Nearly all stress-related information projected to the hypothalamus is congregated to the lateral hypothalamus, where combinations of numerous ascending and descending fibres are integrated from areas including the limbic system, medial hypothalamus, and the autonomic nervous system containing with thousands of interneurons 13.

Numerous viscerosensory signals arise from glossopharyngeal (IX) and vagal (X) cranial nerves in the spinal cord and from the lower brain stem, which project to the nucleus of the solitary tract (NTS), and terminate via multisynaptic pathways at the hypothalamus 14. The NTS is the first region in the central nervous system that processes information about visceral, cardiovascular, respiratory functions as well as taste. Neurons of the NTS project to the paraventricular nucleus, and other hypothalamic nuclei among other destinations 15. The NTS has other viscerosensory fibres terminating on catecholaminergic neurons, which then project to the hypothalamus 14. Somatosensory signals reach the hypothalamus directly via the spinohypothalamic tract 16, by axon collaterals of fibres of the spinoreticulothalamic and/or spinothalamic tracts in the spinal dorsal horn 17, or through the activation of the brainstem catecholaminergic system 14.

Ascending medullary viscero- and somato-sensory neurons have been associated as carriers of autonomic signals to the hypothalamus. Signals may directly project to the hypothalamus, or indirectly through secondary autonomic centres, such as the parabrachial nuclei 13.

The output system involves the recognition of the stress response, and engages both the neuroendocrine and neuronal pathways 13. The higher centres consisting of the cerebral cortex, limbic system and hypothalamus are neuronally connected with the brain stem, autonomic and sensory centres, as well as interconnected with each other. The higher centres do not have connections to the periphery, though they are able to indirectly and bilaterally influence sympathetic and parasympathetic preganglionic neurons via the efferent paraventricular pathway 18.

The hypothalamus is able to exert effects via neurohumoral pathways through the pituitary, autonomic effects via neuronal pathways to preganglionic neurons, and able to exert both parasympathetic and sympathetic effects through the medulla oblongata and spinal cord 14.

The four predominant nuclei containing descending hypothalamic-autonomic fibres include the paraventricular, arcuate, perifornical and dorso-lateral hypothalamic nuclei. The hypothalamic paraventricular nucleus (PVN) is a central site in the complex of interacting systems controlling the stress response 19. It is the foremost source of descending hypothalamic pathways to autonomic centres, with fibres arising from dorsal, posterior and lateral parvicellular subgroups containing a variety of putative neurotransmitters. Toth et al. 20 investigated the decussations of descending fibres of the PVN by using vulgaris-leucoagglutinin in intact brain stem operated rats. Paraventricular fibres descend by the length of the brainstem and spinal cord via two descending tracts: one from the lateral hypothalamus, along the lateral lemniscus and from the pons, moving ventrolaterally and running into the ventrolateral medulla. Some of these fibres loop dorsomedially in the caudal ventrolateral medulla to innervate the NTS, and dorsal motor nucleus of the vagus nerve (X). Secondary fibres run periventicularly and join the above tract at the pontine level 21. Toth et al. 20 found descending fibres of the PVN decussate supramamillary, at the pontine tegmentum, at the commissural part of the NTS (major cross over area), and at Lamina X of the thoracic spinal cord levels. Termination of these pathways has been confirmed in the NTS 22, A1/C1 catecholaminergic cell groups 18, pre-sympathetic (rostroventrolateral) medulla and sympathetic (IML) neurons 23. The PVN has been implicated in a variety of behaviors including feeding, thirst and cardiovascular mechanisms as well as in the organization of autonomic and endocrine responses. The arcuate nucleus projects to preoptic LHRH neurons, and is involved in the regulation of gonadotrophin secretion and sexual behaviour during the female reproductive cycle. The dorso-lateral hypothalamic nuclei project fibres to lateral parts of the brain stem, with numerous fibres terminating in the caudal brainstem lateral tegmentum, including the locus coeruleus, parabrachial nuclei, nucleus subcoeruleus, and the solitary and dorsal vagal nuclei 24.

With arrangements of ascending and descending fibres from various areas including the limbic system, medial hypothalamus, and the autonomic nervous system, the hypothalamic system is able to exert effects on the neuro-endocrine and neuronal pathways, as well as indirect influences to the periphery, playing an extremely important role in mediation of the stress response.

The limbic system is located in the boundary between the telecephalon and the diencephalon. Environmental stimuli, posing as external stressors, are recognized by specific sensory receptors systems, which transmit information via the nucleus of the solitary tract to respective sensory areas of the thalamus from spinal or cranial sensory neurons. These inputs include mechanoreceptors. 25

Sensory information is transmitted to the amygdala through direct thalamo-amygdala connections, or indirectly though thalamo-cortico-amygdala connections 27. The lateral nucleus of the amygdala receives and processes information from both pathways, and then projects to central, basal and basal accessory nuclei of the amygdala 28, as well as to the hippocampus, orbitofrontal cortex, cingulate 29 and via the reticular activating system to the sensory cortex 3031. The sensory cortex then directs information directly to the amygdala, or via the hippocampus and then to the amygdala. 32.

The hippocampus does not receive information involving individual sensory stimuli, but more general contextual cues 27. Contextual cues can be seen as tasks performed in a predefined movement. When a cue is available, the motor system forms an internal model that uses both serial order and target direction to program motor commands 33. The hippocampus thereby receives information on a universal basis, participating in declarative memory function, and integrating important contextual elements such as the time and place of events. This is important for retrieval and utilization of stored information into the future 29. External stimuli present information to sensory processing systems of the neocortex, which creates a memory context through primary and higher order sensory cortices 27. These systems project to association cortices, such as the parieto-temporo-occipital and prefrontal, and then to the transitional cortex, including entorhinal, parahippocampal and perirhinal areas of the limbic system, where different memory contexts are incorporated. The entorhinal cortex projects these incorporated contexts to the hippocampus where even more complex contexts are established 34. Back through the same pathways, the hippocampus projects to the neocortex and forward to the amygdala and paraventricular nucleus (PVN) of the hypothalamus 30. Retrieval and utilization of stored information is carried out through the hippocampus and other related cortical areas, and projected to the amygdala, which may trigger a stress response of context memories, even without external events 35.

Individual stimuli presenting as external stressors, or emotional evaluation of internal stressors are fundamentally analyzed by the amygdala 34. Therefore the central nucleus of the lateral amygdala is involved in the coordination of stress behaviour and modulating memory consolidation 6, as well as controlling neuroendocrine and autonomic responses 3637. The regulation of these systems occurs through numerous connections including direct projections through the bed-nucleus of the stria terminalis to the hypothalamus 8, which projects to the lateral hypothalamus to mediate the activation of sympathetic component of the ANS 36; projections to the dorsal motor nucleus of the vagus are involved in the activation of the parasympathetic component of the ANS 37; projections to the NLC and ventral tegmental area are involved, respectively in the activation of the noradrenergic and dopaminergic systems 38 and projections to the midbrain central gray mediate certain behavioural responses and importantly direct projections to the PVN of the hypothalamus 39.

The hippocampus also regulates the neuroendocrine stress response by inhibition of the HPA axis through glucocorticoid negative feedback 40. Network functions within the hippocampus are altered by persistent corticosteroid actions, resulting in decreased accuracy and reliability of contextual memories 6. In a situation where a decision needs to be made whether or not there is a stress, this decreased accuracy and reliability prevents access to important information. The amygdala has neuronal projections to the paraventricular nucleus of the hypothalamus, and this amygdalo-hypothalamic pathway is believed to influence the activity of the neuro-endocrine hypothalamic-pituitary system, and behavioural functions under a range of physiological conditions 41. This amygdalo-hypothalamic pathway is believed to perform an essential role in the adreno-cortical response to a number of somatosensory stimuli 42.

Thus, the limbic system is actively involved in the body's stress response and this stress response is affected by memory and emotion. It is important these interactions are considered in terms of the known associations of chronic pain and psychosocial variables 434445. It is likely that such associations should receive greater attention in diagnosis and treatment by chiropractors, particularly those managing chronic pain syndromes. New techniques such as the neuroemotional technique (NET) that claim to consider such variables in the diagnosis and management of pain should endeavour to measure variables of the stress response to support rhetoric that their management approaches can manage chronic pain and disease by the application of techniques associated with cognitive and behavioural principles.

The autonomic nervous system is a rapidly responding mechanism, controlling numerous systems including cardiovascular, gastrointestinal, respiratory, renal and endocrine which are under control of the sympathetic, parasympathetic or both nervous systems 47. Activation of the SAS system functions to reduce blood flow, reduce activity of the gastro-intestinal system and reproductive organs, as well as mobilise energy to the brain, heart and muscles 48. It does this via synapses of sympathetic preganglionic fibres in the intermediolateral column of the spinal cord with the postganglionic sympathetic neurons innervating the smooth muscle 49. This evolutionary mechanism has evolved to create quick compensatory changes in homeostasis for intense physical activity, by increasing the capacity of the 'fight or flight' reaction and therefore promote survival.

During an antecedent event, activation of the SAS system (locus coerulus/norepinephrine/sympathetic nervous system) evokes the release of noradrenaline and neuropeptide-Y from postganglionic nerve terminals, while preganglionic innervation of the adrenal medulla results in an increased secretion of adrenaline and dihydroxyphenylaline (DOPA) 50. Activation also results in the increased secretion of Interleukin-6, an important cytokine that connects the stress system and various immunological and inflammatory processes 6.

The hypothalamo-pituitary-adrenocortical (HPA) axis plays a fundamental role in adaptation of the organism to homeostatic challenge, and should be thought of as the body's energy regulator, as it is ultimately responsible for controlling virtually all of the hormones, nervous system activity, and mineral homeostasis 13. Activation of the HPA system results in secretion of glucocorticoids, which act at numerous levels to redirect bodily energy resources 51. These hormones are recognized by glucocorticoid receptor molecules in numerous organ systems, and act by genomic mechanisms to modify transcription of key regulatory proteins 51.

The HPA axis is readily activated by stressful stimuli 46. Sensory information reaches the cortex via the thalamus and is conveyed to the central amygdaloid nucleus of the amygdala 8. It responds by providing the stimulus to cortico-releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus to increase the secretion of principal neuropeptide CRH and arginine vasopressin (AVP) into the hypophyseal portal bloodstream. These secretions are thence transported to the anterior pituitary gland 52. The corticotrophin producing cells of the anterior pituitary synergise CRH and the AVP through CRH-RI and VIb receptors respectively to increase expression of the adreno-corticotropin hormone (ACTH) precursor, and further promote the release of ACTH into the systemic circulation 53. Upon release, ACTH stimulates the zona fasciculata cells of the adrenal cortex to release synthesized glucocorticoid (cortisol in humans) and mineralocorticoid hormones (principally aldosterone) 5455. Via a delicate negative feedback loop, glucocorticoids control the termination of the stress response via inhibitory control of the production and release of CRH and ACTH at the level of the hypothalamus and pituitary respectively, via transmitter systems projecting to the hypothalamus 56. Glucocorticoids activate steroid receptor mediated transcriptional regulation and membrane receptors, inducing changes which serve to mobilize energy and inhibit other potentially costly reactions to stress. Glucocorticoids promote gluconeogenesis, increase blood pressure and suppress aspects of immune and reproductive function 57. In addition Inhibition of the ACTH response occurs through the glucocorticoids binding to receptors in the hippocampus, which control CRH production and limiting the period of exposure to the stress response, therefore minimizing the catabolic immunosuppressive and anti-reproductive effects of glucocorticoids 6.

Catecholamines are involved in these pathways as chemical messengers. Brainstem catecholaminergic and non-catecholaminergic neurons, through collateral branching inputs may provide coordinated signaling of visceral input to rostral forebrain sites. This may lead to a synchronized response of the CNA and PVN for the maintenance of homeostasis 58. Thus, emotion and memory effects mediated via these centres have the potential to cause dysfunctioin in the viscera. Such dysfunction should be considered in the management of chronic pain and disease states

The magnoceullular neurons of the supraoptic (SON) and PVN, along with scattered clusters of cells between the two nuclei, comprise the hypothalamo-hypophyseal system. These cells send oxytocin and vasopressin containing fibres to the posterior pituitary where these substances are released into the peripheral circulation. Vasopressin is an antidiuretic hormone (ADH) and is released in response to changes in osmotic pressure of circulating blood or extra-cellular space. ADH controls water balance, in particular retention of water regulated in the distal tubules of the kidneys.

Glucocorticoids, adrenal hormones secreted during stress, are seen as key hormones, which are able to permit, stimulate or suppress the stress response 52. The primary glucocorticoid in humans, cortisol, is secreted continuously by the adrenal cortex in a diurnal pattern, with early morning peaks and evening troughs, but secretion can increase dramatically in the dynamic setting of environmental stressors. Its secretion can adversely affect many bodily functions 7. Glucocorticoids restrict circulating CRH and ACTH levels, preventing inappropriate steroid exposure following a brief episode of stress. Network functions within the hippocampus are disturbed by persistent glucocorticoid activation, triggering secretion outside the normal physiological range, resulting in atrophy of the human hippocampus 64, and alteration of network functioning 65. Damage associated with changes in the regulation of the HPA axis cause deficits in memory, cognition and learning 30, and decreased accuracy and reliability of contextual memories 6, thus contributing to behavioural adaptations to the response to stress. Prolonged elevations of glucocoticoid levels cause diseases such as Cushings Syndrome 67, or contribute to precipitation of disease such as major depressive disease 10, Alzhimers Disease 66, post-traumatic stress disorder 68 and recurrent depressive illness 62.

Uno et al. 69 provided the first evidence that chronic stress resulted in glucocorticoid hypersecretion, resulting in neurodegeneration of the primate after a retrospective, neuropathological study was performed on eight vervet monkeys. At death the monkeys were found to have multiple gastric ulcers. Compared with controls euthanized for other research purposes, ulcerated monkeys had marked hippocampal degeneration that was apparent both quantitatively and qualitatively, and was detected both ultrastructurally and at light-microscopic level. It was discovered that in ulcerated monkeys which appeared to have been subject to sustained social stress, perhaps in the form of social subordinance in captive breeding groups, and which also had had significantly high incidences of bite wounds at death, these monkeys had hyperplastic adrenal cortices, indicative of sustained glucocorticoid release 69.

Excess glucocorticoids, as the end effect of chronic stimulation of the HPA axis, may constitute a base for pathophysiological consequences in the periphery of the body. This includes potentiation of sympathetic nervous system-mediated vasoconstriction, proteolysis and lipolysis 70, energy mobilization (glycogenolysis) in the liver 41, and processes such as reproductive, metabolic and immune functions. Many such changes have often been attributed to spinal based reflex changes associated with chronic somatic dysfunction.

Systems activated by stress can influence reproduction at the hypothalamus, pituitary gland or gonads. There are close relations with the sustained activity of the end-product of the HPA axis and suppressed steroid sex and growth hormones 57. The first wave of hormonal mediators of the stress response stimulates the production of hypothalamic CRH, which inhibits gonado-tropin releasing hormone (GnRH). Via the release of somatostatin, hypothalamic CRH also inhibits growth hormone (GH), thyrotropin-releasing hormone (TRH) and thyrotropin secreting hormone (TSH) secretion thereby suppressing growth, reproduction, and thyroid functions 71. Glucocorticoids directly inhibit the pituitary gonadotropin, GH and TSH secretion, causing target tissues of sex steroids and growth factors to become resistant 7. Increased glucocorticoid secretion significantly reduces peak luteinizing hormone (LH) inhibiting the effect of glucocorticoids on the pituitary gonadotroph 72. Furthermore, suppression of the growth, reproduction and thyroid functions arises from glucocorticoid ability to suppress the 5' deiodinase, which functions to convert virtually inactive tetraiodothyronine (T4) to triiodothyronine (T3) thereby causing s stress induced state of hypothyroidism 73.

The female reproductive system is regulated by the hypothalamic-pituitary-ovarian axis. The principal regulator of the hypothalamic-pituitary-ovarian axis is GnRH 74. GnRH stimulates pituitary follicle stimulating and LH secretion and, subsequently, estradiol and progesterone secretion by the ovary. When activated by stress, the HPA axis exerts an inhibitory effect on the female reproductive system. CRH and CRH-induced proopiomelanocortin peptides such as β-endorphin inhibit hypothalamic GnRH secretion 75. In addition, glucocorticoids suppress gonadal axis function at the hypothalamic, pituitary and uterine level 4476. Furthermore, glucocorticoids inhibit estradiol-stimulated uterine growth 76. These effects of the HPA axis are responsible for the "hypothalamic" amenorrhea of stress, which is observed in anxiety and depression, malnutrition, eating disorders and chronic excessive exercise, and the hypogonadism of the Cushing syndrome 77. On the other hand, estrogen directly stimulates the CRH gene promoter and the central noradrenergic system 50, which may explain women's mood cycles and manifestations of autoimmune/allergic and inflammatory diseases that follow estradiol fluctuations.

Stress is understood to contribute to the pathogenesis of disease, and under chronic conditions contributes to disease by impairing the body's ability to correctly control normal responses of the body. Increased glucocorticoid secretion causes resistance of growth hormone from osteoblastic cells of bones, inhibiting osteoblastic activity that renders them osteoporotic 73. Chronic activation of the stress response can lead to the promotion of visceral adiposity, and is achievable by glucocorticoids stimulating hepatic gluconeogenesis, and inhibiting insulin activity on skeletal muscles and adipose tissue respectively 7. In the abdominal region, fat cells have a higher density of corticosteroid receptors, with cortisol increasing receptor sensitivity metabolism of target fat cells, thereby increasing the storage of fat in this area 79. Furthermore, chronic stress suppresses growth hormone, leutinising hormone, testosterone, TSH and T3 instigating insulin resistance/hyperinsulinemia and dyslipidemia 80. This leads to the exertion of a complex and long-lasting effect involving increased SNS activity and increased cortisol and epinephrine secretion which influences non-genetic factors on the origins of type I diabetes 81 and hampers the control of Type I and Type II diabetes 82. Here we see a demonstration of the manifestation of the "Metabolic Syndrome". As discussed by Chrousos 7 and Girod and Brotman 83, situations associated with chronic activation of the HPA axis may derive some of their associated cardiovascular risk from untoward glucocorticoid effects, leading to myocardial infarction and atherosclerosis. Raadsheer et al., 84 investigated higher circulating glucocorticoid levels, and impaired suppression of cortisol in depressed patients and found that many exhibited symptoms of increased glucocorticoid tone as discussed above, such as central obesity, menstrual irregularity, immunosuppression and osteoporosis. Chrousos 6 stated that stress-induced hypercorticolism, visceral obesity, and other related sequelae have the potential to increase the all-cause mortality of affected subjects by 2–3 times, and shorten life expectancy by several years.

Glucocorticoids have been clinically used to control autoimmune disease, and inflammation, as well as organ donation rejection for many decades 85. The role of glucocorticoids is to inhibit the production of proinflammatory cytokines such as tumor necrosis factor (TNF)-A, interferon (IFN)-Y and interleukin-12 (IL-12), and to stimulate the production of anti-inflammatory cytokines such as IL-10, IL-4 and transforming growth factor (TGF)-B 86. During chronic inflammatory stress, interleukin-6 (IL-6) plays a major role of the endocrine cytokines in the immune stimulation of the HPA axis 73. Chronic activation of the stress response has been found to impair immune functions, and delay the healing process 79. The role of the HPA axis is crucial to regulating the severity of autoimmune disease, though the cause remains obscure. In the absence of corticosteroids the immune system is unrestricted and its activation by either acute or chronic immune challenge is likely to be fatal 87.

Predictable disorders such as low back pain, tension headache and even rheumatoid arthritis may be a result of repeated activation of postural musculature during chronic flight-or-flight responses 88. Jacobson 89 first argued that proprioceptive impulses could be found in conditions of high musculoskeletal tension. It was hypothesized that if such tension was combined with high levels of sympathetic activity, it could contribute to anxiety reactions. Krantz et al. 90 investigated different physiological responses to stress, as well as surface electromyography of the trapezius muscle. They found significant association between sympathetic arousal and electromyography activity, which is of importance when understanding the relation between musculoskeletal disorders and stressful situations. This is of particular interest in the treatment of work-related pain disorders in psychosocial stress syndromes as they may cause the development of pain disorders 9192. Therefore, chiropractors may require additional interventions to manage all aspects of chronic pain syndromes presenting to them. Combined psychological and manual interventions may provide the most appropriate healing of chronic conditions of the musculoskeletal neurohormonal systems commonly associated with chronic stress and disease. Further research is needed on the physiological and psychological effects of stress and its manifestation on the musculoskeletal system, as well as the effects of manipulative treatment on physiological and psychological functions. Emphasis should be given to the potential measurement of the stress response on various bodily systems after the application of manipulative therapy in normal and disease states.

It seems reasonable to examine physiological systems involved in the processing of symptoms such as pain in the many conditions reported to be managed by chiropractic intervention strategies. Whilst the somatoviseral reflex has been used as an example of a possible mechanism for the cause and management of these conditions, the scope of conditions that cannot be addressed by this mechanism is still large. We contend that a higher centre system impacting on the spinal cord could better explain the diversity of conditions.

In doing so, a consideration should be given to the role of psychosocial variables resulting from the stress of various events including trauma 121. Findings from animal studies have interestingly suggested that hormones of the HPA axis, pain-processing pathways, and autonomic nervous system may be underlying peripheral as well as central substrates of chronic pain and broad system dysfunction 122123. Traumatic physical or psychological stress can have enduring impact on functioning of these systems, and chiropractors manage conditions incorporating elements of these systems 124. An impaired HPA axis could serve as a physiological mechanism of medically unexplained symptoms as well as function as a mediator between psychological distress and observed symptoms 125.

Chiropractic management strategies have been used to manage or co-manage a number of non-musculoskleletal, non-malignant conditions. The pubmed database was searched in June of 2006 with the terms "chiropractic" and "case" and returned more than 589 hits. Of these, more than 40 related to non-musculoskeletal care. Some examples included: Ehlers-Danlos syndrome 126, gastroesophageal reflux 127, cervical spinal cord compression128, congestive heart failure 129, asthma 130, cervical dystonia 131, ulnar tunnel syndrome 132 and myaesthenia gravis 133. Unfortunately more examples of complications were returned in the pubmed database with this search string than there were examples of non-musculoskeletal treatment. The ratio appeared to be at least 3 to one.

By contrast, 416 hits were returned from the same search string on the Index to Chiropractic Literature database (ICL). There appeared to be fewer reports of negative outcomes, and the scope of the reports appeared just as broad as that presented on the Pubmed databases. Some examples include: otitis media 134, post polio syndrome 135, urinary incontinence 136, Dejerine-Roussy syndrome 137 and infantile colic 138.

It appears that the two databases present very different perspectives based on the content of their contributing journals, one (Pubmed) largely a medical database and the other largely chiropractic (ICL). This differential may explain and or reflect the different perspectives that chiropractors hold with regard to the management of non-musculoskeletal conditions when compared with their medical counterparts.

As mentioned previously, chiropractic often postulates the somatovisceral reflex as being the vehicle for the changes noted in the above conditions 101. However, less speculation is given to the potential role of supraspinal or cortical processes in the etiology and management of such conditions. As a large body of research currently supports the role of psychosocial variables in the generation and maintenance of disease 139140141142143144145, chiropractic should look to this research to potentially explain some of the clinical observations being made and recorded in the journals.

A review by Siegrist and Marmot discusses psychosocial variables as causative, aggravating, and perpetuating factors for the stress response, as well as stress implicating elevated psychosocial variables 146. The stress response has been associated with the propagation of numerous disorders including: dermatological 147, cardiovascular 148149, diabetic 150, Hepatic 151, immune 152, thyroid 153, gastrointestinal 154155, reproductive 156157158, renal 159, metabolic 160, rheumatic 161 and musculoskeletal 162163.

Future studies could utilize a randomized controlled trial design and measure variables such as: self reported levels of pain, disability, anxiety, depression, as well as objective blood and urine based measures of stress including: proinflammatory cytokines (TNF-alpha, IL-1, IL-6, IL-8, IL-18) 121164165 and anti inflammatory cytokines such as IL-4 and IL-10 122165166. These tests could be cross-referenced to the expression of collagen expressed in the inflammatory reaction frequently associated with chronic disease. Research designs such as the above would provide information on the effect of chiropractic management on subjective variables of pain as well as objective measures of stress and provide insight into the mechanism of action. It is only with similar studies can the association of stress be investigated thoroughly and its relevance to chiropractic measured accurately.