodulation


The sympathetic nervous system (SNS) goes into action to prepare the organism for physical or mental activity of ’fight or flight’. When the organism faces a major stressor, it is the SNS that orchestrates the fight-or-flight response. It dilates the bronchi and the pupils, accelerates heart rate and respiration, and increases perspiration and arterial blood pressure, but reduces digestive activity. Two neurotransmitters are primarily associated with this system: epinephrine and norepinephrine. The parasympathetic nervous system (PNS), on the other hand, causes a general slowdown in the body’s functions in order to conserve energy. Whatever was dilated, accelerated or increased by the SNS is contracted, decelerated or decreased by the PNS. The only things that the PNS augments are digestive functions and sexual appetite. One neurotransmitter is primarily associated with this system: acetylcholine. The two divisions of the ANS and their functions are illustrated in Figure 2.7.

Figure 2.7 Schematic diagram of the autonomic nervous system


Source: Adapted from Geo-Science-International

Emotion, Reward, Punishment and Inhibition

The earliest scientific studies of human emotion were by Cannon (1915). Both in language and behavioural terms, we differentiate distinctive emotional responses. For example, in fear, humans go through basically the same steps: we stop what we are doing, turn towards the source of the threat, and initially show behavioural inhibition while trying to assess the threat. If this assessment confirms a threat, typically we try to flee or hide rather than engage in confrontation. If confrontation is unavoidable, fighting the threat becomes the last remaining option.

Attempts have been made to identify NS activity components associated with different emotions. The amygdala triggers bodily responses to emotional events, including the release of adrenalin by the adrenal glands. Adrenalin helps memories to be encoded more effectively in the hippocampus and the temporal lobe. We are better at remembering things that trigger our emotions. A review by Kreibig (2010) concerning emotion in healthy individuals suggested some level of response specificity in the ANS to different emotions, with some overlaps. See Box 2.1 for a few examples.

Box 2.1 Differentiation of Human Emotions in the Autonomic Nervous System

· Anger: reciprocal sympathetic activation and increased respiratory activity, particularly faster breathing.

· Anxiety: sympathetic activation and vagal deactivation, a pattern of reciprocal inhibition, together with faster and shallower breathing (overlaps with anger).

· Disgust (A) in relation to contamination and pollution: sympathetic—parasympathetic co-activation and faster breathing, particularly decreased inspiration.

· Disgust (B) in relation to mutilation, injury and blood: sympathetic cardiac deactivation, increased electrodermal activity, unchanged vagal activation and faster breathing.

· Embarrassment: largely overlaps with anger and anxiety but includes facial blushing.

· Fear: broad sympathetic activation, including cardiac acceleration, increased myocardial contractility, vasoconstriction and increased electrodermal activity.

· Sadness: a heterogeneous pattern of sympathetic—parasympathetic coactivation.

· Affection, love, tenderness or sympathy: decreased heart rate (similar to sadness), unspecific increase in skin conductance.

· Amusement: increased cardiac vagal control, vascular-adrenergic, respiratory and electrodermal activity, together with sympathetic cardiac-adrenergic deactivation.

· Contentment: a strong sympathetically deactivating component.

· Happiness: increased cardiac activity due to vagal withdrawal, vasodilation, increased electrodermal activity and increased respiratory activity.

· Joy: increased cardiac vagal control, decreased-adrenergic, increased-adrenergic and increased cholinergically mediated sympathetic influence as well as increased respiratory activity.

Source: Kreibig (2010)

Another approach has been to identify the brain areas and circuits responsible for reward and punishment (Figure 2.8).

Figure 2.8 The reward and punishment circuits


The main centres of the brain’s reward circuit are located along the medial forebrain bundle (MFB). The ventral tegmental area (VTA) and the nucleus accumbens are the two major centres in this circuit, but it also includes several others, such as the septum, the amygdala, the prefrontal cortex and parts of the thalamus. All of these centres are interconnected and innervate the hypothalamus, informing it of the presence of rewards. The lateral and ventromedial nuclei of the hypothalamus are especially involved in this reward circuit. The hypothalamus then acts in return not only on the ventral tegmental area, but also on the autonomic and endocrine functions of the entire body, through the pituitary gland.

In a study with monkeys, Stauffer et al. (2014) observed that the brain’s response to unpredicted rewards follows the utility function of the reward (Figure 2.9).

Turning from rewarding to aversive stimuli, fight-or-flight responses activate the brain’s punishment circuit (the periventricular system, or PVS), which enables us to cope with unpleasant situations. The PVS was identified by De Molina and Hunsperger (1962). It includes the hypothalamus, the thalamus and the central grey substance surrounding the aqueduct of Sylvius. Some secondary centres of this circuit are found in the amygdala and the hippocampus. The punishment circuit functions by means of acetylcholine, which stimulates the secretion of adrenal cortico-trophic hormone (ACTH). ACTH in turn stimulates the adrenal glands to release adrenalin to prepare the body’s organs for fight-or-flight actions.

Figure 2.9 Dopamine responses to unpredicted reward reflect marginal utility


(A) Population histogram of dopamine neurons from monkey A (n = 16). (B and C) Average population dopamine responses to different juice amounts for monkeys A and B. The curved line shows the utility gained from each specific reward over zero (marginal utility) and is identical to the utility function measured separately in each animal

Source: Adapted from Stauffer et al. (2014)

The MFB and the PVS provide two motivational systems that enable people to suppress their instinctive impulses and avoid painful experiences. A third circuit is known as the ’behavioural inhibition system’ (BIS). The BIS is associated with the septo-hippocampal system, the amygdala and the basal nuclei. It receives inputs from the prefrontal cortex and transmits its outputs via the noradrenergic fibres of the locus coeruleus and the serotininergic fibres of the medial Raphe nuclei. The BIS is activated when both fight and flight seem impossible and the only remaining option is to passively submit by doing nothing. Long-term behavioural inhibition can be stressful, with an increased probability of long-term illness (Pennebaker, 1985). Large individual differences are observed in behavioural inhibition which, in adolescents, can be associated with anxiety and depression (Muris et al., 2001).

Neuroplasticity, Learning and Memory

The hippocampus has been a focus for research on synaptic plasticity, the ability to potentiate transmission at the synapse by repeated stimulation, providing a neural foundation for learning and memory in terms of ’long-term potentiation’ (LTP) (Bliss and Lømo, 1973). When we learn something, the efficiency of hippocampal synapses increases, facilitating the passage of nerve impulses along a particular circuit. For example, when exposed to a new word, we have to make new connections among certain neurones to deal with it: some neurones in the visual cortex to recognize the spelling, others in the auditory cortex to hear the pronunciation, and still others in the associative regions of the cortex to relate the word to our existing knowledge. All memories of events, words and images correspond to particular activities of neuronal networks that have strengthened interconnections with one another.

As noted, at least half of the synapses in the CNS are glutamatergic. Glutamate is the major excitatory neurotransmitter in the NS. Glutamatergic pathways are linked to many other neurotransmitter pathways, and receptors are found throughout the brain and spinal cord in neurons and glia. As an amino acid and neurotransmitter, glutamate has multiple normal physiological functions and any dysfunction can have profound effects both in disease and injury. At least 30 proteins at, or near, the glutamate synapse control or modulate neuronal excitability. The N-methyl-D-aspartate receptor (NMDA receptor) is a glutamate receptor found in nerve cells. It is activated when glutamate and glycine (or D-serine) bind to it, and when activated it allows positively charged ions to flow through the cell membrane. These are especially important in synaptic plasticity and the encoding and intermediate storage of memory traces, while AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors mediate fast synaptic transmission necessary for memory retrieval (Tsien et al., 1996).

Collingridge and Singer (1990) discovered that excitatory amino acid receptors mediate synaptic transmission at many synapses that display LTP-type synaptic efficiency. These amino acids are one mechanism of synaptic plasticity in health and disease and alterations in these processes may lead to brain disorders, such as Alzheimer’s disease.

Humour and Laughter

Psychologists have attempted to study the mechanisms of humour and laughter. The results have been somewhat bizarre. Jokes that these psychologists have claimed to be the funniest do not seem very funny, at least to this author, and the theories they propose seem to fall wide of the mark (e.g., Wiseman, 2002). We felt that we could not complete our review of the NS without a brief mention of this ticklish subject.

We turn here to the second of the three biological systems that are fundamental to health and illness, the endocrine system.

Box 2.2 Funny Haha vs. Funny Peculiar: Why You Can’t Tickle Yourself and the Role of the Brain’s Laughter Centre in the Cerebellum

We all know that you cannot tickle yourself. Why? Studies by Blakemore et al. (2000) suggested two brain regions are involved in processing how tickling feels. The somatosensory cortex processes touch and the anterior cingulate cortex processes pleasant information. Blakemore et al. found that both regions are less active during self-tickling than they are during tickling performed by someone else, which helps to explain why it doesn’t feel tickly and pleasant when you tickle yourself. They suggest that the cerebellum predicts sensations caused by your own movement but not by someone else’s. Thus, when you try to tickle yourself, your cerebellum predicts the sensation and this prediction is used to ’cancel’ the response of other brain areas to the tickle. Job done.

What about inappropriate and uncontrollable laughter? Uncontrolled laughter at almost nothing at all? For some people, this type of laughter is not at all funny but highly embarrassing. Parvizi et al. (2001) studied a patient with pathological laughter and crying (PLC). The episodes occur either without an apparent triggering stimulus or would change from laughter into crying. Critical PLC lesions were found in the cerebro-ponto-cerebellar pathways and, as a consequence: the cerebellar structures that automatically adjust the execution of laughter or crying to the cognitive and situational context of a potential stimulus, operate on the basis of incomplete information about that context, resulting in inadequate and even chaotic behaviour. … Moreover, he noted that, in spite of the lack of an appropriate laughter — or crying — inducing stimulus, he would eventually feel jolly or sad after a long episode of laughter or crying. A feeling was in fact being produced, consonant with the emotional expression, and in the absence of an appropriate stimulus for that emotional expression. (Parvizi et al., 2001: 1711)

The latter observation is in line with the James-Lange view of emotion: ’I am laughing. Therefore, I am happy.’

Laughter is said to be the ’best medicine’, a saying that is supported by evidence. Laughter is associated with modulation of neuroimmune parameters (Berk et al., 2001; Bennett et al., 2003) and can improve well-being (Shahidi et al., 2011) at least as much as exercise in some cases.

The Endocrine System

The endocrine system consists of the ductless glands of the body and the hormones produced by those glands. Endocrine glands release their secretions directly into the intercellular fluid or into the bloodstream. Hormones act as ’messengers’ carried by the bloodstream to different cells in the body, which interpret these messages and act on them. In regulating the functions of organs in the body, the ES maintains physiological homeostasis. Cellular metabolism, reproduction, sexual development, sugar and mineral homeostasis, heart rate and digestion are processes regulated by the actions of hormones.

Without hormones we could not grow, maintain a constant temperature, produce offspring, or perform the essential actions and functions of our everyday lives. The ES provides an electrochemical connection from the hypothalamus to the organs that control the metabolism, growth, development and reproduction. The ES operates 24/7 for the entire lifespan. It operates throughout sleep and waking — without tea-breaks, weekends or holidays.

The main endocrine glands are the pituitary (anterior and posterior lobes), thyroid, parathyroid, adrenal (cortex and medulla), pancreas and gonads. The pituitary gland is attached to the hypothalamus of the lower forebrain. The thyroid gland consists of two lateral masses, connected by a cross bridge, that are attached to the trachea. They are slightly inferior to the larynx. The parathyroid glands are four masses of tissue, two embedded posterior in each lateral mass of the thyroid gland. One adrenal gland is located on top of each kidney. The cortex is the outer layer of the adrenal gland. The medulla is the inner core. The pancreas is along the lower curvature of the stomach, close to where it meets the first region of the small intestine, the duodenum. The gonads are in the pelvic cavity.

Figure 2.10 The endocrine system


Many studies indicate that hormonal changes influence cognition. For example, research by Sherwin (1997) suggested that estrogen helps to maintain verbal memory and enhances the capacity for new learning in women, whereas other cognitive functions, such as verbal memory, are seemingly unaffected by this steroid hormone. Even the human imagination is related to hormones. Drake et al. (2000) found evidence that both estrogen and testosterone have associations with cognitive performance and that estrogen may enhance, and depress, specific cognitive skills. Wassell et al. (2015) found that the strength and vividness of imagery is greater for females in the mid-luteal phase (second half of menstrual cycle) than for both females in the late follicular phase (first half of cycle) and males. The changes in hormone concentrations over time provide a possible basis for individual differences in visual mental imagery, cognitive functions and mental disorders.

Endocrine glands release hormones as a response to three kinds of stimuli: (1) hormones from other endocrine glands; (2) chemical characteristics of the blood (other than hormones); and (3) neural stimulation. Most hormone production is managed by a negative feedback system. The NS and certain endocrine tissues monitor the internal condition of the body. If action is required to maintain homeostasis, hormones are released, either directly by an endocrine gland or indirectly through the action of the hypothalamus of the brain, which stimulates other endocrine glands to release hormones. When homeostasis is restored, the corrective action is ceased. Thus, in negative feedback, when the subnormal condition has been rebalanced, the corrective action is stopped. One of the many vital functions that is taken care of by the ES is the circadian rhythm and clock.

The Circadian Clock

The ES regulates the circadian rhythm and sleep/waking cycle with a variety of hormone releases. Melatonin is produced in the pineal gland, under the control of the central circadian pacemaker in the suprachiasmatic nucleus (SCN) region of the hypothalamus (Gamble et al., 2014). Melatonin relays information about the light—dark cycle in response to day length changes, triggering endocrine changes. Melatonin production is low in the presence of light and increases during the night when it induces and supports sleep. Melatonin supplementation is used for the treatment of winter depression, sleep disorders, and as an adjuvant therapy for epilepsy.

The hypothalamo-pituitary-adrenal (HPA) axis produces corticotropin releasing hormone (CRH) from the hypothalamus and conveys it to the anterior pituitary gland. There, CRH triggers release of adrenocorticotropic hormone (ACTH) into the general circulation whereupon ACTH binds to receptors in the adrenal gland and stimulates cortisol release. Cortisol levels exhibit a robust ultraradian rhythm normally peaking during the morning (0700—0800), preparing the body for the energetic demands of waking.

Growth hormone (GH) is produced in the anterior pituitary in response to the integrated stimulatory and inhibitory effects of GH releasing hormone (GHRH) and somatostatin (SMS), respectively, from the hypothalamus. GH has powerful metabolic effects in opposition to insulin (e.g., decreasing glucose utilization). Circulating GH levels exhibit both circadian and ultradian variation, as well as sexual dimorphism. GH is secreted throughout the day with an increased secretion during sleep.

Adiponectin exhibits a time-of-day-dependent rhythm, peaking between 1200 and 1400 and is best known as an insulin sensitizer, whose circulating levels vary inversely with body mass index (BMI). Hypoadiponectinemia is associated with metabolic syndrome, but conversely, elevated levels are seen in chronic heart failure and chronic renal failure. Insulin is secreted by beta cells of pancreatic islets in response to increased levels of circulating nutrients, particularly glucose. Insulin stimulates glucose utilization and protein synthesis by the liver, skeletal muscle and fat. It displays a diurnal rhythm which peaks at around 1700 hours, suggestive of nutrient storage during the awake/fed state and mobilization during the fast period of sleep.

The EC responds in a complex manner during sleep (Van Cauter and Tasali, 2011). The secretion of some hormones increases during sleep (e.g., growth hormone, prolactin and luteinizing hormone), while the secretion of other hormones is inhibited (e.g., thyroid stimulating hormone and cortisol). Some hormones are directly linked to a particular sleep stage. Growth hormone is typically secreted in the first few hours after the onset of sleep and generally occurs during slow-wave sleep. Cortisol is tied to the circadian rhythm and peaks in late afternoon, regardless of the person’s sleep status or the darkness/light cycle. Melatonin is released in the dark and is suppressed by light (Buxon et al., 2002). Thyroid hormone secretion occurs in the late evening (Institute of Medicine, 2006). Endocrine dysfunction has been linked to sleep disturbances such as insomnia (Institute of Medicine, 2006). It has been suggested that over-activity of the HPA axis in response to stress affects sleep and subsequently increases the secretion of cortisol and norepinephrine (Buckley and Schatzberg, 2005).

Figure 2.11 Circadian clock control of endocrine factors


Time of day at which circulating levels of key endocrine factors peak in humans. Abbreviations utilized include: GH, growth hormone; TSH, thyroid stimulating hormone; PRL, prolactin; T3, triiodothyronine; RAAS, renin-angiotensin-aldosterone system; FGF21, fibroblast growth factor 21; (F), females only; (M), males only

Source: Reproduced by permission from Gamble et al. (2014)

Diabetes is associated with the ES’s ability to produce the insulin which is affected by sleep. Adults who report having five or fewer hours of sleep a night are 2.5 times more likely to have diabetes, compared to people who sleep 7—8 hours per night. People who sleep six hours a night are 1.7 times more likely to have diabetes than their peers who sleep longer. People who sleep for nine or more hours also have higher rates of diabetes (Institute of Medicine, 2006). A European epidemiological study followed sleep patterns and illness among 23,630 people for up to eight years (von Ruesten et al., 2012). Short sleep, defined as less than six hours in a 24-hour period, was associated with a 31% increased risk of overall chronic disease, including stroke, myocardial infarction and cancer. In non-hypertensive people, the overall risk of chronic disease, primarily cancer, was reduced by a daytime nap. Sleep duration of less than six hours is a ’risky behaviour’ for the development of chronic disease.

The regular daily oscillations in hormone releases do not appear to be solely a response to the sleep/wake and feeding/fasting cycles, but are ’orchestrated in part by a timekeeping mechanism called the circadian clock’ (Gamble et al., 2014: 466). Recent studies suggest that the circadian clock has been a feature of evolution for at least 2.5 billion years (see Box 2.3). Disruption of the clock through genetic or environmental means can precipitate disorders, including cardio-metabolic diseases and cancer. Realigning circadian rhythms can be beneficial in the treatment of endocrine-related disorders.

Box 2.3 Circadian Clocks

Figure 2.12 Evolution of the circadian clock


Source: Louden (2014)

Circadian clocks may have evolved at the time of the Great Oxidation Event 2.5 billion years ago in order to drive detoxification of reactive oxygen species.

The regular 24-hourly rotation of the earth has led to the evolution of circadian oscillators in virtually all life forms, from prokaryotes (unicellular organisms) to eukaryotes (organisms whose cells contain a nucleus and other organelles enclosed within membranes). Synchronized circadian rhythms provide an organism with a predictive mechanism to tune its internal physiology to the external world, a significant competitive advantage. Despite widely divergent origins, a common design principle applies to the molecular clockwork of all organisms in which the timing mechanisms have been investigated, from bacteria to man. The Great Oxidation Event (GOE) led to a catastrophic change in earth ecology, with the loss of many anaerobic life forms, while the most ancient clockwork mechanism, found in cyanobacteria (bacteria that obtain their energy through photosynthesis), is thought to have evolved at around this time. Thus, during the GOE, rhythms of oxygen consumption/generation and reactive oxygen species production would be driven by the solar cycle, leading to the evolution of a metabolic clock.

Ibizan night owls had better think twice before clubbing several nights in a row. You could be fighting 2.5 million years of evolution.

Source: Louden (2014). Reproduced by permission

Gender, Sexual Dimorphism and Identity

The biological basis for gender identity, if there is one, is unknown. The basis of biological sex is better understood. A single factor — the steroid hormone testosterone — accounts for most, and perhaps all, of the known sex differences in neural structure (Morris et al., 2004). Testosterone is said to ’sculpt’ the developing NS by inhibiting or exacerbating cell death and/or by modulating the formation and elimination of synapses. Testosterone masculinizes both the brain and the body, yet experience can interact with testosterone to enhance or diminish its effects on the CNS.

The steps leading to masculinization of the body appear to be consistent across mammals. The Y chromosome contains the sex-determining region of the Y (Sry) gene and induces the undifferentiated gonads to form as testes (rather than as ovaries). The testes secrete hormones to masculinize the rest of the body. Two masculinizing testicular hormones are antimullerian hormone, a protein that suppresses female reproductive tract development, and testosterone, a steroid that promotes the development of the male reproductive tract and masculine external genitalia (Morris et al., 2004). In masculinizing the body, testosterone binds to the androgen receptor protein and then this steroid-receptor complex binds to DNA, promoting differentiation as a male. If the Sry gene is absent (as in females, who receive an X chromosome from the father), the gonad develops as an ovary, and the body, unexposed to testicular hormones, forms a feminine configuration. The genitalia will only respond to testicular hormones during a particular time in development, which constitutes a sensitive period for hormone action: hormonal treatment of females in adulthood is claimed to have negligible effects on genital morphology (Morris et al., 2004).

Researchers study transgender individuals in an attempt to understand the factors associated with gender identity. Leinung and Wu (2017) sought an association with a second digit to fourth digit (2D:4D) ratio and gender identity in a transgender clinic population in Albany, NY, consisting of 118 transgender subjects undergoing hormonal therapy (50 female to male (FTM) and 68 male to female (MTF)) for finger length measurement. Leinung and Wu observed that, in comparison to controls, FTM transsexuals have a low masculinized 2D:4D ratio in their dominant hand. However, they found no differences between the 2D:4D ratio of MTF transsexuals and controls. Their findings would be consistent with a biological basis for transgender identity and the possibility that FTM gender identity is affected by prenatal androgen activity, but that MTF transgender identity has a different basis. Replication of this study is necessary.

Contrary to the mainstream hormonal accounts of gender identity, the concept of sexual neutrality at birth, after which infants differentiate as masculine or feminine as a result of social experiences, was proposed by John Money and colleagues (Money and Erhardt, 1972). In the human brain, structural differences have been described that seem to be related to gender identity and sexual orientation (Swaab, 2004). However, the evidence is highly equivocal. Solid evidence for the importance of postnatal social factors in gender identity is lacking. The truth is we simply do not know.

Vitamin D and its Deficiency

The importance of the molecule vitamin D has been recognized since its discovery by Edward Mellanby in 1920. The chemical structure of vitamin D was determined in 1932, and it was only then found to be a steroid hormone, more specifically, a secosteroid. Vitamin D normally arises in the skin from sunlight or it can come from food, such as oily fish, or from supplements. It is metabolized in the liver and kidney. Vitamin D metabolites appear to be involved in a host of cellular processes, including calcium homeostasis, immunology, cell differentiation and regulation of gene transcription (Bouillon et al., 1995). Vitamin D is the main hormone regulating calcium phosphate homeostasis and mineral bone metabolism. A variety of tissues can express vitamin D receptor (VDR) and vitamin D is implicated in the regulation of the IS, the cardiovascular system, oncogenesis and cognitive functions (Halfon et al., 2015).

Hormones can act as immunomodulators, altering the sensitivity of the IS. T cells have a symbiotic relationship with vitamin D, by binding to the steroid hormone version of vitamin D, calcitriol, but T cells express the gene CYP27B1, the gene responsible for converting the pre-hormone version of vitamin D, calcidiol, into the steroid hormone version, calcitriol. The decline in hormone levels with age is partially responsible for the weakened immune responses in older people. Conversely, some hormones are regulated by the IS, notably thyroid hormone activity. The age-related decline in immune function is also related to decreasing vitamin D levels in the elderly. As people age, two things happen that negatively affect their vitamin D levels. First, they stay indoors more due to decreased activity levels. This means that they get less sun and therefore produce less vitamin D via solar radiation. Second, as a person ages the skin produces less vitamin D.

Hypovitaminosis D is associated with decreased muscle function and performance and an increase in disability. On the other hand, vitamin D supplementation improves muscle strength and gait, especially in elderly patients. A reduced risk of falls has been attributed to vitamin D supplementation due to direct effects on muscle cells. Finally, a low vitamin D status is associated with a frail phenotype. Many authorities recommend vitamin D supplementation for frail patients.

Vitamin D deficiency is a factor in a variety of illnesses. Pereira-Santos et al. (2015) found that the prevalence of vitamin D deficiency was 35% higher in obese people and 24% higher in overweight people. Vitamin D deficiency was associated with obesity irrespective of age, latitude, cut-offs to define vitamin D deficiency and the Human Development Index of the study location. Altered vitamin D and calcium homeostasis are also associated with the development of Type 2 diabetes mellitus. Pittas et al. (2007) reviewed observational studies and clinical trials in adults with outcomes related to glucose homeostasis. Observational studies showed an association between low vitamin D status, calcium or dairy intake and prevalent Type 2 diabetes mellitus or metabolic syndrome. There are inverse associations with the incidence of Type 2 diabetes mellitus or metabolic syndrome. Trials with vitamin D and/or calcium supplementation suggests that combined vitamin D and calcium supplementation may have a preventive role for Type 2 diabetes mellitus only in populations at high risk (i.e., those with glucose intolerance).

Microbiome Research

The new field of microbiome research studies the microbes within the gut and the effects of these microbes on the host’s well-being. Microbes influence metabolism, immunity and behaviour. One mechanism appears to involve hormones because specific changes in hormone levels correlate with the presence of the gut microbiota. The microbiota produce and secrete hormones, respond to host hormones and regulate expression levels of host hormones (Neuman et al., 2015). Increasing evidence links both hormones and the microbiome to immune responses under both healthy conditions and autoimmune disease. There are many interconnections and the microbiome and hormones may work through shared pathways to affect the immune response (Neuman et al., 2015).

Organisms within the gut play a role in the early programming and later responsivity of the stress system. The gut is inhabited by 1013—1014 micro-organisms, which is ten times the number of cells in the human body, and contains 150 times as many genes as our genome (Dinan and Cryan, 2012) or, according to Verdino (2017), 360 times. When pathogens such as Escherichia coli enter the gut, the HPA can be activated. Stress can induce an increased permeability of the gut, allowing bacteria and bacterial antigens to cross the epithelial barrier and activate a mucosal immune response, which in turn alters the composition of the microbiome and leads to an enhanced HPA drive. Research indicates that patients with irritable bowel syndrome and major depression show alterations of the HPA which are induced by increased gut permeability. In the case of irritable bowel syndrome, the increased permeability can respond to probiotic therapy. The gut microbiota play a role in regulating the HPA. In a double-blind, placebo-controlled trial, participants were given a fruit bar that contained either the probiotic formula or a similarly tasting placebo bar for 30 days (Messaoudi et al., 2011). The experimental fruit bar group reported significantly lower levels of anxiety, anger, depression, and somatization, on a number of self-report measures. Lower levels of cortisol were also evident in the fruit bar condition compared to the control group. Verdino (2017) cautiously concludes his review of the growing connection between gut health and emotional well-being as follows: “… it is crucial not to oversimplify the idea that nutritional intervention and a healthy gut will be the panacea for profound psychological difficulties. Severe mood and paralyzing anxiety disorders are not going to be cured with probiotic yogurt and prebiotic fiber, alone” (Verdino, 2017: 4).

The immune and neuroendocrine systems share a common set of hormones and receptors. Glucocorticoids, such as corticosterone and cortisol, regulate inflammation levels and have effects both on the innate and adaptive immune responses. Additionally, vitamin D affects immune cell responses by enhancing antigen presentation. Moreover, sex hormones affect the immune response in numerous ways. The effects of hormones on microbiota are summarized in Figure 2.13.

Figure 2.13 Host effects on gut microbiota.


A variety of host factors (such as diet, exercise, mood, general health state, stress and gender) lead to alterations in hormonal levels, which in turn lead to a variety of effects on the microbiota (including growth, virulence and resistance)

Source: Reproduced with permission from Neuman et al. (2015)

We now turn to consider the role of the immune system in health and illness.

The Immune System

The immune system (IS) is a network of cells, tissues and organs that protects the body against disease or other potentially damaging foreign bodies. When properly functioning, the IS identifies and attacks a variety of threats using billions of diverse antibodies, including viruses, bacteria and parasites, while distinguishing them from the body’s own healthy tissue. For each type of invader the body needs a distinct antibody. Antibodies are made by B cells using a combination of 20,000 genes and an enzyme called ’RAG’, which is a DNA shuffler. This enables the immune system to create a vast diversity of antibodies and respond to diseases it has never encountered before.

The IS is composed of two parts: the innate IS and the adaptive IS. Both change as people get older. The main features of the IS are illustrated in Figure 2.14.

Figure 2.14 Organs of the immune system


Our innate IS is made up of barriers and cells that keep harmful germs from entering the body. These include our skin, the cough reflex, mucous membranes and stomach acid. If germs are able to pass through these physical barriers, they encounter a second line of innate defence, composed of specialized cells that alert the body to the impending danger.

The IS changes over the lifespan. Newborn babies have an immature IS. Immunological competence is gained after birth partly as a result of maturation factors present in breast milk and partly as a result of exposure to antigens from food and environmental micro-organisms. Early encounters with antigens help the development of tolerance, and a breakdown in ’immune education’ can lead to disease (Calder, 2013). At the end of the life-cycle, older people experience progressive dysregulation of the IS, leading to decreased acquired immunity and a greater susceptibility to infection. Innate immunity appears to be less affected by ageing than acquired immunity.

A healthy, young person’s body produces numerous T cells and is able to fight off infections and build a storehouse of memory T cells. With age, people produce fewer naïve T cells, which makes them less able to combat new health threats. This also makes older people less responsive to vaccines because vaccines generally require naïve T cells to produce a protective immune response (except in the case of the shingles vaccine). Negative, age-related changes in our innate and adaptive immune systems are known as immunosenescence. A lifetime of stress on our bodies is thought to contribute to immunosenescence. Radiation, chemical exposure and exposure to certain diseases can also speed up the deterioration of the IS.

The adaptive IS is more complex than the innate IS and includes the thymus, spleen, tonsils, bone marrow, circulatory system and lymphatic system. These different parts of the body work together to produce, store and transport specific types of cells and substances to combat health threats. T cells, a type of white blood cell (called lymphocytes) attack infected or damaged cells directly or produce powerful chemicals that mobilize an army of other IS substances and cells. Before a T cell is programmed to recognize a specific harmful germ, it is in a ’naïve’ state. After a T cell is assigned to fight off a particular infection, it becomes a ’memory’ cell. Because these cells remember how to resist a specific germ, they help to fight a second round of infection faster and more effectively. Memory T cells remain in our systems for many decades.

An important part of our adaptive IS is the lymphatic system consisting of bone marrow, spleen, thymus and lymph nodes. Bone marrow produces white blood cells, or leukocytes. The spleen is the largest lymphatic organ in the body and contains white blood cells that fight infection or disease. The thymus is where T cells mature. T cells help destroy infected or cancerous cells. Lymph nodes produce and store cells that fight infection and disease. Lymphocytes and leukocytes are small white blood cells that play a large role in defending the body against disease. The two types of lymphocyte are B cells, which make antibodies that attack bacteria and toxins, and T cells, which help destroy infected or cancerous cells.


Inflammation is a critical defence response in our innate IS wherein white blood cells protect us from infection by foreign organisms, bacteria and viruses. Inflammation occurs following infection or tissue damage when a rapid and complex series of reactions takes place to prevent tissue damage, isolate and destroy the infective organism, conserve and protect some micronutrients and activate the repair processes to restore normal function (Thurnham, 2014). Inflammation is a homoeostatic process that is only intended to last a few days but, if it is continued indefinitely, there is a poor prognosis in many conditions. Inflammatory responses take precedence over normal body metabolism with the objective of restoring normality as quickly as possible.

In a young person, bouts of inflammation are vital for fighting off disease. As people age, they tend to have mild, chronic inflammation, which is associated with an increased risk for heart disease, arthritis, frailty, Type 2 diabetes, physical disability and dementia. Whether inflammation leads to disease, disease leads to inflammation, or whether both scenarios are true, currently remains uncertain. Centenarians and other people who have grown old in relatively good health generally have less inflammation and more efficient recovery from infection and inflammation when compared to people who are unhealthy or have average health. Acute inflammation on a timescale of seconds to days allows the host to heal and protect damaged tissue from disease. Chronic inflammation lasting weeks or months is linked to many pathologies and age-related diseases, including sleep apnea, insomnia, neurodegeneration, Alzheimer’s disease, atherosclerosis, cancer, kidney and lung diseases, metabolic syndrome and Type 2 diabetes mellitus.

Disorders of the IS can result in autoimmune diseases, inflammatory diseases and cancer. When the IS is less active than normal, which is called immunodeficiency, recurring and life-threatening infections can occur. Immunodeficiency can result from a genetic disease, acquired conditions such as HIV infection (see Chapter 23), or the use of an immunosuppressive medication.

The opposite situation of autoimmunity results from a hyperactive IS attacking normal tissues as if they were foreign organisms. Common autoimmune diseases include Hashimoto’s thyroiditis, rheumatoid arthritis, Type 1 diabetes mellitus (see Chapter 24) and systemic lupus erythematosus. Autoimmune diseases are chronic conditions with no cure. Treatment requires controlling the disease process to decrease the symptoms, especially during flare-ups. The following actions can alleviate symptoms of autoimmune disease: a balanced and healthy diet, regular exercise, plenty of rest, vitamin supplements (especially A and D), a decrease of stress, and the avoidance of any known triggers of flare-ups. Sound familiar? Hippocrates knew about them and your doctor’s waiting room has a poster.

Circadian Rhythm of the Immune System

Circadian variation occurs in immunocompetent cells and cytokines as an anticipatory process for the preservation of body homeostasis and defence (Cermakian et al., 2013). Cytokines are small protein cells responsible for cell signalling. The IS shows reliable daily variations, for example, immunocompetent cell counts and cytokine levels vary according to the time of day and the sleep—wake cycle. Different immune cell types, such as macrophages, natural killer (or NK) cells, and lymphocytes, all contain circadian molecular clockwork.

The biological clocks of immune cells and lymphoid organs, together with the central pacemaker of the suprachiasmatic nuclei via humoural and neural pathways, regulate the IS, including its response to signals and their effector functions. There is a diurnal variation in the response to immune challenges (e.g., a bacterial injection) and circadian control of allergic reactions. The circadian—immune connection is bidirectional, and immune challenges and immune mediators (e.g., cytokines) affect circadian rhythms at the molecular, cellular and behavioural levels. Cross-talk between the circadian and immune systems has implications for disease, as shown by the higher incidence of cancer and the exacerbation of autoimmune symptoms upon circadian disruption (Cermakian et al., 2013).

Sleep and Rest

Sleep and rest are necessary for a properly functioning IS. Feedback loops involving cytokines in response to infection participate in the regulation of non-rapid eye movement sleep. In sleep deprivation, active immunizations may have a diminished effect, resulting in lower antibody production and a lower immune response than for well-rested individuals. Proteins such as NFIL3, which are closely intertwined with both T-cell differentiation and our circadian rhythms, are affected by disturbances of natural light and dark cycles through instances of sleep deprivation, travelling across time zones or shift work. Such disruptions on a regular and frequent basis can lead to an increase in chronic conditions such as heart disease, chronic pain and asthma.

Sleep, sleep loss and disrupted sleep are strongly linked to acute and chronic inflammation (Opp and Krueger, 2015). People suffering from sleep deprivation demonstrate changes in circulating pro-inflammatory and anti-inflammatory cytokines, soluble receptors, inflammatory signalling pathways and innate immunity. Circadian misalignment also induces inflammation, which has ramifications for shift workers. Shift work is a risk factor for inflammatory diseases, including cancer and diabetes. In addition to the negative consequences of sleep deprivation, sleep and the circadian system have regulatory effects on immunological functions in both innate and adaptive immunity.

Chronic diseases that are associated with suboptimal sleep are inflammatory diseases. Chronic insufficient sleep is a risk factor in part because of the inflammatory state that results from sleep disruption. Inflammation, defined by elevated local and systemic cytokines and other pro-inflammatory mediators, occurs in response to many stimuli, including pathogen exposure, cellular damage, irritants, cellular dysregulation and waking activity.

Nutrition and Diet

Consumption of high-fat (e.g., ice cream — 11g fats per 100g serving) and high-sugar (e.g., tomato ketchup — 23.6g sugar per 100g serving) foods is associated with diseases such as diabetes and obesity, which can affect immune function. Moderate malnutrition, as well as certain specific trace mineral and nutrient deficiencies, also can compromise the immune response. Undernutrition-associated impairment of immune function can be due to insufficient intake of energy and macronutrients and/or due to deficiencies in specific micronutrients. Foods rich in certain fatty acids may foster a healthy IS. Foetal undernourishment is especially risky as it can cause a lifelong impairment of the IS. A variety of micronutrients have been implicated in improving the immune response, especially Vitamin A, Vitamin D, Vitamin E, zinc, iron and selenium.

We end this section with the photograph (Figure 2.15) which shows a different kind of ’eating’. A cancer cell about to be consumed and poisoned by a collection of microphages. This photograph shows one part only (step 3) of a six-step sequence of the death of a cancer cell:

1. A cancer cell has migrated through the holes of a matrix-coated membrane from the top to the bottom, simulating the natural migration of an invading cancer cell between, and sometimes through, the vascular endothelium. Notice the spikes or ’pseudopodia’ that are characteristic of an invading cancer cell. A buffy coat containing red blood cells, lymphocytes and macrophages is added to the bottom of the membrane.

2. A group of macrophages identify the cancer cell as foreign matter and start to stick to the cancer cell, which still has its spikes.

3. Macrophages begin to fuse with, and inject their toxins into, the cancer cell (shown in the photograph).

4. The cell starts rounding up and loses its spikes. As the macrophage cell becomes smooth, the cancer cell appears lumpy in the last stage before it dies.

5. These lumps are actually the macrophages fused within the cancer cell.

6. The cancer cell then loses its morphology, shrinks up and dies.


The study of the interactions between psychological, neurological and immunological processes constitutes the field of ’psychoneuroimmunology’, but ’PNI’ will do just fine. As we have already seen, the immune system and CNS maintain extensive communications. The brain modulates the IS by hardwiring sympathetic and parasympathetic nerves to lymphoid organs. The IS modulates brain activity, including sleep and body temperature. Based on close functional and anatomical links, the immune and nervous systems act in a highly reciprocal manner. From fever to stress, the influence of one system on the other has evolved in an intricate manner to help sense danger and to mount an appropriate adaptive response. Research over recent decades suggests that these brain-to-immune interactions are highly modulated by psychological factors that influence immunity and IS-mediated disease.

Figure 2.15 Macrophages have identified a cancer cell (the large, spiky mass). Upon fusing with the cancer cell, the macrophages (smaller white cells) inject toxins that kill the tumour cell. Photo magnification: x 8,000. Public domain


The brain and the IS are involved in functionally relevant cross-talk, with homeostasis being the main function. The CNS is without lymphatic drainage and so lacks the immune surveillance available for the rest of the body. However, there are mechanisms to exclude the potentially destructive lymphoid cells from the brain, spinal cord and peripheral nerves, ranging from small molecules, such as nitric oxide, to large proteins, including cytokines and growth factors, which tie the two systems together.

Recent studies in PNI are indicating many empirical links between the psychological, endocrinological and immunological systems. PNI research remains at a relatively early stage of development, with many publications having an empirical rather than a theoretical focus.

In a randomized controlled experiment, people who performed kind acts for others showed favourable changes in immune cell gene expression profiles (Nelson-Coffey et al., 2017). High sensitivity C-reactive protein (hs-CRP) has emerged as a marker of inflammation in atherosclerotic vascular disease.

Tayefi et al. (2017) measured symptoms of depression and anxiety and serum hs-CRP levels in 9,759 participants (40% males and 60% females) aged 35—65 years in north-eastern Iran. They found that depression and anxiety are associated with serum levels of hs-CRP, higher BMI in women, and smoking in men.

Blair and Berry (2017) analysed a prospective longitudinal sample of 1,292 infants in predominantly low-income and rural communities from infancy through to age 60 months. For children with relatively low cortisol levels between the ages of 7, 15, 24 and 48 months, those illustrating moderate fluctuations in their cortisol levels over this span tended to show subsequently better executive function (EF) performance at 60 months than did children with either highly stable or highly variable temporal profiles. This curvilinear function did not extend to children whose cortisol levels were high on average, who tended to show lower EF performance, irrespective of the stability of their cortisol levels over time.

PNI research suffers from the same ailments as most other areas of health psychology: underpowered with small sample sizes, cross-sectional designs and lack of replication. It is a field that has been hyped but is yet to reach its full potential.


Homeostasis refers to the principle by which the internal environment of the body is kept in a state of equilibrium by a multitude of fine adjustments at a hierarchy of levels ranging from the molecular level to the level of the organism as a whole. Claude Bernard (1865) first described what he called the ’internal milieu’ and showed that this internal environment was ordinarily maintained within fixed limits. Walter Cannon (1932), in The Wisdom of the Body, coined the term ’homeostasis’ for the coordinated physiological processes by which an organism maintains an internal steady state. Both Bernard and Cannon focused almost entirely on physiological homeostasis. Curt Richter (1942) expanded the idea of the protection of the internal milieu to include behavioural or ’total organism regulators’. From this viewpoint, behaviour lies on a continuum with physiological events. Richter combined the perspective of Bernard with that of Cannon and he added behavioural regulation.

Behaviour, for Richter, was broadly conceived to include all aspects of identification, acquisition and ingestion of the substances needed to maintain the internal environment. The current theory extends the homeostasis concept one step further in suggesting that not only feeding, but all human behaviour, follows the principle of homeostasis. Psychological homeostasis is best explained in two stages, starting with the classic version in Physiology, followed by the new version extended to Psychology. Physiological homeostasis is illustrated in Figure 2.16.

There are five critical components that a regulatory system must contain in order to be counted as homeostasis:

1. It must contain a sensor that measures the value of the regulated variable.

2. It must contain a mechanism for establishing the ’normal range’ of values for the regulated variable. In the model shown in Figure 2.16, this mechanism is represented by the ’Set point, Y’. Arguably, the term ’set range’ would be more appropriate than ’set point’.

3. It must contain an ’error detector’ that compares the signal being transmitted by the sensor (representing the actual value of the regulated variable) with the set point or range. The result of this comparison is an error signal that is interpreted by the controller.

4. The controller interprets the error signal and determines the value of the outputs of the effectors. In the vast majority of cases, the controller is an automatic, nonconscious process.

5. The effectors are those elements that determine the value of the regulated variable.

Figure 2.16 A complete representation of physiological homeostatic mechanisms (adapted from Modell et al., 2015)


We turn next to consider psychological homeostasis. Identical principles to those described above for physiological homeostasis apply to the regulation of behaviour and experience (Figure 2.17). For psychological homeostasis, however, the internal effectors remain active but the boundary between the internal and external environments lies between the controller and the outward effectors of the somatic nervous system, i.e., the muscles that control speech and action.

Let us consider how psychological homeostasis works in practice. All people are oriented towards seeking and/or preserving physical and subjective well-being at a set point that is kept at the highest possible level. Hence, we tend to approach new resources in the hope of finding a reward for this behaviour and equally to avoid punishing or confrontational situations. If we do encounter threat, our behavioural options include either ’fight or flight’ or inhibiting our behaviour so as to go unnoticed and to avoid confrontation. One can easily imagine the adaptive value of behavioural inhibition. A mouse scurrying through the grass suddenly notices a buzzard flying overhead. Out of fear, the mouse freezes, thus avoiding attracting the buzzard’s attention. Playing dead until a predator has passed can be beneficial, as long as the tension of waiting does not have to go on for too long. Figure 2.18 shows a homeostatic strategy for choosing optimal behaviours and the brain structures that may be involved in the process. The diagram shows the feedback loops whereby our memories associate positive or negative connotations with situations that we experience, and then guide behaviour the next time they arise.

Figure 2.17 A complete representation of psychological homeostatic mechanisms (adapted from Modell et al., 2015)


Figure 2.18 Approach and avoidance behaviours that maximize well-being


Source: Copyleft,

Life isn’t always this simple, however. The whole process could fall apart if you’re not a mouse hiding from a buzzard but, for example, you’re a worker dealing with an exploitative boss. The worker cannot fight or flee, or they would be out of a job. So they can either join a labour union and talk to the union representative or they can let months and years go by while they inhibit their behaviour. This ’do-nothing’ strategy ultimately can have disastrous effects on their health. For one thing, such inhibition causes hormonal changes that produce high blood levels of glucocorticoids, whose depressive effect on IS function is well known. This weakening of the IS is why remaining in a prolonged state of behavioural inhibition can cause all kinds of health problems.

One source of inhibition is our imagination — our fear of failure. This can lead us to foresee so many potentially negative scenarios that we end up doing nothing. To do nothing, and to maintain a dream, may be a better option than to act and to fall flat on one’s face. Whichever way one looks at the issue of inhibition, it has an obvious connection with homeostasis, a striving towards equilibrium.

Initiated by the brain, homeostasis also can act in an anticipatory mode. The preprandial (prior to having a meal) secretion of insulin, ghrelin and other hormones enables the consumption of a larger nutrient load with only minimal postprandial homeostatic consequences. When a meal containing carbohydrates is to be consumed, a variety of hormones is secreted by the gut that elicit the secretion of insulin from the pancreas before the blood sugar level has actually started to rise. This starts lowering the blood sugar level in anticipation of the influx of large quantities of glucose from the gut into the blood. This has the effect of blunting the blood glucose concentration spike that would otherwise occur. The relevance of psychological homeostasis has been underestimated in the study of behaviour, health and illness. In this book, psychological homeostasis is given its rightful position at the ’hightable’ of psychological constructs.

Quack’s Corner and the Placebo Effect

The placebo effect can be viewed as a form of anticipatory homeostasis. When a patient feels unwell, for example with depression, and seeks help from a trusted medical practitioner, (s)he is given a prescription. Upon receiving the medicine, (s)he anticipates feeling better and, after swallowing the allegedly curative pill, sits back and looks for the signs of increased well-being and improvement. Lo and behold, in many such cases (s)he actually does feel better, and her/his well-being is restored. If it is an active placebo with somatic side effects, then even better (Thomson, 1982). To the degree that any treatment is perceived to be effective, then expectancy must play a role. Homeopathic medicine, which has no active content by definition, provides a cogent example of anticipatory homeostasis with no harmful side effects. Homeopathic medicine is a 100% placebo masquerading as active medicine. Yet this form of medicine is used worldwide by hundreds of millions of people who swear by its efficacy.

Homeopathy has two principal ’laws’, the first being ’similia similibus curentur’ or ’let likes be cured by likes’. This ’law’ means that treatments that cause specific symptoms (e.g., onions cause runny eyes and nose) can cure conditions that cause the same symptoms (e.g., a bad cold). As if that isn’t kooky enough, there is the ’law of infinitesimal doses’ that when treatments are diluted in water or alcohol, they actually increase in therapeutic potency. This means that a 1-in-1,000 solution should be more effective than a 1-in-100 dilution. It’s an inverted dose response curve.

The anticipatory phenomena of placebos are certainly not confined to complementary and alternative medicines. The placebo effect has wide application in all areas of medicine. There is no harm in it whatsoever, as long as one doesn’t swallow the quack claims that come along as part of the package with the pills.

Consider antidepressants. These are supposed to work by fixing a chemical imbalance, specifically, a lack of serotonin in the brain. Irving Kirsch (2015) reviews analyses of published and unpublished data that were hidden by drug companies revealing that:

most (if not all) of the benefits are due to the placebo effect. Some antidepressants increase serotonin levels, some decrease it, and some have no effect at all on serotonin. Nevertheless, they all show the same therapeutic benefit. Even the small statistical difference between antidepressants and placebos may be an enhanced placebo effect, due to the fact that most patients and doctors in clinical trials successfully break blind. The serotonin theory is as close as any theory in the history of science to having been proved wrong. Instead of curing depression, popular antidepressants may induce a biological vulnerability making people more likely to become depressed in the future. (Kirsch, 2015: 128, italics added)

Whatever people may believe will help them to feel better may indeed help them to feel better, at least for a short while. Long-term, however, placebo effects almost always fade. This isn’t being snootily cynical. It’s a brutal fact about human nature. All the more reason, then, to apply ’hard-nosed’, sceptical analysis to outlandish treatment claims. Carl Sagan and other wise people have suggested that ’Extraordinary claims require extraordinary evidence’. There can be nothing more extraordinary or outlandish than the claims of homeopathic medicine. To turn our discussion full circle, there is not a single replicated piece of scientific evidence of a homeopathic remedy influencing the NS, ES or IS. The biological systems of the body carry the traces of every physical and mental stimulus we encounter. Homeopathic medicine leaves no trace. QED.

Future Research

1. Advanced imaging techniques such as ’serial section electron microscopy’ could be applied to study the mechanisms of inflammation.

2. We need to know more about misalignments of the circadian clock, emotion, and susceptibility to inflammation and acute and chronic conditions.

3. PNI research is needed to investigate the relationships between individual differences in cognitive ability, such as IQ test scores and changes in the immune system.

4. We need more studies of the impact of psychological homeostasis on the development of physical illnesses.


1. Three important biological systems in health and illness are the nervous system (NS), the endocrine system (ES) and the immune system (IS). They activate and deactivate tissues, organs and muscles to control and regulate action, emotion and mental activity.

2. The NS uses neurotransmitters and the ES uses neuromodulators and hormones. The brain modulates the IS by hardwiring sympathetic and parasympathetic nerves to lymphoid organs. The IS modulates brain activity, including sleep and body temperature.

3. Two important classes of cell in the NS are neurones and microglia cells. Microglial cells are highly plastic and act as macrophage (’big eater’) cells, the main form of active immune defence in the CNS.

4. Decisions made by the CNS are communicated via the peripheral NS to the effector division and inputs to the CNS are conducted by the afferent division. The autonomic nervous system deals with the non-conscious control of cardiac muscles, smooth muscles and glands, while the somatic nervous system deals with skeletal muscular responses in speech and behaviour.

5. The hypothalamo-pituitary-adrenal (HPA) axis produces corticotropin releasing hormone from the hypothalamus and conveys this to the anterior pituitary gland. The HPA axis has a primary role in emotion and stress. The amygdala triggers bodily responses to emotional events, including the release of adrenalin by the adrenal glands.

6. The endocrine system consists of the ductless glands and the hormones produced by those glands. Endocrine glands release their secretions directly into the intercellular fluid or into the bloodstream. Cellular metabolism, reproduction, sexual development, sugar and mineral homeostasis, heart rate and digestion are all regulated by hormones.

7. The ES regulates the circadian rhythm and sleep/waking cycle with a variety of hormone releases. Melatonin is produced in the pineal gland, under the control of the central circadian pacemaker in the suprachiasmatic nucleus (SCN) region of the hypothalamus.

8. The IS protects the body against disease or other potentially damaging foreign bodies. When functioning properly, the IS identifies and attacks a variety of threats, including viruses, bacteria and parasites, while distinguishing them from the body’s own healthy tissue.

9. Psychoneuroimmunology is the study of the interactions and relationships between psychological, neurological and immunological processes. Research over recent decades suggests that brain-to-immune interactions are highly modulated by psychological factors which influence immunity and IS-mediated disease.

10. The principle of physiological homeostasis is extended to psychological homeostasis. Identical mechanisms exist in both forms of homeostasis. In seeking to maximize physical and subjective well-being to a high set point, we approach new sources of potential reward and try to avoid aversive or confrontational situations.