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The aim of this study was to analyze the impact of circadian variation of blood pressure (BP) in patients with chronic musculoskeletal pain (CPM). A further purpose was to study differences in circadian variation of BP between genders and the correlation between BP circadian variation and pain. We performed a cross-sectional, observational study in which seventy-five participants with CMP participated. Circadian variation in BP was calculated using the diurnal/nocturnal BP ratio, and all participants used validated self-measurement BP devices. The Numeric Pain Rating Scale was used to assess pain perception. All circadian BP values from participants who suffered from CPM followed pathologic cardiovascular parameters (BP ratio < 10%). When comparing BP ratios between genders, statistically significant differences were found (p = 0.011). BP itself did not correlate with pain in any subgroup. Circadian variations of BP in those suffering from CMP are shown and new possibilities of research and treatment are proposed., University Chair in Clinical Psychoneuroimmunology (University of Granada), University Chair in Clinical Psychoneuroimmunology (PNI Europe)

The objective of this study is to analyse differences in the thickness of the patellar (PT) and Achilles tendons (AT) among athletes with different number of meals per day. The design is a cross-sectional, observational study. A total of thirty-six male athletes (with mean age groups ranging from 31 to 40) were recruited and divided into three groups based on the number of daily meals they had (3, 4 or 5 meals). PT and AT were assessed by ultrasound. There were statistically significant differences in PT when comparing groups 1 and 3, at both longitudinal (p < 0.03) and transversal (p < 0.002) planes. There were no differences when comparing groups 1 and 2 or groups 2 and 3. There was a negative correlation between the number of meals per day and tendon thicknesses in both PT (longitudinal plane: r = −0.384; p = 0.02/transversal plane: r = −0.406; p = 0.01) and AT (transversal plane: r = −0.386; p = 0.02). In conclusion, there were patellar tendon thickness differences between participants and the number of daily meals could play a key role in tendon thickness, healing and performance.

Obesity, and obesity-associated conditions such as hypertension, chronic kidney disease, type 2 diabetes, and cardiovascular disease, are important risk factors for severe Coronavirus disease-2019 (COVID-19). The common denominator is metaflammation, a portmanteau of metabolism and inflammation, which is characterized by chronically elevated levels of leptin and pro-inflammatory cytokines. These induce the “Suppressor Of Cytokine Signaling 1 and 3” (SOCS1/3), which deactivates the leptin receptor and also other SOCS1/3 sensitive cytokine receptors in immune cells, impairing the type I and III interferon early responses. By also upregulating SOCS1/3, Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 adds a significant boost to this. The ensuing consequence is a delayed but over-reactive immune response, characterized by high-grade inflammation (e.g., cytokine storm), endothelial damage, and hypercoagulation, thus leading to severe COVID-19. Superimposing an acute disturbance, such as a SARS-CoV-2 infection, on metaflammation severely tests resilience. In the long run, metaflammation causes the “typical western” conditions associated with metabolic syndrome. Severe COVID-19 and other serious infectious diseases can be added to the list of its short-term consequences. Therefore, preventive measures should include not only vaccination and the well-established actions intended to avoid infection, but also dietary and lifestyle interventions aimed at improving body composition and preventing or reversing metaflammation. Sin financiación 6.706 JCR (2021) Q1, 15/90 Nutrition & Dietetics 1.287 SJR (2021) Q1, 19/338 Food Science No data IDR 2021 UEM

Nowadays, there is evidence that relates the amount of physical activity, as well as the impact of psychological factors, to the intensity of symptoms present in patients with fibromyalgia (FM). However, there are no studies which correlate the level of association of physical activity, psychological factors and vegetative symptoms in the FM population. The study has a cross-sectional observational design with 41 participants being recruited from a private clinic and rehabilitation service. The Autonomic Symptom Profile (Compass-31) to assess vegetative symptoms, the GODIN questionnaire to evaluate the level of leisure activity, and the pain catastrophizing scale, Tampa Kinesiophobia Scale and Self-Efficacy Scale to assess psychological factors, were used. A low and significant level of association was found between pain catastrophizing (PCS) and Kinesiophobia (r = 0.398; p < 0.01), as well as with catastrophizing and vegetative symptoms (r = 0.428; p < 0.05). Furthermore, a low and significant level of association was also found between self-efficacy and vegetative symptoms (r = 0.397; p < 0.05). No association was found between the level of daily physical activity (measured by the Godin Leisure questionnaire) and vegetative symptoms, nor with any psychological factor studied. There is an association between vegetative symptoms and psychological factors. Nevertheless, more research which takes other factors into account, such as lifestyle and nutritional, is needed., University Chair in Clinical Psychoneuroimmunology (University of Granada), University Chair in Clinical Psychoneuroimmunology (PNI Europe)

Treating sarcopenia in older individuals remains a challenge, and nutritional interventions present promising approaches in individuals that perform limited physical exercise. We assessed the efficacy of leucine administration to evaluate whether the regular intake of this essential amino acid can improve muscle mass, muscle strength and functional performance and respiratory muscle function in institutionalized older individuals. The study was a placebo-controlled, randomized, double-blind design in fifty participants aged 65 and over (ClinicalTrials.gov identifier NCT03831399). The participants were randomized to a parallel group intervention of 13 weeks&rsquo, duration with a daily intake of leucine (6 g/day) or placebo (lactose, 6 g/day). The primary outcome was to study the effect on sarcopenia and respiratory muscle function. The secondary outcomes were changes in the geriatric evaluation scales, such as cognitive function, functional impairment and nutritional assessments. We also evaluated whether leucine administration alters blood analytical parameters and inflammatory markers. Administration of leucine was well-tolerated and significantly improves some criteria of sarcopenia in elderly individuals such as functional performance measured by walking time (p = 0.011), and improved lean mass index. For respiratory muscle function, the leucine-treated group improved significantly (p = 0.026) in maximum static expiratory force compared to the placebo. No significant effects on functional impairment, cognitive function or nutritional assessment, inflammatory cytokines IL-6, TNF-alpha were observed after leucine administration compared to the placebo. The use of l-leucine supplementation can have some beneficial effects on sarcopenia and could be considered for the treatment of sarcopenia in older individuals.

Chronic non-communicable diseases (CNCD) are the leading cause of mortality in developed countries. They ensue from the sum of modern anthropogenic risk factors, including high calorie nutrition, malnutrition, sedentary lifestyle, social stress, environmental toxins, politics and economic factors. Many of these factors are beyond the span of control of individuals, suggesting that CNCD are inevitable. However, various studies, ours included, show that the use of intermittent challenges with hormetic effects improve subjective and objective wellbeing of individuals with CNCD, while having favourable effects on immunological, metabolic and behavioural indices. Intermittent cold, heat, fasting and hypoxia, together with phytochemicals in multiple food products, have widespread influence on many pathways related with overall health. Until recently, most of the employed challenges with hormetic effects belonged to the usual transient live experiences of our ancestors. Our hypothesis; we conclude that, whereas the total inflammatory load of multi-metabolic and psychological risk factors causes low grade inflammation and aging, the use of intermittent challenges, united in a 7-10 days lasting hormetic intervention, might serve as a vaccine against the deleterious effects of chronic low grade inflammation and it's metabolic and (premature) aging consequences.

Objective: The purpose of this study was to examine whether a prebiotic formulation reduces frailty index (FI) levels in older people. Design: We conducted secondary analysis of a placebo-controlled, randomized, double-blind design study. Setting/Participants: The study included non-demented people over the age of 65 who were living in nursing homes and were able to walk. Fifty participants completed the study (75.3±7.3 years, 70% females). Intervention: Participants were randomly assigned to either a group who received daily Darmocare Pre® (inulin and fructooligosaccharides) for 13 weeks or a placebo group (maltodextrin). Measurement: The primary outcome in this secondary analysis was change in level of a 62-item FI compared to baseline. Results: At the 13-week follow-up, the placebo group had higher FI levels (preFI 0.23±0.11, postFI 0.24±0.12, p=0.012) and the intervention group had lower FI levels (preFI 0.22±0.09, postFI 0.20±0.08, p0.3, N=5) had the greatest reduction in their FI (0.04±0.01). Conclusion: A prebiotic intervention can reduce frailty levels in nursing home residents especially in those with higher levels of frailty.

Understanding how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) highjacks epithelial cells and infiltrates the lung, as well as other organs and tissues, is essential for developing treatment strategies and vaccines against this highly contagious virus. Another major goal is to fully elucidate the mechanisms by which SARS-CoV- 2 bypasses the innate immune system and induces a cytokine storm, and its effects on mortality. Currently, SARS- CoV-2 is thought to evade innate antiviral immunity, undergo endocytosis, and fuse with the host cell membrane by exploiting ACE2 receptors and the protease TMMPRSS2, with cathepsin B/L as alternative protease, for entry into the epithelial cells of tissues vulnerable to developing coronavirus disease 2019 (COVID-19) symptoms. However, the incorporation of new and unique binding sites, i.e., O-linked glycans, and the preservation and augmentation of effective binding sites (N-linked glycans) on the outer membrane of SARS-CoV-2 may represent other strategies of infecting the human host. Here, I will rationalize the possibility that other host molecules-i.e., sugar molecules and the sialic acidsN-glycolylneuraminic acid, N-acetylneuraminic acid, and their derivates could be viable candidates for the use as virus receptors by SARS-CoV-2 and/or serve as determinants for the adherence on ACE2 of SARS-CoV-2.

Looking at a waterhole, it is surprising that so many animals share the same space without visible signs of anxiety or aggression. Although waterholes are the preferred feeding locations of large carnivores, water holes are shared by all type of herbivores of all sizes and shapes, including elephants. Recent research shows that the homeostatic disturbances leading to the "thirst feeling" not only activate specific substances regulating water and mineral household, but also the "trust and love" hormone oxytocin, while decreasing the production of the typical stress hormone cortisol. People using drugs, seem to be in search for oxytocin, as evidenced in studies with individuals on drugs such as ecstasy and gamma-hydroxybyturate. Hot environment, drought and increased sweating also activate specific oxytocin-producing parts of the hypothalamus, just as breastfeeding does in mother and infant. Water homeostasis is the only allostatic system activating trust neuro-anatomy and we suggest that this is due to the fact that all animals depend on water, whereas food type is species specific. Our hypothesis; regulating drinking behaviour through intermittent bulk drinking could increase oxytocin signalling, recover human trust and increase health by down-regulation of stress axis activity and inflammatory activity of the immune system. Intermittent bulk drinking should be defined as water (including tea and coffee) drinking up to a feeling of satiety and regulated by a mild feeling of thirst. This would mean that people would not drink less quantity but less frequently and that's how all animals, but also human newborns behave. It is the latter group, which is probably the only group of humans with a normal fluid homeostasis. (C) 2016 Elsevier Ltd. All rights reserved.

Chronic low-grade inflammation and insulin resistance are intimately related entities that are common to most, if not all, chronic diseases of affluence. We hypothesized that a short-term intervention based on "ancient stress factors" may improve anthropometrics and clinical chemical indices. We executed a pilot study of whether a 10-day mimic of a hunter-gatherer lifestyle favorably affects anthropometrics and clinical chemical indices. Fifty-five apparently healthy subjects, in 5 groups, engaged in a 10-day trip through the Pyrenees. They walked 14 km/day on average, carrying an 8-kilo backpack. Raw food was provided and self-prepared and water was obtained from waterholes. They slept outside in sleeping bags and were exposed to temperatures ranging from 12 to 42°C. Anthropometric data and fasting blood samples were collected at baseline and the study end. We found important significant changes in most outcomes favoring better metabolic functioning and improved anthropometrics. Coping with "ancient mild stress factors," including physical exercise, thirst, hunger, and climate, may influence immune status and improve anthropometrics and metabolic indices in healthy subjects and possibly patients suffering from metabolic and immunological disorders.

Various positively selected adaptations to new nutrients have been identified. Lactase persistence is among the best known, conferring the ability for drinking milk at post weaning age. An augmented number of amylase gene (AMY1) copies, giving rise to higher salivary amylase activity, has been implicated in the consumption of starch-rich foods. Higher AMY1 copy numbers have been demonstrated in populations with recent histories of starchy-rich diets. It is however questionable whether the resulting polymorphisms have exerted positive selection only by providing easily available sources of macro and micronutrients. Humans have explored new environments more than any other animal. Novel environments challenge the host, but especially its immune system with new climatic conditions, food and especially pathogens. With the advent of the agricultural revolution and the concurrent domestication of cattle came new pathogens. We contend that specific new food ingredients (e.g., gluten) and novel pathogens drove selection for lactase persistence and higher AMY gene copy numbers. Both adaptations provide ample glucose for activating the sodium glucose-dependent co-transporter 1 (SGLT1), which is the principal glucose, sodium and water transporter in the gastro-intestinal tract. Their rapid uptake confers protection against potentially lethal dehydration, hyponatremia and ultimately multiple organ failure. Oral rehydration therapy aims at SGLT1 activity and is the current treatment of choice for chronic diarrhoea and vomiting. We hypothesize that lifelong lactase activity and rapid starch digestion should be looked at as the evolutionary covalent of oral rehydration therapy. (C) 2014 Elsevier Ltd. All rights reserved.

In this review, we focus on lifestyle changes, especially dietary habits, that are at the basis of chronic systemic low grade inflammation, insulin resistance and Western diseases. Our sensitivity to develop insulin resistance traces back to our rapid brain growth in the past 2.5 million years. An inflammatory reaction jeopardizes the high glucose needs of our brain, causing various adaptations, including insulin resistance, functional reallocation of energy-rich nutrients and changing serum lipoprotein composition. The latter aims at redistribution of lipids, modulation of the immune reaction, and active inhibition of reverse cholesterol transport for damage repair. With the advent of the agricultural and industrial revolutions, we have introduced numerous false inflammatory triggers in our lifestyle, driving us to a state of chronic systemic low grade inflammation that eventually leads to typically Western diseases via an evolutionary conserved interaction between our immune system and metabolism. The underlying triggers are an abnormal dietary composition and microbial flora, insufficient physical activity and sleep, chronic stress and environmental pollution. The disturbance of our inflammatory/anti-inflammatory balance is illustrated by dietary fatty acids and antioxidants. The current decrease in years without chronic disease is rather due to "nurture" than "nature," since less than 5% of the typically Western diseases are primary attributable to genetic factors. Resolution of the conflict between environment and our ancient genome might be the only effective manner for "healthy aging," and to achieve this we might have to return to the lifestyle of the Paleolithic era as translated to the 21st century culture. (C) 2013 Elsevier Inc. All rights reserved.

Aging can result in major changes in the composition and metabolic activities of bacterial populations in the gastrointestinal system and result in impaired function of the immune system. We assessed the efficacy of prebiotic Darmocare Pre (R) (Bonusan Besloten Vennootschap (BV), Numansdorp, The Netherlands) to evaluate whether the regular intake of this product can improve frailty criteria, functional status and response of the immune system in elderly people affected by the frailty syndrome. The study was a placebo-controlled, randomized, double blind design in sixty older participants aged 65 and over. The prebiotic product was composed of a mixture of inulin plus fructooligosaccharides and was compared with placebo (maltodextrin). Participants were randomized to a parallel group intervention of 13 weeks' duration with a daily intake of Darmocare Pre (R) or placebo. Either prebiotic or placebo were administered after breakfast (between 9-10 a.m.) dissolved in a glass of water carefully stirred just before drinking. The primary outcome was to study the effect on frailty syndrome. The secondary outcomes were effect on functional and cognitive behavior and sleep quality. Moreover, we evaluated whether prebiotic administration alters blood parameters (haemogram and biochemical analysis). The overall rate of frailty was not significantly modified by Darmocare Pre (R) administration. Nevertheless, prebiotic administration compared with placebo significantly improved two frailty criteria, e.g., exhaustion and handgrip strength (p

Chronic low-grade inflammation and insulin resistance are intimately related entities that are common to most, if not all, chronic diseases of affluence. We hypothesized that a short-term intervention based on “ancient stress factors” may improve anthropometrics and clinical chemical indices. We executed a pilot study of whether a 10-day mimic of a hunter-gatherer lifestyle favorably affects anthropometrics and clinical chemical indices. Fifty-five apparently healthy subjects, in 5 groups, engaged in a 10-day trip through the Pyrenees. They walked 14 km/day on average, carrying an 8-kilo backpack. Raw food was provided and self-prepared and water was obtained from waterholes. They slept outside in sleeping bags and were exposed to temperatures ranging from 12 to 42°C. Anthropometric data and fasting blood samples were collected at baseline and the study end. We found important significant changes in most outcomes favoring better metabolic functioning and improved anthropometrics. Coping with “ancient mild stress factors,” including physical exercise, thirst, hunger, and climate, may influence immune status and improve anthropometrics and metabolic indices in healthy subjects and possibly patients suffering from metabolic and immunological disorders.

The evolution of human kind has taken millions of years in which environmental factors gradually shaped the actual genome adapted to those circumstances. One of the most vital behavioural adaptations of mammals in general and especially humans is their capability of self-sufficiency through physical activity. Physical activity abilities, including long distance running, jumping, climbing and carrying things have probably been necessary to outrun wild animals, search for food and hide for danger. In contrast, individuals physically or psychologically unable to ‘‘take care of themselves’’ were more susceptible for early death and therefore for genetic extinction. The actual society is characterized by sedentary instead of ‘‘moving’’ individuals. Physical inactivity is not just a possible factor related with chronic disease, but should be considered the actual cause of the majority of human illness. Individuals know that exercise is necessary and beneficial. Nevertheless almost 75% of the actual population does not reach the estimated minimum of necessary activity. Physical inactivity belongs to the characteristics of sickness behaviour; the latter which probably is protective for the organism. Sickness behaviour, including depressive mood, seems to protect against infection, injury, social conflict and facilitates energy conservation. Sickness behaviour is based on immune-brain mechanisms and can be defined as non-permissive behaviour. Long-term non-permissive behaviour can lead to chronic disease because of reduction of physical activity and self-defeating coping styles, converting non-permissive behaviour in a non-permissive brain disorder. We propose that physical inactivity disease is synonymous for a non-permissive brain disorder and that NPBD produces a so called ‘‘reptile phenotype’’, characterized by hypothermia, poor hair growth, decreased fertility and low basal metabolic rate.

Gluten-containing cereals are a main food staple present in the daily human diet, including wheat, barley, and rye. Gluten intake is associated with the development of celiac disease (CD) and related disorders such as diabetes mellitus type I, depression, and schizophrenia. However, until now, there is no consent about the possible deleterious effects of gluten intake because of often failing symptoms even in persons with proven CD. Asymptomatic CD (ACD) is present in the majority of affected patients and is characterized by the absence of classical gluten-intolerance signs, such as diarrhea, bloating, and abdominal pain. Nevertheless, these individuals very often develop diseases that can be related with gluten intake. Gluten can be degraded into several morphine-like substances, named gluten exorphins. These compounds have proven opioid effects and could mask the deleterious effects of gluten protein on gastrointestinal lining and function. Here we describe a putative mechanism, explaining how gluten could "mask" its own toxicity by exorphins that are produced through gluten protein digestion.

In recent years, it has become clear that chronic systemic low-grade inflammation is at the root of many, if not all, typically Western diseases associated with the metabolic syndrome. While much focus has been given to sedentary lifestyle as a cause of chronic inflammation, it is less often appreciated that chronic inflammation may also promote a sedentary lifestyle, which in turn causes chronic inflammation. Given that even minor increases in chronic inflammation reduce brain volume in otherwise healthy individuals, the bidirectional relationship between inflammation and sedentary behaviour may explain why humans have lost brain volume in the last 30,000 years and also intelligence in the last 30 years. We review evidence that lack of physical activity induces chronic low-grade inflammation and, consequently, an energy conflict between the selfish immune system and the selfish brain. Although the notion that increased physical activity would improve health in the modern world is widespread, here we provide a novel perspective on this truism by providing evidence that recovery of normal human behaviour, such as spontaneous physical activity, would calm proinflammatory activity, thereby allocating more energy to the brain and other organs, and by doing so would improve human health.

On their way from the Stone Age via the Agricultural Revolution to current high-tech conditions, humans lost their primal foraging behavior. Today, energy expenditure is not necessary anymore for gathering nor hunting, and metabolic diseases are epidemically arising wherever our original Paleolithic lifestyle is turning into a modern sedentary lifestyle. In this pilot study, we followed through the concept that a radical change towards a Paleolithic hunter-gatherer lifestyle could serve as therapy against any metaflammatory disease, even in the short term. Thirteen healthy adult volunteers were transferred to the DELUX National Park (Germany and Luxembourg) for four days and three nights, where Stone Age conditions where mimicked. Thirty-eight biochemical and bioelectrical parameters were measured from participants before and after this relocation. Body weight (-3,9%), body fat (-7,5%), body mass index (-3,8%), visceral fat area (-14,4%) and metaflammation-related parameters (fasting glucose = -18,2%; fasting insulin = -50,1%; HOMA = -57,8%) decreased significantly. C-reactive protein, as the main indicator for low-grade inflammation, increased up to an average of 169,6 %. Our data show that returning to our Paleolithic roots may have positive effects on risk factors commonly associated with metabolic disorders, such as obesity and type 2 diabetes. These findings may lead the way to further research to answer the question whether the already existing metabolic conditions and/or autoimmune and neuroinflammatory diseases could be influenced by a Paleolithic lifestyle.

Wheat is one of the most consumed cereal grains worldwide and makes up a substantial part of the human diet. Although government-supported dietary guidelines in Europe and the U.S.A advise individuals to eat adequate amounts of (whole) grain products per day, cereal grains contain “anti-nutrients,” such as wheat gluten and wheat lectin, that in humans can elicit dysfunction and disease. In this review we discuss evidence from in vitro, in vivo and human intervention studies that describe how the consumption of wheat, but also other cereal grains, can contribute to the manifestation of chronic inflammation and autoimmune diseases by increasing intestinal permeability and initiating a pro-inflammatory immune response.

Serhan and colleagues introduced the term "Resoleomics" in 1996 as the process of inflammation resolution. The major discovery of Serhan's work is that onset to conclusion of an inflammation is a controlled process of the immune system (IS) and not simply the consequence of an extinguished or "exhausted" immune reaction. Resoleomics can be considered as the evolutionary mechanism of restoring homeostatic balances after injury, inflammation and infection. Under normal circumstances, Resoleomics should be able to conclude inflammatory responses. Considering the modern pandemic increase of chronic medical and psychiatric illnesses involving chronic inflammation, it has become apparent that Resoleomics is not fulfilling its potential resolving capacity. We suggest that recent drastic changes in lifestyle, including diet and psycho-emotional stress, are responsible for inflammation and for disturbances in Resoleomics. In addition, current interventions, like chronic use of anti-inflammatory medication, suppress Resoleomics. These new lifestyle factors, including the use of medication, should be considered health hazards, as they are capable of long-term or chronic activation of the central stress axes. The IS is designed to produce solutions for fast, intensive hazards, not to cope with long-term, chronic stimulation. The never-ending stress factors of recent lifestyle changes have pushed the IS and the central stress system into a constant state of activity, leading to chronically unresolved inflammation and increased vulnerability for chronic disease. Our hypothesis is that modern diet, increased psycho-emotional stress and chronic use of anti-inflammatory medication disrupt the natural process of inflammation resolution ie Resoleomics.

One of the major problems in modern medicine is to find remedies for the group of people with chronic pain syndromes. Low back pain is one of the most frequent syndromes and perhaps the most invalidating of all of them. Chronic pain seems to develop through several pathways affecting the spinal cord and the brain: (1) neuro-anatomical reorganisation, (2) neuro-physiological changes, and (3) activation of glia cells (immune reaction in the central nervous system). Although all of these pathways seem to provide a (partial) plausible explanation for chronic pain, treatments influencing these pathways often fail to alleviate chronic pain patients. This could be because of the probability that chronic pain develops by all three mechanisms of disease. A treatment influencing just one of these mechanisms can only be partially successful. Other factors that seem to contribute to the development of chronic pain are psychosocial. Fear, attention and anxiety are part of the chronic pain syndrome being cause or consequence. The three pathways and the psycho-emotional factors constitute a psycho-neuro-immunological substrate for chronic pain syndromes; a substrate which resembles the substrate for phantom pain and functional invalidity after stroke. Both phantom pain and functional invalidity are considered non-use syndromes. The similarity of the substrate of both these two neurological disorders and chronic pain makes it reasonable to consider chronic pain a non-use disease (the hypothesis). To test this hypothesis, we developed a "paradoxal pain therapy". A therapy which combines the constraint induced movement therapy and strategies to dissociate pain from conditioning factors like fear, anxiety and attention. The aim of the therapy is to establish a behaviour perpendicular on the pathological pain-behaviour. Clinically, the treatment seems promising, although we just have preliminary results. Further clinical and laboratory studies are needed to measure eventual changes at neuro-anatomical and neuro-psychological level using modern neuro-imaging instruments (PET, SPECT, fMRI). Randomised clinical trials should be carried out to test our hypothesis for all-day use in clinical practice. The hypothesis: chronic pain is a non-use disease produced by psycho-emotional factors like fear, attention and anxiety. Optimal treatment should be based on physiological use, and dissociation of pain and the mentioned psycho-emotional factors. Paradoxal pain therapy could serve these treatment conditions.