Psychotherapy and Neuroscience

Neurohormones in Autoimmune populations

Individuals with psychiatric diagnoses, like those having diagnoses of PTSD or major depression, can also have co-occurring physical illness. This would suggest that the neurobiological composite underlying certain psychiatric disorders may also co-occur or even underlie certain chronic illness. For example one middle aged man and former combat veteran diagnosed with fibromyalgia i.e. presenting multiple tender points also presented comorbid PTSD with symptoms of sleep disturbance, depressed mood, etc. (Culclasure et al., 1993). Of twenty-nine patients meeting DSM criteria for PTSD, 21% of the sample had co-occurring diagnosed fibromyalgia. Those with fibromyalgia reported more tenderness, pain, higher functional impairment and more psychological distress than patients without comorbid illness (Amir et al., 1997). Of twenty-seven patients with irritable bowel syndrome (IBS) 54% met criteria for psychiatric diagnosis at some point in their lives, twenty-two (54%) reported a trauma history and eighteen (36%) also had co-occurring psychiatric diagnosis of PTSD (Irwin et al., 1996). An inpatient sample of seventeen or 61% met DSM criteria for PTSD and also presented symptoms of functional gastrointestinal symptoms, e.g. IBS (Fass et al., 1995). Finally certain physical illnesses have comorbidity with other physical conditions, like fibromyalgia with IBS (Veal et al., 1991; Cohen et al., 2000). It is important for medical service providers to recognize the comorbidity for certain psychiatric and physical conditions to best meet each patient’s treatment needs. Although certain physical illnesses may be biological in nature, they may also be physical manifestations of the toll of chronic stress on the body over time.

Many physical illnesses also have different stress-induced neurohormonal composites, as do psychiatric populations. Irritable Bowel Syndrome (IBS) is a functional gastrointestinal disorder with associated symptoms of visceral pain hypersensitivity, especially in the small bowel or colon, back pain, tiredness or lethargy, frequent headaches, urinary urgency and frequency, nocturia, dyspareunia, and thigh pain (Sheikh & Wright, 1999). IBS patients present alterations in resting diurnal cortisol levels; they present higher mean and prolonged evening urinary cortisol levels when compared with controls (Heitkemper et al., 1996). ACTH plasma levels increase in response to CRH challenge (Fukudo et al., 1998) and in response to recto-sigmoid stimulation (Munakata et a., 1998). Heart rates reduce for this population when compared with controls in response to a cold pressor challenge (Punyabati et al., 2000). The former reflects dysregulation of the HPA (Mayer et al., 2001).

IBS is a functional gastrointestinal disorder that also presents comorbity with fibromyalgia and vice versa (Veal et a., 1991; Canataroglu et al., 2001). Primary fibromyalgia syndrome is a condition that is symptomatic for high levels of pain, fatigue, morning stiffness, depression, anxiety, etc. (Cohen et al., 2000). Certain studies have demonstrated that primary fibromyalgia patients present dramatic and prolonged plasma ACTH increases (as long as two hours) in response to CRH challenge. CRH induced plasma cortisol levels do not differ or tend to be somewhat higher when compared with controls. Fibromyalgia patients also fail to suppress cortisol (i.e. presenting significant cortisol increases) in response to dexamethasone (DEX) challenge (Griep et al., 1993, 1998). Ovine CRH challenge induces significant and prolonged CRH increases, insignificant increases in ACTH, and significant decreases in net integrated cortisol response in fibromyalgia patients when compared with controls, suggesting adrenal hyporesponsiveness (Crofford et al., 1994; Riedel et al., 2002). ACTH challenge yields prolonged cortisol decreases in fibromyalgia patients when compared with controls (Kirnap et al., 2001). Fibromyalgia patients also present lower urinary cortisol excretion and lower binding affinity of glucocorticoids (GCs) to glucocorticoid receptors (GRs) in blood lymphocytes (Lentjes et al., 1997). Overall findings suggest that fibromyalgia presents a greater ACTH:cortisol ratio along with mild hypocortisolemia. The nature and balance of this ratio can explain the above-noted disparate findings that are probably due to methodological differences. As noted in section 1.46a PTSD patients present a similar but more robust composite of significant ovine CRH-induced increases in ACTH concentrations, greater DEX induced super suppression of cortisol and higher binding affinity of GCs to lymphocyte GRs.

The majority of patients with chronic fatigue syndrome (CFS) tend to identify symptoms of fatigue, pain, reduced physical activity, reduced motivation, etc. three months after reported viral infection (Cleare et al., 2001; Gaab et al., 2002). CFS patients in response to human CRH (hCRH) challenge present serum ACTH levels that are commensurate with normal controls and decreasing cortisol levels (Cleare et al., 2001). DEX challenge presents greater serum and salivary cortisol suppression which is reflective of lower cortisol levels when compared with controls (Kavelaars et al., 2000; Gaab et al., 2002). Resting ACTH and cortisol levels are similar between CFS patient populations and healthy controls (Kavelaars et a., 2000). In chronic pelvic pain (CPP) 66.7% and 60% patients report having been sexually and physically abused during childhood or adulthood, respectively. Despite the fact that diurnal salivary cortisol levels do not differ from infertile and healthy controls, human CRH (hCRH) challenge produces few group differences in ACTH secretion, but produces pronounced and prolonged salivary cortisol suppression in CPP subjects (Heim et al., 1998). In summary CFS and CPP tend to present a composite of normal ACTH response with apparent reductions in adrenal activity

Initial dexamethasone challenge (Harbuz et al., 2003) profoundly increases unmedicated rheumatoid arthritis patients plasma ACTH along with lower but significant cortisol concentrations when compared with controls. After delayed CRF infusion three of seven rheumatoid arthritis patients are able to escape from cortisol suppression and mount immediate and sustained increases in plasma cortisol along with ACTH blunting. These patients also present fewer rated rheumatoid arthritic symptoms of tender and swollen joints and lower C-reactive protein concentrations that are reflective of reduced disease progression. In response to CRF challenge four of seven patients, like healthy controls, fail to present any changes in plasma cortisol and in ACTH responses (Harbuz et al., 2003). Another sample of patients with rheumatoid arthritis present baseline ACTH levels that are significantly lower than controls; however with CRH stimulation ACTH levels are comparable with controls. CRH induced challenge also produces concurrent cortisol decreases that are significantly steady and prolonged (Gudbjornsson et al., 1996) when compared with controls. Though resting cortisol levels tend toward normal levels in mildly afflicted patients, increasing symptom severity flattens or completely alters cortisol circadian rhythmicity (Neeck et al., 1990) but has little effect on its levels. The former demonstrates that CRH challenge tends to temporarily increase serum ACTH and cortisol to normal levels, which is accompanied by steady and prolonged post-injection cortisol decreases. DEX administration produces robust serum increases in ACTH along with less dramatic significant cortisol increases.

Neuroendocrine analysis of findings relating to another chronic disease, multiple sclerosis, needs to be understood within biological alterations to disease progression. Symptoms in the primary progression stage last up to a few weeks and involve temporary manifestations of localized paralysis, decreasing coordination, sensory disturbances, visual impairment, etc. Initial symptoms subside for 5-10 years or longer in 70% of MS patients in the second stage or the asymptomatic relapsing-remitting stage. In 30% of MS patients the sequencing of genes continues along with the progression for furthering degeneration of myelin sheathes or demyelination that is characteristic of the disease. The demyelination process spreads from the oligodentroglial cells to underlying axons in respective neural cells in the spinal column. (The inflammatory markers underlying this process will be noted in section 1.47b of this web site.) The final stage, the secondary progression stage, is the final and chronic stage where the patient is incapacitated by disease, unable to walk and is wheelchair bound in response to more global paralysis. Disease progression causes neural apotosis and paralysis in its final stage. (Steinman, 2001)

All three stages of disease present diurnal rhythmicity to cortisol secretion, unlike rheumatoid arthritis. The mean cortisol amplitude is significantly different between MS groups, i.e. relapsing-remitting stage presents the highest resting cortisol levels, then the secondary progressive the next highest, and the primary progressive the lowest. The relapsing-remitting group also presents the lowest plasma cortisol response to ACTH challenge when compared with the other groups and controls. Both symptomatic groups present significantly lower resting serum cortisol levels when compared with asymptomatic MS patients and healthy controls (Wei et al., 1997). CRH induced cortisol levels are lowest in the secondary progressive MS groups than when compared to other MS groups and controls. All MS groups present lower serum cortisol levels in response to DEX challenge when compared with healthy control levels (Wei et al., 1997). Combined CRH-DEX findings demonstrate that those MS patients with the highest degree of neurologic disability tend to mount the greatest cortisol and ACTH plasma levels to challenge than healthy controls (Then Bergh et al., 1999a). The findings suggest that the middle stage, the relapsing-remitting stage, is characterized by higher basal cortisol levels, that tends to be less responsive to alterations in other neurohormones. This explains, in part, the lack of symptoms that characterize this asymptomatic stage.

Studies that do not account for multiple sclerosis symptom severity also note alterations in HPA activity. For instance evening baseline plasma cortisol is significantly higher in patients when compared with controls; however ACTH and ovine CRH challenges produce levels that are not significantly different from healthy controls (Michelson et al., 1994). In response to combined dexamethasone-CRH test patients (not accounting for symptom severity) certain MS patients present a wide range of plasma cortisol response that varies from blunted to excessive (Grasser et al., 1996). DEX challenge alone induces high concentrations of cortisol and nonsuppression in MS patients, which is similar with patients with major depression. DEX treatment facilitated MS patient symptom improvement for those who tend to suppress DEX induced cortisol, but nonsuppressors fail to respond (Reder et al., 1987). MS patients pretreated with DEX in response to CRH challenge produce significant plasma ACTH increases along with concomitant resistance for cortisol suppression (Fassbender et at. 1998). GR binding parameters in peripheral blood lymphocytes for MS patients are no different from healthy controls (Then Bergh et al., 1999b).

Due to methodological differences it is difficult to find commonalities between the above-noted findings; however, clearly multiple sclerosis presents alterations in HPA activity. Postmortem tissues of MS patients (Huitinga et al., 2003) with and without sepsis were compared with deceased controls with and without sepsis. Control subjects with sepsis present a strong positive correlation between cortisol and IL-6 secretion; however the cerebrospinal fluid of each MS patient with sepsis does not demonstrate that IL-6 is responsible for cortisol release. In fact, both active (characterized by active demyelination and foamy macrophages) and inactive (distinguished by gliotic demyelinated hypocells) MS lesions were found in 16 of 17 MS patients in the hypothalamus. 50% of these lesions contained lipid-laden foamy macrophages and activated microglial cells. Other brain regions like the internal capsule and anterior commissure presented active MS lesions, whereas chronic inactive lesions were found in the fornix (Huitinga et al., 2003), a structure with mutual projections with the hippocampus (Herman et al., 1992; Cullinan et al., 1993). The former would impair locomotion, the latter, hippocampal inhibition of stress arousal as well as memory formation and retrieval as noted in section 1.42 of this web site. Because the postmortem number of CRH neurons of MS patients are not significantly different from healthy controls, it has been suggested that arginine vasopressin neurons in the median eminence and pituitary, that ordinarily complement CRH neurons in response to chronic stress activation (De Goeij et al., 1992; Aguilera et al., 1994), take over as the major stimulator of the HPA (Harbuz et al., 1997; Michelson & Gold, 1998) in response to chronic stress.

Certain autoimmune and chronic diseases along with psychiatric syndromes present alterations in HPA activity.


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