A unifying neuro-fasciagenic model of somatic dysfunction - Underlying mechanisms and treatment - Part II.

+

MODEL

Journal of Bodywork & Movement Therapies (2015) xx, 1e18

Available online at www.sciencedirect.com

ScienceDirect journal homepage: www.elsevier.com/jbmt

FASCIA SCIENCE AND CLINICAL APPLICATIONS: EXTENSIVE REVIEW

A unifying neuro-fasciagenic model of somatic dysfunction e Underlying mechanisms and treatment e Part II Paolo Tozzi, MSc Ost, DO, PT a,b,* a b

School of Osteopathy C.R.O.M.O.N., Rome, Italy C.O.ME. Collaboration, Pescara, Italy

Received 3 October 2014; received in revised form 20 February 2015; accepted 24 February 2015

KEYWORDS Fascia; Somatic dysfunction; Fascial dysfunction; Fascial mechanisms; Osteopathic manipulative treatment; Osteopathic models; Fascial treatment; Fascial release; Manual therapy

Summary This paper offers an extensive review of the main fascia-mediated mechanisms underlying various therapeutic processes of clinical relevance for manual therapy. The concept of somatic dysfunction is revisited in light of the several fascial influences that may come into play during and after manual treatment. A change in perspective is thus proposed: from a nociceptive model that for decades has viewed somatic dysfunction as a neurologically-mediated phenomenon, to a unifying neuro-fascial model that integrates neural influences into a multifactorial and multidimensional interpretation of manual therapeutic effects as being partially, if not entirely, mediated by the fascia. By taking into consideration a wide spectrum of fasciarelated factors e from cell-based mechanisms to cognitive and behavioural influences e a model emerges suggesting, amongst other results, a multidisciplinary-approach to the intervention of somatic dysfunction. Finally, it is proposed that a sixth osteopathic ‘meta-model’ e the connective tissue-fascial model e be added to the existing five models in osteopathic philosophy as the main interface between all body systems, thus providing a structural and functional framework for the body’s homoeostatic potential and its inherent abilities to heal. ª 2015 Elsevier Ltd. All rights reserved.

Introduction In osteopathic practice there are three main manual approaches that are directed towards the fascia: 1) direct approach e the affected tissue is brought against the

restrictive barrier, described as a “functional limit that abnormally diminishes the normal physiologic range” (E.C.O.P., 2011a). This is maintained until tensions modify; 2) indirect approach e tissues are brought away from the restrictive barrier while a position of ease (a balanced

* School of Osteopathy C.R.O.M.O.N., Rome, Italy. E-mail address: [email protected]. http://dx.doi.org/10.1016/j.jbmt.2015.03.002 1360-8592/ª 2015 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Tozzi, P., A unifying neuro-fasciagenic model of somatic dysfunction e Underlying mechanisms and treatment e Part II, Journal of Bodywork & Movement Therapies (2015), http://dx.doi.org/10.1016/j.jbmt.2015.03.002

+

MODEL

2 tension in all planes and directions) is found and maintained up to a release; 3) combined approach e both the point of ease and the restrictive barrier are consecutively engaged in an interactive fashion (Ward, 2003). Although myofascial and fascial-ligamentous release techniques are the most commonly applied fascial approaches amongst American osteopathic physicians (Johnson and Kurtz, 2003), there are a multitude of fascia related techniques that utilize various levels of aggressiveness (Sergueef and Nelson, 2014), from balanced ligamentous tension technique to counterstrain, from articulatory to cranial and visceral techniques, including soft tissue work from inhibitory pressure to effleurage manoeuvres. Osteopathic treatment of fascia has shown to be effective for a wide variety of conditions, from local musculoskeletal causes, such as acute joint injury (Eisenhart et al., 2003) to general mood disorders such as depression (Plotkin et al., 2001). Other non-osteopathic manual modalities have shown similar results, possibly because of the common therapeutic influence and stimulation of the myofascial complex (Simmonds et al., 2012). Several mechanisms may underlie therapeutic changes in the fascia.

Fascia-related mechanisms involved in the treatment of somatic dysfunction Structural changes Structural modifications in the connective tissue may occur immediately or just after treatment and may account for the palpable changes following manipulation. Myofascial release of the thoracolumbar fascia in patients with chronic low back pain has shown an increase in thickness of fascial layers that remained for at least 24 h (Blanquet et al., 2010). This suggests a sustained change in the architecture and/or hydration of the fascia being worked on. In addition, US measurements applied immediately before and after manual intervention, showed highly significant differences in collagen fibre density and orientation in the structure of the matrix in the dermis, reflecting palpable differences in tension and regularity (Pohl, 2010). These findings are consistent with the re-organization and remodelling of collagen fibres, which have been suggested to result from myofascial work (Martin, 2009) through a breakdown of abnormal collagen cross-links and an increased matrix hydration. Since abnormal palpable findings (such as altered texture) in connective tissue might be related to abnormal cross-links between collagen fibres, it has been shown that human fibroblasts respond better to cyclical (3 min stress-3 minutes relaxation, of about 7% of their length) rather than static stretch by increasing the production of collagenase by 200% (Carano and Siciliani, 1996). This enzyme has a potential role in collagen remodelling in dysfunctional tissue by breaking cross-linking peptide bonds, thus preventing excessive connective tissue formation, as occurs during wound healing. However, the repetitive mechanical stretch-induced collagenase activity can also be suppressed by hormonal (oestradiol and progesterone) influences (Zong et al., 2010), as might occur during the menstrual cycle or in hormonal therapy.

P. Tozzi A static load may also break abnormal tissue collagen crosslinking and stimulate fibroblast differentiation under the influence of IL-6, with a potential role in tissue repair and remodelling (Hicks et al., 2012; Khan and Scott, 2009). In addition, the duration of the load appears to be a significant factor. It seems that brief periods of stretching may decrease the effects of TGF-b1 production of additional collagen, thus reducing the risk of fibrosis or scarring (Langevin et al., 2006). Scars may generate pain syndromes that can be relieved by a direct manual approach to the involved connective tissue (Kobesova and Lewit, 2000), and this could be applied in the first 12 h following surgery to reduce inflammatory reactions and the risk of adhesion formation (Chapelle and Bove, 2013).

Cell-based mechanisms As will be described in this section, various forms of manual loading, whether sustained or cyclical, that differ in direction, speed, magnitude and frequency, appear to exert a strong impact on cell behaviour, gene expression and tissue remodelling through growth factors and enzyme activation. Several cell-based mechanisms may potentially represent crucial factors in the achievement of a palpable release during manual fascial work. Some of these are described in Table 1. Fibroblasts in vitro and in vivo have shown an almost immediate response to traction, pressure and shear forces, followed by a series of changes in chemical signalling pathways and gene activation, ATP release, actin polymerization, and also differential stretch-activated calcium channel signalling (Wall and Banes, 2005; Stoltz et al., 2000). Although most of the proposed mechanisms may require hours or even days before producing desirable effects on tissue texture and function, some of them may take place within minutes from the starting point of a therapeutic manouver. Langevin et al. (2013) note that in response to sustained changes in tissue length, fibroblasts may rapidly modulate such tension by remodelling their cytoskeleton and changing their contractile apparatus. Within minutes they could remodel their cell-matrix contacts (focal adhesions) along the direction of tissue stretch (Ciobanasu et al., 2013; Geiger et al., 2009), or expand microtubule network and actomyosin activation so as to maintain tensional homoeostasis through an equal counter-tension (Eastwood et al., 1998). This may produce a counterforce in the matrix tension that might be palpable. Tensional load appears to be perceived by the cell at a nuclear level too. Ex vivo and in vivo studies demonstrate that fibroblasts respond within minutes to mechanical stretching by dynamically remodelling their cytoskeleton with perinuclear redistribution of alpha-actin (Langevin et al., 2005, 2006; 2010). Although this property of rapidly responding to mechanical stress appears to be specific to areolar connective tissues only, it remains significant for fascial work because loose connective tissues form the interface between subcutaneous and perimuscular layers, and are potentially engaged in manual interventions. However, cytoskeletal remodelling failed to occur when distinct matrix properties were produced in gel, as for denser and stiffer connective tissue with increased crosslinked collagen (Abbott et al., 2013). This shows the


+

MODEL

A unifying neuro-fasciagenic model of somatic dysfunction: Part 2 Table 1

3

Cellular mechanisms that may be involved in the manual fascial treatment of somatic dysfunction.

Fibroblast response

Collagen response

Mechano-coupling

Cellecell communication

Effector cell response

Strain direction, frequency and duration of a (therapeutic) load may influence fibroblast morphology, function and behaviour (Grinnell, 2003; Wang et al., 2004). When equi-radially applied, it may lead to reduction of proinflammatory mediators and decrease of fibroblast proliferation, possibly linked to clinical improvements in range of motion and reduction of pain/inflammation (Standley and Meltzer, 2008). Collagen synthesis and architecture responds to mechanical loading (Kjaer et al., 2009; Thomopoulos, 2006), hence a therapeutic load may stimulate connective tissue remodelling and repair. Physical load produces a transduction into various chemical signals, leading to a modulation of cell metabolism and response, changes in intracellular biochemistry and gene expression (Ingber et al., 2014; Chiquet et al., 2009), depending on the type, duration, amplitude and frequency of the load being applied (Lavagnigno et al., 2003). Stimulus in one location leads to a perturbation of distant cells, although these have not received any direct mechanical stimulus (Lu and Thomopoulos, 2013; Wall and Banes, 2005). Therefore a therapeutic load may produce beneficial effects even at distance to where it is applied. Appropriate mechanical loading stimulates protein synthesis at the cellular level, promoting tissue repair and remodelling (Hardmeier et al., 2010; Wang et al., 2012) as well as cell proliferation and migration in wound healing, by sensitizing fibroblasts to nitric oxide (Cao et al., 2013b)

intrinsic interdependence between matrix and cell properties on determining the tissue response to a mechanical load. During manual fascial techniques, the operator may feel various tissue responses to the applied load that are described as ‘resistance’ or ‘give’ to the stretch. Interestingly, the mechanical loading of fascia causes changes through activation of fibroblast response and the different receptors present in the fascial tissue, leading to modulation of myofascial contraction (Hicks et al., 2014). Spontaneous contractions in fascia suggest the existence of an intrinsic tension or pre-stress in the collagen scaffold (Staubesand et al., 1997); and when an additional load alters this tensional balance, so that the fascia is distended, the myofibroblasts contract and resist this (Tomasek et al., 2002). Various studies in vitro have demonstrated different cell behaviours depending on the type, magnitude and frequency of the artificial load being applied, and may be clinically relevant to understand how tissues respond to different modalities of intervention. Fibroblasts and myofibroblasts are both highly responsive to magnitude (Cao et al., 2013a), direction (Eagan et al., 2007), frequency and duration (Meltzer and Standley, 2007) of a (therapeutic) load, and can regulate cell activity, proliferation or apoptosis (Meltzer et al., 2010), mainly by influencing ion conductance, gene expression and secretion of inflammatory mediators. In particular, the secretion of IL-6 and IL-1 by fibroblasts under equibiaxial stretch can exert powerful pro or anti inflammatory responses, potentially leading towards beneficial or detrimental matrix remodelling and cell behaviour (Tsuzaki et al., 2003). A concomitant autocrine and paracrine release of ATP may also serve as a negative feedback mechanism to limit activation of destructive pathways (Tsuzaki et al., 2003); and all of these factors may influence the clinical efficacy of fascial treatment. Although there were differences in degree and form, most studies showed that heterobiaxial or cyclic short duration strains can produce inflammatory reactions and

increased (occasionally reduced) fibroblast proliferation, whereas a completely reversed pattern was observed with equibiaxial or acyclic long-duration strains. In the latter, even a normalization of the apoptotic rate was found (Meltzer et al., 2010). This means the fascial tissue may respond better to balanced and sustained stretch rather than intermittent and unequal loads. The force and duration of tension applied may also be relevant. It has been shown that high magnitude (therapeutic) load (from 9% to 12% elongation) can produce an upregulation of ECM proteins, while increasing magnitude and duration (1e5 min) loads induce cytokine and growth factors secretions (Cao et al., 2013a). These results are consistent with those obtained by Yang et al. (2005), where large-magnitude loads caused pro-inflammatory responses, and cyclic (0.5 Hz per 4 h), uniaxial, small-magnitude stretching produced anti-inflammatory reactions in human tendon fibroblasts. Similarly, brief, moderate amplitude (20e30% strain), static stretching of connective tissue in vivo and ex vivo has been shown to decrease TGF-b1and collagen synthesis, thus preventing soft tissue adhesions (Bouffard et al., 2008). In conclusion, brief, light/moderate, balanced, static or slow cyclic strains appropriately applied to fascia may be sensed at the cellular level and transduced in normalizing tissue structure and function. It is worth noting that while fibroblast cell orientation, including cell shape and cytoskeleton, changes in a non linear fashion according to different magnitudes of applied cyclic load (Faust et al., 2011), the response of fibroblasts to mechanical loading is also dependent on cell orientation. In cells oriented parallel to a given cyclic stretch, higher levels of alpha-smooth muscle actin were found to be expressed; whereas fibroblasts that were perpendicular to this showed higher activity levels of secretory phospholipase A(2) which has a potential inflammatory role (Wang et al., 2004). This indicates that therapeutic loads applied differently with respect to tissue tension (that


+

MODEL

4 presumably corresponds to cell orientation) may produce different cell and tissue responses. Finally, secretion of IL-6 was significantly induced by 15 min of cyclic biaxial mechanical stretching after 4 and 8 h in human tendon fibroblasts, suggesting that inflammatory reactions following manual intervention may be partially caused by IL-6 secretion (Skutek et al., 2001).

Neuromuscular interaction Fascial oriented work may produce beneficial effects by activating various receptors in the connective tissues that elicit a series of neuromuscular reflexes. According to Schleip’s neurobiological model (2003), these types of events occur together with concomitant autonomic and viscoelastic changes, and are more likely to explain the fast tissue responses that a therapist perceives during fascial techniques. Although the dermis is the first tissue to be loaded during manual treatment, evidence suggests that therapeutic effects such as inhibition on hypertonic muscle and presumably on the myofascial complex, do not originate from mechanical stimulation of superficial cutaneous mechanoreceptors (Merkel, Meissner receptors) during manual therapy (Morelli et al., 1999). Similarly, deep receptors such as Golgi tendon organs mainly exist in the myofascia, joint capsules and myotendinous junctions (Jami, 1992), and are unlikely to come into play during fascial treatment because they have a high threshold that makes them respond to strong and fast manual stimulus, to which they quickly adapt (Pickar and Wheeler, 2001). This is why Golgi organs have been mostly implied as being involved in neurophysiological explanations that underlie the efficacy of spinal manipulation (Pickar, 2002) and not of fascial treatment. In contrast, Pacinian corpuscles are present in dense connective tissue and deep fascia (Benjamin, 2009) and tend to quickly adapt to stimuli, hence they respond better to rapid or intermittent compression and vibrations (Bell et al., 1994) applied to the myofascia, myotendinous junctions and deep capsular layers. They are thought to respond to such stimuli by enhancing proprioceptive feedback and by maintaining muscle tone (Zimny and Wink, 1991). The type of therapeutic force needed to activate Pacinian corpuscles may be applied in some manual interventions such as in highvelocity manipulation or vibratory techniques. Finally, Ruffini’s endings are mainly located in joint capsules and in the dense connective tissue (Halata et al., 1985), including fascia (Yahia et al., 1992). They have a slow adaptation to the stimuli being applied, and are thus generally sensitive to slow, sustained or rhythmic deep pressures, and in particular to lateral (perpendicular) tissue stretches (Van der Wal, 2012). These kind of forces are normally applied in most fascial techniques, such as myofascial release. Although these receptors have traditionally been described as being organized in parallel arrangements, they have more recently been shown to be functionally related within a musculoskeletal and connective tissue continuum that is in series (Van der Wal, 2009). Mechanoreceptors are mainly concentrated in the transitional areas within the continuum of the muscle-connective tissue-skeletal unit,

P. Tozzi and serve to optimize transmission and control of forces. Thus, “because of the architecture, receptors can also be stimulated by changes in muscle tension without skeletal movement, or by skeletal movement without change in muscle tension.” (Van der Wal, 2009). A similar concept of inter-tissue continuity has been advanced by Benjamin et al. (2008), who re-elaborated the existence of the socalled ‘supertendons’. This term refers to the tendon network formed by the anatomically intrinsic interrelation of fascia, tendon sheaths, joint capsules, retinacula, fat pads and bursae, “in which the function of the whole is greater than that of its individual parts” (Benjamin et al., 2008). Such supertendinous structures may be critical for the understanding of neuromuscular control. In fact, cadaveric experiments and computer simulations have shown that the distribution of tensions through these ‘super-structures’ regulates how force is distributed distally, acting as a ‘switching function of a logic gate that nonlinearly enables different torque production capabilities’ (Valero-Cuevas et al., 2007). This would demonstrate the existence of a “non-neural somatic logic” that is able to elaborate information at a macroscopic scale without requiring neural processes. Therefore it is plausible that an interaction of afferent impulses might come at different frequencies and modalities from such a connective tissue complex, including ligaments. The latter are apparently capable of eliciting inhibitory ligament-muscular reflexes with consequent inhibitory effects on related joint muscles (Solomonow, 2009; Voigt et al., 1998), although this has not yet been demonstrated to occur during manual therapy. According to Schleip’s neurobiological model, the immediate effects that occur during fascial release are mediated through Ruffini’s endings and interstitial mechanoreceptors that are abundant in fascia. The latter are polymodal receptors (responsive to different kinds of stimulation): some of them are very low threshold and respond more to light tissue stretching, while others are more sensitive to rapid pressure (Sandku ¨hler, 2009). They may also account for haptic perception (the sense of touch through proprioception and somatosensory perception) in the whole body (Schleip et al., 2014). It has been suggested that they may exert an influence on autonomic activity (by decreasing sympathetic activity) and on the central nervous system, producing an indirect effect on haemodynamics (vasodilation and plasma extrusion) and tissue viscoelasticity together with a descending inhibition of muscular tone (Schleip, 2003). Some of the free nerve endings present in the interstitial myofascial tissue have been defined as interoceptors, since they inform the brain about physiological tissue conditions such as temperature, pH and visceral changes (Craig, 2002). In particular, ‘tactile C-fibres’ have been recently discovered in the human subcutaneous connective tissue. However, whereas classically C-fibres are described as nociceptors or chemoreceptors, these ‘tactile C-fibres’ are low-threshold mechanoreceptive receptors accounting for an alternative and distinctive system signalling touch in humans (Bjo ¨rnsdotter et al., 2010). It appears that activation of these unmyelinated sensory fibres, for example during gentle touch therapy, relay signals to the insular cortex, the medial prefrontal cortex, the dorso-anterior cingulate cortex (but not to the somatosensory areas)


+

MODEL

A unifying neuro-fasciagenic model of somatic dysfunction: Part 2 (McGlone et al., 2014), where sensory and affective information are integrated giving rise to limbic touch, with resultant downstream effects on interpersonal touch, affiliative behaviour, psycho-endocrine function, immune system, autonomic regulation and pain modulation (Olausson et al., 2010). The classical nociceptive model, instead, proposes that indirect fascial techniques may modulate muscle tone and related fascial tension by decreasing mechanical stress and neural inputs (Van Buskirk, 1990). This may in turn reduce the activity of nociceptors and of the correspondent facilitated spinal level that by neurological reflex may produce a consequent modulation of autonomic activity on blood and lymphatic flow. Finally, in response to the proprioceptive input, the central nervous system may change muscle tone, allowing the therapist to follow myofascial paths of least resistance until a palpable release is perceived (Minasny, 2009).

Autonomic influence Somatic dysfunction has been traditionally related to correspondent facilitated spinal levels and aberrant autonomic activity that in turn influences various visceral functions (Korr, 1979; Beal, 1985). Interestingly, autonomic adrenergic fibres have been found in fascia (Tanaka and Ito, 1977), with a plausible major role on vasomotor control of intrafascial blood vessels (Tesarz et al., 2011). It has been suggested that therapeutic touch may produce stimulation of pressure-sensitive mechanoreceptors in the fascia (Ruffini’s and interstitial receptors), followed by a parasympathetic response (Schleip, 2003). This in turn may induce a change in local vasodilatation and tissue viscosity, together with a lowered tonus of intrafascial smooth muscle cells, and such a response has been partially demonstrated. Both massage therapy and myofascial osteopathic treatment have been shown to produce an increase in vagal efferent activity, as shown by changes in heart rate (Field et al., 2010), even in healthy subjects (Giles et al., 2013); while other forms of fascia oriented manual therapy (Danis Bois method) may produce an upregulation of parasympathetics with an influence on blood shear rate and blood flow turbulence (Quere ´ et al., 2009). At the same time, a modulation of hypersympathetic activity may take place (Henley et al., 2008), normalizing various haemodynamic parameters, with improvement of endothelial function (Lombardini et al., 2009), and anxiety levels (Fernandez-Perez et al., 2008). However, reduced psychological distress, anger status, anxiety levels and perceived pain have also been associated with an increase of sympathetic activity and heart rate following manual therapy (Hatayama et al., 2008; Toro-Velasco et al., 2009).

Viscolelastic changes Biological structures exhibit viscoelastic properties and responses under mechanical loads (Kucharova ´ et al., 2007), with significant changes depending on chronological age (Doubal and Klemera, 2002). Generally, the stronger and more rapidly that a load is applied to organic materials, the more rigidly will the tissue respond, up to the point when

5

the elastic potential of tissues is exceeded and a plastic deformation occurs (Ja ¨ger, 2005). Traditionally, it has been suggested that most of the immediate tissue changes following manual fascial work may be the result of a colloidal change in the fascia, which means a transformation of the ground substance from a dense solid-like state (gel) to a more fluid (sol) state (Rolf, 1962). However, a 3D mathematical model for fascial deformation has rejected the idea that palpable sensations of tissue release following manual therapy may be due to plastic deformations of firm type of fascia, such as the fascia lata and plantar fascia, whereas this may be possible in thin and more elastic types of fasciae (Chaudhry et al., 2008). Schleip’s neurobiological model has instead proposed that following proprioceptive stimulation the Ruffini’s endings and interstitial fascia mechanoreceptors may be involved in efferent control of the vasodilation and increase of plasma extravasation via autonomic activation (Schleip, 2003). This would initiate ECM viscosity changes. Nevertheless, there is evidence that a similar phenomenon may take place within minutes of a tensional load being applied and as the result of cellmatrix-induced regulation of fluid flow that is independent of neurological activation. Langevin et al. (2011) have demonstrated that static tissue stretch of areolar connective tissue (w20e25 %) causes fibroblast cytoskeletal remodelling via activation of focal adhesion complexes and initiate signalling pathways mediated by Rho kinase. This in turn leads to remodelling of the cell’s focal adhesions and actomyosin activation that develops countertension. The latter process allows surrounding tissue to relax further and achieve a lower level of resting tension. The study has shown that by changing shape, fibroblasts can dynamically modulate the viscoelastic behaviour of areolar connective tissue through Rho-dependent cytoskeletal mechanisms.

Fluid dynamics The mechanism described above may also potentially regulate extracellular fluid flow into the tissue and protect against osmotically-driven swelling when the matrix is stretched (Langevin et al., 2013). The flow of water in the ECM depends on the opposing forces between the osmotic pull of under-hydrated glycosaminoglycans and the active restraint of the tensioned collagenous network as the result of fibroblast activity. Therefore, as long as the tension in the matrix is maintained by fibroblasts, water is prevented from entering the tissue (Reed et al., 2010). During the acute onset of inflammation, however, the matrix swells as inflammatory mediators disrupt the cell-matrix contacts, causing a drop in matrix tension and interstitial fluid pressure, and allowing water to be ‘sucked into’ the matrix (Reed and Rubin, 2010). A (therapeutic) stretch lasting for a few minutes could then e potentially e un-restrain the matrix and promote transcapillary fluid flow and temporary matrix swelling. Fibroblasts, in turn, can either release their matrix contacts e resulting in a further drop of interstitial fluid pressure e or remodel the contractile cytoskeleton and adhesive matrix contacts, so as to develop a counter-tension sufficient to restore tension equilibrium


+

MODEL

6 (Langevin et al., 2013). This model would also fit with the fascial hydrodynamic response reported by Schleip et al. (2012). In response to mechanical stimuli, such as compression and stretch, fascia may exhibit a sponge-like behaviour, showing a squeezing and refilling response under the opposing forces of the restraint of collagen network and the osmotic pull of proteoglycans complex. Interestingly, the fluid pressure might increase more during tangential oscillation (2e4 Hz) and perpendicular vibration (15e60 Hz) with respect to the fascial layer than during constant sliding or back-and-forth motion, as predicted by 3D mathematical modelling methods (Roman et al., 2013; Chaudhry et al., 2013). This would cause the flow to occur more around the edges of the area under manipulation e due to an increased pressure gradient e producing an enhanced lubrication and an improved sliding potential between fascial layers and muscle tissue. Thus, the use of vibratory and oscillatory techniques e and not just constant sliding motions e should be considered, especially when interstitial fluid dynamics need to be improved such as in the case of fibrotic tissue. Interstitial flow also induces fibroblast-to-myofibroblast differentiation as well as collagen alignment and fibroblast proliferation, playing an important role in fibrogenesis and tissue repair (Ng et al., 2005). Furthermore, it appears to affect intracellular processes (calcium signalling, protein secretion) and influence fibroblast activities such as growth, proliferation, differentiation, alignment, adhesion, migration (Dan et al., 2010), including tissue morphogenesis, remodelling and embryonic development (Rutkowski and Swartz, 2007) through mechanisms such as direct shear stress, matrix-cell transduction and autologous gradient formation. Interstitial flow may also be enhanced by the interplay of calcium ion concentration and unbound water oscillations (Lee, 2008), whose respective electric and pressure gradients improve the transport of oxygenation and nutrients in the tissues. Since fluid flow in the ECM is likely to transport metabolic and messenger substances (Meert, 2012), it may indeed play a role in restoring homoeostasis where it has been compromised. For instance, it could improve drainage of inflammatory mediators, so decreasing chemical irritation and nociceptive stimuli to nerve endings, hence leading to a reset of aberrant reflexes underlying somatic dysfunction.

Endocrine-immunity response The evidence suggests that manual therapy focussed on myofascial tissues could cause hormonally mediated effects that persist for several days and modulate the hypothalamic-pituitary-adrenal axis and immune function (Rapaport et al., 2012, 2010; Morhenn et al., 2012). However, such hormonal response does not occur following isolated articulatory techniques such as the osteopathic technique known as rib raising directed towards enhanced thoracic mobility, respiration efficiency and lymph-flow (Henderson et al., 2010). Interestingly, the response to myofascial treatment can differ quite profoundly depending on the frequency of therapeutic sessions. Consistently with results from a previous study (Rapaport et al., 2010), a once-a-week intervention demonstrated patterns of change

P. Tozzi in circulating lymphocyte markers and cytokine expression, while twice-weekly sessions increased oxytocin levels and production of pro-inflammatory cytokines, together with decreased arginine vasopressine and cortisol levels (Rapaport et al., 2012). Hormonal changes were sustained for up to four days, while cyotokines changes persisted for up to eight days. In another study, the increase of oxytocin was also correlated with a decrease in adrenocorticotropin hormone following manual work (Morhenn et al., 2012). Oxytocin, in particular, could play a role as an endogenous pain controlling system. It has been demonstrated that, following manual intervention, increased levels of this hormone have been found in plasma and periaqueductal grey matter, exhibiting anti-nociceptive effects possibly through interaction with the opioid system (Lund et al., 2002). Furthermore, oxytocin appears to be strongly related to the formation of social bonds as well as of interpersonal bonding involving trust (Lieberwirth and Wang, 2014), thus influencing the psychosocial dimension of the individual. The benefits of osteopathic manipulation, including myofascial work, have also been related to a remarkable increase in nitric oxide (NO) concentration in the blood following therapeutic intervention (Salamon et al., 2004). This has been demonstrated to occur in equal amounts to that released during moderate physical exercise (Overberger et al., 2009). Similarly, results obtained from in vitro studies have confirmed this possibility. For instance, acyclic biophysical strain on normal human dermal fibroblasts has shown a three-fold increase in NO when applied at 10% magnitude for 72 h (Dodd et al., 2006). In addition, an increased sensitivity to NO via phosphokinase signalling, together with a 12.2% increase in NO secretion, were found in fibroblasts following modelled myofascial release (Cao et al., 2013b). This suggests a potential clinical role for NO in wound healing by promoting cell proliferation and migration. NO is an important signalling molecule whose known beneficial effects (Tota and Trimmer, 2011), may explain some of the therapeutic results following fascial work. It may be involved in promoting tissue repair and collagen synthesis, improving clinical symptoms and functions following injury (Bokhari and Murrell, 2012); in smooth muscle relaxation and angiogenesis (Ziche and Morbidelli, 2000); in neurotransmission (Garthwaite, 2008) as well as in the response to immunogens (Wink et al., 2011). There is a strong possibility that the physiological effects of myofascial work may be in part due to stimulation of the endocannabinoid system (McPartland et al., 2005). This system affects fibroblast remodelling and may play a role in fascial reorganisation by diminishing nociception and reducing inflammation in myofascial tissue (McPartland, 2008). Osteopathic treatment, including myofascial work to specific sites of somatic dysfunction, has demonstrated a change in the concentration of several circulatory nociceptive biomarkers in patients with chronic low back pain (Degenhardt et al., 2007). Amongst other results, the increase in N-palmitoylethanolamide (an endogenous fatty acid amide with potent analgesic and anti-inflammatory properties) was found 30 min after intervention, at a concentration two times greater than that observed in control subjects.


+

MODEL

A unifying neuro-fasciagenic model of somatic dysfunction: Part 2 Finally, it has been proposed that fascial work may enhance cytokine pools from actively proliferating fascial fibroblasts (Willard et al., 2010), which may be delivered beyond the sites being treated via intrafascial blood flow (Bhattacharya et al., 2005).

7

together with peripheral blood flow and therefore body temperature (Ahmed et al., 1982). All these interactions appear to be centrally coupled, interconnected and modulated (Dick et al., 2009, 2014), hence suggesting pulmonary respiration as an entry point for the homoeostatic potential of the body during treatment.

Epigenetics Mechanical forces seem to be crucial regulators of cell behaviour and tissue differentiation by affecting gene regulation at the epigenetic level, therefore producing an heritable reduction of DNA methylation (Arnsdorf et al., 2010). In other words, “mechanical stimulation can produce durable alterations in gene expression during cell lineage commitment” (Arnsdorf et al., 2010). It can be speculated that a therapeutic mechanical load might produce the same sort of effects. These epigenetic changes may also regulate extracellular matrix composition, inflammation, angiogenesis and fibroblast activity involved in tissue repair and function (Bavan et al., 2011). Mechanical signals applied in the form of vibration to hydrogelencapsulated fibroblasts in culture have also been demonstrated to be a critical epigenetic factor in regulating the microenvironment of the ECM. In particular, they produce significant increases in glycosaminoglycans and decreases in collagen, thus providing a basis for reducing tissue adhesions and improving connective tissue function (Kutty and Webb, 2010).

Respiration Traditionally, patient respiratory cooperation has been used in osteopathic practice to assess and treat vertebral, appendicular, cranial, visceral and soft tissue dysfunctions, including myofascial ones, especially in acute presentations (Kimberly, 1949). It has also been used to promote patient relaxation, or divert his/her attention. Most osteopathic fascial techniques may require a respiratory co-operation when holding tissues at the barrier point, or while keeping them at a balance point. Sutherland, in particular, proposed it as a specific tool to exaggerate dysfunction and induce correction: “. the respiratory movement picks up the abnormally related parts and swings them into motion in unison with contiguous parts” (In Hoover, 1945). Such respiratory contribution may play a role in relaxation of the myofascia and improvement in joint mobility, indeed breathing frequency seems to be synchronized with cerebral electrical activity (Busek and Kemlink, 2005) and to produce both a mechanical effect on resting myofascial tissue (Cummings and Howell, 1990) and to have a neurological influence on non-respiratory muscles (Kisselkova and Georgiev, 1979). This shows the interaction of respiration with the musculoskeletal system. Furthermore, breathing frequency has the ability to be synchronised with oscillations in blood pressure (De Burgh Daly, 1986), heart rate (Song and Lehrer, 2003) and lymphatic flow (Zawieja, 2009), together with being amplified due to resonance effects between these systems (Courtney, 2009). Through frequency entrainment, pulmonary respiration may also potentially modulate autonomic activity (Gilbey, 2007),

Vibratory and oscillatory activating forces Oscillations and vibrations are frequently applied as activating forces in many fascial manoeuvres. Sutherland (1990) suggested the benefits of vibration applied to the lymphatics, while Mitchell (1999) proposed vibrations as a way to counteract the myotactic reflex in hypertonic muscles. Fulford’s percussion hammer, in particular, is proposed as an effective tool to treat fascial dysfunctions by applying beneficial vibrational frequencies to the affected tissue (Fulford and Stone, 1997). Interestingly, fascial tissue seems to display a physiological oscillatory behaviour at a cellular level. Castella et al. (2010) have shown that myofibroblastic contractions exhibit periodic oscillation periods of approximately 100 s (1 c.p. 100 s), modulated by periodic intracellular calcium oscillations. These in turn are mediated via cell adherence junctions (Follonier Castella et al., 2010) that could explain the increase of calcium oscillation frequencies in myofibroblasts when an increased mechanical load is applied and transmitted through such intercellular junctions. In turn, this also induces reactive changes in the contractile cell behaviour (Godbout et al., 2013). Research suggests that vibration and oscillation of different amplitude, forces or frequencies (from 8 to 110 Hz), applied from seconds to 45 min, and whether manually or artificially induced, may have an influence on a variety of body functions, such as: modulating spinal excitability (Kipp et al., 2011) and pain perception in both healthy and chronic patients (Kosek and Hansson, 1997); increasing tissue blood perfusion with the increase of vibratory load (Fuller et al., 2013); enhancing fascial interstitial fluid flow, as suggested by a mathematical model (Roman et al., 2013); increasing oxygen saturation and improving pulmonary mechanism and perfusion (Doering et al., 1999); modulating blood flow in different cerebral areas (Coghill et al., 1994); improving joint range of motion (Bakhtiary et al., 2011) and reducing muscle stiffness (Peer et al., 2009); enhancing wound healing processes and regeneration of vessels by also reducing local oedema and general congestion (Leduc et al., 1981); regulating the microenvironment of the ECM at an epigenetic level, when applied to fibroblasts in vitro (Kutty and Webb, 2010); and improving cognitive performance in both healthy and pathological conditions (Fuermaier et al., 2014). Furthermore, manual low frequency oscillations may induce myofascial relaxation by influencing motoneuron excitability (Newham and Lederman, 1997), or by producing an inhibitory effect on vestibular nuclei, hence inducing a psychogenic relaxation (Ayres, 1979). As Littlejohn stated (1902): “There is no function of the body that does not have peristaltic or rhythmic vibrations . the power of osteopathic treatment occurs from its effect upon physiologic oscillations”.


+

MODEL

8

Bioenergetic interactions All cells appear to generate and detect electromagnetic fields, ranging from kHz to the visible part of the electromagnetic spectrum (400e790 THz) (Cifra et al., 2011). These fields may be forms of non-chemical cell signalling able to influence cell proliferation rate and morphology (Rossi et al., 2011). In addition, such electromagnetic signals may be amplified by ion channels, with ionic flow oscillating at various coherent frequencies as an intracellular sensing system (Galvanovskis and Sandblom, 1997). Furthermore, ion channels and pumps seem to modulate endogenous transmembrane resting voltage potential that, in turn, may regulate cell proliferation, migration and differentiation, serving as an informational signalling pathway (Adams and Levin, 2013). Importantly, this is a mediator of large-scale anatomical polarity with an effect on gene regulation pathways, hence influencing tissue morphogenesis, development and regeneration (Levin, 2014). Interestingly, endogenous electrical potentials may promote epithelial cell migration and wound healing (Zhao, 2009), as well as angiogenic responses in endothelial cells (Zhao et al., 2004). This phenomenon is mediated by polarized activation of multiple signalling pathways that include kinases, membrane growth factor receptors and integrins. Fibroblasts in particular have shown to be highly responsive to endogenous electrical fields, by aligning themselves perpendicular to the electrical current and consequently modulating their motility (Guo et al., 2010). They also seem to respond to exogenous electricity; exposure to electrical stimulation of 50 or 200 mV/mm promotes wound healing by enhancing growth factor secretion, skin fibroblast migration and fibroblast to myofibroblast differentiation (Rouabhia et al., 2013). Therefore, electromagnetic fields appear to be strictly related to ionic flow and oscillations, and these in turn are highly responsive to mechanical tension via stretchactivated calcium channels (Follonier Castella et al., 2010). (Therapeutic) mechanical pressure or electrical stimulation may be amplified and propagated by proton currents or coherent oscillations and polarization waves throughout the organism (Pang, 2012). Such proton conduction may be coupled with electron transfer (Cukier and Nocera, 1998) and with hydrogen-atom translocation along the watereproteins complex (Cukier, 2004). In this sense, it can be speculated that fascia combines the property of a sol-liquid conductor and of a crystal generator system due to the liquid crystal continuum of the matrix, which can generate and conduct direct currents as well as vibrations. Hypothesis. A yet more interesting possibility is that the liquid crystalline continuum of the body matrix may function as a quantum holographic medium, recording patterns of local activities interacting with a globally coherent field. During bodywork an interaction of vibrational, biomagnetic and bioelectric fields between therapist and client may take place. This would allow an exchange of information about the history and the present status of the living matrix, which is encoded in cell and tissue structure, and which is accessable holographically by tuning to the appropriate frequencies (Oschman and Oschman, 1994). The result may

P. Tozzi be the balancing of resonant vibratory circuits. Osteopathic manipulative treatment may entrain such physiological phenomena, restoring harmonic resonance where dissonance is present (McPartland and Mein, 1997). Finally, the human body has been demonstrated to emit ultra-weak photons in the visible part of the electromagnetic spectrum (380e780 nm) and in the range from 1 to 1000 photons s 1 cm 2 (Schwabi and Klima, 2005). This property is the result of cellular metabolic activities and appears to be enhanced by increased oxidative processes (Rastogi and Pospı´sil, 2010). The quantum state of photons emitted by a subject could be in a coherent state and undergoing constant variations (Van Wijk et al., 2008), displaying a typical anatomic percentage distribution pattern, depending on the individuals’ condition and vitality. Photon emissions may be used by cells and tissues as a modality of communication, independently from chemical and cell-tocell contact signalling (Scholkmann et al., 2013). They may also represent an informational and regulatory system (Ku cera and Cifra, 2013) affecting at least energy uptake, cell division rate and growth correlation (Fels, 2009). This property may be deregulated or altered in case of dysfunction or disease e including those affecting connective tissue e and related to a generally high oxidative status of the organism (Popp, 2009). Interestingly, the emissions intensity decreases with a reduction in body temperature and oxygen concentration (Nakamura and Hiramatsu, 2005), while it reduces in long-term practitioners of meditation, as a probable reflection of different free radical reactions in the organism (Van Wijk et al., 2006). This evidence suggests the integrative use of additional strategies such as nutritional care, appropriate physical activity, ‘mind-body’ therapy to enhance therapeutic effects of manual treatment of somatic dysfunction by reducing the general oxidative status in patients.

Additional strategies - Physical Exercise Specific physical training programs for fascial tissue may be applied (Schleip and Mu ¨ller, 2013), implying elastic recoil, slow and dynamic stretching, rehydration practices and proprioceptive refinement. It has been demonstrated that the elastic storage capacity and subsequent recoil of the elastic energy in tendons may significantly increase, with a decrease in stiffness, following physical exercise programs (Ishikawa and Komi, 2004; Reeves, 2006), without affecting fascial thickness (Uzel et al., 2006). Furthermore, fasciaspecific stretching protocols may produce long-term benefits where there is chronic fascial pain and improve physiological function and patient satisfaction (Digiovanni et al., 2006). - Nutrition A tryptophan or atherogenic diet may increase oxidative damage in muscles, with infiltration of inflammatory cells in muscular fascia (Ronen et al., 1999). Instead, an anti-


+

MODEL

A unifying neuro-fasciagenic model of somatic dysfunction: Part 2 inflammatory diet may provide a natural approach to reduce inflammation, also in the case of musculoskeletal conditions (Marcason, 2010). It mainly implies a reduction of intake of saturated fatty acids, with an increase of plantbased food (Pomari et al., 2014), beverages rich in polyphenolic catechins (such as green tea), cold water fish (Kris-Etherton et al., 2002), culinary herbs and spices with anti-inflammatory effects e such as ginger and turmeric e (Tapsell et al., 2006). In particular, a group of aromatic ketones, called chalcones, present in several plants such as licorice and mulberry, have been linked with immunomodulation, anti-inflammatory and anti-oxidant activities (Yadav et al., 2011). For example: avocado and soybean oils, etc, contain biologically active compounds that are able to produce long-term beneficial effects in the symptoms of osteoarthritis (Ragle and Sawitzke, 2012); devil’s claw has been used to treat degenerative disorders of the musculoskeletal system, and for its pain-relieving, anti-inflammatory and anti-oxidant actions (Akhtar and Haggi, 2012); crude extract of blueberries, rich in phenolic acids and flavonoids, have anti-nociceptive and antiinflammatory properties (Torri et al., 2007); and extracts from plants such as Phyllanthus corcovadensis have demonstrated potent anti-nociceptive effects (Gorski et al., 1993). Finally, the balance in the omega 6/omega 3 ratio in dietary patterns is crucial for the maintenance of health (Go ´mez Candela et al., 2011), as well as for the prevention and management of inflammatory conditions (Simopoulos, 2009), or as an adjunct treatment for chronic arthritis (James and Cleland, 1997). - Meditation Mindfulness meditation and breath therapy seem to play a role in improving quality of life and sense of coherence in people who start with a low health assessment (Fernros et al., 2008). In particular, mindfulness-based treatment may reduce cortisol level, proinflamatory cytokines and blood pressure (Carlson et al., 2007), with enhanced outcomes for health and quality of life in chronic disease, including musculoskeletal disorders (Merkes, 2010). Furthermore, when associated with home meditation practice, it may ameliorate pain intensity and functional limitations in chronic musculoskeletal conditions (Rosenzweig et al., 2010). Breath therapy integrating body awareness, breathing, meditation and movement appears to produce significant improvement in chronic low back pain and coping skills (Mehling et al., 2005). Finally, yoga intervention may reduce pain and catastrophizing, increase acceptance of the condition and alter total cortisol levels in people with chronic disorders (Curtis et al., 2011). Even more, it may improve functional disability in people with chronic low back pain (Holtzman and Beggs, 2013), with both short and longterm effectiveness (Cramer et al., 2013).

Placebo Placebo effects are complex phenomena, possibly mediated by specific physiological and neural mechanisms, but these are currently poorly understood (Miller et al., 2013). In the field of manual therapy, “the term placebo effect is taken to

9

mean not only the narrow effect of an imitation intervention but also the broad amalgam of nonspecific effects present in any patientepractitioner relationship, including attention; communication of concern; intense monitoring; diagnostic procedures; labelling of complaint; and alterations produced in a patient’s expectancy, anxiety, and relationship to the illness” (Kaptchuk, 2002). Traditionally, placebo is thought of as a nuisance in clinical and pharmacological research, and controls are employed to filter out nonspecific, undesired and psychological effects that may interfere with the results from a particular therapeutic intervention. However, it is likely that an individual’s understanding of the intervention influences the effects of any given therapeutic approach, showing the importance of placebo in clinical, scientific and physiological fields (Oeltjenbruns and Scha ¨fer, 2008). This then drives research to further our understanding of the underlying mechanisms, which is needed in order to maximize therapeutic results in clinical practice (Walach and Jonas, 2004). Placebo analgesia is now considered as a biological phenomenon, implying both opioid and non-opioid mechanisms (Carlino et al., 2011) that are measurable through brain imaging technologies and that can be pharmacologically blocked and behaviourally enhanced (Greene et al., 2009). It seems to be dependent on frontal cortical areas that generate and maintain cognitive expectancies, which in turn may be reinforced by dopaminergic reward pathways (Faria et al., 2008). Finally, the ability of placebo to modulate peripheral immune reactivity is plausible (Pacheco-Lo ´pez et al., 2006), although “other placebo responses result from less conscious processes, such as classical conditioning in the case of immune, hormonal, and respiratory functions” (Price et al., 2008). Recent research on placebo response, placebo analgesia and nocebo has shown how the psychosocial aspect of every treatment is crucial in determining the nature and degree of a placebo effect, affecting both research and clinical practice (Koshi and Short, 2007; Marchand and Gaumond, 2013). ‘Alternative and complementary’ medicine may also have an enhanced placebo effect, compared with mainstream medicine, through a ritual-based “performative efficacy” (Kaptchuk, 2002).

Cognitive-behavioural factors and multidisciplinary approach Manual therapeutic intervention should never be focused on the dysfunctional or symptomatic area exclusively, apart from in some presentations such as time-limited emergency situations. Instead, the multidimensional aspect of pain should be considered, especially for chronic patients (Lima et al., 2014), with respect to the tenet of the body, mind and spirit unity (Rogers et al., 2002). Therefore, in order to approach the totality of an individual (not just ‘a pain’), including his/her social environment, it is necessary to wisely apply biopsychosocial models (Flor and Herman, 2004) e considered as congruous with osteopathic principles (Penney, 2010) e as well as interdisciplinary paradigms (Gatchel, 2005), which resonate with osteopathic philosophy (Mackintosh et al., 2011). Instead of just treating a dysfunction, health should be promoted through a salutogenic process (Antonovsky, 1979) that is guiding the patient


+

MODEL

10 from the cure of the disease to the protection and potentiation of their own health and quality of life. Information and education are the key tools to guide the patient and his/her social environment through such a process, where the operator may just be a catalyst for the change to take place (Gafni et al., 1998). In addition, the social coherence of interdisciplinary and inter-sectorial action is crucial to support health-related quality of life (Drageset et al., 2009) as well as the process of health through the course of life (Eriksson and Lindstro ¨m, 2008). Maladaptive behaviours, fears and emotional experience of pain, catastrophism, helplessness, expectations, thrust, cognitive factors, faith, beliefs and personality all need to be addressed in a comprehensive and integrative conceptual model that is applied to the clinical assessment, treatment and management of patients with pain, and in particular when pain is persistent (Keefe et al., 2004; Nicholas et al., 2011). These factors should be identified and managed as far as reasonably possible in order to support and promote active coping strategies (Jensen et al., 1991), mechanisms of self-efficacy (Bandura, 1982) and an empowerment process (Haldeman et al., 2008). These mechanisms may increase tolerance for pain through endogenous opioid activation, when confronted with a painful stimulus (Bandura et al., 1987). Conversely, patients with chronic pain and high levels of depression tend to experience and rate their pain as more severe (Parmelee et al., 1991). Probably through a similar process, a patient’s attitude may strongly influence the effect of myofascial treatment. For instance, patients with cancer-related fatigue who had a positive attitude towards manual therapy showed a significant (p > .05) increase of immune response (IgA), compared to the control group, following myofascial release (although no difference was found in the pressure pain threshold) (Ferna ńdez-Lao et al., 2012a). Furthermore, a positive patient attitude may positively modulate the impact of manual therapy compared to a placebo group (Ferna ńdez-Lao et al., 2012b). A multidisciplinary approach is paramount to achieve the most desirable clinical outcomes, especially in chronic patients (Pergolizzi et al., 2013), also those with musculoskeletal pain (Hildebrandt et al., 1996) and even in a primary care setting (Kim et al., 2010). Multidisciplinary rehabilitation programs have been demonstrated to be more effective than the care given by independent physicians in patients with chronic low back pain, when organized with the cooperation of local health-care providers in the community (Lang et al., 2003). Its clinical implementation may extend to include relaxation training, biofeedback, hypnosis, imagery, cognitive-behavioural therapy (Golden, 2002), social reinforcement and timecontingent medications, but it may also require the interaction of rehabilitative, occupational, pharmaceutical, surgical, orthesic, psychological and nutritional care. Group therapy programs also seem to produce good results. For instance, patients with chronic musculoskeletal pain improve their self-awareness and active coping strategies, with a decreased pain experience, when participating in group sessions of experience-oriented learning programmes (Steen and Haugli, 2001). Psychological support that deals with the patient’s relationship difficulties (such as those related to marital

P. Tozzi status) may also be included, if appropriate, since it appears to have a strong impact on the rehabilitation process of those with chronic musculoskeletal disorders (Hamberg et al., 1997), and improve immune function and cardiovascular health (Kiecolt-Glaser and Newton, 2001; KiecoltGlaser et al., 2010). The interaction between mind, body, behaviour, and the environment is thus a crucial factor affecting the patients physical and psychological health, and is used in ‘mindbody’ medicine clinics to treat stress-related or chronic conditions by improving disease coping strategies and the overall quality of life (Gimpel et al., 2014).

Conclusion It is evident that various factors may interplay with myofascial structure and function as well as with its ability to respond to treatment. The effects of manual fascial interventions can be local (as tissue texture changes), segmental (as via neurological response) and global (as through hormonal effects) in extent, and may occur at different intervals e ranging from minutes to weeks e after a given input, with many interacting mechanisms influencing tissue properties and behaviours, including placebo (Fig. 1). Some of these factors are strongly supported by the available evidence whereas others need further investigation. Nevertheless, connective tissue may serve as a trait d’union of all these elements, potentially representing a meta-system (Langevin, 2006) that coherently influences structure and function of the whole organism and the interaction between its constituents. In the light of what has been presented in this work, the author suggests an integration of the existing five osteopathic models e structural, respiratory-circulatory, metabolic, neurologic and behavioural (E.C.O.P., 2011b). These are conceptual models of assessing, treating and caring for patients in osteopathic practice. They are all based on anatomy, physiology, biochemistry and psychology principles, providing five specific lenses through which osteopaths may interpret and approach patients. In other words, they provide five different relations of structure and function, reflecting five different physiological modalities of body adaptation to inner and outer stressors. They are normally used in integration in osteopathic practice to release dysfunctional patterns, restore function and promote health (Seffinger et al., 2011). In particular, the musculoskeletal system has traditionally been presented as the main interface of these models (Hruby, 1992), by influencing and maintaining communication with all the other body functions. Korr (1976) defined it as the “primary machinery of life”, indicating the musculoskeletal system as more than just a framework which supports and contains the viscera of the body, but as the main dynamic component of the living body through which we function, live, move, interact and express ourselves. However, the major element through which the musculoskeletal system influences the body’s response in health and disease has been traditionally indicated as the nervous system. As an alternative, this paper suggests that fascia might be the overlooked somatic component interplaying between the musculoskeletal system and its function as the ‘primary


+

MODEL

A unifying neuro-fasciagenic model of somatic dysfunction: Part 2

11

Figure 1 Fasciagenic treatment effects. The diagram shows the possible effects of manual fascial treatment, reinforced by activating forces to prompt release. These effects may occur at different times, ranging from minutes during or after intervention, to days and week, producing several tissue responses and changes that normalize somatic dysfunction features (tissue texture changes, asymmetry, restriction of motion, tenderness). Additional strategies may reinforce the therapeutic effects of manual work to fascia. The psychosocial-behavioural aspect could also ultimately influence and be influenced by these processes.

machinery of life’ also because of the shared embryologic origin. As suggested by the work of Blechschmidt and Gasser (2012), each connective tissue in the body presents a functional and anatomical continuity, due to their common embryologic origins in the mesoderm, although loading demands acting through and upon tissues can determine their differentiation by influencing fibre arrangement, length, and density. In addition, due to the multi-functional nature and ubiquitous structure of fascial tissue e that makes it a unique component in the musculoskeletal apparatus e the author suggests the addition of a sixth ‘meta-model’ that integrates but also transcends the musculoskeletal system itself, the connective tissue-fascial model. This is the only tissue providing intracellular and extracellular connection as well as communication at all levels between each body system; it offers various mechanisms for information signalling together with several forms of transducing information; it is an embodying structure that expresses coherent functions from molecular to macroscopic scales, allowing their constant interdependence in health as well as in disease e all features that no other musculo-skeletal element can display to this extent. This sixth osteopathic model is the true interface between all body systems, by

laying between and playing within the other models; by integrating and coordinating their activity; by pervading their essence, but also transcending their contingent nature; and finally by providing a structural and functional framework for the body’s homoeostatic potential and its inherent abilities to heal. By its nature, it is the only model that resonates with A.T. Still’s original intention: “. this philosophy (of Osteopathy) has chosen the fascia as a foundation of which to stand .” (Still, 1899). In conclusion, rather than defining bits and pieces of this body wide fascial structure (Stecco, 2014) e as if it is just a dead tissue to be surgically dissected and named in its single components, and separated from surrounding tissues e the author recalls Hollinshead (1974): “descriptions of fascia tend to be confusing . all connective tissue in the body is continuous with all other connective tissue. Thus, in one sense, a fascia has no beginning and no end, and any description of fascias is necessarily somewhat arbitrary”. This concept of intrinsic multi-tissue continuity has been advanced by various authors, who highlighted the structural and functional interrelationship between muscular, fascial, ligamentous, capsular and articular components. Such whole-body connection has been referred to as ‘ectoskeleton’ (Wood Jones, 1944), ‘ligamentous complex system’


+

MODEL

12 (Willard, 1997), ‘dynament’ (Van der Wal, 2009), and ‘supertendon’ (Benjamin, 2009), with subtle differences despite the same basic principle. Therefore, fascial form and organization should be considered and understood as a living, pulsating, oscillating, coherent whole, responding to and differentiating according to physical, chemical and psychological forces; as a single structural continuum interacting with a multitude of regulatory functional properties.

References Abbott, R.D., Koptiuch, C., Iatridis, J.C., et al., 2013. Stress and matrix-responsive cytoskeletal remodeling in fibroblasts. J. Cell. Physiol. 228 (1), 50e57. Adams, D.S., Levin, M., 2013. Endogenous voltage gradients as mediators of cell-cell communication: strategies for investigating bioelectrical signals during pattern formation. Cell. Tissue Res. 352 (1), 95e122. Ahmed, A.K., Harness, J.B., Mearns, A.J., 1982. Respiratory control of heart rate. Euro. J. Appl. Physiol. Occup. Physiol. 50, 95e104. Akhtar, N., Haqqi, T.M., 2012. Current nutraceuticals in the management of osteoarthritis: a review. Ther. Adv. Musculoskelet. Dis. 4 (3), 181e207. Antonovsky, A., 1979. Health, Stress and Coping. Jossey-Bass, San Francisco. Arnsdorf, E.J., Tummala, P., Castillo, A.B., et al., 2010. The epigenetic mechanism of mechanically induced osteogenic differentiation. J. Biomech. 43 (15), 2881e2886. Ayres, A.J., 1979. Sensory Integration and Learning Disorders. Weston Psychological Services, LA. Bakhtiary, A.H., Fatemi, E., Khalili, M.A., et al., 2011. Localised application of vibration improves passive knee extension in women with apparent reduced hamstring extensibility: a randomised trial. J. Physiother. 57 (3), 165e171. Bandura, A., 1982. Self-efficacy mechanism in human agency. Am. Psychol. 37, 122e147. Bandura, A., O’Leary, A., Taylor, C.B., et al., 1987. Perceived selfefficacy and pain control: opioid and nonopioid mechanisms. J. Pers. Soc. Psychol. 53 (3), 563e571. Bavan, L., Midwood, K., Nanchahal, J., 2011. MicroRNA epigenetics: a new avenue for wound healing research. BioDrugs 25 (1), 27e41. Beal, M.C., 1985. Viscerosomatic reflexes a review. J. Am. Osteopath. Assoc. 85 (12), 786e801. Bell, J., Bolanowski, S., Holmes, M.H., 1994. The structure and function of Pacinian corpuscles: a review. Prog. Neurobiol. 42 (1), 79e128. Benjamin, M., 2009. The fascia of the limbs and backea review. J. Anat. 214 (1), 1e18. Benjamin, M., Kaiser, E., Milz, S., 2008. Structure-function relationships in tendons: a review. J. Anat. 212 (3), 211e228. Bhattacharya, V., Watts, R.K., Reddy, G.R., 2005. Live demonstration of microcirculation in the deep fascia and its implication. Plast. Reconstr. Surg. 115 (2), 458e463. Bjo ¨rnsdotter, M., Morrison, I., Olausson, H., 2010. Feeling good: on the role of C fibre mediated touch in interoception. Exp. Brain Res. 207 (3e4), 149e155. Blanquet, M., Domingo, T., Ortiz, J.C., et al., 2010. Ultrasound study of thoracolumbar fascia and surrounding tissues in chronic low back pain before and after spinal manipulative therapy. In: Vleeming, A., et al. (Eds.), Proceedings of the 7th Interdisciplinary World Congress on Low Back and Pelvic Pain. Los Angeles. Blechschmidt, E., Gasser, R.F., 2012. Biokinetics and Biodynamics of Human Differentiation: Principles and Applications. North Atlantic Books, Berkeley.

P. Tozzi Bokhari, A.R., Murrell, G.A., 2012. The role of nitric oxide in tendon healing. J. Shoulder Elb. Surg. 21 (2), 238e244. Bouffard, N.A., Cutroneo, K.R., Badger, G.J., et al., 2008. Tissue stretch decreases soluble TGF b1 and Type-1 pro-collagen in mouse subcutaneous connective tissue: evidence from ex vivo and in vivo models. J. Cell. Physiol. 214 (2), 389e395. Busek, P., Kemlink, D., 2005. The influence of the respiratory cycle on the EEG. Physiol. Res. 54 (3), 327e333. Cao, T.V., Hicks, M.R., Campbell, D., et al., 2013a. Dosed myofascial release in three-dimensional bioengineered tendons: effects on human fibroblast hyperplasia, hypertrophy, and cytokine secretion. J. Manip. Physiol. Ther. 36 (8), 513e521. Cao, T.V., Hicks, M.R., Standley, P.R., 2013b. In vitro biomechanical strain regulation of fibroblast wound healing. J. Am. Osteopath. Assoc. 113 (11), 806e818. Carano, A., Siciliani, G., 1996. Effect of continuous and intermittent forces on human fibroblasts in vitro. Eur. J. Orthod. 18 (1), 19e26. Carlino, E., Pollo, A., Benedetti, F., 2011. Placebo analgesia and beyond: a melting pot of concepts and ideas for neuroscience. Curr. Opin. Anaesthesiol. 24 (5), 540e544. Carlson, L.E., Speca, M., Faris, P., et al., 2007. One year pre-post intervention follow-up of psychological, immune, endocrine and blood pressure outcomes of mindfulness-based stress reduction (MBSR) in breast and prostate cancer outpatients. Brain Behav. Immun. 21 (8), 1038e1049. Castella, L.F., Buscemi, L., Godbout, C., et al., 2010. A new lockstep mechanism of matrix remodelling based on subcellular contractile events. J. Cell. Sci. 123 (Pt. 10), 1751e1760, 15. Chapelle, S., Bove, G., 2013. Visceral massage reduces postoperative ileus in a rat model. J. Bodyw. Mov. Ther. 17 (1), 83e88. Chaudhry, H., Schleip, R., Ji, Z., et al., 2008. Three-dimensional mathematical model for deformation of human fasciae in manual therapy. J. Am. Osteopath. Assoc. 108 (8), 379e390. Chaudhry, H., Bukiet, B., Roman, M., et al., 2013. Squeeze film lubrication for non-Newtonian fluids with application to manual medicine. Biorheology 50 (3e4), 191e202. Chiquet, M., Gelman, L., Lutz, R., et al., 2009. From mechanotransduction to extracellular matrix gene expression in fibroblasts. Biochim. Biophys. Acta 1793 (5), 911e920. Cifra, M., Fields, J.Z., Farhadi, A., 2011. Electromagnetic cellular interactions. Prog. Biophys. Mol. Biol. 105 (3), 223e246. Ciobanasu, C., Faivre, B., Le Clainche, C., 2013. Integrating actin dynamics, mechanotransduction and integrin activation: the multiple functions of actin binding proteins in focal adhesions. Eur. J. Cell. Biol. 92 (10e11), 339e348. Coghill, R., Talbot, J., Evans, A., et al., 1994. Distributed processing of pain and vibration by the human brain. J. Neurosci. 14, 4095e4108. Courtney, R., 2009. The functions of breathing and its dysfunctions and their relationship to breathing therapy. Int. J. Osteopath. Med. 12 (3), 78e85. Craig, A.D., 2002. How do you feel? Interoception: the sense of the physiological condition of the body. Nat. Rev. Neurosci. 3 (8), 655e666. Cramer, H., Lauche, R., Haller, H., et al., 2013. A systematic review and meta-analysis of yoga for low back pain. Clin. J. Pain 29 (5), 450e460. Cukier, R.I., Nocera, D.G., 1998. Proton-coupled electron transfer. Annu. Rev. Phys. Chem. 49, 337e369. Cukier, R.I., 2004. Theory and simulation of proton-coupled electron transfer, hydrogen-atom transfer, and proton translocation in proteins. Biochim. Biophys. Acta. 1655 (1e3), 37e44, 12. Cummings, J., Howell, J., 1990. The role of respiration in the tension production of myofascial tissues. J. Am. Osteopath. Ass. 90 (9), 842. Curtis, K., Osadchuk, A., Katz, J., 2011. An eight-week yoga intervention is associated with improvements in pain,


+

MODEL

A unifying neuro-fasciagenic model of somatic dysfunction: Part 2 psychological functioning and mindfulness, and changes in cortisol levels in women with fibromyalgia. J. Pain Res. 4, 189e201. Dan, L., Chua, C.K., Leong, K.F., 2010. Fibroblast response to interstitial flow: a state-of-the-art review. Biotechnol. Bioeng. 107 (1), 1e10. De Burgh Daly, M., 1986. Interactions between respiration and circulation. In: Cherniack, N.S., Widdicombe, J.G. (Eds.), Handbook of Physiology: the Respiratory System. Sec. 3, vol. 2. American Physiological Society, Bethesda, MD, pp. 529e594. Part 2. Degenhardt, B.F., Darmani, N.A., Johnson, J.C., et al., 2007. Role of osteopathic manipulative treatment in altering pain biomarkers: a pilot study. J. Am. Osteopath. Assoc. 107 (9), 387e400. Dick, T.E., Baekey, D.M., Paton, J.F., et al., 2009. Cardio-respiratory coupling depends on the pons. Respir. Physiol. Neurobiol. 168 (1e2), 76e85, 31. Dick, T.E., Hsieh, Y.H., Dhingra, R.R., et al., 2014. Cardiorespiratory coupling: common rhythms in cardiac, sympathetic, and respiratory activities. Prog. Brain Res. 209, 191e205. Digiovanni, B.F., Nawoczenski, D.A., Malay, D.P., et al., 2006. Plantar fascia-specific stretching exercise improves outcomes in patients with chronic plantar fasciitis. A prospective clinical trial with two-year follow-up. J. Bone Jt. Surg. Am. 88 (8), 1775e1781. Dodd, J.G., Good, M.M., Nguyen, T.L., et al., 2006. In vitro biophysical strain model for understanding mechanisms of osteopathic manipulative treatment. J. Am. Osteopath. Assoc. 106 (3), 157e166. Doering, T.J., Fieguth, H.G., Steuernagel, B., et al., 1999. External stimuli in the form of vibratory massage after heart or lung transplantation. Am. J. Phys. Med. Rehabil. 78 (2), 108e110. Doubal, S., Klemera, P., 2002. Visco-elastic response of human skin and aging. J. Am. Aging Assoc. 25 (3), 115e117. Drageset, J., Eide, G.E., Nygaard, H.A., et al., 2009. The impact of social support and sense of coherence on health-related quality of life among nursing home residentsea questionnaire survey in Bergen, Norway. Int. J. Nurs. Stud. 46 (1), 65e75. Eagan, T.S., Meltzer, K.R., Standley, P.R., 2007. Importance of strain direction in regulating human fibroblast proliferation and cytokine secretion: a useful in vitro model for soft tissue injury and manual medicine treatments. J. Manip. Physiol. Ther. 30 (8), 584e592. Eastwood, M., McGrouther, D.A., Brown, R.A., 1998. Fibroblast responses to mechanical forces. Proc. Inst. Mech. Eng. H. 212 (2), 85e92. Educational Council on Osteopathic Principles (E.C.O.P.), 2011a. Glossary of Osteopathic Terminology Usage Guide. American Association of Colleges of Osteopathic Medicine (A.A.C.O.M.), Chevy Chase, MD, p. 9. Educational Council on Osteopathic Principles (E.C.O.P.), 2011b. Glossary of Osteopathic Terminology Usage Guide. American Association of Colleges of Osteopathic Medicine (A.A.C.O.M.), Chevy Chase, MD, pp. 25e26. Eisenhart, A.W., Gaeta, T.J., Yens, D.P., 2003. Osteopathic manipulative treatment in the emergency department for patients with acute ankle injuries. J. Am. Osteopath. Ass. 103 (9), 417e421. Eriksson, M., Lindstro ¨m, B., 2008. A salutogenic interpretation of the Ottawa Charter. Health Promot. Int. 23 (2), 190e199. Faria, V., Fredrikson, M., Furmark, T., 2008. Imaging the placebo response: a neurofunctional review. Eur. Neuropsychopharmacol. 18 (7), 473e485. Faust, U., Hampe, N., Rubner, W., et al., 2011. Cyclic stress at mHz frequencies aligns fibroblasts in direction of zero strain. PLoS One 6 (12), e28963. Fels, D., 2009. Cellular communication through light. PLoS One 4 (4), e5086.

13

Ferna ńdez-Lao, C., Cantarero-Villanueva, I., Dıáz-Rodrı´guez, L., et al., 2012a. The influence of patient attitude toward massage on pressure pain sensitivity and immune system after application of myofascial release in breast cancer survivors: a randomized, controlled crossover study. J. Manip. Physiol. Ther. 35 (2), 94e100. Ferna ńdez-Lao, C., Cantarero-Villanueva, I., Dıáz-Rodrı´guez, L., 2012b. Attitudes towards massage modify effects of manual therapy in breast cancer survivors: a randomised clinical trial with crossover design. Eur. J. Cancer Care (Engl) 21 (2), 233e241. Ferna ńdez-Pe ´rez, A.M., Peralta-Ramı´rez, M.I., Pilat, A., et al., 2008. Effects of myofascial induction techniques on physiologic and psychologic parameters: a randomized controlled trial. J. Altern. Complement. Med. 14 (7), 807e811. Fernros, L., Furhoff, A.K., Wa ¨ndell, P.E., 2008. Improving quality of life using compound mind-body therapies: evaluation of a course intervention with body movement and breath therapy, guided imagery, chakra experiencing and mindfulness meditation. Qual. Life Res. 17 (3), 367e376. Field, T., Diego, M., Hernandez-Reif, M., 2010. Moderate pressure is essential for massage therapy effects. Int. J. Neurosci. 120 (5), 381e385. Flor, H., Hermann, C., 2004. Biopsychosocial models of pain. In: Dworkin, R.H., Breitbart, W.S. (Eds.), Psychosocial Aspects of Pain: a Handbook for Health Care Providers, Progress in Pain Research and Management. IASP Press, Seattle, pp. 47e76. Follonier Castella, L., Gabbiani, G., McCulloch, C.A., et al., 2010. Regulation of myofibroblast activities: calcium pulls some strings behind the scene. Exp. Cell. Res. 316 (15), 2390e2401, 10. Fuermaier, A.B., Tucha, L., Koerts, J., et al., 2014. Good vibrationseeffects of whole body vibration on attention in healthy individuals and individuals with ADHD. PLoS One 9 (2), e90747, 28. Fulford, R.C., Stone, G., 1997. Dr. Fulford’s Touch of Life: the Healing Power of the Natural Life Force. Pocket Books, NY. Fuller, J.T., Thomson, R.L., Howe, P.R., et al., 2013. Effect of vibration on muscle perfusion: a systematic review. Clin. Physiol. Funct. Imaging 33 (1), 1e10. Gafni, A., Charles, C., Whelan, T., 1998. The physician-patient encounter: the physician as a perfect agent for the patient versus the informed treatment decision-making model. Soc. Sci. Med. 47 (3), 347e354. Galvanovskis, J., Sandblom, J., 1997. Amplification of electromagnetic signals by ion channels. Biophys. J. 73 (6), 3056e3065. Garthwaite, J., 2008. Concepts of neural nitric oxide-mediated transmission. Eur. J. Neurosci. 27 (11), 2783e2802. Gatchel, R.J., 2005. Clinical Essentials of Pain Management. American Psychological Association, Washington, DC. Geiger, B., Spatz, J.P., Bershadsky, A.D., 2009. Environmental sensing through focal adhesions. Nat. Rev. Mol. Cell. Biol. 10 (1), 21e33. Gilbey, M.P., 2007. Sympathetic rhythms and nervous integration. Clin. Exp. Pharmacol. Physiol. 34 (4), 356e361. Giles, P.D., Hensel, K.L., Pacchia, C.F., et al., 2013. Suboccipital decompression enhances heart rate variability indices of cardiac control in healthy subjects. J. Altern. Complement. Med. 19 (2), 92e96. Gimpel, C., von Scheidt, C., Jose, G., et al., 2014. Changes and interactions of flourishing, mindfulness, sense of coherence, and quality of life in patients of a mind-body medicine outpatient clinic. Forsch. Komplementmed 21 (3), 154e162. Godbout, C., Follonier Castella, L., Smith, E.A., et al., 2013. The mechanical environment modulates intracellular calcium oscillation activities of myofibroblasts. PLoS One 8 (5), e64560, 14. Golden, B.A., 2002. A multidisciplinary approach to nonpharmacologic pain management. J. Am. Osteopath. Assoc. 102 (suppl. 3), S1eS5.


+

MODEL

14 Go ´mez Candela, C., Bermejo Lo ´pez, L.M., Loria Kohen, V., 2011. Importance of a balanced omega 6/omega 3 ratio for the maintenance of health: nutritional recommendations. Nutr. Hosp. 26 (2), 323e329. Gorski, F., Corre â, C.R., Filho, V.C., 1993. Potent antinociceptive activity of a hydroalcoholic extract of Phyllanthus corcovadensis. J. Pharm. Pharmacol. 45 (12), 1046e1049. Greene, C.S., Goddard, G., Macaluso, G.M., et al., 2009. Topical review: placebo responses and therapeutic responses. How are they related? J. Orofac. Pain 23 (2), 93e107. Grinnell, F., 2003. Fibroblast biology in three-dimensional collagen matrices. Trends Cell. Biol. 13 (5), 264e269. Guo, A., Song, B., Reid, B., et al., 2010. Effects of physiological electric fields on migration of human dermal fibroblasts. J. Invest. Dermatol. 130, 2320e2327. Halata, Z., Rettig, T., Schulze, W., 1985. The ultrastructure of sensory nerve endings in the human knee joint capsule. Anat. Embryol. Berl. 172 (3), 265e275. Haldeman, S., Carroll, L.J., Cassidy, J.D., 2008. The empowerment of people with neck pain: introduction: the Bone and Joint Decade 2000e2010 task force on neck pain and its associated disorders. Spine (Phila Pa 1976) 33 (4 Suppl.), S8eS13, 15. Hamberg, K., Johansson, E., Lindgren, G., et al., 1997. The impact of marital relationship on the rehabilitation process in a group of women with long-term musculoskeletal disorders. Scand. J. Soc. Med. 25 (1), 17e25. Hardmeier, R., Redl, H., Marlovits, S., 2010. Effects of mechanical loading on collagen propeptides processing in cartilage repair. J. Tissue Eng. Regen. Med. 4 (1), 1e11. Hatayama, T., Kitamura, S., Tamura, C., et al., 2008. The facial massage reduced anxiety and negative mood status, and increased sympathetic nervous activity. Biomed. Res. 29 (6), 317e320. Henderson, A.T., Fisher, J.F., Blair, J., 2010. Effects of rib raising on the autonomic nervous system: a pilot study using noninvasive biomarkers. J. Am. Osteopath. Assoc. 110 (6), 324e330. Henley, C.E., Ivins, D., Mills, M., et al., 2008. Osteopathic manipulative treatment and its relationship to autonomic nervous system activity as demonstrated by heart rate variability: a repeated measures study. Osteopath. Med. Prim. Care 5 (2), 7. Hicks, M.R., Cao, T.V., Standley, P.R., 2014. Biomechanical strain vehicles for fibroblast-directed skeletal myoblast differentiation and myotube functionality in a novel coculture. Am. J. Physiol. Cell. Physiol. 307 (8), C671e683. Aug 13. pii: ajpcell.00335.2013. Hicks, M.R., Cao, T.V., Campbell, D.H., et al., 2012. Mechanical strain applied to human fibroblasts differentially regulates skeletal myoblast differentiation. J. Appl. Physiol. (1985) 113 (3), 465e472. Hildebrandt, J., Pfingsten, M., Franz, C., et al., 1996. Multidisciplinary treatment program for chronic low back pain, part 1. Overview [Article in German] Schmerz 10 (4), 190e203, 26. Hollinshead, W.H., 1974. Textbook of Anatomy, third ed. Harper & Row, Hagerstown, MD, pp. 14e15. Holtzman, S., Beggs, R.T., 2013. Yoga for chronic low back pain: a meta-analysis of randomized controlled trials. Pain Res. Manag. 18 (5), 267e272. Hoover, H.V., 1945. Use of respiratory movement as an aid in correction of osteopathic spinal lesions. J. Am. Osteopath. Ass. 45, 109e111. Hruby, R.J., 1992. Pathophysiologic models and the selection of osteopathic manipulative techniques. J. Osteopath. Med. 6 (4), 25e30. Ingber, D.E., Wang, N., Stamenovic, D., 2014. Tensegrity, cellular biophysics, and the mechanics of living systems. Rep. Prog. Phys. 77 (4), 046603. Ishikawa, M., Komi, P.V., 2004. Effects of different dropping intensities on fascicle and tendinous tissue behaviour during

P. Tozzi stretch-shortening cycle exercise. J. Appl. Physiol. (1985) 96 (3), 848e852. Ja ¨ger, I.L., 2005. Viscoelastic behaviour of organic materials: consequences of a logarithmic dependence of force on strain rate. J. Biomech. 38 (7), 1451e1458. James, M.J., Cleland, L.G., 1997. Dietary n-3 fatty acids and therapy for rheumatoid arthritis. Semin. Arthritis Rheum. 27 (2), 85e97. Jami, L., 1992. Golgi tendon organs in mammalian skeletal muscle: functional properties and central actions. Physiol. Rev. 72 (3), 623e666. Jensen, M.P., Turner, J.A., Romano, J.M., et al., 1991. Coping with chronic pain: a critical review of the literature. Pain 47 (3), 249e283. Johnson, S., Kurtz, M., 2003. Osteopathic manipulative treatment techniques preferred by contemporary osteopathic physicians. J. Am. Osteopath Assoc. 103 (5), 219e224. Kaptchuk, T.J., 2002. The placebo effect in alternative medicine: can the performance of a healing ritual have clinical significance? Ann. Intern. Med. 136 (11), 817e825, 4. Keefe, F.J., Rumble, M.E., Scipio, C.D., 2004. Psychological aspects of persistent pain: current state of the science. J. Pain 5 (4), 195e211. Khan, K.M., Scott, A., 2009. Mechanotherapy: how physical therapists’ prescription of exercise promotes tissue repair. Br. J. Sports Med. 43 (4), 247e252. Kiecolt-Glaser, J.K., Newton, T.L., 2001. Marriage and health: his and hers. Psychol. Bull. 127 (4), 472e503. Kiecolt-Glaser, J.K., Gouin, J.P., Hantsoo, L., 2010. Close relationships, inflammation, and health. Neurosci. Biobehav. Rev. 35 (1), 33e38. Kim, M.M., Barnato, A.E., Angus, D.C., et al., 2010. The effect of multidisciplinary care teams on intensive care unit mortality. Arch. Intern. Med. 170 (4), 369e376. Kimberly, P.E., 1949. The application of the respiratory principle to osteopathic manipulative procedures. J. Am. Osteopath. Assoc. 48 (7), 331e334. Reprint 2001, J. Am. Osteopath. Assoc. 101(7): 410-413. Kipp, K., Johnson, S.T., Doeringer, J.R., et al., 2011. Spinal reflex excitability and homosynaptic depression after about of wholebody vibration. Muscle Nerve 43 (2), 259e262. Kisselkova, H., Georgiev, V., 1979. Effects of training on postexercise limb muscle EMG synchronous to respiration. J. Appl. Physiol. Respir. Environ. Exerc. Physiol. 46 (6), 1093e1095. Kjaer, M., Langberg, H., Heinemeier, K., et al., 2009. From mechanical loading to collagen synthesis, structural changes and function in human tendon. Scand. J. Med. Sci. Sports 19 (4), 500e510. Kobesova, A., Lewit, K., 2000. A case of a pathogenic active scar. Australas. Chiropr. Osteopat. 9 (1), 17e19. Korr, I.M., 1979. The neural basis of osteopathic lesion. In: Peterson, B. (Ed.), The Collected Papers of Irvin M. Korr. Am. Acad. Osteopath., Colorado. Korr, I.M., 1976. The spinal cord as organizer of disease processes: some preliminary perspectives. J. Am. Osteopath. Ass. 76, 35e45. Kosek, E., Hansson, P., 1997. Modulatory influence on somatosensory perception from vibration and heterotopic noxious conditioning stimulation (HNCS) in fibromyalgia patients and healthy subjects. Pain 70 (1), 41e45. Koshi, E.B., Short, C.A., 2007. Placebo theory and its implications for research and clinical practice: a review of the recent literature. Pain Pract. 7 (1), 4e20. Kris-Etherton, P.M., Harris, W.S., Appel, L.J., 2002. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation 106 (21), 2747e2757. Kucera, O., Cifra, M., 2013. Cell-to-cell signaling through light: just a ghost of chance? Cell. Commun. Signal. 12 (11), 87.


+

MODEL

A unifying neuro-fasciagenic model of somatic dysfunction: Part 2 Kucharova S., Klemera, P., et al., 2007. Viscoelasticity ´, M., Doubal, of biological materials e measurement and practical impact on biomedicine. Physiol. Res. 56 (Suppl. 1), S33eS37. Kutty, J.K., Webb, K., 2010. Vibration stimulates vocal mucosa-like matrix expression by hydrogel-encapsulated fibroblasts. J. Tissue Eng. Regen. Med. 4 (1), 62e72. Lang, E., Liebig, K., Kastner, S., et al., 2003. Multidisciplinary rehabilitation versus usual care for chronic low back pain in the community: effects on quality of life. Spine J. 3 (4), 270e276. Langevin, H.M., Storch, K.N., Cipolla, M.J., et al., 2006. Fibroblast spreading induced by connective tissue stretch involves intracellular redistribution of alpha- and beta-actin. Histochem. Cell. Biol. 125 (5), 487e495. Langevin, H.M., Nedergaard, M., Howe, A.K., 2013. Cellular control of connective tissue matrix tension. J. Cell. Biochem. 114 (8), 1714e1719. Langevin, H.M., Storch, K.N., Snapp, R.R., et al., 2010. Tissue stretch induces nuclear remodeling in connective tissue fibroblasts. Histochem. Cell. Biol. 133 (4), 405e415. Langevin, H.M., Bouffard, N.A., Badger, G.J., et al., 2005. Dynamic fibroblast cytoskeletal response to subcutaneous tissue stretch ex vivo and in vivo. Am. J. Physiol. Cell. Physiol. 288 (3), C747eC756. Langevin, H.M., Bouffard, N.A., Fox, J.R., et al., 2011. Fibroblast cytoskeletal remodeling contributes to connective tissue tension. J. Cell. Physiol. 226 (5), 1166e1175. Langevin, H.M., 2006. Connective tissue: a body-wide signalling network? Med. Hypotheses 66 (6), 1074e1077. Lavagnino, M., Arnoczky, S.P., Tian, T., et al., 2003. Effect of amplitude and frequency of cyclic tensile strain on the inhibition of MMP-1 mRNA expression in tendon cells: an in vitro study. Connect. Tissue Res. 44 (3e4), 181e187. Leduc, A., Lievens, P., Dewald, J., 1981. The influence of multidirectional vibrations on wound healing and on the regeneration of blood and lymph vessels. Lymphology 14 (4), 179e185. Lee, R.P., 2008. The living matrix: a model for the primary respiratory mechanism. Explore (NY) 4 (6), 374e378. Levin, M., 2014. Endogenous bioelectrical networks store nongenetic patterning information during development and regeneration. J. Physiol. 592 (Pt. 11), 2295e2305, 1. Lieberwirth, C., Wang, Z., 2014. Social bonding: regulation by neuropeptides. Front. Neurosci. 24 (8), 171. Lima, D.D., Alves, V.L., Turato, E.R., 2014. The phenomenologicalexistential comprehension of chronic pain: going beyond the standing healthcare models. Philos. Ethics Humanit. Med. 10 (9), 2. Littlejohn, J.M., 1902. The physiological basis of the therapeutic law. J. Am. Osteopath. Assoc. 2, 42e60. Lombardini, R., Marchesi, S., Collebrusco, L., et al., 2009. The use of osteopathic manipulative treatment as adjuvant therapy in patients with peripheral arterial disease. Man. Ther. 14 (4), 439e443. Lu, H.H., Thomopoulos, S., 2013. Functional attachment of soft tissues to bone: development, healing, and tissue engineering. Annu. Rev. Biomed. Eng. 15, 201e226. Lund, I., Ge, Y., Yu, L.C., et al., 2002. Repeated massage-like stimulation induces long-term effects on nociception: contribution of oxytocinergic mechanisms. Eur. J. Neurosci. 16 (2), 330e338. Mackintosh, S.E., Adams, C.E., Singer-Chang, G., et al., 2011. An osteopathic approach to implementing and promoting interprofessional education. J. Am. Osteopath. Assoc. 111 (4), 206e212. Marcason, W., 2010. What is the anti-inflammatory diet? J. Am. Diet. Assoc. 110 (11), 1780. Marchand, S., Gaumond, I., 2013. Placebo and nocebo: how to enhance therapies and avoid unintended sabotage to pain treatment. Pain Manag. 3 (4), 285e294.

15

Martin, M.M., 2009. Effects of myofascial release in diffuse systemic sclerosis. J. Bodyw. Mov. Ther. 13 (4), 320e327. McGlone, F., Wessberg, J., Olausson, H., 2014. Discriminative and affective touch: sensing and feeling. Neuron 82 (4), 737e755, 21. McPartland, J.M., Giuffrida, A., King, J., et al., 2005. Cannabimimetic effects of osteopathic manipulative treatment. J. Am. Osteopath. Assoc. 105 (6), 283e291. McPartland, J.M., 2008. Expression of the endocannabinoid system in fibroblasts and myofascial tissues. J. Bodyw. Mov. Ther. 12 (2), 169e182. McPartland, J.M., Mein, E.A., 1997. Entrainment and the cranial rhythmic impulse. Altern. Ther. Health Med. 3 (1), 40e45. Meert, G., 2012. Fluid dynamics in fascial tissues. In: Schleip, R., Findley, T., Chaitow, L., Huijing, P. (Eds.), Fascia: the Tensional Network of the Human Body. Churchill Livingstone, Edinburgh, pp. 177e182. Mehling, W.E., Hamel, K.A., Acree, M., et al., 2005. Randomized, controlled trial of breath therapy for patients with chronic lowback pain. Altern. Ther. Health Med. 11 (4), 44e52. Meltzer, K.R., Cao, T.V., Schad, J.F., et al., 2010. In vitro modeling of repetitive motion injury and myofascial release. J. Bodyw. Mov. Ther. 14 (2), 162e171. Meltzer, K.R., Standley, P.R., 2007. Modeled repetitive motion strain and indirect osteopathic manipulative techniques in regulation of human fibroblast proliferation and interleukin secretion. J. Am. Osteopath. Assoc. 107 (12), 527e536. Merkes, M., 2010. Mindfulness-based stress reduction for people with chronic diseases. Aust. J. Prim. Health 16 (3), 200e210. Part II. Experimental studies of the placebo effect. In: Miller, F.G., Colloca, L., Crouch, R.A., et al. (Eds.), 2013. The Placebo: a Reader. JHU Press, pp. 71e82. Minasny, B., 2009. Understanding the process of fascial unwinding. Int. J. Ther. Massage Bodyw. 2 (3), 10e17. Mitchell Jr., F.L., 1999. The Muscle Energy Manual, vol. 1. MET Press, East Lansing, MI, p. 14. Morelli, M., Chapman, C.E., Sullivan, S.J., 1999. Do cutaneous receptors contribute to the changes in the amplitude of the Hreflex during massage? Electromyogr. Clin. Neurophysiol. 39 (7), 441e447. Morhenn, V., Beavin, L.E., Zak, P.J., 2012. Massage increases oxytocin and reduces adrenocorticotropin hormone in humans. Altern. Ther. Health Med. 18 (6), 11e18. Nakamura, K., Hiramatsu, M., 2005. Ultra-weak photon emission from human hand: influence of temperature and oxygen concentration on emission. J. Photochem. Photobiol. B 80 (2), 156e160, 1. Newham, D.J., Lederman, E., 1997. Effect of manual therapy techniques on the stretch reflex in normal human quadriceps. Disabil. Rehab. 19 (8), 326e331. Ng, C.P., Hinz, B., Swartz, M.A., 2005. Interstitial fluid flow induces myofibroblast differentiation and collagen alignment in vitro. J. Cell. Sci. 118 (Pt. 20), 4731e4739. Nicholas, M.K., Linton, S.J., Watson, P.J., et al., 2011. Early identification and management of psychological risk factors (“yellow flags”) in patients with low back pain: a reappraisal. Phys. Ther. 91 (5), 737e753. Oeltjenbruns, J., Scha ¨fer, M., 2008. Clinical significance of the placebo effect [Article in German] Anaesthesist 57 (5), 447e463. Olausson, H., Wessberg, J., Morrison, I., et al., 2010. The neurophysiology of unmyelinated tactile afferents. Neurosci. Biobehav. Rev. 34 (2), 185e191. Oschman, J.L., Oschman, N.H., 1994. Somatic recall. Part II. Soft tissue holography. Massage Ther. J. 34, 66e67, 106e10. Overberger, R., Hoyt, J.A., Daghigh, F., et al., 2009. Comparing changes in serum nitric oxide levels and heart rate after osteopathic manipulative treatment (OMT) using the Dalrymple


+

MODEL

16 pedal pump to changes measured after active exercise. J. Am. Osteopath. Assoc. 109 (1), 41e42. Pacheco-Lo ´pez, G., Engler, H., Niemi, M.B., et al., 2006. Expectations and associations that heal: immunomodulatory placebo effects and its neurobiology. Brain Behav. Immun. 20 (5), 430e446. Pang, X.F., 2012. The properties of bio-energy transport and influence of structure nonuniformity and temperature of systems on energy transport along polypeptide chains. Prog. Biophys. Mol. Biol. 108 (1e2), 1e46. Parmelee, P.A., Katz, I.R., Lawton, M.P., 1991. The relation of pain to depression among institutionalized aged. J. Gerontol. 46 (1), P15eP21. Peer, K.S., Barkley, J.E., Knapp, D.M., 2009. The acute effects of local vibration therapy on ankle sprain and hamstring strain injuries. Phys. Sportsmed. 37 (4), 31e38. Penney, J.N., 2010. The biopsychosocial model of pain and contemporary osteopathic practice. Int. J. Osteopath. Med. 13 (2), 42e47. Pergolizzi, J., Ahlbeck, K., Aldington, D., et al., 2013. The development of chronic pain: physiological CHANGE necessitates a multidisciplinary approach to treatment. Curr. Med. Res. Opin. 29 (9), 1127e1135. Pickar, J.G., 2002. Neurophysiological effects of spinal manipulation. Spine J. 2 (5), 357e371. Pickar, J.G., Wheeler, J.D., 2001. Response of muscle proprioceptors to spinal manipulative-like loads in the anesthetized cat. J. Manip. Physiol. Ther. 24 (1), 2e11. Plotkin, B.J., Rodos, J.J., Kappler, R., et al., 2001. Adjunctive osteopathic manipulative treatment in women with depression: a pilot study. J. Am. Osteopath. Assoc. 101 (9), 517e523. Pohl, H., 2010. Changes in the structure of collagen distribution in the skin caused by a manual technique. J. Bodyw. Mov. Ther. 14 (1), 27e34. Pomari, E., Stefanon, B., Colitti, M., 2014. Effect of plant extracts on H2O2-induced inflammatory gene expression in macrophages. J. Inflamm. Res. 24 (7), 103e112. Popp, F.A., 2009. Cancer growth and its inhibition in terms of coherence. Electromagn. Biol. Med. 28 (1), 53e60. Price, D.D., Finniss, D.G., Benedetti, F., 2008. A comprehensive review of the placebo effect: recent advances and current thought. Annu. Rev. Psychol. 59, 565e590. Quere ´, N., Noe ¨l, E., Lieutaud, A., et al., 2009. Fasciatherapy combined with pulsology touch induces changes in blood turbulence potentially beneficial for vascular endothelium. J. Bodyw. Mov. Ther. 13 (3), 239e245. Ragle, R.L., Sawitzke, A.D., 2012. Nutraceuticals in the management of osteoarthritis : a critical review. Drugs Aging 29 (9), 717e731. Rapaport, M.H., Schettler, P., Bresee, C., 2010. A preliminary study of the effects of a single session of swedish massage on hypothalamic-pituitary-adrenal and immune function in normal individuals. J. Altern. Complement. Med. 16 (10), 1079e1088. Sep 1. Rapaport, M.H., Schettler, P., Bresee, C., 2012. A preliminary study of the effects of repeated massage on hypothalamic-pituitaryadrenal and immune function in healthy individuals: a study of mechanisms of action and dosage. J. Altern. Complement. Med. 18 (8), 789e797. Rastogi, A., Pospı´sil, P., 2010. Ultra-weak photon emission as a noninvasive tool for monitoring of oxidative processes in the epidermal cells of human skin: comparative study on the dorsal and the palm side of the hand. Skin. Res. Technol. 16 (3), 365e370. Reed, R.K., Lide ń, A., Rubin, K., 2010. Edema and fluid dynamics in connective tissue remodelling. J. Mol. Cell. Cardiol. 48 (3), 518e523.

P. Tozzi Reed, R.K., Rubin, K., 2010. Transcapillary exchange: role and importance of the interstitial fluid pressure and the extracellular matrix. Cardiovasc Res. 87 (2), 211e217. Reeves, N.D., 2006. Adaptation of the tendon to mechanical usage. J. Musculoskelet. Neuronal. Interact. 6 (2), 174e180. Rogers, F.J., D’Alonzo, G.E., Glover, J., et al., 2002. Proposed tenets of osteopathic medicine and principles for patient care. J. Am. Osteopath. Assoc. 102 (2), 63e65. Rolf, I., 1962. Structural Dynamics. British Acad. Appl. Osteopath. Yearb., Maidstone. Roman, M., Chaudhry, H., Bukiet, B., et al., 2013. Mathematical analysis of the flow of hyaluronic acid around fascia during manual therapy motions. J. Am. Osteopath. Assoc. 113 (8), 600e610. Ronen, N., Livne, E., Gross, B., 1999. Oxidative damage in rat tissue following excessive L-tryptophan and atherogenic diets. Adv. Exp. Med. Biol. 467, 497e505. Rosenzweig, S., Greeson, J.M., Reibel, D.K., et al., 2010. Mindfulness-based stress reduction for chronic pain conditions: variation in treatment outcomes and role of home meditation practice. J. Psychosom. Res. 68 (1), 29e36. Rossi, C., Foletti, A., Magnani, A., et al., 2011. New perspectives in cell communication: Bioelectromagnetic interactions. Semin. Cancer Biol. 21 (3), 207e214. Rouabhia, M., Park, H., Meng, S., et al., 2013. Electrical stimulation promotes wound healing by enhancing dermal fibroblast activity and promoting myofibroblast transdifferentiation. PLoS One 8 (8), e71660, 19. Rutkowski, J.M., Swartz, M.A., 2007. A driving force for change: interstitial flow as a morphoregulator. Trends Cell. Biol. 17 (1), 44e50. Salamon, E., Zhu, W., Stefano, G.B., 2004. Nitric oxide as a possible mechanism for understanding the therapeutic effects of osteopathic manipulative medicine (Review). Int. J. Mol. Med. 14 (3), 443e449. Sandku ¨hler, J., 2009. Models and mechanisms of hyperalgesia and allodynia. Physiol. Rev. 89 (2), 707e758. Schleip, R., 2003. Fascial plasticity e a new neurobiological explanation. Part 1. J. Bodyw. Mov. Ther. 7 (1), 11e19. Schleip, R., Mechsner, F., Zorn, A., et al., 2014. The bodywide fascial network as a sensory organ for haptic perception. J. Mot. Behav. 46 (3), 191e193. Schleip, R., Duerselen, L., Vleeming, A., et al., 2012. Strain hardening of fascia: static stretching of dense fibrous connective tissues can induce a temporary stiffness increase accompanied by enhanced matrix hydration. J. Bodyw. Mov. Ther. 16 (1), 94e100. Schleip, R., Mu ¨ller, D.G., 2013. Training principles for fascial connective tissues: scientific foundation and suggested practical applications. J. Bodyw. Mov. Ther. 17 (1), 103e115. Scholkmann, F., Fels, D., Cifra, M., 2013. Non-chemical and noncontact cell-to-cell communication: a short review. Am. J. Transl. Res. 5 (6), 586e593, 25. Schwabl, H., Klima, H., 2005. Spontaneous ultraweak photon emission from biological systems and the endogenous light field. Forsch Komplementarmed Klass. Naturheilkd 12 (2), 84e89. Seffinger, M.A., King, H.H., Ward, R.C., et al., 2011. Osteopathic phylosophy. In: Chila, A.G. (Ed.), Foundations of Osteopathic Medicine, third ed. Lippincott, Williams & Wilkins, Philadelphia, PA, pp. 3e22. Sergueef, N., Nelson, K., 2014. Osteopathy for the over 50s. Maintaining Function and Treating Dysfunction. Handspring Publishing, Pencaitland, UK, pp. 80e82. Simmonds, N., Miller, P., Gemmell, H., 2012. A theoretical framework for the role of fascia in manual therapy. J. Bodyw. Mov. Ther. 16 (1), 83e93. Simopoulos, A.P., 2009. Omega-6/omega-3 essential fatty acids: biological effects. World Rev. Nutr. Diet. 99, 1e16.


+

MODEL

A unifying neuro-fasciagenic model of somatic dysfunction: Part 2 Skutek, M., van Griensven, M., Zeichen, J., et al., 2001. Cyclic mechanical stretching enhances secretion of interleukin 6 in human tendon fibroblasts. Knee Surg. Sports Traumatol. Arthrosc. 9 (5), 322e326. Solomonow, M., 2009. Ligaments: a source of musculoskeletal disorders. J. Bodyw. Mov. Ther. 13 (2), 136e154. Song, S.H., Lehrer, P., 2003. The effects of specific respiratory rates on heart rate and heart rate variability. Appl. Psychophysiol. Biofeedback 28 (1), 13e23. Standley, P.R., Meltzer, K., 2008. In vitro modeling of repetitive motion strain and manual medicine treatments: potential roles for pro- and anti-inflammatory cytokines. J. Bodyw. Mov. Ther. 12 (3), 201e203. Staubesand, J., Baumbach, K.U., Li, Y., 1997. La structure fine de l’apone ´vrose jambie `re. Phle `bologie 50 (1), 105e113. Stecco, C., 2014. Why are there so many discussions about the nomenclature of fasciae? J. Bodyw. Mov. Ther. 18 (3), 441e442. Steen, E., Haugli, L., 2001. From pain to self-awarenessea qualitative analysis of the significance of group participation for persons with chronic musculoskeletal pain. Patient Educ. Couns. 42 (1), 35e46. Still, A.T., 1899. Philosophy of Osteopathy. A.T. Still, Kirksville, MO, p. 162. Stoltz, J.F., Dumas, D., Wang, X., et al., 2000. Influence of mechanical forces on cells and tissues. Biorheology 37 (1e2), 3e14. Sutherland, W.G., 1990. Dysfunction in the vascular system. In: Sutherland, W.G. (Ed.), Teachings in the Science of Osteopathy. Sutherland Cranial Teaching Foundation, Fort Worth, Tex, pp. 135e136. Tanaka, S., Ito, T., 1977. Histochemical demonstration of adrenergic fibres in the fascia periosteum and retinaculum. Clin. Orthop. Relat. Res. 126, 276e281. Tapsell, L.C., Hemphill, I., Cobiac, L., et al., 2006. Health benefits of herbs and spices: the past, the present, the future. Med. J. Aust. 185 (4 Suppl.), S4eS24, 21. Tesarz, J., Hoheisel, U., Wiedenho ¨fer, B., et al., 2011. Sensory innervation of the thoracolumbar fascia in rats and humans. Neuroscience 27 (194), 302e308. Thomopoulos, S., Marquez, J.P., Weinberger, B., et al., 2006. Collagen fibre orientation at the tendon to bone insertion and its influence on stress concentrations. J. Biomech. 39 (10), 1842e1851. Tomasek, J.J., Gabbiani, G., Hinz, B., et al., 2002. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat. Rev. Mol. Cell. Biol. 3 (5), 349e363. Toro-Velasco, C., Arroyo-Morales, M., Ferna ńdez-de-Las-Pen ãs, C., et al., 2009. Short-term effects of manual therapy on heart rate variability, mood state, and pressure pain sensitivity in patients with chronic tension-type headache: a pilot study. J. Manip. Physiol. Ther. 32 (7), 527e535. Torri, E., Lemos, M., Caliari, V., et al., 2007. Anti-inflammatory and antinociceptive properties of blueberry extract (Vaccinium corymbosum). J. Pharm. Pharmacol. 59 (4), 591e596. Tota, B., Trimmer, B. (Eds.), 2011. Nitric Oxide. Elsevier Health Sciences. Tsuzaki, M., Bynum, D., Almekinders, L., et al., 2003. ATP modulates load-inducible IL-1beta, COX 2, and MMP-3 gene expression in human tendon cells. J. Cell. Biochem. 89 (3), 556e562. Uzel, M., Cetinus, E., Ekerbicer, H.C., et al., 2006. The influence of athletic activity on the plantar fascia in healthy young adults. J. Clin. Ultrasound 34 (1), 17e21. Valero-Cuevas, F.J., Yi, J.W., Brown, D., et al., 2007. The tendon network of the fingers performs anatomical computation at a macroscopic scale. IEEE Trans. Biomed. Eng. 54 (6 Pt. 2), 1161e1166. Van Buskirk, R.L., 1990. Nociceptive reflexes and the somatic dysfunction: a model. J. Am. Osteopath. Ass. 90 (9), 792e805.

17

Van der Wal, J., 2009. The architecture of the connective tissue in the musculoskeletal system-an often overlooked functional parameter as to proprioception in the locomotor apparatus. Int. J. Ther. Massage Bodyw. 2 (4), 9e23, 7. Van der Wal, J., 2012. Proprioception. In: Schleip, R., Findley, T., Chaitow, L., Huijing, P. (Eds.), Fascia: the Tensional Network of the Human Body. Churchill Livingstone, Elsevier, Edinburgh, pp. 80e87. Van Wijk, E.P., Van Wijk, R., Bajpai, R.P., 2008. Quantum squeezed state analysis of spontaneous ultra weak light photon emission of practitioners of meditation and control subjects. Indian J. Exp. Biol. 46 (5), 345e352. Van Wijk, E.P., Koch, H., Bosman, S., 2006. Anatomic characterization of human ultra-weak photon emission in practitioners of transcendental meditation(TM) and control subjects. J. Altern. Complement. Med. 12 (1), 31e38. Voigt, M., Jakobsen, J., Sinkjaer, T., 1998. Non-noxious stimulation of the glenohumeral joint capsule elicits strong inhibition of active shoulder muscles in conscious human subjects. Neurosci. Lett. 254 (2), 105e108, 25. Walach, H., Jonas, W.B., 2004. Placebo research: the evidence base for harnessing self-healing capacities. J. Altern. Complement. Med. 10 (Suppl. 1), S103eS112. Wall, M.E., Banes, A.J., 2005. Early responses to mechanical load in tendon: role for calcium signaling, gap junctions and intercellular communication. J. Musculoskelet. Neuronal Interact. 5 (1), 70e84. Wang, J.H., Guo, Q., Li, B., 2012. Tendon biomechanics and mechanobiologyea minireview of basic concepts and recent advancements. J. Hand Ther. 25 (2), 133e140 quiz 141. Wang, J.H., Yang, G., Li, Z., et al., 2004. Fibroblast responses to cyclic mechanical stretching depend on cell orientation to the stretching direction. J. Biomech. 37 (4), 573e576. Ward, R.C., 2003. Integrated Neuromusculoskeletal Release and Myofascial Release. Foundations for Osteopathic Medicine, second ed. Lippincott Williams & Wilkins, Philadelphia, PA, pp. 931e932. Willard, F.H., Fossum, C., Standley, P.R., 2010. The fascial system of the body. In: Chila, A. (Ed.), Foundations of Osteopathic Medicine, third ed. Lippincott Williams & Wilkins, Philadelphia, PA, p. 89. Willard, F.H., 1997. The muscular, ligamentous and neural structure of the low back and its relation to back pain. In: Vleeming, A., Mooney, V., Snijders, C.J., et al. (Eds.), Movement, Stability and Low Back Pain: the Essential Role of the Pelvis. Churchill Livingstone, Edinburgh. Wink, D.A., Hines, H.B., Cheng, R.Y., et al., 2011. Nitric oxide and redox mechanisms in the immune response. J. Leukoc. Biol. 89 (6), 873e891. Wood Jones, F., 1944. Structure and Function as Seen in the Foot. Baillie `re, Tindall and Cox, London. Yadav, V.R., Prasad, S., Sung, B., et al., 2011. The role of chalcones in suppression of NF-kB-mediated inflammation and cancer. Int. Immunopharmacol. 11 (3), 295e309. Yahia, L., Rhalmi, S., Newman, N., et al., 1992. Sensory innervation of human thoracolumbar fascia. An immunohistochemical study. Acta. Orthop. Scand. 63 (2), 195e197. Yang, G., Im, H.J., Wang, J.H., 2005. Repetitive mechanical stretching modulates IL-1beta induced COX-2, MMP-1 expression, and PGE2 production in human patellar tendon fibroblasts. Gene 19 (363), 166e172. Zawieja, D.C., 2009. Contractile physiology of lymphatics. Lymphat. Res. Biol. 7 (2), 87e96. Zhao, M., 2009. Electrical fields in wound healing-an overriding signal that directs cell migration. Semin. Cell. Dev. Biol. 20 (6), 674e682. Zhao, M., Bai, H., Wang, E., et al., 2004. Electrical stimulation directly induces pre-angiogenic responses in vascular


+

MODEL

18 endothelial cells by signaling through VEGF receptors. J. Cell. Sci. 117 (Pt. 3), 397e405. Ziche, M., Morbidelli, L., 2000. Nitric oxide and angiogenesis. J. Neurooncol. 50 (1e2), 139e148. Zimny, M.L., Wink, C.S., 1991. Neuroreceptors in the tissues of the knee joint. J. Electromyogr. Kinesiol. 1 (3), 148e157.

P. Tozzi Zong, W., Jallah, Z.C., Stein, S.E., et al., 2010. Repetitive mechanical stretch increases extracellular collagenase activity in vaginal fibroblasts. Female Pelvic Med. Reconstr. Surg. 16 (5), 257e262, 1.


A unifying neuro-fasciagenic model of somatic dysfunction - underlying mechanisms and treatment - Part I.

Erectile dysfunction in Arab countries. Part II: Diagnosis and treatment.

Neural mechanisms underlying lower urinary tract dysfunction.

Pathophysiology and treatment of focal cerebral ischemia. Part II: Mechanisms of damage and treatment.

A review of hyperacusis and future directions: part II. Measurement, mechanisms, and treatment.

[Mechanisms underlying dysfunction of retinal blood vessels in diabetic rats].

Redox-sensitive mechanisms underlying vascular dysfunction in heart failure.

The aqueous humor outflow pathways in glaucoma: A unifying concept of disease mechanisms and causative treatment.

Anticancer Natural Compounds: Molecular Mechanisms and Functions  Part II.

Mechanisms underlying somatosensory cortical dynamics: II. In vitro studies.

Mechanisms underlying the antidepressant response and treatment resistance.

[Interdisciplinary treatment of osteosarcomas: Part II].

Treatment of superficial mycoses: review. Part II.

[Granulocyte dysfunction. Part II. Secondary defects. (authors transl)].

Mechanisms underlying cyclosporin A nephrotoxicity.

Neural mechanisms underlying pain's ability to reorient attention: evidence for sensitization of somatic threat detectors.

Endotoxic shock. Part II: A review of treatment.

Cutaneous porphyrias part II: treatment strategies.

A model to investigate the mechanisms underlying the emergence and development of independent sitting.

Autonomic dysfunction in early breast cancer: Incidence, clinical importance, and underlying mechanisms.

Organic nitrates: update on mechanisms underlying vasodilation, tolerance and endothelial dysfunction.

Treatment of Gonorrhea and syphilis: Part II--syphilis.

Obesity and headache: Part II--potential mechanism and treatment considerations.

A Unifying Model of Orientation Crowding in Peripheral Vision.