Exercícios de força com intensidade preferida ou prescrita resultam em efeitos analgésicos semelhantes em pacientes com FM, sugerindo que o modelo de treinamento deve ser recomendado para melhorar a aderência ao exercício. O objetivo foi comparar o efeito de sessões de exercícios de força com intensidade preferida e prescrita na dor de pacientes com FM. De forma aleatória, as mulheres do sexo feminino (n = 32, idade 20-55 anos) foram submetidas às seguintes sessões de exercício: i) prescrição padrão (STD, 6 x 10 repetições com 60% de uma repetição máxima); ii) carga auto-selecionada com número fixo de repetições (SS); iii) carga auto-selecionada com volume total correspondente ao volume STD (SS-VM); e iii) carga auto-selecionada com um número livre de repetições até atingir o escore 7 na Escala de Percepção ao esforço (SS-PSE). A dor foi avaliada através da Escala Visual Analógica (EVA) e do Questionário de Dor de McGill Short-Form (SF-MPQ) antes imediatamente após e 24, 48, 72 e 96 horas após as sessões de exercícios de força. O humor, escala de afetividade ao exercício e a PSE da sessão também foram medidos. A intensidade foi significativamente menor em SS, SS-VM, SS-PSE do que em STD, enquanto o volume total, humor, afetividade ao exercício e PSE não tiveram diferença entre as sessões. As pontuações de VAS também aumentaram imediatamente após todas as sessões de exercício (p < 0,0001) e, em seguida, reduziram significativamente após 48, 72, 96 h (p < 0,0001), permanecendo elevada em relação aos prévalores. Os valores de SF-MPQ aumentaram significativamente imediatamente após todas as sessões de exercício de resistência (p = 0,025), depois diminuíram gradualmente ao longo do tempo, atingindo os níveis basais às 24 h. Não houve efeito de interação significativa para a dor. As sessões de exercício de força prescrita e preferida não foram capaz de induzir analgesia em pacientes com FM, sugerindo que os modelos de exercícios de força que levem a menores intensidades percebidas podem ser necessários para superar essa resposta anormal nesta síndrome / Preferable and prescribed resistance exercises result similar analgesic effects in FM patients suggesting that the training model should be recommended to improve exercise adherence. Compare the effect of preferred and prescribed resistance exercises on pain in FM patients. In a randomized cross-over fashion, FM female patients (n = 32, age 20-55 years) underwent the following exercise sessions: i) standard prescription (STD; 6 x 10 repetitions at 60% of one-maximum repetition); ii) self-selected load with fixed number of repetitions (SS); iii) self-selected load with total volume matched for STD volume (SS-VM); and iii) self-selected load with a free number of repetitions until achieving score 7 in the rating of perceived exertion (SS-RPE). Pain was assessed through the Visual Analogic Scale (VAS) and the Short-Form McGill Pain Questionnaire (SF-MPQ) before and 0, 24, 48, 72 and 96 hours after the resistance exercise sessions. Mood, affective valence scale and session RPE were also measured. Intensity was significantly lower in SS, SS-VM, SS-RPE than in STD, whereas total volume, mood, affective and RPE were comparable between the sessions. VAS scores equally increased immediately after all the exercise sessions (p < 0.0001), and then significantly reduced after 48, 72, 96 h (p < 0.0001), remaining elevated as compared to pre-values. SF-MPQ values significantly increased immediately after all the resistance exercise sessions (p = 0.025), then gradually reduced across time, reaching baseline levels at 24 h. There was no significant interaction effect for pain. Prescribed and preferable resistance exercise equally failed to induce analgesia in FM patients, suggesting that resistance exercise models leading to lower perceived intensities might be needed to overcome this dysfunctional response in this syndromes

Alors que la douleur physiologique est essentielle à la survie de l'individu, les douleurs chroniques sont purement délétères pour l'organisme et la qualité de la vie. Malheureusement, les traitements actuels se limitent à des médicaments peu efficaces ou présentant un mauvais rapport bénéfice / risque. Il est donc urgent de mieux comprendre les mécanismes d'établissement et de persistance des douleurs chroniques, comme les douleurs neuropathiques, afin de concevoir des stratégies thérapeutiques efficaces contre ces pathologies. De nombreuses études ont montré que les canaux calciques de type T sont impliqués dans les états douloureux chroniques. Par exemple, le sous-type Cav3.2, est exprimé tout au long du circuit neuronal nociceptif. Dans le système nerveux périphérique, les canaux Cav3.2 ont un rôle pronociceptif et sont désormais validées comme cibles pour la recherche de thérapies innovantes. En revanche, le rôle du canal Cav3.2 au niveau central, et en particulier dans la moelle épinière, un point névralgique de convergence, d'intégration et de transmission des informations nociceptives, reste à explorer.Grâce à un modèle murin Cav3.2GFP-Lox knock-in créé par l'équipe, nous avons pu identifier/localiser précisément les neurones Cav3.2 positifs dans tout le système nerveux et induire une délétion tissulaire spécifique de Cav3.2 par l’action de la Cre recombinase, pour ensuite en évaluer les effets sur la sensibilité à la douleur. Dans la moelle épinière, nous avons constaté que Cav3.2 est fortement exprimé dans les neurones des laminae superficielles, et sont principalement des neurones excitateurs. La suppression de Cav3.2 spinal par une approche virale a démontré comportementalement : i) l’abolition de l’allodynie au froid et mécanique, de l’hyperalgésie mécanique, ainsi que des douleurs spontanées, en condition neuropathiques chez les mâles et les femelles, ii) une altération de la perception au chaud en condition neuropathique avec un effet différentiel dépendant du sexe, et iii) une réduction de l’anxiété associée aux douleurs chroniques, iv) la suppression des effets analgésiques d’un traitement systémique d’un bloqueur pharmacologique de canaux calciques de type T. Mécanistiquement, les enregistrements extracellulaires in vivo des neurones de projection spinaux démontrent une diminution de l'intégration et de la transmission des messages nociceptifs pathologiques des fibres périphériques C et A-delta lorsque le canal Cav3.2 est délété dans les réseaux spinaux. Cette approche de délétion a été développée avant et après l'induction du modèle de douleur neuropathique pour en évaluer les effets préventifs et curatifs.Les résultats démontrent que la délétion du canal spinal Cav3.2 a des effets préventifs et curatifs sur les symptômes des douleurs neuropathiques. Dans une perspective clinique pour le développement d'analgésiques basés sur les inhibiteurs calciques de type T, nous suggérons de cibler Cav3.2 spinal en plus des canaux dans les neurones afférents primaires par des molécules pénétrant le système nerveux central. / Physiological pain is essential for individual survival, but chronic pains are purely deleterious for the organism and the life quality. Unfortunately, current therapies are limited to drugs with a low efficacy or with a bad benefit/risk ratio. It is thus urgently necessary to better understand the establishment and persistence mechanisms of those chronic pains, like neuropathic pain in order to design efficient therapeutic strategies against this pathology. Many studies have shown that T-type calcium channels are involved in chronic pain states, like Cav3.2 subtypes, all along the nociceptive circuit. In the peripheral nervous system, Cav3.2 channels have pronociceptive impact and are now approved as a target for innovative therapies development. In contrast, the role of Cav3.2 channel in the central nervous system, and especially in the spinal cord, a crucial hotspot of nociceptive information convergence, integration and transmission, remains to be explored.Thanks to a Cav3.2-GFP-Lox murine model created by the team, we were able to i/ identify and precisely localize Cav3.2 positive neurons in all the nervous system and ii/ induce tissue specific deletion of Cav3.2 by the Cre recombinase action, to evaluate effects on pain sensitivity. At the spinal level, we found that Cav3.2 is prominently expressed in lamina II neurons comprising mostly excitatory neurons. Knocking-out spinal Cav3.2 by a viral approach has demonstrated behaviorally i) an abolition of cold and mechanical allodynia, mechanical hyperalgesia and spontaneous pain like behaviors under neuropathic conditions in males and females, ii) an alteration of the hot perception, under pathological pain conditions, with a differential effect in a sex dependent manner, and iii) a modification of anxiety associated to chronic pain, iv) a suppression of the analgesia induced by a systemic treatment with a brain penetrant T-type channel blocker. Mechanistically, extracellular in vivo recordings of spinal projection neurons demonstrate a decrease in integration and transmission of pathologic nociceptive messages from peripheral C- and A-delta fibers by Cav3.2 ablation in spinal networks. This approach has been developed before and after induction of the pain model to evaluate the preventive and curative effect of the treatment.Altogether, the results demonstrate that spinal Cav3.2 channel deletion has preventive and curative effects regarding neuropathic pains symptoms. In a clinical perspective for the development of analgesics based on T-type calcium channel blockers, we suggest the utility of targeting spinal Cav3.2 additionally to channels in primary afferent neurons, a notion already well established.

L’interocezione è definita come il senso della condizione fisiologica dell’intero organismo. Le sensazioni interocettive comprendono un ampio raggio di funzioni biologiche sia consce sia inconsce, e costituiscono la dimensione interna del nostro senso del Se. L’obiettivo primario di questa tesi è stato di capire come le percezioni interne del corpo siano in grado di modificare il nostro senso del se e come questi processi possano essere cambiati, modificati e alterati per migliorare il benessere psicofisiologico. Gli scopi di questa dissertazione sono stati 1) capire come gli input interocettivi sono processati e come contribuiscono al nostra percezione del se e al nostro benessere. 2) sviluppare nuove tecnologie per manipolare il sistema interocettivo al fine di promuovere il benessere. 3) testare queste nuove tecnologie interocettive su soggetti sani e su popolazioni cliniche. La tesi propone nuovi contributi sia teorici sia sperimentali. Nella sezione sperimentale, le tecnologie interocettive sono state testate per promuovere il benessere in popolazioni cliniche e non. I risultati hanno indicato che i trattamenti interocettivi possono promuovere il benessere nei soggetti sani e ridurre la severità dei sintomi in soggetti patologici (i.e., con dolore cronico) confermando la possibilità di manipolare la dimensione interocettiva per promuovere il benessere dell’individuo. / Interoception can be defined as the sense of the physiological condition of the entire organism (Craig, 2003). From this point of view interoceptive sensations entail a broad range of relevant biological functions that serve conscious and unconscious processes and constitute the embodied inner dimension of our sense of Self. The main objective of this thesis was to understand how the perceptions that arise from our body are able to shape our sense of Self and moreover, how these processes can be changed, modified, and altered to improve both our physiological both our psychological well-being. The purpose of this dissertation was 1) to understand how interoceptive inputs are processed and how they contribute to our self-perception and well-being. 2) to develop new interoceptive technologies to manipulate the interoceptive system to promote well-being. 3) to test these new technological applications on healthy and clinical populations. The thesis proposes both theoretical both experimental contributes. In the experimental section interoceptive technologies are tested to promote well-being in healthy and clinical populations. Results indicated that “interoceptive treatment” can both promote well-being in healthy subjects both reduce symptoms severity in clinical subjects (i.e. chronic pain) confirming the possibility to manipulate the interoceptive dimension to enhance healthy functioning.

La recherche dans le domaine de la prise en charge de la douleur, notamment chronique, a un besoind’innovation car les traitements disponibles à l’heure actuelle sont pour la plupart anciens et souventliés à des effets indésirables. Il est maintenant admis que les études précliniques de la douleur ont denombreuses limites : pertinence des modèles, utilisation d’une stimulation douloureuse surajoutée,détermination d’un simple seuil ou délai, prise en compte de la seule composante sensoridiscriminative…De ce fait, certaines molécules efficaces chez l’animal et donc prometteuses, n’ontpas eu les effets escomptés chez l’homme. La base de notre travail de recherche s’attache donc àproposer de nouvelles méthodes d’appréciation de la douleur chronique chez l’animal en prenant encompte ses aspects multidimensionnels. De nombreuses études ont mis en évidence une altération dela qualité de vie chez des patients atteints de douleur chronique. Cette altération se caractérisenotamment par des perturbations émotionnelles et cognitives. Ces paramètres ne sont pas toujours prisen compte chez l’animal dans l’évaluation de traitements antalgiques mais pourrdouleurnt amener denouvelles possibilités et perspectives précliniques. Notre travail a consisté à étudier l’impact de ladouleur sur les comportements spontanés (automatisation du test au formol), la composanteémotionnelle et les capacités cognitives chez le rongeur. Il a été complété par l’exploration du rôle del’amygdale dans les mécanismes impliqués dans ces modifications comportementales.L’amélioration du test au formol a été réalisée dans le but de visualiser au mieux les comportementsspécifiques observés lors d’une douleur aiguë de type inflammatoire. Notre adaptation a permis, chezles mêmes animaux, de pouvoir dissocier l’effet antalgique et l’effet sédatif d’une molécule à l’aided’une méthode automatisée plus rapide et moins subjective.Parallèlement, nous avons apprécié l’impact de la douleur chronique sur la composante émotionnelleet les performances cognitives dans deux modèles de douleur chronique (inflammatoire etneuropathique). Les animaux souffrant de douleur chronique inflammatoire présentent desperturbations plus importantes que les animaux neuropathiques, perturbations pouvant être amélioréespar un traitement pharmacologique. Des études mécanistiques utilisant des micro-injections demorphine au niveau de l’amygdale ont souligné une implication importante du complexe basolatéraldans ces composantes émotionnelles et cognitives de la douleur.Ces nouvelles approches comportementales pourrdouleurnt permettre de mieux caractériser l’impact globalde la douleur chronique chez l’animal et de compléter la batterie de tests couramment utilisés enpréclinique. Ceci pourrait déboucher sur une transposition plus réaliste des résultats obtenus chezl’animal à l’homme, et donc conduire à une meilleure prédictibilité clinique de l’efficacité destraitements. Enfin, la mise en évidence de nouvelles cibles thérapeutiques innovantes implique l’étudedes mécanismes responsables de ces altérations comportementales. / Research in the field of pain management, including chronic pain management, needs innovationbecause available treatments are mostly old and often associated with many side effects. It is now wellrecognized that preclinical studies on pain have many limitations: the relevance of the models, the useof imposed painful stimulations, determination of simple thresholds or delays, taking into account thesensory-discriminative component of pain alone… Indeed, some molecules that are efficient inanimals and that are considered as promising, didn’t have the desired effect in humans. Therefore, thebasis of our research aims to propose new methods to assess chronic pain in animals taking intoaccount its multidimensional aspects. Many studies have shown impaired quality of life in patientssuffering from chronic pain. This alteration is characterized by emotional and cognitive disturbances.These components of pain are not always taken into account in animal when studying analgesictreatments, but could bring new preclinical possibilities and perspectives. Our work consisted instudying the impact of pain on spontaneous behaviours (automated formalin test), emotionalcomponent and cognitive capacities in rodents. This work has been completed by the exploration ofthe role of the amygdala in the mechanisms underlying those behavioural modifications.Improvement of the formalin test was conducted in order to better visualize the specific behaviorsobserved during an acute inflammatory pain. Our adaptation has allowed dissociating the analgesicand sedative effect of a molecule in a same animal, using an automated method which is faster and lesssubjective than the manual method.In the meantime, we assessed the impact of chronic pain on the emotional and cognitive performancesin two models of chronic pain (inflammatory and neuropathic). Animals suffering from chronicinflammatory pain have more important impairments than animal suffering from neuropathic pain,impairments that can be improved with a pharmacological treatment. Mechanistic studies using microinjectionsof morphine in the amygdala have emphasized an important involvement of the basolateralcomplex in these emotional and cognitive components of pain.These new behavioural approaches may help better characterize the overall impact of chronic pain inanimals and complete the battery of tests commonly used in preclinical studies. This could lead to amore realistic transposition of the results obtained from animals to humans, and thus lead to betterpredictability for the clinical efficacy of treatments. Finally, the identification of new targets forinnovative therapies involves the study of mechanisms responsible for these behavioral impairments.

<p>As the number one cause of sick absenteeism and disability pension, musculoskeletal pain is considered a major health problem in Sweden and many other industrialized countries. Medical findings are often insufficient to explain the pain’s intensity or duration, and psychological factors are known to be important in understanding the aetiology and maintenance of pain. The current thesis examines the relationship between non-specific chronic musculoskeletal pain and cognitions, emotions and behaviours. In Study I, chronic pain patients were interviewed about pain experiences and the results indicated that some patients use psychological defences to deal with chronic pain. Study II was an experimental approach set up to study the association between chronic pain and selective memory. In a pictorial memory game, no differences were found between patients and controls in the neutral game. In the pain-related game patients decreased – and controls improved – their performance, a finding discussed in terms of cognitive avoidance. Study III used questionnaire and register data to examine the predictive value of psychosocial variables on sustained pain-related sick absenteeism and the results showed sense of mastery and recovery beliefs to be especially important. The studies are discussed in terms of emotional and defensive coping and it is suggested that defences can be related to excessive activity, which may increase the risk of future relapses. It was suggested that an increased acceptance of pain, at both an individual and a societal level – would favour rehabilitation and return-to-work for those suffering from persistent pain.</p>

<p>This thesis deals with clinical pain intervention research from a behavioural medicine perspective. The general aim was to develop and evaluate an individually tailored treatment protocol focused on pain management in everyday life in people who experience persistent musculoskeletal pain. Another aim was to develop and incorporate an idiographic outcome measure for behavioural goal assessment in the formal evaluation of the clinical significance of treatment outcomes. </p><p>The studies were conducted in a primary health care setting demonstrating a contribution from physical therapists in the field of behavioural medicine. Two separate samples of patients with musculoskeletal pain with a duration exceeding one month, n = 197 (Study I, descriptive and correlational design), and n = 97/82 (Study III/IV, randomized group-study) were included. In addition, four women were recruited for a series of experimental single-case studies (Study II).</p><p>The treatment protocol that was individually tailored to each participant’s behavioural treatment goals and assumed determinants of pain-related disability was more effective in reducing pain-related disability, pain intensity, fear-avoidance, and in increasing pain control when compared to an intervention including physical exercises. The individually tailored treatment was generally more beneficial for resumption of everyday life activity, increasing satisfaction, fulfilling pre-treatment expectations, and in preparing individuals for self-management of pain. The Patient Goal Priority Questionnaire that was elaborated over the course of the project can be used to a) identify and assess behavioural treatment goals, b) elaborate individual functional behavioural analyses relevant for everyday life functioning, and c) determine the clinical significance of treatment outcomes – that is, whether interventions produce outcomes of relevance for each individual’s everyday life. The inclusion of idiographic outcome measures in clinical pain intervention research is necessary and improves the ecological validity of the evaluation of clinical significance. </p>

Groin hernia is common, and each year 200 repairs per 100 000 adult inhabitants are performed in Sweden. Groin hernias are either inguinal or femoral (2-4%). Elective repair is not associated with an excess mortality, but adverse outcomes include recurrence and long-term pain. Emergency procedures have a 4% mortality rate with an increased risk for bowel resection and postoperative complications. The aim of this thesis was to identify risk factors for adverse outcomes and to propose measures to improve groin hernia treatment. Twenty-three per cent of female hernias were femoral. Thirty-six per cent of femoral hernias, and 5% of inguinal hernias, have emergency procedures. Females (OR 1.47) and patients above 65 years-of-age (OR 2.24) were at higher risk for emergency repair. Bowel resection was performed in 23% of emergency femoral repairs, and the 30-day mortality was 10 times that of an age- and gender-matched population. The majority of emergency patients were unaware of their hernia, and one third had previously had no groin symptoms. Femoral repairs were at larger risk for recurrence than inguinal repairs. The surgical techniques with least risk for recurrence were preperitoneal mesh repairs (open HR 0.28, and laparoscopic HR 0.31). Long-term pain was present in 24% of femoral hernia patients, of whom 5.5% described pain interfering with daily activities. The only factor predicting the risk for long-term pain was pain preoperatively. Pain decreased with time. In a randomized study on inguinal hernia, TEP resulted in less pain six weeks after surgery than Lichtenstein repair performed under local anesthesia (LLA). TEP patients were to a larger extent able to perform sporting activities. No difference was seen in intra-operative complications. Femoral hernias should be given high priority for repair and preperitoneal techniques should be used. Earlier diagnosis, in the elective setting, is probably difficult to attain. Heightened awareness in the emergency department is required. TEP is safe, and results in less pain than LLA six weeks after surgery. A widening of indications for TEP in primary inguinal hernia repair is justifiable.

This thesis deals with clinical pain intervention research from a behavioural medicine perspective. The general aim was to develop and evaluate an individually tailored treatment protocol focused on pain management in everyday life in people who experience persistent musculoskeletal pain. Another aim was to develop and incorporate an idiographic outcome measure for behavioural goal assessment in the formal evaluation of the clinical significance of treatment outcomes. The studies were conducted in a primary health care setting demonstrating a contribution from physical therapists in the field of behavioural medicine. Two separate samples of patients with musculoskeletal pain with a duration exceeding one month, n = 197 (Study I, descriptive and correlational design), and n = 97/82 (Study III/IV, randomized group-study) were included. In addition, four women were recruited for a series of experimental single-case studies (Study II). The treatment protocol that was individually tailored to each participant’s behavioural treatment goals and assumed determinants of pain-related disability was more effective in reducing pain-related disability, pain intensity, fear-avoidance, and in increasing pain control when compared to an intervention including physical exercises. The individually tailored treatment was generally more beneficial for resumption of everyday life activity, increasing satisfaction, fulfilling pre-treatment expectations, and in preparing individuals for self-management of pain. The Patient Goal Priority Questionnaire that was elaborated over the course of the project can be used to a) identify and assess behavioural treatment goals, b) elaborate individual functional behavioural analyses relevant for everyday life functioning, and c) determine the clinical significance of treatment outcomes – that is, whether interventions produce outcomes of relevance for each individual’s everyday life. The inclusion of idiographic outcome measures in clinical pain intervention research is necessary and improves the ecological validity of the evaluation of clinical significance.

As the number one cause of sick absenteeism and disability pension, musculoskeletal pain is considered a major health problem in Sweden and many other industrialized countries. Medical findings are often insufficient to explain the pain’s intensity or duration, and psychological factors are known to be important in understanding the aetiology and maintenance of pain. The current thesis examines the relationship between non-specific chronic musculoskeletal pain and cognitions, emotions and behaviours. In Study I, chronic pain patients were interviewed about pain experiences and the results indicated that some patients use psychological defences to deal with chronic pain. Study II was an experimental approach set up to study the association between chronic pain and selective memory. In a pictorial memory game, no differences were found between patients and controls in the neutral game. In the pain-related game patients decreased – and controls improved – their performance, a finding discussed in terms of cognitive avoidance. Study III used questionnaire and register data to examine the predictive value of psychosocial variables on sustained pain-related sick absenteeism and the results showed sense of mastery and recovery beliefs to be especially important. The studies are discussed in terms of emotional and defensive coping and it is suggested that defences can be related to excessive activity, which may increase the risk of future relapses. It was suggested that an increased acceptance of pain, at both an individual and a societal level – would favour rehabilitation and return-to-work for those suffering from persistent pain.

This thesis is on chronic neck pain after a rear impact car injury, so called whiplash associated disorder (WAD). Three empirical studies using positron emission tomography (PET) with different radioligands have been performed. The first study evaluated resting state regional cerebral blood flow (rCBF) in WAD patients and in healthy, pain-free controls, by use of oxygen-15 labeled water. Patients had heightened resting rCBF bilaterally in the posterior parahippocampal and the posterior cingulate gyri, in the right thalamus and in the right medial prefrontal gyrus. Attenuated tempero-occipital blood flow was also observed in the patient group as compared to healthy controls. Alterations in rCBF were related to patients’ neck disability ratings. Study I suggests an involvement of the posterior cingulate, the parahippocampal and the medial prefrontal gyri in WAD. This altered resting state neural activity may be linked to an increased self-relevant evaluation of pain and stress. The second study evaluated central expression of the neurokinin-1 (NK1) receptor in WAD patients and healthy controls. Using a carbon-11 labeled specific NK1 antagonist, the receptor availability was measured. Patients displayed lowered NK1 receptor availability in the insula, anterior cingulate, frontal lobe, hippocampus, amygdala and in the periaqueductal gray matter, consistent with results from animal models of chronic pain. NK1 receptor availability was most reduced in the ventromedial orbitofrontal cortex, where attenuations were linearly related to patients fear and avoidance of movement. Thirdly, carbon-11 labeled D-deprenyl was used to investigate the presence of locally inflamed soft tissue in the cervical neck in WAD patients. Although the retention mechanism of [11C]D-deprenyl is not known, the results suggest that WAD patients have chronic inflammatory processes in the neck, most commonly in the adipose tissue at the spineous process of the second vertebra. In summary, this thesis provides evidence for altered central blood flow and receptor characteristics in WAD patients. Further, WAD patients may also have signs of persistent peripheral tissue damage. Both central and peripheral pain mechanisms have been demonstrated and visualized in patients with whiplash associated disorder.