GUT-BRAIN PEPTIDES give us the concept of the MINIBRAIN in the intestinaltract. They include vasoactive intestinal polypeptide (VIP), Cholecystokinin (CCK), Substance P, Neurotensin, Methionine enkephalin, Leucine enkephalin, Insulin and Glucagon.
GASTRO-INTESTINAL (GI) FUNCTION. The stomach and intestines have been known for a long time to have a large nerve supply, mainly of non-medullated sympathetic fibers and medullated preganglionic fibers of the parasympathetic. Nerve fibers between two layers of smooth circular muscle form the plexus of Auerbach. From there they pass to the submucosa of the gut to form the plexus of Meissner.
Details of the enteric nervous system are now described with brain peptides effecting GI transit (motility), and this gives the concept ot the MINIBRAIN in the gut. Many neuropeptides are involved: the Opioids, Bombesin, CRF, Thyrotropin-releasing hormone (TRH), Somatostatin, Calcitonin, Neurotensin and Substance P. Opium and opiates such as morphine have been known since antiquity to inhibit gastro-intestinal transit. Endogenous (naturally produced) opioid peptides like beta-Endorphin act on gut motility, mainly inhibiting it. CRF is a critical mediator of stress responses acting on the hypothalamus as described above. It has been shown experimentally to inhibit transit in the small intestine and to stimulate it in the colon. Biofeedback techniques can be helpful in reducing stress, plus modulating neuropeptide activity, and thereby regulating the motility of the gut, and altering patterns of motility.
The CARDIO-VASCULAR SYSTEM.
CARDIO-VASCULAR REGULATION. Adreno-cortico-trophic hormone (ACTH) has important effects on blood pressure and sodium metabolism. Chronic treatment with ACTH can cause hypertension and sodium retention. ACTH is primarily synthesized in the anterior pituitary and its major role is the regulation of the adrenal cortex, but its role within the CNS is unclear. (see below in mood-regulation). Vasopressin can cause excitation of the sympathetic system. Endogenous opioid peptides appear to confer protection against the arrhythmias that arise during stress, (Verrier). Indeed, many investigators have shown that these opioids play a role in modulating the cardiovascular response to circulatory stressors, (Frantz and Liang).
The IMMUNE SYSTEM.
IMMUNE FUNCTION. There is strong evidence for a functional effect of opioids on the immune system. Opioid peptides have an effect onreceptor sites of many subgroups of leucocytes (white blood cells) including natural killers (NK) cells, monocytes, macrophages, mast cells, lymphocytes and thymocytes which are all involved in reactions to infections, and in auto-immune disease processes, such as multiple sclerosis.
Natural killer (NK) cells are thought to play an important role as tumor cell scavengers and also in transplant rejection. NK cell activity has been shown in humans to be enhanced by exercise (Brahmi et al.).
The COGNITIVE - EMOTIONAL SYSTEM
Neuropeptides have effects which overlap several systems and therefore repetition is inevitable when we review some of the chemical control mechanisms of mood, behavior and reactions to stressors.
The age-old drug from the poppy, opium, gives a "pleasurable" or antidepressant effect. Substances produced in the body which give"pleasure" are therefore called opioids. ENDOGENOUS OPIOID PEPTIDES have been implicated as being either causative or curative agents in a variety of mental disorders. Stress, opioid peptides (endorphins) and cardiac arrhythymias are often inter-related, and this aspect of the cardio-vascular system is well-known as suitable for biofeedback treatment.
Stress stimulates the secretion of corticopin-releasing- factor (CRF) from the hypothalamus. CRF is carried down the pituitary stalk and stimulates secretion of ACTH and beta-endorphin into the periphery. CRF produces activation of the sympathetic nervous system resulting in secretion of epinephrine (adrenaline) and nor-epinephrine from the adrenal medulla.
Leu-and met-enkephalin are co-secreted along with epinephrine and nor-epinephrine from the adrenal medulla into the bloodstream. Also, inhibitory feedback pathways go from the pituitary to the adrenal and cortisol in the blood stream can inhibit the hypothalamus as well as ACTH and endophins in the pituitary.
ENDOCRINE REGULATION for the prevention of stress and/or depression involves the hypothalamic-pituitary-adrenal axis.
Corticotrophin-releasing factor (CRF) is the hypothalamic releasing hormone that controls the hypothalamic-pituitary-adrenal axis (HPA axis). Stress increases ACTH and glucocortisol concentrations. Apparently the activation of the HPA axis by stress is due to the release of several neuro-modulators including CRF, Arginine, Vasopressin, Oxytocin, Angiotensin II, Vasoactive intestinal peptide (VIP). Epinephrine, and Norepinephrine.
Corticotrophin-releasing factor (CRF), however, is THE major regulator of ACTH.
Patients suffering from major depression, when not medicated, are as a group hypercorticolemic (too much cortisol in the blood), and they may therefore be chronically over (hyper) secreting CRF. The possible mechanisms involving CRF and the pathogenesis of depression are numerous and await detection. Biofeedfack as a treatment can help the symptom by modifying the behavior.
4. THE BRAIN AS A SYSTEM OF ADAPTATION
There is a plethora of data generated in the last decade on the various physiological alterations that occur after exposure to stressful stimuli. This shows how the brain functions for adaptation. It is important for biofeedback professionals to have some understanding of these alterations, because the technique of biofeedback teaches the subject to modify his/her responses to stressors in order to maintain psycho-physiological balance when battered by these stimuli.
The hypothalamic-pituitary-adrenal (HPA) axis has been the focus of many investigations on the manifestations of the stress response ever since Hans Selye described in 1936 the hypertrophy of the adrenal gland and the atrophy of lymph glands in response to chronic stress. With the discovery of corticotropin-releasing factor (CRF) by Vale and co-workers in 1981, the hypothalamic component of this axis became available for investigation.
The HPA axis is a multistep integrated process involving several CNS sites (cerebral cortex, amygdala, locus caeruleus, hippocampus, etc). In the hypothalamus these signals are transduced to humoral-type messages, release and release- inhibiting hormones. These travel a short distance to the anterior pituitary where they are funneled into the general circulation and travel to their appropriate target organs. The responses that these signals engender have major influences on blood pressure, reproductive function and energy mobilization. In addition the various neuroendocrine axes are also influenced by a variety of feedback control loops. These feedback controls can be of both a fast and a slow nature and involve both central and peripheral sites (Ritchie and Nemeroff). In major depression, corticotropin-releasing factor ( CRF) is most likely hypersecreted (see above).
It is also possible that the precipitous fall in CRF, in ACTH and in cortisol levels in maternal plasma at the time of delivery leaves the HPA axis uncompensated, and postpartum depression may develop because of sudden changes.
The locus caeruleus is important in the process of adaptation to the environment because it is rich in nor-epinephrine, (nor-adrenaline). The locus caeruleus (literally the "blue spot") is so-called because of melanin-pigment granules found in human infants and increasing with age. It has a very rich blood supply enabling this nor-epinephrive to be rapidly transported over the body. It is a microscopic nucleus in the floor of the 4th ventricle in the upper pons, near structures that regulate respiration with changes in the relative carbon dioxide and oxygen content of the blood.
It is important to understand something of the neuropeptide involvement in STRESS. Since stress is the result of an individual's response to stressors, we can see that the brain is the organ of adaptation, acting through its neuro-humoral network. Neuropeptides are part of this network. They mediate the regulation of the neuroendocrine and the autonomic responses to stress.
The neuropeptides identified in this network include : (1)Corticotropin-releasing-factor (CRF); (2) thyrotropin-releasing factor (TRF); (3) Bombesin and related peptides: and (4) Somatostatin-related peptides. All 4 groups of these peptides effect both the sympathetic and the parasympathetic systems. For example, CRF increases the plasma concentration of glucose and glucagon, increases cardiac output, heart rate and blood pressure, decreases kidney and mesenteric blood flow, gastric motility and acid secretion, and inhibits ovulation, (Brown). TRF and Somatostatin-related peptides have cardiorespiratory, metabolic, gastrointestinal and pancreatic effects demonstrated in animal experiments (Brown). "Bombesin acts within the CNS to decrease regulatory heat production and oxygen consumption during cold exposure" (Brown). Thus Bombesin slows an animal's metabolism.
The brain reacts in many ways to drinking behavior, drinking bouts and signals that initiate or terminate drinking. For example, Angiotensin II is a neuropeptide with three physiological mechanisms appropriate to a response to water loss. (a) vasoconstriction (b) increased release of aldosterone and (c) increased release of antidiuretic hormone.
5. MOOD RELATED TO PATHO-PHYSIOLOGY
Dr. Eliot Stellar, a physiological psychologist, author of the well-known books "Physiological Psychology" in 1950 and "The Neurobiology of Motivation and Reward" in 1985, illuminated the interdependence of psychology and physiology. This interdependence may seem self-evident but must be understood in detail.
Mood and emotional reactions are sensitively related to our physiological well-being or our pathological ill-state. Everyone is aware that sleep and food intake effect mood. Thus a sleep deprived person is "grumpy", irritable and lacks judgement. People are less aware that sleep deprivation can cause seizures; that over-activity (hyperfunction) of the thyroid gland can lead to thyrotoxic emotional lability; and that under-activity (hypo-function) of the thyroid gland (myxedema) can lead to "myxedema madness". With an insulin tumor, a patient may develop bursts of irrational behavior. A phaeochromocytoma is a tumor of certain cells of the adrenal medulla. The tumors secrete an excess of adrenaline and noradrenaline but because the output may be continuous or paroxysmal, the clinical features vary greatly. Apart from hypertension, anxiety and fear can be severe in attacks, (Lishman, 1987). Depression is frequent after influenza and other viral infections. Episodes of abnormal behavior may occur in patients with epilepsy, unrelated in time to a seizure.
Other evidence of mood related to pathology includes depression in Parkinson's disease, the on-off drug effects in the treatment of Parkinson's disease; chemical imbalance in manic-depression; pre-menstrual syndrome; depression in cerebral arteriosclerosis; drug-related mood changes; hallucinatory drugs; oxygen lack causes loss of judgement; sensory deprivation illusions; vitamin deficiences cause lack of energy; and toxic disorders like lead poisoning are associated with low IQ.
Changes in personality are frequently observed due to cerebral tumors (mainly frontal), to head injury, to cerebrovascular disorders, to senile dementia, and to presenile dementia (Alzheimer's disease). All these disorders show that disfunction in any organ, including the brain, changes mood, emotions and behavior.
For many people, mood is associated with the "mind". However they can understand that the brain is as much part of the body as all the other organs, such as heart, lungs, thyroid. They can see that disfunction of any of these organs can cause psychological disfunction. Because the brain regulates the other organs through feedback mechanisms, it is pivotal in psychology. The "mind"is a concept and from the physiological point of view its workings are those of the brain.
Biofeedback treatment is directed to the brain mechanisms that control all our physiological functions. When this biofeedback treatment is inappropriate for patients because of their significant cognitive deterioration, biofeedback may be offered to their relatives suffering from reactive anxiety and distress.
6. THE BRAIN CONTROLS ACTIVITY.
Charles SHERRINGTON, the founder of modern motor physiology, wrote that : "To move is all mankind can do and for such, the sole executant is muscle, whether in whispering a syllable or in felling a forest".
Here the CNS operates through the peripheral nervous system. "Spinal interneurons constitute an important set of networks for processing both peripheral inputs and commands descending from higher brain centers" (Sherrington)
Both too little (hypo) and too much (hyper) activity can be pathological. HYPOACTIVITY is one of the hallmarks of clinical depression. The patho-physiology of depression is described in detail in the book:"Neuropeptides and Psychiatric disorders" edited by Charles B. Nemeroff.
Inability to "get going" can be pathologically based as in Parkinson's disease where patients have great difficulty in initiating a movement, for example walking; here the dopamine metabolism is disturbed. Many patients with Parkinsonism suffer from depression because their musculature does not respond to their desires; actual slowing of thinking processes may also be involved. On the other hand inability to "get going" may be psychologically based through lack of motivation or sensory deprivation on a socio-economic background.
HYPERACTIVITY with its corollary of defective attention in childhood is in many cases a contemporary phenomenon caused by excessive television-watching, an environment of "sound-bites" and methods of education.
Hyperactivity associated with various forms of neurological retardation is associated with lack of neuronal inhibition and poor control of responses.
The LIMBIC CHILDREN is a concept (Fischer-Williams ) that arose from the clinical observation of certain patients with "retardation"on an organic neurological basis. These subjects, children and young adults, have frequent mood changes with outbursts of uncontrolled activity, disturbed behavior and abnormal "drives". The limbic system regulates emotions and the activities of the frontal cerebral cortex through many anatomo-physiological pathways. When there is a lack of feedback control from the limbic system to the frontal cortex (where judgement is formed and social activity is analysed), these subjects show inappropriate hyperactivity. A more correct term would be "a-limbic children" because the condition indicates that the limbic structures never developed their functions or were lost through early disease. Information on the neuropeptides operating in the limbic system (particularly of the amygdala which are part of the limbic system) is now detailed.
THE BRAIN NEEDS FEEDING WITH BLOOD. Clearly, brain function depends on a healthy supply of blood. This subject, however, will not be discussed in this chapter. except to say that the heart can be likened to a pump, the blood vessels to a garden hose, and the brain to a garden.
7. STIMULUS - RESPONSE MECHANISMS
In biofeedback, there is a primary concern with two mechanisms: first, when the subject or patient becomes continuously aware of the stimulus of certain physiological activities, such as muscle tone or heart rate, and second when the subject has incentives or rewards for changing or controlling the feedback and therefore learns to control voluntarily the physiological response associated with the feedback. The continuous information fed back to the subject brings to consciouness something which has not previously been registered at a conscious level. Consequently information travels a different neuronal pathway.
It is therefore important to understand the principle of divergence and convergence of information, and some of the complex neuronal systems that can modify or modulate behavior. For example a great deal of information arrives (converges) at the retinal nerve cells. This information is compacted (reduced) and then passed down the visual pathways. At the occipital cortex it is received by cells with very specialized functions, so that the information is sorted out (teased out) and diverges to individual groups of cells. However the brain has learned to converge vision and the "normal" individual sees one picture. Psycho-physiological techniques can teach an individual to separate or to converge sensations.
The "expectancy " wave of Grey Walter. Another phenomenon may be relevant in this context. When two stimuli are associated and the subject is instructed to terminate the second one by pressing a button, a low voltage "intention" or "expectancy " wave develops and can be recorded in normal subjects with DC recording on the scalp. It is termed the negative contingent wave (Walter), and this electrical cortical event is important because it comes just before action. Grey Walter once suggested that a disturbance of this "intention" wave was related to the indecision sometimes seen in "neurotic" patients. It might be related to the "jitters" described in some golf players just before the action of putting.
Other phenomena may exist similar to those seen in patients with "split brains", where the two hemispheres have been disconnected after section of the corpus callosum and the anterior commissure in the treatment of intractable epilepsy. Division (separation) of information has been demonstrated in regard to perception, cognition, volition, learning and memory (Sperry). These phenomena allow one to speculate that during biofeedback training, new linkage pathways may be established between perception of the monitor measurements fed back and the unconcious physical changes in whatever modality is being monitored at the time. The patient's body makes physical changes in by-passing the ordinary sequence of volitional motor activity, just as motor skills are acquired by constant repetition.
8.Biofeedback as a treatment modality in Neuropsychiatry
Neuropsychiatry is based on the "delicate balance between our knowledge and understanding of the brain and our knowledge and understanding of people", (Lishman). As a neuropsychiatrist, Dr. Lishman wrote: "I tend to see patients with brain disease- - - and the decision we must often try to make is on whether the problems we see in the clinic are "organic" or "functional"--- more precisely whether they derive from a primary brain malfunction or from difficulties the patients are encountering in their lives," (Lishman). He wisely comments that "we must sidestep the risk of becoming too far seduced by one or other pole of this dual requirement". "Brain biochemistry - - with increasing relevance to emotional and behavioral disorder" (Lishman), pharmacotherapy, psycho-pharmacology, imaging of many areas in the brain including the limbic system during cognitive activities, all open up exciting vistas for health therapists to explore.
For example, Lishman quoted Weinberger: "We can visualize the increased blood flow to frontal regions when a normal subject engages in a category sorting task and show that equivalent dynamic shifts are defective in the schizophrenic brain". (Weinberger et al.)
We can ask other questions: is there a neurologic cause for obsessive-compulsive disorder? (Insel). How much is pre-menstrual tension a neurochemical dysfunction, and how much is it a psychological reaction to feedback mechanisms in normal cyclical events? Similar questions arise with sleep disorders when observed with the electroencephalogram (EEG) in the study of wake-sleep behavioral mechanisms.
9. Biofeedback as a treatment modality in RESTORATIVE NEUROLOGY.
Biofeedback treatment is useful as an adjunct in the therapy of neurological disorders. Criteria for sucessful treatment include basic knowledge of brain function, and honest motivation of both patient and therapist with reasonable self-knowledge. Expectations both of the patients and the therapist must be realistic.
The sad consequences of not keeping this in mind are described in the book: The Bitter Pill: Doctors, Patients and Failed Expectations, by Martin R. Lipp. They can often be avoided by close co-ordination with other treatment modalities and on-going co-operation with specialists in other fields.
Biofeedback is a technique to help reconnect the feedback systems. We can"listen to our thalamus" (part of the limbic system, sometimes designated as the emotional brain), we can use our dreams, our sensations, whatever messages come from our "unconscious". Add to this, we can "use our brain", meaning we can use our cerebral cortex to analyse our 10 emotions. This control of thought and action (cognitive and behavioral activities) can lead to synthesis and the acceptance of paradox.
Biofeedback can play an interventory role at many levels within the nervous system. It can facilitate re-inhibition, activation, re-balancing , stabilization or re-assignment of function. Once a patient is properly evaluated neurologically, biofeedback can be an adjunct or primary treatment of neurological disorders. The criteria for the use of biofeedback is discussed in A Textbook of Biological Feedback (Fischer-Williams, Nigl and Sovine) and in many chapters of this book. For cost-effective results, the expectations of both the patient and the therapist must be realistic. For long-lasting results, biofeedback effectiveness is often enhanced when co-ordinated with other modalities (Fischer-Williams, 1993).
For a better future, we trust that there will be expansion of methods of preventive medicine. This, however, depends on the health of therapists and the imaginative education of the public.
Benarroch EE. (1993). The Central Autonomic Network: Functional Organization, Dysfunction, and Perspective. Mayo Clin. Proc. 68, 988-1001.
Brahmi Z, Thomas JE, Park M, and Dowdeswell JRG. (1985). The effect of acute exercise on natural killer cell activity of trained and sedentary human subjects. J. Clin. Immunol. 5, 321-328.