Neuroendocrine dysrhythmias

Medical Hypotheses Medical Hypotheses(1995) 44, 319-324 © PearsonProfessionalLtd 1995

Neuroendocrine Dysrhythmias M. L. ELKS Internal Medicine, Texas Technical University Health Sciences Center, Lubbock, TX 79430, USA

Abstract - - Neuroendocrine rhythms play a major role in the regulation of physiological function. Stress can disrupt these rhythms and produce neuroendocrine dysrhythmias. A paradigm of classification of these dysrhythmias is presented and includes diurnal (phase and amplitude), autonomic (adrenergic or cholinergic excess or imbalance), and muscle tension (skeletal or smooth). By placing common psychosomatic conditions in this paradigm, one c a n model these conditions as exaggerations of normal responses producing disruption in normal neuroendocrine rhythms. This can also lead to a focus of therapy on restoring neuroendocrine balance and rhythm. To every thing there is a season, and time to every purpose under heaven: A time to be born, and a time to die; a time to plant and a time to pluck up that which is planted; A time to kill, and a time to heal; a time to break down and a time to build up; A time to weep, and a time to laugh; a time to mourn, and a time to dance; Ecclesiastes 3:1-4 Timing and rhythm are critical aspects of physiology - systole and diastole, activity and rest. Neuroendocrine controls and inputs play a major role in the co-ordination of the intrinsic body rhythms with the diurnal rhythms of our planet (1-9). Interruption or dyssynergy of these rhythms can lead to multiple problems, for instance, the insomnia and the abnormal somnolence that are characteristic of jet lag and shift work (1). The impact of our externally imposed schedules and unexpected crises on our intrinsic rhythms have effects on our physiology and function that are far beyond the simple annoyances of jet lag (1-9). The important role of stress in producing

ill-effects and disease is well recognized (10-15). In this paper, I will present a biodynamic theory, elaborating on prior work on stress and biological rhythms. The paradigm proposed here links the underlying pathophysiology of several functional, psychosomatic, and psychiatric problems, focusing on the pathology generated by external influences on neuroendocrine rhythms. This theory of neuroendocrine dysrhythmias provides a framework for understanding the similarities among these diverse conditions and an approach to their management. By externalizing the initiation of these conditions, this paradigm allows an approach that could decrease the stigma of these conditions.

Circadian rhythms Diurnal rhythms are, perhaps, the best-understood neuroendocrine rhythms. There are well-documented 24-h rhythms for sleep/wake, body temperature, activity, eating, hormones, and other activities (1-9). Some of these rhythms are independent of each other, i.e., not entrained by the same clock or zeitgeber

Date received 23 S e p t e m b e r 1994 Date accepted 24 O c t o b e r 1994

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320 (1-9). Nonetheless, reinforced by light and activity patterns, they often mesh in a predictable 24-h rhythm. Time-shifts in these diurnal rhythms, i.e., a change in (acro)phase, have been associated with certain disease states. Jet lag, as noted, is a minor example. More serious, however, are conditions like melancholic depression with early morning awakening that appear to be associated with an early shift in the diurnal cycle (16-17). The improvement in depression seen with the resetting of the body clock by sleep deprivation would support a role of disturbed body rhythms in the pathogenesis of this condition (16-19). The disturbance in rhythm is also shown by the altered suppression of the cortisol axis that is characteristic of melancholic depression (16-18). Normally, the cortisol rhythm is one of the more strongly diurnally entrained hormonal rhythms. Certainly, it is easy to see how a dis-coordination between the sleep-wake rhythms of the body and the needed sleep-wake rhythms for the individual can impair well-being and performance and even lead to disease. The problems of shift workers also fall into this category. Insomnia and abnormal somnolence patterns are also often caused by conflicts between the natural biorhythm for an individual and that imposed by environmental or societal factors (but may be caused by other biodynamic reasons, as in sleep apnea). Interruption of sleep also poses health problems by disrupting this rhythm. New parents can attest to the fatigue and malaise generated by repeated sleep interruptions. Fibromyalgia can be produced by loss of normal deep sleep or interruptions that diminish such restorative sleep (20). The stress of sleep loss and disruption is well evinced by its common role in the precipitation of psychotic crises in susceptible individuals. Thus, diurnal timing changes in biorhythms, changes in phase, are associated with disease. In addition to the characteristic of timing in biorhythms, there is also the characteristic of amplitude. In post-traumatic stress disorder and chronic fatigue syndrome, it may be the amplitude of the cortisol rhythm that appears to be more disturbed rather than the diurnal timing (21). In fibromyalgia and chronic fatigue patients, the amplitude of sleep (amount of restorative deep or Stage IV sleep) may be the major diurnal disturbance (20-21). Simplistically speaking, it may be necessary to have enough contrast between the periods of activity and the periods of rest in order for the activity to be productive and the rest to be restorative. It is unclear whether in some instances, attention deficits many be due to erratic or disordered rhythms that result in a mismatch between the needs for activity and mental focus.

MEDICALHYPOTHESES

Autonomic balance and rhythms In addition to the diurnal rhythms are the minuteto-minute rhythms as in heartbeat and respiration, hour-to-hour rhythms related to feeding and digestion, and annual and seasonal rhythms. Each of these rhythms is controlled by neural input and impacted by environmental and emotional changes mediated by neural and endocrine changes. Many subcircadian rhythms are under the control of the autonomic nervous system. Activation of the autonomic nervous system can occur both for conscious and unconscious neural input (22-24). The autonomic nervous system has been divided into anatomically, and perhaps physiologically distinct units - sympathetic and parasympathetic systems. These have been said to have predominantly activating or ergotropic effects (sympathetic) or trophotrophic and anabolic effects (parasympathetic), although this yang-yin balance is probably an oversimplification. At any rate, conscious and unconscious neural inputs influence the activity of these autonomic control systems and hence, of physiology. These effects are often opposite - as in the heart rate increase by sympathetic input and decrease by parasympathetic. Usually for bowel and bladder, sympathetic activity decreases motility and parasympathetic activity increases motility (but again, this is an oversimplification) (22-24). At any rate, one could see that stimulation of both systems would have dysfunctional results on bowel function. An imbalance of magnitude and timing could easily result in the function and symptoms of irritable bowel. Instead of a predictable activity/rest cycle, the bowel is in neuroendocrine confusion and resulting cramping and distention and pain. It is unclear what role abnormal rhythms of GI hormones and parahormones may play in this process. A similar imbalance in the autonomic control of airway dilation may result in asthma and may be the root of dysfunction and pain in interstitial cystitis. For all of these entities, as well as others, conscious and unconscious central neural input and intrinsic tone appear to interact to result in the disease physiology. There is a balance between the sympathetic and parasympathetic control of the heartrate. If an individual suddenly loses 20% of the blood volume, the sympathetic nervous system would be activated enhancing heart rate and vascular resistance and the adrenals would release cortisol and catecholamines to enhance the response to this stress. If, on the other hand, only the individual's mind perceives a threat, these same hormones and neural inputs may be activated without the physiological threat. The brain and body may generate such stress-related changes

NEUROENDOCRINE DYSRHYTHMIAS

even without the overt perception of the stressor or distress (25-30). This, too, could be another mode of neuroendocrine dysrhythmia - neuroendocrine activation of the stress response without actual physiological stress. This has often been termed the 'flightor-fight' response. The reality of current civilization is that while the responses are often activated (as by a 'near-miss' in traffic), they are rarely under circumstances when the preparation for flight-or-fight can be discharged as such. Rather than experiencing the natural release of this neuroendocrine signal in action, we are simply stuck with pondering our annoyance. After millenia, to develop and adapt the neuroendocrine response to danger, our bodies have not had time to develop more productive neuroendocrine responses. Once elicited, these responses may result in persistent pathological arousal and may accumulate with repeated arousal and lead to the pathologies of the stress response (14,22-24). In effect, the lack of the natural mode of discharge of the stress response by activity that remediates the stress (flight or fight in the past), modern circumstances generate a neuroendocrine dysrhythmia - a neuroendocrine response that is n o t appropriate to the biodynamic needs of the situation. Furthermore, repetition of such stresses without resolution may generate a chronic neuroendocrine distress syndrome of chronic anxiety and/or depression and have impacts on other neuroendocrine rhythms. Cardiovascularly, activation of the sympathetic nervous system without obvious provocation appears to be characteristic of panic attacks. Indeed, there is little or no difference in the subjective experience of sympathetic activation for physiological reasons in severe anemia or for psychodynamic reasons in anxiety disorder (31). Panic attacks and anxiety disorders are also neuroendocrine dysrhythmias as they appear to be due to inappropriately timed but otherwise normal neuroendocrine adrenergic responses. It is unclear whether this stress response is due to build-up of environmentally stimulated arousal/ activation without appropriate release or whether it is simply endogenously driven (misfire of normal response).

Muscle tension Control of voluntary muscles is under both reflex and conscious control. There is also central synergistic coordination so that opposing muscle groups are not usually activated simultaneously. The rhythm of normal activity involves contraction/relaxation cycles. Interruption of this unconscious rhythmic cycle can cause abnormal muscle tension, strain, damage and

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pain (32-40). Stress is well-recognized as causing skeletal muscle tension (32-40). There is a characteristic startle or alert posture that involves contraction of muscles commonly associated with stress and tension related pain in the head, neck, shoulders, and back (41, 42). As noted above, repeated minor 'alerts' can result in cumulative tension and pain in these areas.

Psychosomatic symptoms Physical changes can occur in bodily function on the basis of conscious or unconscious emotions and reflex responses to sensory input (22-24). An individual may or may not be aware of such phenomena. As noted above, neural input can govern activity in most body parts and this neural control can be influenced by central processes including emotions and sensory input. Thus, psychosomatic symptoms often result from real physiological dysfunction - there really is abnormal motility and distention of the bowel in irritable bowel syndrome; there really is altered vasomotor tone in patients with migraine; there is real bronchospasm in those with asthma. The fact that psychological distress or repeated unresolved arousal may bring out these dysfunctions does not make them any less real. A notable characteristic of psychosomatic symptoms is their patient specificity - some patients have irritable bowel syndrome, some have migraines, some have asthma, some have combinations, and so forth. One could postulate an intrinsic susceptibility to dysfunction, i.e. reactive airways, or bowel, or central vasculature that dictates a given individual's reactivity pattern. There is also reason to postulate an environmental kindling aspect as is seen in the abnormal autonomic and neuroendocrine regulation in animals subjected to maternal deprivation or in people after severe trauma (25). Thus, a spectrum of psychosomatic neuroendocrine dysfunctions would be reflective of intrinsic balance, prior trauma, and the nature of recent stresses. Psychosomatic symptoms are very common and contribute greatly to the costs of medical care (43). More effective recognition and management would not only be important in terms of decreasing personal suffering, but also in terms of decreasing medical costs. In addition to this, psychosomatic factors also probably enhance the degree of suffering experienced with other anatomic disease. Secondary fibromyalgia can occur in other painful rheumatologic conditions, perhaps brought out by the muscle tension from bracing against the pain or by the disturbance in deep, restorative sleep caused by pain. Indeed, a

322 characteristic of these psychosomatic neuroendocrine dysrhythmias, is that, to some degree, they are a universal experience and a source of much (potentially remediable) suffering. An attribute common to many of these conditions is that they are often labeled as functional. Indeed, so they are. They do not involve a major abnormality of physical structure, but rather of physiology, of function. Unfortunately, this word has accrued a psychiatric, even malingering connotation. Notable in the parlance of both physicians and patients with respect to such diagnoses is that 'It' s all in your head' is equivalent to 'It's imaginary'. Certainly, neuroendocrine dysrhythmias as posited here are influenced or even brought about by central (i.e. brain) perceptions. This does not mean that the heart racing of panic attacks is imaginary or the abdominal pain from the abnormal bowel motility in irritable bowel syndrome is not real. Certainly, one could argue that all suffering is 'in the head' since suffering can be defined in the context of processes that imply cognitive function. It is ludicrous, however, to suggest that all suffering is imaginary. Too often, Westem medicine has been trapped by the limited expectation that all function is in structure and that mechanical approaches are correct for all diseases. This complex of disease conditions can be approached as problems in the physiological balance of control. As such, some can be addressed by pharmacological means to achieve neuroendocrine balance, while others can be best approached by efforts to correct the rhythmic balances, or a combination of these factors. We must move from the trap of 'anatomy is destiny' and look again to the values of restoring rhythm and balance.

Neuroendocrine dysrhythmias The proposed paradigm (Table 1) is a modification of prior classifications of psychosomatic illness with two major differences. Firstly, they are grouped by major effects on diurnal rhythms, autonomic balance, and muscle balance. Second, the underlying disruptions in rhythm are presented as universal experiences varying in degree. At some time, all normal people experience emotion and stress-related changes in bowel motility and action; in some people, this is more persistent, severe, or disturbing, and thus constitutes a disease. By this classification, and seeing the conditions as a spectrum that includes normals, one can develop an approach to these conditions that enhances their recognition in 'early stages', allowing for circumvention of a full attack by mild and early intervention. The first group is that of circadian dysrhythmias, and is divided into time-shift (acrophase) mismatches

MEDICAL HYPOTHESES

Table 1 Neuroendocrine dysrhythmias Circadian dysrhythmias Phase mismatch

Amplitude or acrophase

Depression (melancholic) Jet lag Shift work Sleep-apnea Seasonal affectivedisorder

Atypical depression Chronic fatigue syndrome Fibromyalgia Post-traumatic stress syndrome (Some) attentiondeficit disorder Premenstrual syndrome

Autonomic dysrhythmias Hyperadrenergic

Hypercholinergic

Panic disorder

Esophageal spasm

Anxiety disorders Hyperventilation Hypoglycemia Mitral valveprolapse

Asthma Spastic bowel

Adrenergic/cholinergicimbalance Irritablebowel Neurasthenia Other GI disturbances (nausea, abnormalmotilityor emptying) Interstitialcystitis Neuroasthenia(vasoregulatoryasthenia) Dizziness Muscle tension effects

Skeletal

Smooth

Tension headache Fibromyalgia Chronic pelvicpain Temperomandibularjoint syndrome Myofascialpain syndromes

Interstitialcystitis Migraine Esophageal spasm Asthma Spasticbowel

and amplitude mismatches. For the former group, including melancholic depression and shift work, the biorhythms are out of sync with the expected diurnal schedule. For the latter group, the degree of diurnal difference appears to be more affected - individuals are not as fully awake or aroused when they should be aroused, nor as relaxed or restful when they should be at rest. Obviously, a given individual may have problems both with phase or synchrony as well as with amplitude. Treatments for these conditions might include phase modifiers including activity, sleep/ wake, light/dark, and feeding patterns that enhance the adaptation to an acceptable rhythm. Timing of activity and relaxation exercises may also enhance the

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amplitude of the diumal rhythms, allowing for more effective 'on' and 'off' phases. Imbalance of autonomic control appears to play a major role in many disorders. The symptoms of panic disorder, mitral valve prolapse, hypoglycemia, and anxiety disorders may be due to overactive adrenergic release or responses. In other conditions, including asthma, esophageal spasm, and spastic bowel, cholinergic hyperactivity may predominate. For others, there appears to be antagonistic hyperactivity - as in irritable bowel and other gastrointestinal motility disturbances, and the neurocirculatory dysfunctions of neurasthenia and dizziness. It is unclear whether altered allergic reactivity might also be neurally mediated. Muscle tension effects may be predominantly in skeletal or smooth muscle. Skeletal muscle tension syndromes include fibromyalgia, TMJ (temporomandibular joint) syndrome, myofascial pain syndromes (with trigger points), and tension headache. Smooth muscle tension syndromes are often due to autonomic dysregulation as noted above and include interstitial cystitis, esophageal spasm, irritable bowel, and asthma. Thus, these categories are not mutually exclusive, but rather mechanistic and explanatory. In addition, a given individual may experience many of these conditions simultaneously, e.g., many with chronic fatigue also have fibromyalgia and/or irritable bowel syndrome.

Treatment approaches Since stress and inadequate or inappropriate coping skills can bring out these problems, obviously reduction of stress or strengthening of appropriate coping skills is an indicated aspect of the treatment for these conditions. In addition, since erratic rhythms appear to play a role, regularization of habits to coincide with needed biological rhythms is also appropriate. In some instances, neuroendocrine reset by pharmacologic means is necessary - as in the use of antidepressants or specific serotonin reuptake inhibitors. Often in these conditions, patients are reluctant to accept the diagnosis and the proposed treatment. Modeling the conditions as specific exaggerations of universal phenomena makes these approaches more acceptable to many patients.

Conclusions Neuroendocrine rhythms and external and internal disruptions of those rhythms are a universal and

daily experience. Individuals, based on their genetic heritage and prior experience can display a unique pattern of disruption of the rhythms with resulting subclinical or clinical disease. By focusing on identifying and correcting the abnormal neuroendocrine balances early, one may be able to prevent more significant disruptions and disease, as well as to relieve suffering.

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