Allostatic Response and Allostatic Intervention Relevance to Oral Biology and Medicine

2.2.1 Allostasis

The nineteenth-century French physiologist, Claude Bernard (1813-1878) proposed that preservation of the internal milieu (le milieu intérieur, 1856) is a fundamental process of physiological regulation. The phrase "homeostasis" was coined. However, the concept of the benefits reaped by a state of physiological balance goes back millennia and across cultures, medical traditions and civilizations.

In Western civilization, we need to go beyond the classic Roman view of a healthy mind in a healthy body (mens sana in corpore sano), to the ancient Greek concept of Kalokagathia (from kalos kai agathos, Greek: Kakoa Kat ayax^oa). In Greek mythology, Kalokagathia was the female form of the spirit (=Daimon), and represented nobility and goodness. She was related to Virtue (Arete) and to Excellence (Eukleia). In Greek philosophy (cf., Plato), it came to represent the ideal and harmonious bodily, moral and spiritual whole. Harmony, it was defended, was reached when the mind and the body dimensions of a human being were appropriately balanced.

Cannon (1871-1945) described the dynamic process that organisms use to maintain physiological balance in response to changing environmental demands. Hans Selye (1907-1982) labeled the concerted responses to stressful challenges as the "Generalized Stress Response." Contemporaneously, Polany, described consciousness and related perceptions of motivation and control as fundamental phenomena processed by the central nervous system (CNS).

The role of the psyche in the fine and dynamic balance that signifies physical health emerged as psychosomatic medicine, a discipline that evolved from Speransky's "neurodystrophic processes" theory. Today, this paradigm argues that all forms of human disease, oral and systemic, are related to alterations in the interaction among genetic, endocrine, nervous, immune, and psychic (including consciousness), behavioral, cognitive, and emotional factors (Chiappelli et al. in press-c; Prolo and Chiappelli in Press; Chiappelli et al. 2004; Vgontzas et al. 1999). The subdiscipline that specifically describes the cross talk among the central and peripheral nervous, the psychoneuroendocrine, and the immune systems refers to psychoneuroimmunology (Solomon and Moos 1964; Solomon 1987; Chrousos and Gold 1992; Kiecolt-Glaser et al. 2002; Irwin 2002; Chiappelli et al. in press-c; Prolo and Chiappelli in press; Chiappelli et al. 2004; Vgontzas et al. 1999).

The central process of the psychoneuroimmunologic response entails allostasis, which consists of the totality of intertwined psychosocial and psychophysiological responses that regulate the psychobiological adaptation to change in homeostasis (Sterling and Eyer 1988; McEwen and Wingfield 2003; Schulkin 2003; Chiappelli and Cajulis 2004; Chiappelli et al. in press-c). Allostasis pertains to the complex interaction of variable set points according to circadian and circa-mensual rhythmicity, and which are characterized by individual differences, themselves associated with anticipatory behavioral and physiological responses, and vulnerable to physiological overload and to the breakdown of regulatory capacities (Sterling and Eyer 1988; McEwen and Wingfield 2003; Schulkin 2003; Chiappelli and Cajulis 2004). In brief, allostasis represents the set of intertwined processes in the face of all possible challenges, including challenges to the immune system (e.g., bacterial and viral infection of the stoma) in the context of orderly biological fluctuations. In this framework, these challenges to psychobiological rhythmicity, including sleep, represent the allostatic load (Chiappelli et al. in press-c; Prolo and Chiappelli in press; Chiappelli et al. 2004; Vgontzas et al. 1999). The cumulative load to the allostatic process, the allostatic load, produces the pathological side effects of failed adaptation, which are commonly observed in a variety of states. These outcomes can lead to unease and dis-ease, endanger mental and physical health, and may result in serious sickness well described in psychosomatic medicine (Sterlin and Eyer 1988; McEwen and Wingfield 2003; Schulkin 2003; Chiappelli et al. in press-c).

In most situations, subjects position themselves along a spectrum of allostatic regulation, somewhere between allostasis (=toward regaining physiological balance), and allostatic overload (=toward physiological collapse, and associated potential onset of varied pathologies). In other words, allostasis refers to the entirety of the complexity of psychobiological processes that bring about stability through change of state consequential to stress or trauma (Sterling and Eyer 1988; McEwen and Wingfield 2003; Chiappelli et al. in press-c). Stress can be defined by a variety of models. For instance, stress may signify perceived lack of fit of one's perceived abilities and the demands of the environment (i.e., person/environment fit) (French, Rodgers, and Cobb 1974; Chiappelli, Manfrini, Edgerton, Rosenblum, Cajulis, and Prolo 2006b), or which is essentially equivalent to a serious threat to the perception of self (Gruenewald, Kemeny, and Aziz, 2006).

Regardless of its construct, psychoemotional or physiological stress leads to anxiety, irritability and anger, tension, depressed moods, fatigue, and a compendium of symptoms referred to as the "sickness behavior" (e.g., lethargy, nausea, fever). Sickness behavior is evident, among others, as an elevation in IL-6 and in tumor necrosis factor (TNF)-a (i.e., cachectin) in body fluids, including saliva. Stress results in a set of bodily manifestations, including perspiration, blushing or blanching of the face, increased heart beat or decreased blood pressure, intestinal cramps and discomfort, and suppressed immune resistance to antigenic threats (Solomon and Moos 1964; Solomon 1987; Chrousos and Gold 1992; Kiecolt-Glaser et al. 2002; Irwin 2002; Chiappelli et al. in press-c; Chiappelli et al. 2004). In the oral cavity, reactions to stress manifest as clenching of the teeth, with consequential pain, discomfort and trauma to the masticatory musculature, the temporomandibular joint, and various odontalgias with no clear etiology (Chiappelli et al. in press-c).

2.2.2 Allostatic Load

We noted that the process of allostatic regulation signifies the recovery and the maintenance of internal balance and viability amidst circadian rhythmicity and changing circumstances consequential to stress. This process encompasses a range of behavioral and physiological functions that direct the adaptive function of the regulating homeostatic systems in response to stress, trauma and other challenges. The allostatic load, in brief, refers to the set of physiological, psychological, and pathological sequelae of the allostatic process. Allostatic overload signifies the psychobiological collapse that is inevitably associated with a variety of health outcomes systemically (Schulkin 2003; Chiappelli and Cajulis 2004; Chiappelli et al. in press-c).

Type 1 allostatic load often utilizes the psychobiological responses to the challenge as a mean of self-preservation by developing and establishing temporary or permanent adaptation skills. The organism aims at surviving the perturbation in the best condition possible, and seeks to normalize its normal circadian life cycle. An example of Type 1 allostatic response in oral biology and medicine is, as noted elsewhere (Chiappelli and Cajulis 2004), recurrent aphthous stomatitis (RAS, i.e., canker sores). This is a stress-associated T cell-dependent pathology of the gingival mucosa. RAS lesions are characterized with increased TH1 patterns of cytokine (e.g., IL-2) in situ (Chiappelli and Cajulis 2004). Other examples of Type I allostatic response manifested in the oral cavity include teeth grinding, and tooth pain that cannot be attributed to carries, cracked tooth syndrome, pulpitis or other circum-dental inflammatory process (e.g., gum disease), temporomandibular disorder and pain, and pain at palpation of the masticatory muscles (vide supra). Stress and trauma to the dentition alters dental anatomy at the coronal surfaces such that, when subjects are followed up prospectively, changes in vertical distance of occlusion and the angle of Spee, the curved line that follows the occlusal surface of the posterior teeth of the mandible and is viewed from a sagittal plane, are clearly noted (Chiappelli et al. in press-c). Our data, cited elsewhere (Chiappelli et al. in press-c), on the relationship among dental pain, dental anxiety, and the perception of wellness show that dental patients can be dichotomized on the basis of pain perception: patients stratified for perceived pain intensity (high pain median 5.5 versus low pain: 3.0 [significant by t comparison of means, p = 0.004]), do not differ in terms of reported dental anxiety (medians: 1.6 versus 1.7 [not significant by Wilcoxon comparison of means]). Perception of pain impacts negatively (significant inverse correlation by Pearson coefficient: r = -0.5) upon dental patients' overall perception of wellness (medians: 2.3 versus 3.3 [significant by t comparison of means, p = 0.049]) (Chiappelli et al. in press-c).

In Type 2 allostatic load, the challenge is excessive, sustained, or continued, and drives allostasis chronically: an escape response cannot be found, and allostatic overload irremediably obtains. Type 2 drives allostasis beyond any possibility of return to homeostatic rhythmicity. The psychobiological and pathological responses to stress become permanent, with consequential erosion in health and immune surveillance mechanisms (McEwen and Wingfield 2003; Chiappelli and Cajulis 2004; Chiappelli et al. in press-c; Prolo and Chiappelli 2007 in press). Oral lichen planus (OLP, Fig. 2.1) is an example of a Type II allostatic response with evident mucosal inflammation of the oral cavity.

The typical pathology, which involves basal cell lysis, and lymphocyte transmigration into the epithelial compartment, favors a statistically significant increase in incidence of oral squamous cell carcinoma. This premalignant lesion manifests in most patients as a chronic inflammatory disorder, and affect in 2 to 3% of the US population. The prevalence of OLP is higher in women than in men, and increases with age with onset in middle age. Human hepatitis C virus may be a

Figure 2.1. Oral lichen planus - Pathological manifestation (intraoral photograph) reticular stage.

predisposing factor, and there may be a genetic propensity for this condition since expression of HLA-Bw57 favors OLP, whereas HLA-Dql expression provides resistance against it. OLP is a life-long condition, which require serious commitment to long-term adaptability on the part of the afflicted patient, and of the significant others as well (Chiappelli and Cajulis 2004).

2.2.3 Allostatic Testing and Intervention

The process of testing for the allostatic response yields important information about the organism's psychobiological status. Therefore, several experimental protocols have been characterized for testing allostasis in animal and in human research. Human subjects under stress can be subjected to cognitive, sensory, or physiological challenges aimed at monitoring the allostatic process of immunephysiological adaptation to the experimental challenge in addition to basal states of the stress response.

Case in point the Stroop color-word interference test is an example of a cognitive challenge that was originally developed (1935) to examine patterns of cognitive decline. The Stroop challenge is measured as reaction time, and becomes evaluated in subjects who suffer from organic or stress-related cognitive dysfunction. One important caveat of this test is that patients with severe dementia show less Stroop interference effect, when the reaction time is adjusted for color naming performance, which suggests the need and the importance of partitioning out underlying deficits for the understanding of complex cognitive processes. Principal-components analyses, however, show that disruption of semantic knowledge and speeded verbal processing in certain patient (e.g., patients with Neuro-AIDS, patients with DAT) is a major contributor to the incongruent trial. The Stoop challenge is unquestionably an effective modality for testing the allostatic response of the glucocorticoids-cytokine (i.e., HPA-CMI) response in normal, healthy young men and women. Two groups of responders can be distinguished based on salivary and plasma glucocorticoids response to the challenge. The bottom 40% of the responders for Cortisol responses to the challenge characteristically manifest significantly higher salivary and plasma levels of IL-6, but lower subjective experience of stress, compared to the high-glucocorticoids responders (top 40 percentile). This confirms that individual variations exist in the response of the HPA-CMI axis to a mild cognitive dissonance stress, and that these variations can have potentially adverse health outcomes (Chiappelli et al. in press-c; Prolo and Chiappelli in press; KunzEbrecht, Mohamed-Ali, Feldman, Kirschbaum, and Steptoe 2003).

Another widely used stress paradigm for testing allostasis in human subjects is the dexamethasone-suppression test (DST), which tests the functional response of the HPA-CMI axis directly. Administration of 1 to 5 mg of dexamethasone (DEX) to normal subjects in the evening (23:00 h) results in a flattened cortisol circadian pattern, which lasts up to 24 h. The cortisol-suppression response is an indication of DEX-sensitivity and normal HPA response. A significant change in the migratory properties of circulating CD4+CD62L+T cells occurs in DEX-sensitive control subjects. This observation is significant since the CD4+CD62L+T lymphocyte subpopulation overlaps to a large extent with regulatory T cells (i.e., Tregs, CD4+CD25+FoxP3+), which play a central coordinating role in CMI (Chiappelli in press). The DST challenge is used in monitoring the HPA-CMI response in a variety of patient populations. In DEX-resistant patients who show failed suppression of cortisol following DST (e.g., most patients with anorexia nervosa, a large proportion of patients with Alzheimer's disease, or with major depression), the migratory properties of CD4+CD62L+T cells are also not altered. Therefore, this test provides a useful experimental tool to study the intimate relationship between the physiological regulation of the neuroendocrine and cellular immune systems in vivo in normal subjects and in certain patient populations. However, the DST is a static challenge to the HPA-CMI axis, and solely presents a reflection of the regulatory feedback response of the axis, rather than of the potential of the system per se. Moreover, a principal caveat of this test of the allostatic response is that it lacks of reliability, validity and specificity as a clinical diagnostic instrument. The test can be used in research protocols in oral biology and medicine, and we have shown that patients with OLP exhibit significant alterations in HPA-CMI regulation (Chiappelli and Cajulis 2004).

In brief, maladaptation of the person to the environment can cause psychological turmoil, with serious psychosomatic sequelae. A general "stress-coping-social support" model was proposed with the goal of identifying psychosocial risk factors for progression and to develop effective psychosocial modes of intervention (Mulder 1994). The model established social support as a beneficial mediating variable, and proposes certain underlying psychobiological "causal paths" among stress, coping, social support, and disease progression. Numerous traditional and alternative modes of interventions are beneficial in allostatic load and overload in psychosomatic medicine in general and in oral biology and medicine in particular. It is not the purpose of this chapter to discuss them, except to note that, within the context of allostatsis described above, their aim focuses at restoring the mind-body balance and harmony (e.g., mindfulness-based stress reduction program, Kabat-Zinn et al. 1992; Miller, Fletcher, and Kabat-Zinn 1995; Robert McComb, Tacon, Randolph, and Caldera 2004; Carlson, Speca, Patel, and Goodey 2004; Williams, Kolar, Reger, and Pearson 2001; Roth and Stanley 2002).

2.2.4 Allostasis Is Not Chaos-Or Is It?

The multitude of intertwined cellular and humoral events that characterize the complex process of allostasis behave according to ordered and organized randomness. At least two complex "strange attractors" may be hypothesized to determine and to characterize the chaotic behavior of psychobiological rhythmicity. Psychoneuroendocrine responses to basal homeostasis and to stress challenges may compound intrinsic immune regulatory events under basal condition and following antigenic threats in the form of a pathogen (=non-self) or autoimmune recognition (=self).

Georg Cantor (1845-1918) and Karl Theodor Wilhelm Weierstrass (1815-1897) first opened the field of fractal mathematics in the late nineteenth-century, but their work received little recognition until Benoit Mandelbrot (1924)1 characterized a set of mathematical equations to represent graphs with self-similar properties in the mid-1970s. He introduced the terms "fractal" (Latin, fractus = broken into pieces; from the verb frango, frangere, fregi, fractus) to the scientific discourse, and defined fractals as graphical representations of relatively simple mathematical equations (Mandelbrot 1977, 1986). Computer visualization applied to fractal geometry offers a powerful visual argument by integrating into the scientific domain nonlinear dynamics and chaos theory (i.e., ordered nonlinear behavior), and object complexity.

"Strange attractors" have fractal structure. Fractal recurrence is one characteristic feature of inherent pattern of repetition of the fractal structure, which, together with certain attractors, which the MIT meteorologist Edward Lorenz named "strange," and which are now recognized to occur manifested by all biological systems (e.g., HPA-CMI axis) (Lorenz 1963). Chaotic motion can be represented as a phase diagram of that motion, with time as implicit, and each axis representing one dimension of the physiological state under study. This type of phase diagram depends on the initial state of the system as well as on a set of parameters, and certain forces toward which the system is attracted in its motion (cf., allostasis). Such forces are attractors, and chaotic motion is driven and characterized by these "strange attractors," which of course can have great detail and complexity (Dalgleish 1999; Rew 1999; Glenny, Robertson, Yamashiro, and Bassingthwaighte 1991).

Fractal objects can be regular (or geometric) if they consist of large and small structures that are exact copies of each other, except for their size. Random fractals, by contrast, are characterized by the property of having the large-scale and the small-scale structures differ in the details (e.g., the shape of cell membranes). Fractal objects are either self-similar or self-affine, and are composed of subunits and of sub-subunits that are precisely or statistically similar (or affine) to the structure of the original.

1 Sterling Professor Emiritus of Mathematics, Department of Mathematics, Yale University, [email protected]

Deterministic fractals have the characteristic of precise similarity (or affinity), whereas statistical similarity (or affinity) characterizes statistical fractals. Self-similarity is proper to isotropic fractals, which are invariant under orthogonal scale transformation. Self-affinity pertains to fractals that are invariant under anisotropic (=affine) scale transformation (Nygard and Glattre 2003).

In brief, fractal analysis provides the means to quantify the irregularity of the contour of objects with a measurable value, the fractal dimension, which is rendered as:

log(number of self-similar units)

log(magnification factor)

In mathematically stricter terms, for any fractal object of size P, and made up of smaller units of size p, the number of units (N) that fits into the larger object is equal to the size ratio (P/p) raised to the power of d, the Hausdorff dimension2:

Fractal analysis opens several areas of biological inquiry, including the study of the phenomenon of self-organized criticality, which refers to organisms continually driven out of balance striving to maintain or to regain a state of organized and poised critical balance (Rew 1999). Self-organized criticality corresponds to the characteristic state of criticality, or change that results from the process of self-organization during the time-dependent and transient period that lies between stability and chaos (Glenny et al. 1991). In the context of psychoneuroimmunology, of course, one example of self-organized criticality is the physiological events associated with allostasis noted above, and in this context, the fractal & recurrence analysis-based score (FRAS) may be an effective measuring tool. Case in point its use to quantify heart rate and pulse transit time in patients with probable Chronic Fatigue syndrome and in normal cohorts following the head-up tilt test (Naschitz et al. 2002). In the patient group, the challenge is likely to arise a Type II allostatic response due to the chronicity of the condition. By contrast, a Type I response is expected in normal control subjects. The data showed significant (p < 0.0001) elevation in FRAS in the patient compared to the control group (Naschitz et al. 2002). The FRAS index describes the reemergence of fractal structure within the context of the object under study—in this study, heart and pulse rate. It is timely to

Named after Felix Hausdorff (1868-1942), but also referred to as Hausdorff-Besicovitch (Abram S. Besicovitch, 1891-1970) dimension, the capacity dimension, or the fractal dimension.

conceive of research paradigms that will incorporate the FRAS index in the context of investigations in oral biology and medicine. In that context, one possible patient population to be studied might be patients afflicted with oral mucositis.

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