Annals of Neurosciences, Vol 16, No 1 (2009)
Annals of Neurosciences, Volume 16, Issue 1 (January), 2009
Circadian rhythm in patients with spinal cord injuries
ABSTRACT
Spinal Cord Injury (SCI) is damage to the spinal cord that may result in the loss of mobility. Frequent causes of damage are trauma (motor vehicle accident, falls, etc.) or disease (polio, spina bifida, Friedreich's Ataxia, etc.). However, abnormality in circadian rhythm has been observed in SCI. Melatonin is the primary hormone of the pineal gland and acts to regulate the body's circadian rhythm. Normally, melatonin levels begin to rise in the mid-to-late evening, remains high for most of the night, and then decreases in the early morning hours. Patients with SCI have a lower melatonin secretion during the hours of darkness than in healthy subjects. This may contribute to impaired sleep at night, fatigue during the day and affect pain perception. Disturbed level of melatonin has also been reported in SCI patients that are associated with disturbances in circadian rhythm. Therefore, circadian rhythm can be important in the pathophysiology and treatment of SCI patients and it is important to know the time and the level of melatonin in order to prescribe the appropriate treatment regimen. The expanding science of circadian rhythm biology and a growing interest in human clinical research on circadian rhythm in patients with spinal cord injuries inspired this review. This article reviews the relationship of circadian rhythm in patients with SCI.
KEYWORDS : Spinal Cord Injury; Circadian Rhythm; Melatonin
Corresponding Author: V.P. Sharma,E-mail : Vijaipsharma@yahoo.com
doi: 10.5214/ans.0972.7531.2009.160110
Introduction
A spinal cord injury usually begins with a sudden, traumatic blow to the spine that fractures or dislocates vertebrae. The damage begins at the moment of injury when displaced bone fragments, disc material, or ligaments bruise or tear into spinal cord tissue. However, injury is more likely to cause fractures and compression of the vertebrae, which then crush and destroy the axons, extensions of nerve cells that carry signals across the spinal cord and between the brain and the rest of the body. An injury to the spinal cord can damage a few or almost all of these axons. Some injuries will allow almost complete recovery. Others will result in complete paralysis. A patient with SCI suffers from higher ratings of pain intensity, anxiety and depression and these patients have poor sleep quality due to disturbed melatonin levels.
Circadian rhythm is characterized by the dynamics of 24 hour cycle. Human bodies are in harmony with 24hr light and dark cycles and therefore the secretion of hormones that are sensitive to light and dark orchestrate around the 24 hour cycle and thus ensure optimal functioning. The disturbances in secretion of hormones that are sensitive to dark and light cycle results in abnormal circadian rhythm. Melatonin secretion normally follows a circadian pattern and is highest at night and decreased during the day.
Many of the symptoms associated with SCI, such as difficulty in sleeping, anxiety and depression, are similar to those observed in individuals whose circadian pacemaker is abnormally aligned with their sleep-wake schedule. Many studies have indicated that cervical spine injury results in the complete loss of pineal melatonin production which further affects sleep, causes anxiety and depression1. This review will focus on the circadian rhythm in patients with spinal cord injuries. A detailed knowledge of circadian rhythm in patients with spinal cord injuries facilitates designing of novel drugs which combats.the disturbed sleep and pain associated with this abnormal circadian rhythm in these patients.
Circadian Rhythm in Spinal Cord
Light plays dominant role in the body, affecting the secretion of melatonin and other hormones thereby affecting the person's wakefulness, blood pressure and body temperature. Serum melatonin levels in patients with spinal lesions at the cervical, thoracic or lumbar region have been formed to be low without diurnal rhythm in patients with cervical lesion (C4-5). However, diurnal rhythms were maintained with high levels in the dark period in the patient with upper thoracic spinal (T2-3) transactions. This study suggests that the cervical region of the spinal cord is part of the neural pathway essential for the diurnal rhythm of pineal melatonin secretion in human beings.2
Cervical spinal cord lesions disrupt the circadian rhythm and alter the human melatonin excretion. Levels of serum Cortisol, aldosterone, and growth hormone have reflected the rhythmic variations in subjects with SCI. The absence of significant increase in nocturnal melatonin distinguishes quadriplegic subjects from normal males and from subjects presenting with a lesion of the lumbar spinal cord. These differences may be caused by “decentralization” of the pineal organ due to a lesion within the cervical spinal cord interrupting descending sympathetic fibers. The human pineal, like that of other mammals, is regulated, at least in part, by activity within the central nervous system via sympathetic nervous connections. 3
Circadian blood pressure rhythm was observed in patients with higher and lower spinal cord injury when simultaneous evaluation of autonomic nervous activity and physical activity was done. This study indicated that the central sympatho-excitatory pathway to the upper thoracic cord plays a critical role in the maintenance of normal circadian blood pressure rhythm in humans. Motor nerve functioning and sympathoadrenal secretion are not essential to this regulation.4 Reduced sleep efficiency in cervical spinal cord injury causes abolished melatonin secretion. Thus, the absence of nocturnal melatonin level in cases of cervical SCI may help in explaining the sleep disturbances which raises the possibility that melatonin replacement therapy could be a plausible alternative to resume normal sleep. 5
In freely moving rats and monkeys, H-reflex amplitude displays a marked circadian variation without change in background motor neuron tone. In rats, the Η-reflex is the largest around noon and the smallest around midnight. This study investigated the effects on circadian rhythm for calibrated contusions of mid-thoracic spinal cord as well as mid-thoracic transection on specific spinal cord pathways. It is also reported that the Η-reflex circadian rhythm depends on descending influence from the brain and that, this influence is conveyed by the main corticospinal tract. 6 Thus, circadian rhythm and spinal cord injuries are found to be closely linked and hence an alteration in circadian rhythm in patients with SCI, several symptoms may arise.
Is Melatonin a Circadian Rhythm Hormone Important in Treatment of SCI Patients?
In reality circadian rhythms control the timing, quantity and quality of the hormones and neurotransmitters to be secreted by the body. Hormones and neurotransmitters are the elements that determine how we feel, the sleep patterns, appetite, sex drive and other sleep and mood-related issues. Under normal circumstances our circadian rhythms create circadian balance. When out of balance, the timing and release of hormone and neurotransmitter is disturbed which leads to circadian rhythm disorder (CRD).
A circadian rhythm disorder refers to the condition where the body produces hormones, chemicals and neurotransmitters which are not within the normal limits at the appropriate time of the day. In patients with SCI, melatonin is produced less in the evening thus affecting sleep. Circadian rhythms stimulate the timing and production of several hormones and neurotrasmitters that affect sleep and mood.
Circadian rhythms permeate practically every aspect of our lives because they strongly influence the chemicals that determine our mood and sleep. If we possess prior knowledge about various disturbances in circadian rhythm of melatonin secretion in patients with SCI, it would be helpful in the treatment of SCI patients. SCI is characterized by the diffused pain, disturbed sleep, fatigue, anxiety and depression. Previous reports suggest that in patients with SCI melatonin level remains low,5 which causes disturbed sleep at night accompanied with diffuse pain in the morning hours.
Several studies reveal that, melatonin is potentially important as a treatment of acute spinal cord injury. The human circadian system regulates the temporal organization of several endocrine functions, including the production of melatonin (via a neural pathway that includes the spinal cord), TSH, and Cortisol. In traumatic spinal cord injury, afferent and efferent circuits that influence the basal production of these hormones may be d isru pted. The resu Its of this study indicate that neurological complete cervical spinal injury results in the complete loss of pineal melatonin production and that neither the loss of melatonin nor the loss of spinal afferent information disrupts the rhythmicity of Cortisol or TSH secretion.7 One of the studies demonstrated that the treatment with melatonin reduces the development of inflammation and tissue injury events associated with spinal cord trauma. 8
In a study on treatment of methylprednisolone (MP), melatonin, and combined treatment of MP and melatonin, there was functional recovery in patients with spinal cord injuries.9 The effect of melatonin on an experimental spinal cord ischemia was observed and found to be protective with the result that melatonin administration may significantly reduce the incidence of spinal cord injury following temporary aortic occlusion. 10 Melatonin and oxytetracycline are effective in preventing lipid peroxidation in spinal cord injury. Paraoxonase and homocysteine can be used in monitoring the antioxidant defense system as well as superoxide dismutase and plasma glutathione peroxidase, both in injury and medicated groups.11
Melatonin has been shown to be very effective in protecting the injured spinal cord from secondary injury.12 In another study on protective effects of melatonin on experimental spinal cord injury, it was indicated that injection of melatonin reduced thiobarbituric acid reactive substances content and myeloperoxidase activity, facilitating recovery of the damaged spinal cord. 13
Melatonin may also be potentially helpful for neuropathic pain, activation of the endogenous melatonin system in the spinal cord can reduce the generation, development and maintenance of central sensitization, with a resultant inhibition of capsaicin-induced secondary mechanical allodynia and hyperalgesia.14 Shift in melatonin production may play a crucial role in pain and abnormal sleep pattern. Thus, the treatment of melatonin in patients with SCI can reduce the pain and also help to overcome the disturbed sleep pattern.
Conclusion
Circadian rhythmicity can be important in the pathophysiology and treatment of SCI patients. The observations of abnormalities in melatonin is highly regulated by circadian pacemaker raising the possibility that there is an abnormality of circadian rhythm in patients with SCI. Controlled studies of circadian rhythm have not been performed in patients with SCI. A clear understanding on circadian pattern of SCI patients will provide useful information to augment the understanding of pathophysiology and help in the treatment of SCI patients. Until the circadian rhythms of SCI are accurately known, appropriate treatment cannot be designed.
Abbreviations
SCI- spinal cord injuries; CRD- circadian rhythm disorder; TSH- thyroid stimulating hormone; MP- Methylprednisolone.
Competing interests - None
Received Date : 14 March 2009
Revised Date : 27 March 2009
Accepted Date : 9 April 2009
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