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VESTIBULAR MODULATION OF THYROID FUNCTION IN FORCED COLD WATER SWIMMING STRESS INDUCED Wistar albino RATS BY VARSHA VARGHESE P Dissertation Submitted to the Kerala University of Health Sciences, Thrissur In partial fulfillment of the requirements for the degree of MASTERS In MEDICAL PHYSIOLOGY Under the guidance of G Sai Sailesh Kumar DEPARTMENT OF PHYSIOLOGY LITTLE FLOWER INSTITUTE OF MEDICAL SCIENCES AND RESEARCH ANGAMALY 2016 KERALA UNIVERSITY OF HEALTH SCIENCES THRISSUR DECLARATION BY THE CANDIDATE I hereby declare that this dissertation entitled “VESTIBULAR MODULATION OF THYROID FUNCTION IN FORCED COLD WATER SWIMMING STRESS INDUCED Wistar albino RATS” is a bonafide and genuine research work carried out by me under the guidance of Mr.G Sai Sailesh Kumar, Head of the Department, Department of Physiology, LIMSAR, Angamaly. Date: VARSHA VARGHESE P Place: Reg No: 132860006 COPYRIGHT Declaration by the Candidate I hereby declare that the Kerala University of Health Sciences, Thrissur shall have the rights to preserve, use and disseminate this dissertation/thesis in print or electronic format for academic/research purpose. Date: Place: VARSHA VARGHESE P ABSTRACT OBJECTIVE The present study was undertaken to provide experimental evidence for vestibular modulation of thyroid function in cold water swimming stress induced Wistar albino rats. MATERIALS AND METHOD 24 healthy, adult male albino rats of Wistar strain were used in the present study. Rats were forced to swim in the plastic tubs (height: 60 cm, diameter: 40 cm) containing cold water, maintained at 10°C. Depth of the water in the plastic tub was 30 cm. The swimming session lasted for 45 minutes daily. The middle ear cavity was irrigated with hot (40 degree centigrade) or cold (15 degree centigrade) water through a polyethylene tube for 15 days. RESULTS Significant decrease in T3, T4 levels, an increase in cholesterol and body weight was observed in stress only group, whereas no such changes observed in vestibular stimulation group. CONCLUSION Our study provides preliminary evidence that vestibular stimulation can effectively prevent stress induced changes in body weight and thyroid hormones secretion. We recommend translational research in this area to elucidate the mechanism of vestibular modulation of thyroid hormones secretion. KEY WORDS: Caloric vestibular stimulation; Cold water swimming stress; Thyroid hormones. I TABLE OF CONTENTS SL.NO: CONTENTS PAGES 1. INTRODUCTION 1 2. OBJECTIVE 4 3. REVIEW OF LITERATURE 6 4. METHODOLOGY 37 5. RESULTS 41 6. DISCUSSION 46 7. CONCLUSION 50 8. REFERENCES 52 9. ANNEXURES 62 II LIST OF FIGURES SL.NO: FIGURES PAGES 1 Thyroid gland and larynx 7 2 Hypothalamo pituitary thyroid axis. 9 3 Vestibular apparatus 21 4 Typical hair cells (flask and cuboid) 23 synapsing with afferent and efferent nerve 5 Change in hair cells with respect to 24 movement 6 Swing- controlled vestibular stimulation 29 7 Sympathetic Adrenal Medullary axes 32 8 Hypothalamo Pituitary Adrenal Axis 34 III 9 Caloric vestibular stimulation 40 10 Body weight before and after vestibular 42 stimulation. 11 T3 levels before and after vestibular 43 stimulation T4 levels before and after vestibular 12 44 stimulation Cholesterol levels before and after vestibular 13 45 stimulation IV ANNEXURES SL.NO: TITLE PAGES Acknowledgement 63 1 2 List of abbreviations used 3 Publications 65 67 V INTRODUCTION 1 CHAPTER I INTRODUCTION Stress is the generalized, non-specific response of the body to any factor that overwhelms or threatens to overwhelm, the body’s compensatory abilities to maintain homeostasis. Stress causes physiological changes, biochemical changes and behavioral changes in our body.1,2 Stress can cause thyroid autoimmunity.3 In laboratory animals forced swimming is most widely accepted for studying physiological variations in response to stress. It was reported that rats could survive 80 hours in lukewarm water (36°C). Increase or decrease in the temperature of water influences the behavior of the animal and changes the influence of glucocorticoids.4, 5 Stress modulates secretion of hormones and may lead to endocrine disorders. Stress increases secretion of Glucocorticoids, growth hormone, prolactin and catecholamines. Increase in these hormones will help the individual to cope up with the stressful condition. However stress will decrease secretion of thyroid hormone and insulin. Both T3, T4 levels decreases in response to stress. Stress inhibits thyroid stimulating hormone through the action of glucocorticoids on the nervous system.6Stress causes hypothyroid symptoms by disrupting HPA axis, reduces the conversion of T4 to T3, promote autoimmunity by weakening immune barriers, causes thyroid hormone resistance and causes hormonal imbalances.7 Vestibular apparatus is known as membranous labyrinth and is enclosed in bony labyrinth of temporal bone. Vestibular apparatus consists of otolith organs and three semi circular canals. Vestibular stimulation relieves stress, pain, promotes sleep, 2 improves cognition, immunity, balance food intake and also treats endocrine disorders.8-13Vestibular stimulation modulates thyroid hormone secretion through its connections with paraventricular nucleus and arcuate nucleus.14The present study was undertaken to provide preliminary experimental evidence for vestibular modulation of thyroid function in cold water swimming stress induced Wistar albino rats and to suggest further research to recommend vestibular stimulation as an intervention for thyroid disorders. 3 OBJECTIVES 4 CHAPTER 2 OBJECTIVES MAIN OBJECTIVE To study the Effect of caloric vestibular stimulation on modulation of thyroid function in cold water swimming stress induced Wistar albino rats. OTHER OBJECTIVE To compare the effect of hot and cold water vestibular stimulation on thyroid function. HYPOTHESIS Vestibular stimulation may prevent stress induced changes in thyroid function. 5 REVIEW OF LITERATURE 6 CHAPTER 3 REVIEW OF LITERATURE THYROID GLAND IT’S METABOLIC ROLES Thyroid gland is one of the largest glands (15-20 gms in adult) in endocrine system. The butter fly shaped gland located immediately below the larynx on each side anterior to trachea. It has 2 lobes connected by isthmus (figure 1). When the TSH from the hypothalamus comes, the thyroid follicles become active and secrete 2 hormones, thyroxin (T4) and triiodothyronine (T3). Parafollicular cells or C cells present in between follicles which secrete calcitonin, it helps to regulate calcium homeostasis.15 Figure 1: The thyroid gland and larynx 16 7 BIOSYNTHESIS AND STORAGE OF THYROID HORMONES T3 and T4 are synthesized from tyrosine and iodine by enzyme peroxidase. First step is uptake of iodine by thyroid. It is an energy requiring process. TSH controls the iodine uptake and antithyroid agents inhibit iodine transport. Thyrosine residue serves as the substrate for hormone synthesis and is present in thyroglobulin which is a large glycoprotein. Next step is the oxidation of iodide. Pendrin is the transporter helps to move the iodide to apical surface of epithelial cells where it is oxidised to by the enzyme peroxidase. After that iodination Thyrosine residue of thyroglobulin initially to monoiodotyrosine (MIT) and then to diiodotyrosine (DIT). Next is coupling reaction. 2 molecules of DIT couple to form cone molecule of MIT and one molecule of DIT coupled to form T3 with the help of peroxidase. Iodinated thyroglobulin is stored in follicle as colloid for several months.30 SECRETION, TRANPORT AND METABOLISM OF THYROID HORMONES Through endocytosis colloid containing iodinated thyroglobulin is retrieved and by pinocytosis colloid enters the cytoplasm as colloid droplets. Colloid droplets then fuse with lysosome vesicles and digest the thyroglobulin molecule releasing T3 ,T4, DIT, MIT .among them DIT and MIT are rapidly deiodinated and the iodine is reused. Transport of T3 and T4 either by bound form by thyroxine binding globulin, thyroxine binding prealbumin and by thyroxine binding albumin or by free form. These free unbound hormones represent the biologically active hormone. Metabolism of circulating hormone includes deiodination, deamination and conjugation. T4 is deiodinated in to T3 and reverse T3 which are then in to DIT and 8 MIT. DIT is further deiodinated to MIT. Very small amount of T3 and T4 undergoes decarboxylation to form tetraiodothyroaceticacid and triiodothyroacetic acid. Thyroid hormones are conjugated in liver to form glucuronides and sulphates. Metabolites of T3 and T4 are mainly excreted through faeces with a small amount in urine.30 REGULATION OF THYROID HORMONE SECRETION Regulation is mainly by negative feedback mechanism through HPT axis and auto regulation of thyroid gland (figure 2). TSH from the anterior pituitary regulates the thyroid hormone secretions. Increased TSH increase all the steps of biosynthesis, increase the number and size of follicular epithelial cells and increase the vascularity of thyroid gland. A fall in thyroid hormone stimulates TSH secretion and rise in thyroid hormone inhibit TSH secretion. Figure 2: Hypothalamo Pituitary Thyroid axis 9 30 TSH from anterior pituitary is controlled by hypothalamic tyrotropin releasing hormones (TRH). TRH is secreted by arcuate nucleus of hypothalamus and stored in median eminence which is released into hypothalamo hypophyseal portal vessels to reach anterior pituitary. Exposure to cold, emotions, stress and negative control by plasma T3 and T4 levels will regulate the TRH production from hypothalamus. Autoregulation is according to the availability iodine content in the food. If availability is high iodine trapping mechanism is less efficient and if the availability is minimum iodine trapping mechanism is super efficient.16 FUNCTIONS OF THYROID HORMONES (T3, T4) Thyroid hormones increase the Transcription of large number of genes along with steroids and retinoids.17 Most of the T4 secreted by the thyroid is converted to T3.18 Thyroid hormones activate nuclear receptors.19 Thyroid hormones increase cellular metabolic activity.20 It increase the number and activity of mitochondria.21 It has positive role in growth. It regulate chondrocyte cell growth and differentiation in the endochondral growth plate.22 Stimulates carbohydrate and fat metabolism.23.Increased basal metabolic rate.24 Increase in the hormone secretion will decreases the body weight.25 Patients with thyroid disease, usually has altered cardiac function such as heart rate, cardiac output, and systemic vascular resistance which are closely related to thyroid status.26 Thyroid hormones play an important role in CNS especially in maturation phase. Absence of thyroid hormones produce multiple morphological and biochemical 10 alteration and in humans leads to irreversible mental retardation.27 Thyroid hormones may either have a direct vasodilating effect or increase shunting in vascular beds of rats.28 Pregnancy has a profound impact on thyroid gland function, it is a stress test for the thyroid resulting in hypothyroidism in women with limited thyroid reserve and postpartum thyroiditis in women with Hashimoto’s disease who were euthyroid prior to conception.29 Above studies revealed that thyroid hormones involved in almost all functions in our body. Any change in the level of hormone will alter the vital process in our body. Under functioning of thyroid is hypothyroidism, over functioning of thyroid is hyperthyroidism and normal thyroid is euthyroid. DISEASES OF THE THYROID 1-Hyperthyroidism (over functioning of thyroid) In most patients with hyperthyroidism, the thyroid gland is increased to two to three times' normal size, with tremendous hyperplasia and infolding of the follicular cell lining into the follicles, so the number of cells is increased greatly. Also, each cell increases its rate of secretion several fold; radioactive iodine uptake studies indicate that some of these hyperplastic glands secrete thyroid hormone at rates 5 to 15 times normal. Graves' disease, the most common form of hyperthyroidism, is an autoimmune disease in which antibodies called thyroid-stimulating immunoglobulins (TSIs) form against the TSH receptor in the thyroid gland. These antibodies bind with the same membrane receptors that bind TSH and induce continual activation of the 11 cAMP system of the cells, with resultant development of hyperthyroidism. The TSI antibodies have a prolonged stimulating effect on the thyroid gland, than TSH. The high level of thyroid hormone secretion caused by TSI in turn suppresses anterior pituitary formation of TSH. Therefore, TSH concentrations are less than normal (often essentially zero) rather than enhanced in almost all patients with Graves' disease.3 2- Thyroid Adenoma Hyperthyroidism occasionally results from a localized adenoma (a tumor) that develops in the thyroid tissue and secretes large quantities of thyroid hormone. This is different from the more usual type of hyperthyroidism in that it is usually not associated with evidence of any autoimmune disease. An interesting effect of the adenoma is that as long as it continues to secrete large quantities of thyroid hormone, secretory function in the remainder of the thyroid gland is almost totally inhibited because the thyroid hormone from the adenoma depresses the production of TSH by the pituitary gland. Symptoms of Hyperthyroidism The symptoms of hyperthyroidism are a high state of excitability, intolerance to heat, increased sweating, mild to extreme weight loss (sometimes as much as 100 pounds), varying degrees of diarrhea, muscle weakness, nervousness or other psychic disorders, extreme fatigue but inability to sleep, and tremor of the hands.30 3- Exophthalmos Most people with hyperthyroidism develop some degree of protrusion of the eyeballs. This condition is called exophthalmos. A major degree of exophthalmos occurs in 12 about one third of hyperthyroid patients, and the condition sometimes becomes so severe that the eyeball protrusion stretches the optic nerve enough to damage vision. Much more often, the eyes are damaged because the eyelids do not close completely when the person blinks or is asleep. As a result, the epithelial surfaces of the eyes become dry and irritated and often infected, resulting in ulceration of the Cornea. The cause of the protruding eyes is edematous swelling of the retro-orbital tissues and degenerative changes in the extraocular muscles. In most patients, immunoglobulins that react with the eye muscles can be found in the blood. Furthermore, the concentration of these immunoglobulins is usually highest in patients who have high concentrations of TSIs. Therefore, there is much reason to believe that exophthalmos, like hyperthyroidism itself, is an autoimmune process. The exophthalmos is usually greatly ameliorated with treatment of the hyperthyroidism. Diagnostic Tests for Hyperthyroidism For the usual case of hyperthyroidism, the most accurate diagnostic test is direct measurement of the concentration of "free" thyroxine (and sometimes triiodothyronine) in the plasma, using appropriate radioimmunoassay procedures. Other tests that are sometimes used are as follows: - The basal metabolic rate is usually increased to +30 to +60 in severe hyperthyroidism. -The concentration of TSH in the plasma is measured by radioimmunoassay. In the usual type of thyrotoxicosis, anterior pituitary secretion of TSH is so completely 13 suppressed by the large amounts of circulating thyroxine and triiodothyronine that there is almost no plasma TSH. - The concentration of TSI is measured by radioimmunoassay. This is usually high in thyrotoxicosis but low in thyroid adenoma. Physiology of Treatment in Hyperthyroidism The most direct treatment for hyperthyroidism is surgical removal of most of the thyroid gland. In general, it is desirable to prepare the patient for surgical removal of the gland before the operation. This is done by administering propylthiouracil, usually for several weeks, until the basal metabolic rate of the patient has returned to normal. Then, administration of high concentrations of iodides for 1 to 2 weeks immediately before operation causes the gland itself to recede in size and its blood supply to diminish. By using these preoperative procedures, the operative mortality is less than 1 in 1000 in the better hospitals, whereas before development of modern procedures, operative mortality was 1 in 25. Treatment of the Hyperplastic Thyroid Gland with Radioactive Iodine80 to 90 percent of an injected dose of iodide is absorbed by the hyperplastic, toxic thyroid gland within 1 day after injection. If this injected iodine is radioactive, it can destroy most of the secretory cells of the thyroid gland. Usually 5 mill curies of radioactive iodine is given to the patient, whose condition is reassessed several weeks later. If the patient is still hyperthyroid, additional doses are administered until normal thyroid status is reached.30 14 4- Hypothyroidism The effects of hypothyroidism, in general, are opposite to those of hyperthyroidism, but there are a few physiological mechanisms peculiar to hypothyroidism. Hypothyroidism, like hyperthyroidism, is often initiated by autoimmunity against the thyroid gland (Hashimoto disease), but immunity that destroys the gland rather than stimulates it. The thyroid glands of most of these patients first have autoimmune "thyroiditis," which means thyroid inflammation. This causes progressive deterioration and finally fibrosis of the gland, with resultant diminished or absent secretion of thyroid hormone. Several other types of hypothyroidism also occur, often associated with development of enlarged thyroid glands, called thyroid goiter, as follows.30 5-Thyroid goiter Endemic Colloid Goiter Caused by Dietary Iodide Deficiency. The term "goiter" means a greatly enlarged thyroid gland. As pointed out in the discussion of iodine metabolism, about 50 milligrams of iodine are required each year for the formation of adequate quantities of thyroid hormone. In certain areas of the world, notably in the Swiss Alps, the Andes, and the Great Lakes region of the United States, insufficient iodine is present in the soil for the foodstuffs to contain even this minute quantity. Therefore, in the days before iodized table salt, many people who lived in these areas developed extremely large thyroid glands, called endemic goiters. The mechanism for development of large endemic goiters is the following: Lack of iodine prevents production of both thyroxine and triiodothyronine. As a result, no hormone is 15 available to inhibit production of TSH by the anterior pituitary; this causes the pituitary to secrete excessively large quantities of TSH. The TSH then stimulates the thyroid cells to secrete tremendous amounts of thyroglobulin colloid into the follicles, and the gland grows larger and larger. But because of lack of iodine, thyroxine and triiodothyronine production does not occur in the thyroglobulin molecule and therefore does not cause the normal suppression of TSH production by the anterior pituitary. The follicles become tremendous in size, and the thyroid gland may increase to 10 to 20 times' normal size. Idiopathic Nontoxic Colloid Goiter: Enlarged thyroid glands similar to those of endemic colloid goiter can also occur in people who do not have iodine deficiency. These goitrous glands may secrete normal quantities of thyroid hormones, but more frequently, the secretion of hormone is depressed, as in endemic colloid goiter. The exact cause of the enlarged thyroid gland in patients with idiopathic colloid goiter is not known, but most of these patients show signs of mild thyroiditis; therefore, it has been suggested that the thyroiditis causes slight hypothyroidism, which then leads to increased TSH secretion and progressive growth of the non inflamed portions of the gland. This could explain why these glands are usually nodular, with some portions of the gland growing while other portions are being destroyed by thyroiditis. In some persons with colloid goiter, the thyroid gland has an abnormality of the enzyme system required for formation of the thyroid hormones. Among the abnormalities often encountered are the following: 16 -Deficient iodide-trapping mechanism, in which iodine is not pumped adequately into the thyroid cells - Deficient peroxidase system, in which the iodides are not oxidized to the iodine state -Deficient coupling of iodinated tyrosines in the thyroglobulin molecule so that the final thyroid hormones cannot be formed -Deficiency of the deiodinase enzyme, which prevents recovery of iodine from the iodinated tyrosines that are not coupled to form the thyroid hormones (this is about two thirds of the iodine), thus leading to iodine deficiency Finally, some foods contain goitrogenic substances that have a propylthiouracil-type of antithyroidactivity, thus also leading to TSH-stimulated enlargement of the thyroid gland. Such goitrogenic substances are found especially in some varieties of turnips and cabbages. Physiological Characteristics of Hypothyroidism Whether hypothyroidism is due to thyroiditis, endemic colloid goiter, idiopathic colloid goiter, destruction of the thyroid gland by irradiation, or surgical removal of the thyroid gland, the physiological effects are the same. They include fatigue and extreme somnolence with sleeping up to 12 to 14 hours a day, extreme muscular sluggishness, slowed heart rate, decreased cardiac output, decreased blood volume, sometimes increased body weight, constipation, mental sluggishness, failure of many trophic functions in the body evidenced by depressed growth of hair and scaliness of the skin, development of a froglike husky voice, and, in severe cases, development of an edematous appearance throughout the body called myxedema. 17 6-Myxedema Myxedema develops in the patient with almost total lack of thyroid hormone function. Such patient, demonstrating bagginess under the eyes and swelling of the face. In this condition, for reasons not explained, greatly increased quantities of hyaluronic acid and chondroitin sulfate bound with protein form excessive tissue gel in the interstitial spaces and this causes the total quantity of interstitial fluid to increase. Because of the gel nature of the excess fluid, it is mainly immobile and the edema is the nonpitting type.30 7-Atherosclerosis in Hypothyroidism Lack of thyroid hormone increases the quantity of blood cholesterol because of altered fat and cholesterol metabolism and diminished liver excretion of cholesterol in the bile. The increase in blood cholesterol is usually associated with increased atherosclerosis. Therefore, many hypothyroid patients, particularly those with myxedema, develop atherosclerosis, which in turn results in peripheral vascular disease, deafness, and coronary artery disease with consequent early death. Diagnostic Tests in Hypothyroidism The tests already described for diagnosis of hyperthyroidism give opposite results in hypothyroidism. The free thyroxine in the blood is low. The basal metabolic rate in myxedema ranges between -30 and -50. And the secretion of TSH by the anterior pituitary when a test dose of TRH is administered is usually greatly increased (except in those rare instances of hypothyroidism caused by depressed response of the pituitary gland to TRH). 18 Treatment of Hypothyroidism The effect of thyroxine on the basal metabolic rate, demonstrating that the hormone normally has duration of action of more than 1 month. Consequently, it is easy to maintain a steady level of thyroid hormone activity in the body by daily oral ingestion of a tablet or more containing thyroxine. Furthermore, proper treatment of the hypothyroid patient results in such complete normality that formerly myxedematous patients have lived into their 90s after treatment for more than 50 years. 30 8-Cretinism Cretinism is caused by extreme hypothyroidism during fetal life, infancy, or childhood. This condition is characterized especially by failure of body growth and by mental retardation. It results from congenital lack of a thyroid gland (congenital cretinism), from failure of the thyroid gland to produce thyroid hormone because of a genetic defect of the gland, or from iodine lack in the diet (endemic cretinism).The severity of endemic cretinism varies greatly, depending on the amount of iodine in the diet, and whole populaces of an endemic geographic iodine-deficient soil area have been known to have cretinoid tendencies. A neonate without a thyroid gland may have normal appearance and function because it was supplied with some (but usually not enough) thyroid hormone by the mother while in utero. A few weeks after birth, however, the neonate's movements become sluggish and both physical and mental growth begin to be greatly retarded. Treatment of the neonate with cretinism at any time with adequate iodine or thyroxine usually causes normal return of physical growth, but unless the cretinism is treated within a few weeks after birth, mental 19 growth remains permanently retarded. This results from retardation of the growth, branching, and myelination of the neuronal cells of the central nervous system at this critical time in the normal development of the mental powers. Skeletal growth in the child with cretinism is characteristically more inhibited than is soft tissue growth. As a result of this disproportionate rate of growth, the soft tissues are likely to enlarge excessively, giving the child with cretinism an obese, stocky, and short appearance. Occasionally the tongue becomes so large in relation to the skeletal growth that it obstructs swallowing and breathing, inducing a characteristic guttural breathing that sometimes chokes the child.30 VESTIBULAR APPARATUS Vestibular system was discovered by a French anatomist, Pierre Flourens. Vestibular apparatus is known as membranous labyrinth and is enclosed in bony labyrinth of temporal bone. Vestibular apparatus consists of otolith organs and three semi circular canals (figure 3). The balance (vestibular) system in the ears develops very early and begins to function at five months of gestation.10, 11 The semicircular canals, the utricle, and the saccule are all integral parts of the equilibrium. SEMICIRCULAR CANALS In semicircular canals hair cells are located in ampulla. The ampulla opens into utricle. Each ampulla contains crista terminalis located on pendular hillock. Hair cells are presented in the crista ampullaris. 20 Figure 3: vestibular apparatus 16 The cilia of ampullary hair cells are embedded in gelatinous mass known as cupula that forms a water tight space between the canal and the utricle. However it does not contain otoliths. Thus specific gravity of copular fluid is same as that of endolymph.31 MECHANISM OF ACTION When head rotates to one side, canals being part of the head automatically rotate to that side. However endolymph does not move immediately for about 20 sec due to natural inertia of gelatinous fluid. If head rotates to right, for initial 20 sec endolymph practically rotate to the left. Cupular fluid having the same specific gravity as that of endolymph moves along the direction of endolymph. The copular deflection bends the 21 cilia of hair cells. In the ampulla, the kinocilia are located towards the utricle. Therefore displacement of cupula towards the utricle bends cilia towards kinocilium and stimulates hair cells. Thus head rotation is detected in the first 20 sec. After the initial lag period the movement of endolymph equalizes with the movement of canal. Therefore rotation is not detected after the initial phase. When head rotation stops endolymph in the canal continues to move in the same direction of about 20 secs, which causes deflection of cupula away from the utricle and the hair cells are inhibited. However, arrangement of hair cells in the canal of both the ears is such that the beginning of rotation is detected by the hair cells in the ear towards which rotation takes place, and the termination of rotation is detected by the hair cells in the opposite ear. HAIR CELL Macula is a small sensory area of utricle and saccule which sense orientation of head when the head is upright (utricle) and also when the person in lying down (saccule) layer. The bases and sides of the hair cells synapse with sensory endings of the vestibular nerve. Macula is covered by a gelatinous layer which contains statoconia (calcium carbonate crystals). Thousands of hair cells are present in macula. Hair cell project cilia up into the gelatinous. Each hair cell has 50 to 70 small cilia (stereocilia) and one large cilium (kinocilium). The kinocilium is always located to one side, and the stereocilia become progressively shorter toward the other side of the cell. Minute filamentous attachments present between these cilia. (Figure 4) Hair cells of otolith organs are stimulated by linear acceleration.31 22 Figure 4 : Typical hair cells (flask and cuboid) synapsing with afferent and efferent nerve Thus saccule detects linear acceleration in vertical direction (eg: experiencing acceleration while using the lift) and utricle detects linear acceleration in horizontal direction (eg: experiencing acceleration in a car when the car starts moving). They also detect change in head position like tilting or bending of head. MECHANISM OF ACTION Cilia of hair cells are embedded in otolith membrane that contains otoliths. They are heavier than endolymph. Thus specific gravity of otolith membrane is more than that of the endolymph. Therefore a change in the direction of gravitational pull exerted on the otolith membrane bends the cilia of hair cells. Otolith organ detect change in head position and linear acceleration. 23 Figure 5: Change in hair cells with respect to movement. 37 With change in head position like tilting of head, change occurs in the direction of gravitational pull exerted on its otolith membrane. This results in gravitational movement of otolith membrane. (figure 5) As cilia are entrenched in otolith membrane, head tilt bends cilia of some During linear acceleration, due to higher specific gravity of otolith membrane, the membrane lags behind because of greater inertia imparted to it than the endolymph. This causes bending of cilia that are embedded in the otolith membrane. Thus action potential frequency in eighth nerve increases. 24 VESTIBULAR PATHWAYS Vestibular informations are conveyed to CNS via vestibular division of eighth cranial nerve. The cell bodies of afferent fibers are located in the scarpa’s ganglion (vestibular ganglion). They are bipolar neurons. The central axons travel in eighth cranial nerve which enters the brain at the level of Pons and terminating vestibular nuclei in the brain stem. There are four nuclei: lateral, medial, superior and inferior.31 1. Lateral vestibular nucleus: this receives fibers from utricle, cerebellum and spinal cord. Efferent fibers from lateral vestibulospinal tract that facilitate extensor group of motor neurons supplying antigravity muscles. 2. Medial and superior vestibular nuclei: these two nuclei receive fibers from otolith organs, semicircular canal and cerebellum. Efferent fibers medial nucleus form medial vestibulospinal tract. Fibres from superior nucleus project to the vestibulocerebellum and occulomotor nerve nucleus. 3. Inferior vestibular nucleus: it receives fibers from cerebellum and project to the cervical spinal cord. Thus, vestibular apparatus conveys information to three major structures- cerebellum, occulomotor nuclei and spinal cord motor neurons. Through cerebellar connections it maintains equilibrium and coordinates postural movements. Through occulomotor nucleus it regulate eye movements coordinate with bodily movements. Through spinal motor neurons it controls postural reflexes. By controlling postural muscles of head and neck vestibular apparatus maintain postural stability during movement.31 25 VESTIBULAR STIMULATION The need for vestibular stimulation can be observed throughout the life.9 vestibular stimulation system is the stimulation element that performs the actual stimulation of the vestibular tissue, a sensor to detect a physiological condition of the patient, and a power/control unit that receives the signals provided by the sensor and causes stimulation energy to be provided to the stimulation element at an appropriate timing, level, pattern, and/or frequency to achieve the desired function.32 The selection of stimulation must be suitable for the subject to achieving the desired physiological function. TECHNIQUES OF VESTIBULAR STIMULATION * Electrical Stimulation— in this electrically conductive electrodes in, on, and/or near the tissue to be stimulated so that an electric current can be delivered to the adjacent tissue via the electrode. The electrode or electrodes can have a variety of sizes and configurations depending on the stimulation pattern to be provided. For example, a point electrode can be used to stimulate a very specific site, or a spot or strip electrode can be provided to induce stimulation over a larger area. Eg. Galvanic vestibular stimulation – in these two electrodes placed over the mastoid process, stimulates and/or inhibits all peripheral vestibular afferents of both the semicircular canals and the otoliths. 33 *Mechanical Stimulation— In this pressure application device is used. eg, inflatable balloon. It place near the tissue to be stimulated so that inflating the balloon applies a pressure on the adjacent tissue. This type of mechanical stimulation system provides 26 pressure fluctuations to the subject to promote a particular sensation. Another example is a pressure cuff, which is placed either completely or partially around the canal or nerve to be stimulated so that inflating the pressure cuff exerts pressure on the underlying portion of the semicircular canal or nerve. Yet another mechanical stimulation device is a vibrating element that produces a mechanical vibration at a selected frequency. *Sonic Stimulation— In this, stimulating the vestibular area or specific sites within this area using a sonic or ultrasonic device that delivers stimulation on a carrier wave typically above 20,000 Hz, which is not in the audible range for humans. * Magnetic Stimulation— In this a magnetic field generator in the form of one or more coils in and/or near the inner ear. The coils generate a time varying magnetic field that created a spatially varying electric field that induces stimulation in the target tissue. *Chemical Stimulation— In this introduces chemicals causes chemical reactions at a stimulation site to control the stimulation at that site. For example, an injection or medicine pump can be provided at the inner ear to introduce the desired stimulation medication at the stimulation site. *Radio-Frequency Stimulation— In this using radio frequency wavelengths generated by a suitable device to provide the desired stimulation. For example, power and control data using radio frequencies (rf) received by one or more micro stimulators implanted in the subject. Different micro stimulators implanted at different 27 locations in the patient can be tuned to different frequencies so that a wide variety of stimulation patterns can be achieved. *Infrared Stimulation— In this using infrared technology to deliver the stimulation to the patient's tissues. Short wave, 7,200-15,000Å, or long wave, 15,000-150,000Å, systems can be used to deliver the stimulation to the target site.32 *Motion Devices – It includes conventional swings, hanging bed, rotational chair, cradles etc.33 o Rotational Movement by Barany Chair- the subject is made sit in the chair with head tilted forward at 300. The chair rotated at 30rpm for 20s. During rotation with eyes open, nystagmus occurs continuously throughout the period of rotation. After rotation in Barany’s chair for 20s at 30rpm, following effects are noted: Post rotational nystagmus occurs for 30s. Dizziness it is associated with feeling of rotation in the opposite direction. Vertigo i.e. feeling of rotation in even after stoppage of rotation. Nausea and vomiting may occur after rotation for a longer period. 16 *Caloric stimulation is performed by irrigating cold and warm water into the ear canals. This is done one ear at a time. The water stimulates the nerves of the inner ear. It is according to Barany’s principle. This changes the temperature of the inner ear and decrease specific gravity and causes rapid, side-to-side eye movements called nystagmus.31 Here we practiced caloric vestibular stimulation. 28 o Swing on a swing is a standardised, cheap, comfortable and effective method for vestibular stimulation. In this method, the participants swing on a swing, according to their comfort. (Back to front direction).( Figure 6).9 223.52 cm Observer Observer Observer 200.66cm Observer 200.66cm Observer 238.76 cm Figure 6 : Swing- controlled vestibular stimulation9-13 Recent studies shows that vestibular stimulation had a potent soothing effect in infants, their crying time was decreased.33 Following vestibular stimulation hippocampus, retrosplenial cortex and subiculum were activated in humans; it is due to spacial disorientation and self rotation experienced by the subjects during vestibular stimulation.34 29 Caloric vestibular stimulation in humans shows wide spread cortical network and also right hemispheric dominance of vestibular cortex areas regardless of side of stimulation.35Galvanic vestibular stimulation helps in figure copying ability in right hemi sphere stroke individual and there by uncovering the vestibular information processing and visual task performance.36 STRESS Stress is defined as a state of disharmony or threatened homeostasis. Stress was coined by Hens Seyle. The concept of stress and homeostasis can be traced back to ancient Greek history, however, the integration of these notions with related physiologic and pathophysiologic mechanism and their association with specific illnesses is much more recent.54 Stress is the generalized, non-specific response of the body to any factor that overwhelms or threatens to overwhelm, the body’s compensatory abilities to maintain homeostasis. Stress causes physiological changes, biochemical changes and behavioral changes in our body.1,2 A stressor is any person or situation that produces anxiety responses. Stress and stressors are different for each person. Environmental stressors include noise, pollution, traffic, crowding and weather. Physiological stressors include illness, injuries, hormonal fluctuation, inadequate sleep or nutrition. Social stressors include financial problems, work demands, social events, losing a loved one, exams, interview and some thoughts like negative self talk, catastrophe and perfectionism are also cause stress. 30 GENERAL ADAPTATION SYNDROME Homeostatic mechanisms are aimed at counteracting the everyday stress of living. If they are successful, the internal environment maintains normal physiological limits of temperature, chemistry and pressure. If stress is extreme or long lasting the normal mechanisms may not be sufficient. In this case, the stress triggers a wide ranging set of bodily changes called the General Adaptation Syndrome (GAS). When stress appears, it stimulates the hypothalamus to initiate the GAS through two pathways: - First pathway is stimulation of the sympathetic division of the automatic nervous system and adrenal medulla (sympathetic adrenal medullary axis- SAM axis). This produces an immediate set of responses called alarm reaction. - The second pathway, called the resistance reaction involves the anterior pituitary gland and adrenal cortex (HPA axis); the resistance reaction is slower to start but its effect last longer. SAM axis It is body’s initial reaction to a stressor. It is a set of reactions initiated when hypothalamus stimulates the sympathetic division of the autonomic nervous system, and the adrenal medulla. The alarm reaction is meant to counteract a danger by mobilizing the body’s resources for immediate physical activity. The reactions include-Heart rate and strength of cardiac muscle contraction increases; this circulates blood quickly to areas where it is needed to fight the stress. 31 STRESSORS STIMULATE HYPOTHALAMUS STIMULATE SYMPATHETIC NERVOUS SYSTEM STIMULATE ADRENAL MEDULLA RELEASE CATECHOLAMINES (EPINEPHRINE, NOR EPINEPHRINE) FIGHT/FLIGHT RESPONSE Figure: 7 Sympathetic Adrenal Medullary axes -Blood vessels that supply to the skin and viscera, except heart and lungs constrict; at the same time blood vessels supplying to the skeletal muscles and brain dilate; these responses route more blood to organs active in the stress responses, thus decreasing blood supply to organs which do not assume an immediate active role. -RBC production is increased leading to an increase in the ability of the blood to clot. This helps control bleeding. -Liver converts glycogen in to glucose and releases it into the blood stream; this provides the energy needed to fight the stressor -The rate of breathing increases and respiratory passages widen to accommodate more air; this enables the body to acquire more oxygen. 32 - Production of saliva and digestive enzymes reduces. This reaction takes place as digestive activity is not essential for counteracting stress. HPA axis HPA mediated resistance reaction is the second stage in the stress response. It is initiated by regulating hormones secreted by the hypothalamus, and is long term reaction. These regulating hormones are corticotrophin releasing hormone (CRH), growth hormone releasing hormone (GHRH) and thyrotrophic releasing hormone (TRH). CRH stimulates the anterior pituitary to increase the secretion of adrenocorticotropic hormone (ACTH). ACTH stimulates the adrenal cortex to secrete more of its hormones. The action of these hormones helps to control bleeding, maintain blood pressure etc. GHRH stimulates anterior pituitary to secrete human growth hormone (HGH). TRH causes the anterior pituitary to secrete thyroid stimulating hormone (TSH). The combined action of HGH and TSH helps to supply additional energy to the body. The resistance reaction allows the body to continue fighting a stressor for a long time. Thus it helps us to meet emotional crisis, perform sternus tasks, fighting infection or resist the threat of bleeding to death. Generally, the resistance reaction is successful in helping us cope with a stressful situation, and our bodies then return to normal. Occasionally it fails to fight the stressor, especially if it is too severe or long lasting. In this case, GAS moves into the stage of exhaustion.38 33 STRESS HYPOTHALAMUS CRH,TRH,GHRH ANTERIOR PITUITARY ACTH TSH HGH ADRENAL CORTEX THYROID GLAND LIVER ADRENAL HORMONES (GLUCOCORTICOIDS, MINERALOCORTICOIDS) SUPPLIES ENERGY THROUGH INCREASED BREAKDOWN OF CARBOHDRATES SUPPLIES ENERGY THROUGH GLYCONEOGENESIS AND INCREASED BREAKDOWN OF FATS Figure: 8 Hypothalamo Pituitary Adrenal Axis (ACTH-adrenocorticotropic hormone, HGHhuman growth hormone, TSH- thyroid stimulating hormone) INTERACTION OF STRESS AND THYROID HORMONES Stress will produce neurohumoral changes especially in hypothalamo-pituitary-adrenal axis and early stress and maltreatment leads to the emergence of psychiatric disorders during development.39 stress will stimulate the HPA axis and increase the production of corticosteroids and vestibular stimulation will relieves stress related changes in HPA axis. 40,10 Anxiety patients with poor adaptation to vestibular lesion are parallel to quality and quantity of stress.41Evidence indicating that stressful conditions causes adaptation in thyroid functions, initial change observed in serum protein bound iodine levels comes similar to the initial level following intervention.42 34 Cortisol have an inhibitory effect on neurons in the PVN of hypothalamus through depression of the noradrenergic system in rats.43Stress causes hypothyroid symptoms by disrupting HPA axis, reduces the conversion of T4 to T3, promote autoimmunity by weakening immune barriers, causes thyroid hormone resistance and causes hormonal imbalances. The impact of cold mild stress will reduce the T3 and T4 levels, these altered thyroid function in turn alter the immunity.44During stress Corticotrophin-releasing hormone suppress the thyroid function by inhibiting the secretion of thyroid releasing hormone and thyroid stimulating hormone.45 Prenatal stress in pregnant female rats, the fetuses exhibit altered somatotopic and endocrine activities due to alteration in HPA axis.46 INTERACTION BETWEEN THYROID FUNCTION AND VESTIBULAR SYSTEM The interaction between the endocrine system and the vestibular system is mainly unexplored.41 But vestibular stimulation is considered as a supplementary treatment for hypothyroidism.13 Tyrotropin releasing hormone from the hypothalamus plays key role in the regulation of thyroid secretions. Medial vestibular nucleus receives direct connections from hypocretin (orexin) neurons of lateral hypothalamus.47 Thyroid deficiency may cause vestibulopathy to central vestibular disorders affecting cerebellum.48 35 Studies shows that caloric vestibular stimulation causes changes in neuronal activity both inhibition and excitation of paraventricular nucleus in guinea pig.49 Caloric stimulation of endolymph in guinea pig traced the direct connections between vestibular nucleus and supraoptic nucleus and paraventricle nucleus of hypothalamus.50 During starvation exogenous supplement of leptin blunts the changes in thyroid axis in male mice.51 Leptin stimulate TRH biosynthesis7 folds, in addition of alpha-melanocyte-stimulating hormone (3.5-fold increase in TRH), whereas neuropeptide Y suppress pro-TRH biosynthesis (3-fold) and melanocortin-4 receptor antagonist SHU9119 partially inhibited leptin-stimulated TRH release from the neuronal culture of fetal rat hypothalamus.52 NPY plays major role in controlling HPT axis, when administering NPY in blood it will cause suppression of thyroid hormone and stable or low level in TSH. 53 Vestibular stimulation suppresses the stress induced changes on thyroid function, directly through HPT axis and indirectly through the stress axis.65 36 RESEARCH METHODOLOGY 37 CHAPTER 4 RESEARCH METHODOLOGY RESEARCH APPROACH It is an experimental study to test the hypothesis that vestibular stimulation may prevent stress induced changes in thyroid function. The study was conducted between November 2014 – February 2015. VARIABLES Independent variable – caloric vestibular stimulation Dependent variables – T3, T4, cholesterol, body weight SETTING OF THE STUDY The study was conducted at Department of Physiology, Little Flower Institute of Medical science and Research Centre, Angamaly, Kerala. ETHICAL CONSIDERATION The present study was approved by institutional animal ethical committee of Little Flower Hospital and Research Centre, Angamaly, No EC/5. MATERIALS AND METHODS Animals: 24 healthy, adult male albino rats of Wistar strain with body weight ranging 50-125 gms, were used in the present study. All Rats were housed in polypropylene cages (30x22x14cm), fed with standard rat-chow and water ad-libitum. Rats were randomly assigned into four groups, following inclusion and exclusion criteria. 38 Group A: (n=6) Control Group (Neither stress nor vestibular stimulation) Group B: (n=6) Stress Group (Cold water swimming stress was given for 15 days) Group C: (n=6) Cold water swimming stress + cold water vestibular stimulation.(15 days) Group D: (n=6) Cold water swimming stress+ hot water vestibular stimulation.(15days) 1. Inclusion criteria Healthy adult rats Male rats 2. Exclusion criteria Female rats Unhealthy diseased rats METHODS Cold water swimming stress: Rats were forced to swim in the plastic tubs (height: 60 cm, diameter: 40 cm) containing cold water, maintained at 10°C. Depth of the water in the plastic tub was 30 cm. The swimming session lasted for 45 minutes daily. Experiments were done between 9 AM and 12 Noon to minimize the circadian variability. Caloric vestibular stimulation: The middle ear cavity was irrigated with hot (40 degree centigrade) or cold (15degree centigrade) water through a polyethylene tube for15 days.( Figure 8) 39 Figure 9: caloric vestibular stimulation After recording the baseline values of T3, T4 and cholesterol, Group B,C,D rats were exposed to cold water swimming stress for 15days. Cold and hot water (caloric) vestibular stimulation was administered along with cold water swimming stress to group C, D rats respectively. After values were collected on 7th day and 15th day to evaluate the effect of vestibular stimulation on prevention of stress induced changes in thyroid hormone secretion. T3 and T4 are estimated by using semi luminescent immune assay used for humans but TSH is not equalent to humans.64 Cholesterol estimation was performed by CHOD PAP (cholesterol oxidase- phenol + aminophenasone) method. ANALYSIS AND INTERPRETATION Data was analyzed by SPSS 20.0. Statistical tests used are Two-way ANOVA and Bonferroni post tests. P value ˂ 0.05 was considered as significant. 40 RESULTS 41 CHAPTER 5 RESULTS BODY WEIGHT: Body weight increased significantly followed by forced cold water swimming stress in stress only group on 7th day and 15th day. However no significant change was observed in body weight in cold and hot water vestibular stimulation groups. (Figure 10) Figure 10: Body weight before and after vestibular stimulation (g-gms) 42 T3 LEVELS: T3 Levels decreased significantly in stress only group on 7th day followed by forced cold water swimming stress then comes to normal. However no significant change was observed in T3 Levels in cold and hot water vestibular stimulation groups. (Figure 11) Figure 11: T3 levels ( ng/dl ) before and after vestibular stimulation 43 T4 LEVELS : T4 Levels decreased significantly in stress only group on 7th day followed by forced cold water swimming stress then comes to normal. However no significant change was observed in T4 Levels in cold and hot water vestibular stimulation groups.(Figure 12) Figure 12: T4 levels ( ng/dl ) before and after vestibular stimulation 44 SERUM CHOLESTEROL: Cholesterol levels increased significantly followed by forced cold water swimming stress in stress only group on 1st , 7th and 15th days. However no significant change was observed in cholesterol levels in cold and hot water vestibular stimulation groups. (Figure 13) Figure 13: Cholesterol levels before and after vestibular stimulation 45 DISCUSSION 46 CHAPTER 6 DISCUSSION Stress is what everybody experiences in daily life.Stress causes physiological, biochemical and behavioral changes in our body. Stress at work is a relatively new phenomenon of modern lifestyles. It covers all professions, starting from a daily wages employ to employer, artist to a surgeon, patient to hospital staff. Any change in the environment demands some coping; and little stress helps us adapt. But, beyond some point stress becomes distress basically individual’s response to fight/flight a situation. Stress when pathological, causes lot of physical and mental health problems.54 It was reported that body weight decreases significantly followed by cold water swimming stress,13 in contrast it was also reported that chronic stress will results in obesity and metabolic disorders.55 Oliver and Wardle in their study in college students’ observed thathealthy eating is related to stress, some eat much more, and some eat much less than usual.56 Studies also reported that stressed female students eat more fast foods, snacks, beverages than others.57 In the present study, we have observed increase in the body weight followed by cold water swimming stress. This stress induced change in the body weight was not observed in hot and cold water vestibular stimulation groups. This may be due to vestibular balance of food intake through vagal stimulation, insulin, arcuate nucleus, HPA axis through thyroid hormones by promoting sleep.8 47 It was reported that long term exposure to cold decreases T3 and T4 levels.16 We agree with these results as we have observed decrease in the T3 and T4 levels followed by forced cold water swimming stress. Evidence indicating that stressful conditions causes adaptation in thyroid functions, initial change observed in serum protein bound iodine levels comes similar to the initial level following intervention.42 Short time exposures to cold air do not cause any changes in serum levels of thyroid hormones or TSH. Long-term exposures to cold air speed up the consumption of thyroid hormones. It firstly manifests as low levels of free T3 and free T4.58 Recent studies shows that, mood disturbances are very common in humans working in Antarctica, their serum free T3 levels were found to be low59 and supplementation with T4 was found to improve cognitive performance.60 Hence changes in thyroid function in stress is inevitable. Vestibular stimulation can suppresses the stress induced thyroid changes directly through the HPT axis and indirectly through the stress axis.65 In the present study, stress induced changes in thyroid hormones are prevented by both hot and cold water vestibular stimulation. This may be due to inhibition of stress axes by vestibular stimulation. It was reported that total serum cholesterol decreased in response to forced cold water swimming stress.13 G.H Werstuck, S. R Lents et al., reported that, homocystein induced endoplasmic reticular stress results in increased hepatic biosynthesis and uptake of cholesterol and triglycerides.61 An increase in cholesterol levels were observed in toads maintained in cold water (200C).62 Similar results to the current data have been reported previously that, an enhancement is observed in mice 48 following stress induction.63 Our study results are in accordance with earlier reports as we have observed an increase in cholesterol levels following exposure to stress. However vestibular stimulation by hot and cold water effectively prevented this stress induced rise in cholesterol levels. This may be due to suppression of stress axes which in turn control the stress induced decrease in thyroid hormone that takes part in lipid metabolism. Vestibular stimulation also increases the leptin and decease the ghrelin production that controls satiety centre and regulates food intake.8 LIMITATIONS AND RECOMMENDATIONS OF THE STUDY Only male rats were included in the present study. We recommend further detailed study by including more biomarkers and also including both the genders. 49 CONCLUSION 50 CHAPTER 7 CONCLUSION Our study provides preliminary evidence for prevention of stress induced changes in thyroid secretion and body weight by vestibular stimulation. We recommend translational research in this area to elucidate the mechanism of vestibular modulation of thyroid hormones secretion to recommend vestibular stimulation in the management of stress and thyroid disorders. 51 REFERENCES 52 CHAPTER 8 REFERENCES 1. H. S. Nagarajaand P.S. Jeganathan. Forced swimming stress induced changes in the physiological and biochemical parameters in albino rats. Indian J PhysiolPharmacol. 1999; 43(1): 53-59. 2. Tripathi J S. 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Acute stress – induced changes in hormone and lipid levels in mouse plasma. Veterinarni Medicina.2016;61(2): 57-64. 60 64. Grabherr L, Macauda G,Lenggenhager B. The Moving History of Vestibular Stimulation as a Therapeutic Intervention. Multisensory research.2015;28(5):653687. 65. Mukkadan J K, Archana R, Kumar SS, Varsha VP, Arati A, Reddy UK et al. Stress, thyroid hormone secretion and vestibular stimulation: A review of links. BEMS report. 2015;1(2) :31-34. 61 ANEXURES 62 ACKNOWLEDGEMENT I remember with gratitude and owe my success to the God Almighty for having given me strength and courage to overcome the difficulties and complete this dissertation successfully. I express my deep sense of gratitude to my guide, Mr. SAI SAILESH KUMAR, Head of the Department of Physiology, LIMSAR, Angamaly, who laid a strong foundation in moulding this research study and devoted his valuable hours in solving my doubts, constructive guidance, corrections in time and support in various stages of study and also he is the one who motivated me to publish my work in a reputed journal. I am deeply obliged to Dr. J K. MUKKADAN, Professor and Research Director, LFMRC for his support and suggestions for the successful completion of the study. I express my sincere gratitude to Rev. Fr.(Dr).GEORGE M.D, Principal, LIMSAR Angamaly, for giving the opportunity to utilize all facilities in this reputed institution for the successful completion of this dissertation. I extend my sincere gratitude to Rev. Fr. BAIJU KANNAMPILLY, for his motivating suggestions for proceeding my work. I would like to acknowledge Mr. POLY P V and Mrs. THRESSIAMMA PETER, Animal House Assistants, LIMSAR, Angamaly, who have helped in caring and handling the animals. I am highly indebted to Wistar albino rats which sacrificed its lives for the completion of my thesis work successfully. 63 On a personal note, I extend my hearty thanks to my husband Mr. ANTU MAVELY, my parents Mr. VARGHESE P J and Mrs. MOLY VARGHESE for their continued and unfailing love, support, encouragement to overcome the tides of heavy schedule and problems in the path of progress in the study. I appreciate my baby, my little girl JEWEL REETHA for abiding my ignorance and patience she showed during my project work. I am indebted to my Classmates for their constant support, concern and help to make this attempt an interesting one. DATE VARSHA VARGHESE P PLACE 64 LIST OF ABBREVATIONS USED 1. ACTH Adrenocorticotropic Hormone 2. ANOVA Analysis Of Variants 3. Camp Cyclic Adenosine Mono Phosphate 4. CHOD PAP Cholesterol Oxidase phenol Aminophenasone 5. CNS Central Nervous System 6. CRH Cortico Tropic Releasing Hormone 7. DIT DiiodoThyrosine 8. GAS General Adaptation Syndrome 9. GHRH Growth Hormone Releasing Hormone 10. HGH Human Growth Hormone 11. HPA Hypothalamo Pituitary Adrenal axis 12. HPT Hypothalamo Pituitary Thyroid axis 13. MIT MonoiodoThyrosine 14. NPY Neuropeptide Y 15. PVN Paraventricle Nucleus 16. RBC Red Blood Corpuscles 17. SAM Sympathetic Adrenal Medullary Axis 65 18. SPSS Statistical Package for the Social Sciences 19. T3 Triiodothyronine 20. T4 Thyroxine 21. TRH Thyroid releasing Hormone 22. TSH Thyroid stimulating Hormone 23. TSI Thyroid Stimulating Immunoglobulins 66 PUBLICATIONS Varsha VP, Kumar SS, Archana R, Mukkadan JK. Vestibular modulation of thyroid function in forced cold water swimming stress induced wistar albino rats. IJRAP. 2014;6(4):513-5. Mukkadan J K, Archana R, Kumar SS, Varsha VP, Arati A, Reddy UK et al. Stress, thyroid hormone secretion and vestibular stimulation: A review of links. BEMS report. 2015;1(2) :31-34. 67