Protease-Induced Excitation of Dorsal Root Ganglion Neurons in Response to Acute Perturbation of the Gut Microbiota Is Associated With Visceral and Somatic Hypersensitivity.

BACKGROUND & AIMS: Abdominal pain is a major symptom of diseases that are associated with microbial dysbiosis, including irritable bowel syndrome and inflammatory bowel disease. Germ-free mice are more prone to abdominal pain than conventionally housed mice, and reconstitution of the microbiota in germ-free mice reduces abdominal pain sensitivity. However, the mechanisms underlying microbial modulation of pain remain elusive. We hypothesized that disruption of the intestinal microbiota modulates the excitability of peripheral nociceptive neurons. METHODS: In vivo and in vitro assays of visceral sensation were performed on mice treated with the nonabsorbable antibiotic vancomycin (50 µg/mL in drinking water) for 7 days and water-treated control mice. Bacterial dysbiosis was verified by 16s rRNA analysis of stool microbial composition. RESULTS: Treatment of mice with vancomycin led to an increased sensitivity to colonic distension in vivo and in vitro and hyperexcitability of dorsal root ganglion (DRG) neurons in vitro, compared with controls. Interestingly, hyperexcitability of DRG neurons was not restricted to those that innervated the gut, suggesting a widespread effect of gut dysbiosis on peripheral pain circuits. Consistent with this, mice treated with vancomycin were more sensitive than control mice to thermal stimuli applied to hind paws. Incubation of DRG neurons from naive mice in serum from vancomycin-treated mice increased DRG neuron excitability, suggesting that microbial dysbiosis alters circulating mediators that influence nociception. The cysteine protease inhibitor E64 (30 nmol/L) and the protease-activated receptor 2 (PAR-2) antagonist GB-83 (10 µmol/L) each blocked the increase in DRG neuron excitability in response to serum from vancomycin-treated mice, as did the knockout of PAR-2 in NaV1.8-expressing neurons. Stool supernatant, but not colonic supernatant, from mice treated with vancomycin increased DRG neuron excitability via cysteine protease activation of PAR-2. CONCLUSIONS: Together, these data suggest that gut microbial dysbiosis alters pain sensitivity and identify cysteine proteases as a potential mediator of this effect.

Immune determinants of CAR-T cell expansion in solid tumor patients receiving GD2 CAR-T cell therapy.

Chimeric antigen receptor T cells (CAR-Ts) have remarkable efficacy in liquid tumors, but limited responses in solid tumors. We conducted a Phase I trial (NCT02107963) of GD2 CAR-Ts (GD2-CAR.OX40.28.z.iC9), demonstrating feasibility and safety of administration in children and young adults with osteosarcoma and neuroblastoma. Since CAR-T efficacy requires adequate CAR-T expansion, patients were grouped into good or poor expanders across dose levels. Patient samples were evaluated by multi-dimensional proteomic, transcriptomic, and epigenetic analyses. T cell assessments identified naive T cells in pre-treatment apheresis associated with good expansion, and exhausted T cells in CAR-T products with poor expansion. Myeloid cell assessment identified CXCR3+ monocytes in pre-treatment apheresis associated with good expansion. Longitudinal analysis of post-treatment samples identified increased CXCR3- classical monocytes in all groups as CAR-T numbers waned. Together, our data uncover mediators of CAR-T biology and correlates of expansion that could be utilized to advance immunotherapies for solid tumor patients.

Trends in Brain Research: A Bibliometric Analysis.

BACKGROUND: Bibliometrics methods have allowed researchers to assess the popularity of brain research through the ever-growing number of brain-related research papers. While many topics of brain research have been covered by previous studies, there is no comprehensive overview of the evolution of brain research and its various specialties and funding practices over a long period of time. OBJECTIVE: This paper aims to (1) determine how brain research has evolved over time in terms of number of papers, (2) countries' relative and absolute positioning in terms of papers and impact, and (3) how those various trends vary by area. METHODS: Using a list of validated keywords, we extracted brain-related articles and journals indexed in the Web of Science over the 1991-2020 period, for a total of 2,467,708 papers. We used three indicators to perform: number of papers, specialization, and research impact. RESULTS: Our results show that over the past 30 years, the number of brain-related papers has grown at a faster pace than science in general, with China being at the forefront of this growth. Different patterns of specialization among countries and funders were also underlined. Finally, the NIH, the European Commission, the National Natural Science Foundation of China, the UK Medical Research Council, and the German Research Foundation were found to be among the top funders. CONCLUSION: Despite data-related limitations, our findings provide a large-scope snapshot of the evolution of brain research and its funding, which may be used as a baseline for future studies on these topics.

Advanced Dynamic Weight Bearing as an Observer-independent Measure of Hyperacute Hypersensitivity in Mice.

Background: Standard methods assessing pain in rodents are often observer dependent, potentially resulting in biased outcomes. Advanced dynamic weight bearing (ADWB) offers an observer-independent approach that can provide objective, reliable data in preclinical pain research. Aims: The aim of this study was to characterize the use of ADWB in assessing murine responses to allyl isothiocyanate (AITC)-induced hyperacute hypersensitivity and identify best practices for use of the device. Methods: Male C57BL/6J mice received intraplantar injections of saline or 0.1% AITC solution and were assessed using the ADWB system; simultaneous observer-dependent durations of paw licking and biting were measured. ADWB data were analyzed using the proprietary software from Bioseb and correlated to observer-dependent results, with parameters assessed to optimize data collected. Results: ADWB detected pain-directed changes in weight and surface area distribution in AITC-treated mice, with paw weight and surface area placement correlating to paw licking and biting. Optimization of adjustable threshold parameters allowed for reduced coefficients of variability and increased duration of validated data. Conclusions: The ADWB assay provides an efficient and unbiased measure of chemical-induced hyperacute hypersensitivity in mice. ADWB detection parameters influence amount of validated data and variability, a consideration for data analysis in future studies.

Contexte: Les méthodes standard d'évaluation de la douleur chez les rongeurs dépendent souvent de l'observateur, ce qui peut fausser les résultats. La mise en charge dynamique avancée offre une approche indépendante de l'observateur qui peut fournir des données objectives et fiables dans la recherche préclinique sur la douleur.Objectifs: L'objectif de cette étude était de caractériser l'utilisation de la mise en charge dynamique avancée dans l'évaluation des réponses murines à l'hypersensibilité hyperaiguë induite par l'isothiocyanate d'allyle et de répertorier les meilleures pratiques d'utilisation de l'appareil.Méthodes: Des souris C57BL/6J mâles ont reçu des injections intraplantaires de solution saline ou de solution d'isothiocyanate d'allyle à 0,1 % et ont été évaluées à l'aide du système de mise en charge dynamique avancée; les durées simultanées de léchage et de morsure des pattes, dépendantes de l'observateur, ont été mesurées. Les données obtenues par la mise en charge dynamique avancée ont été analysées à l'aide du logiciel propriétaire de Bioseb et corrélées aux résultats dépendants de l'observateur, avec des paramètres évalués pour optimiser les données collectées.Résultats: L'essai réalisé à l'aide de la mise en charge dynamique avancée a détecté des changements de poids et de distribution de surface liés à la douleur chez les souris traitées à l'isothiocyanate d'allyle, le poids des pattes et le placement de la surface étant corrélés au léchage et à la morsure des pattes. L'optimisation des paramètres de seuil ajustables a permis de réduire les coefficients de variabilité et d'augmenter la durée des données validées.Conclusion: L'essai réalisé à l'aide de la mise en charge dynamique avancée fournit une mesure efficace et impartiale de l'hypersensibilité hyperaiguë induite par les produits chimiques chez la souris. Les paramètres de détection du système de mise en charge dynamique avancée influencent la quantité de données validées et la variabilité, ce qui doit être pris en compte pour l'analyse des données dans les études futures.

Skin-resident dendritic cells mediate postoperative pain via CCR4 on sensory neurons.

Inflammatory pain, such as hypersensitivity resulting from surgical tissue injury, occurs as a result of interactions between the immune and nervous systems with the orchestrated recruitment and activation of tissue-resident and circulating immune cells to the site of injury. Our previous studies identified a central role for Ly6Clow myeloid cells in the pathogenesis of postoperative pain. We now show that the chemokines CCL17 and CCL22, with their cognate receptor CCR4, are key mediators of this response. Both chemokines are up-regulated early after tissue injury by skin-resident dendritic and Langerhans cells to act on peripheral sensory neurons that express CCR4. CCL22, and to a lesser extent CCL17, elicit acute mechanical and thermal hypersensitivity when administered subcutaneously; this response abrogated by pharmacological blockade or genetic silencing of CCR4. Electrophysiological assessment of dissociated sensory neurons from naïve and postoperative mice showed that CCL22 was able to directly activate neurons and enhance their excitability after injury. These responses were blocked using C 021 and small interfering RNA (siRNA)-targeting CCR4. Finally, our data show that acute postoperative pain is significantly reduced in mice lacking CCR4, wild-type animals treated with CCR4 antagonist/siRNA, as well as transgenic mice depleted of dendritic cells. Together, these results suggest an essential role for the peripheral CCL17/22:CCR4 axis in the genesis of inflammatory pain via direct communication between skin-resident dendritic cells and sensory neurons, opening therapeutic avenues for its control.

A chronic eyelid lesion in a child: multi-disciplinary approach to diagnosis, treatment and management of a highly atypical histiocytic lesion.

Malignant histiocytic neoplasm with histiocytic sarcoma phenotype is a rare malignant neoplasm, distinguished by malignant cells with phenotypic characteristics of mature tissue histiocytes. Histiocytic sarcoma typically presents as a primary malignancy, although can also present as a secondary malignancy, and is rarely seen in the pediatric population. Due to the rarity of this condition, diagnosis of histiocytic sarcoma is difficult and considered a diagnosis of exclusion. We describe a unique case of a chronic upper eyelid lesion with biopsy findings of a highly atypical histiocytic neoplasm initially concerning for histiocytic sarcoma; however, after integration of clinical findings, non-progressive and quiescent molecular profile, concluded to be an atypical juvenile xanthogranuloma in a child treated with excision and observation alone. This report highlights the importance of an integrated team approach to diagnosis of unusual histiocytic neoplasms.

Spinal cord injury in mice affects central and peripheral pathology in a severity-dependent manner.

ABSTRACT: Chronic pain is a common medical complication experienced by those living with spinal cord injury (SCI) and leads to worsened quality of life. The pathophysiology of SCI pain is poorly understood, hampering the development of safe and efficacious therapeutics. We therefore sought to develop a clinically relevant model of SCI with a strong pain phenotype and characterize the central and peripheral pathology after injury. A contusion (50 kdyn) injury, with and without sustained compression (60 seconds) of the spinal cord, was performed on female C57BL/6J mice. Mice with compression of the spinal cord exhibited significantly greater heat and mechanical hypersensitivity starting at 7 days postinjury, concomitant with reduced locomotor function, compared with those without compression. Immunohistochemical analysis of spinal cord tissue revealed significantly less myelin sparing and increased macrophage activation in mice with compression compared with those without. As measured by flow cytometry, immune cell infiltration and activation were significantly greater in the spinal cord (phagocytic myeloid cells and microglia) and dorsal root ganglia (Ly6C+ monocytes) after compression injury. We also decided to investigate the gastrointestinal microbiome, as it has been shown to be altered in patients with SCI and has recently been shown to play a role in immune system maturation and pain. We found increased dysbiosis of the gastrointestinal microbiome in an injury severity-dependent manner. The use of this contusion-compression model of SCI may help advance the preclinical assessment of acute and chronic SCI pain and lead to a better understanding of mechanisms contributing to this pain.

Weight bearing as a measure of disease progression in experimental autoimmune encephalomyelitis.

Motor disability in multiple sclerosis is often modeled using experimental autoimmune encephalomyelitis (EAE) and assessed using the clinical score (CS), an observer-dependent tool that can lead to potential bias. The Advanced Dynamic Weight Bearing (ADWB) system was evaluated as an observer-independent measurement of EAE symptoms. ADWB detected weight shifts onto the front paws as mice develop hindlimb motor disability. CS and ADWB were strongly correlated, indicated that these measures are comparable and suggesting that ADWB may be an appropriate observer-independent tool for the assessment of EAE progression.

Systemic and Nodular Hyperinflammation in a Patient with Refractory Familial Hemophagocytic Lymphohistiocytosis 2.

Familial hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome resulting from defective cytotoxicity. A previously healthy 3-month-old female presented with fever, irritability, abdominal distention, and tachypnea. She ultimately met all eight HLH-2004 diagnostic criteria, accompanied by elevated CXCL9. Initial empiric anti-inflammatory treatment included anakinra and IVIg, which stabilized ferritin and cytopenias. She had molecular and genetic confirmation of perforin deficiency and was started on dexamethasone and etoposide per HLH-94. She clinically improved, though CXCL9 and sIL-2Ra remained elevated. She was readmitted at week 8 for relapsed HLH without clear trigger and HLH-94 induction therapy was reinitiated. Her systemic HLH symptoms failed to respond and she soon developed symptomatic CNS HLH. She was incidentally found to have multifocal lung and kidney nodules, which were sterile and consisted largely of histiocytes and activated, oligoclonal CD8 T cells. The patient had a laboratory response to salvage therapy with alemtuzumab and emapalumab, but progressive neurologic decline led to withdrawal of care. This report highlights HLH foci manifest as pulmonary/renal nodules, demonstrates the utility of monitoring an array of HLH biomarkers, and suggests possible benefit of earlier salvage therapy.

Chronic mechanical hypersensitivity in experimental autoimmune encephalomyelitis is regulated by disease severity and neuroinflammation.

Chronic pain severely affects quality of life in more than half of people living with multiple sclerosis (MS). A commonly-used model of MS, experimental autoimmune encephalomyelitis (EAE), typically presents with hindlimb paralysis, neuroinflammation and neurodegeneration. However, this paralysis may hinder the use of pain behavior tests, with no apparent hypersensitivity observed post-peak disease. We sought to adapt the classic actively-induced EAE model to optimize its pain phenotype. EAE was induced with MOG35-55/CFA and 100-600 ng pertussis toxin (PTX), and mice were assessed for mechanical, cold and thermal sensitivity over a 28-day period. Spinal cord tissue was collected at 14 and 28 days post-injection to assess demyelination and neuroinflammation. Only mice treated with 100 ng PTX exhibited mechanical hypersensitivity. Hallmarks of disease pathology, including demyelination, immune cell recruitment, cytokine expression, glial activation, and neuronal damage were higher in EAE mice induced with moderate (200 ng) doses of pertussis toxin, compared to those treated with low (100 ng) levels. Immunostaining demonstrated activated astrocytes and myeloid/microglial cells in both EAE groups. These results indicate that a lower severity of EAE disease may allow for the study of pain behaviors while still presenting with disease pathology. By using this modified model, researchers may better study the mechanisms underlying pain.

A Central Component of the N1 Event-Related Brain Potential Could Index the Early and Automatic Inhibition of the Actions Systematically Activated by Objects.

Stimuli of the environment, like objects, systematically activate the actions they are associated to. These activations occur extremely fast. Nevertheless, behavioral data reveal that, in most cases, these activations are then automatically inhibited, around 100 ms after the occurrence of the stimulus. We thus tested whether this early inhibition could be indexed by a central component of the N1 event-related brain potential (ERP). To achieve that goal, we looked at whether this ERP component is larger in tasks that could increase the inhibition and in trials where reaction times (RTs) happen to be long. The illumination of a real space bar of a keyboard out of the dark was used as a stimulus. To maximize the modulation of the inhibition, the task participants had to perform was manipulated across blocks. A look-only task and a count task were used to increase inhibition and an immediate press task was used to decrease it. ERPs of the two block-conditions where presses had to be prevented and where the largest central N1s were predicted were compared to those elicited in the press task, differentiating the ERPs to the third of the trials where presses were the slowest from the ERPs to the third of the trials with the fastest presses. Despite larger negativities due to lateralized readiness potentials (LRPs) and despite greater attention likely in immediate press-trials, central N1s were found to be minimal for the fastest presses, intermediate for the slowest ones and maximal for the two no-press conditions. These results thus provide a strong support for the idea that the central N1 indexes an early and short lasting automatic inhibition of the actions systematically activated by objects. They also confirm that the strength of this automatic inhibition spontaneously fluctuates across trials and tasks. On the other hand, just before N1s, parietal P1s were found larger for fastest presses. They might thus index the initial activation of these actions. Finally, consistent with the idea that N300s index late inhibition processes, that occur preferentially when the task requires them, these ERPs were quasi absent for fast presses trials and much larger in the three other conditions.

γδ T Cells Modulate Myeloid Cell Recruitment but Not Pain During Peripheral Inflammation.

Circulating immune cells, which are recruited to the site of injury/disease, secrete various inflammatory mediators that are critical to nociception and pain. The role of tissue-resident immune cells, however, remains poorly characterized. One of the first cells to be activated in peripheral tissues following injury are γδT cells, which serve important roles in infection, disease, and wound healing. Using a mouse line lacking these cells, we sought to identify their contribution to inflammatory pain. Three distinct models of peripheral inflammatory pain were used: intraplantar injection of formalin (spontaneous inflammatory pain), incisional wound (acute inflammatory pain), and intraplantar injection of complete Freund's adjuvant (chronic inflammatory pain). Our results show that absence of γδT cells does not alter baseline sensitivity, nor does it result in changes to mechanical or thermal hypersensitivity after tissue injury. Myeloid cell recruitment did show differential changes between models of acute and chronic inflammatory pain. These results were consistent in both male and female mice, suggesting that there are no sex differences in these outcomes. This comprehensive characterization suggests that γδT cells do not contribute to basal sensitivity or the development and maintenance of inflammatory pain.

Chronobiological regulation of psychosocial and physiological outcomes in multiple sclerosis.

There is mounting scientific evidence showing the importance of innate biological rhythms on disease onset and progression. Perhaps the most important of these is the circadian rhythm, a cycle of oscillations lasting approximately 24 h. Recent work has shown that circadian rhythms are intrinsically linked to the immune system in a bidirectional fashion, and that disruption of these cycles can contribute to changes in pathology and quality of life (including fatigue, mood, and disability). This is particularly true in diseases of the nervous and immune systems. We review here the current preclinical and clinical literature to highlight interactions between circadian rhythms and multiple sclerosis, as well as its animal model, experimental autoimmune encephalomyelitis. We highlight potential benefits of chronotherapy (the temporal administration of immunomodulatory drugs) in an effort to increase treatment efficacy and reduce the negative side-effects of the drugs that often burden those suffering from the disease.

Circadian control of pain and neuroinflammation.

The importance of a neuroinflammatory response to the development and maintenance of inflammatory and neuropathic pain have been highlighted in recent years. Inflammatory cells contributing to this response include circulating immune cells such as monocytes, T and B lymphocytes, and neutrophils, as well as microglia in the central nervous system. Pain signals are transmitted via sensory neurons in the peripheral nervous system, which express various receptors and channels that respond to mediators secreted from these inflammatory cells. Chronobiological rhythms, which include the 24-hr circadian cycle, have recently been shown to regulate both nervous and immune cell activity and function. This review examines the current literature on chronobiological control of neuroinflammatory processes, with a focus on inflammatory and neuropathic pain states. While the majority of this work has stemmed from observational studies in humans, recent advances in using animal models have highlighted distinct mechanisms underlying these interactions. Better understanding interactions between the circadian and neuroimmune systems can help guide the development of new treatments and provide improved care for patients suffering from acute and chronic pain.

Post-concussion symptoms and chronic pain after mild traumatic brain injury are modulated by multiple locus effect in the BDNF gene through the expression of antisense: A pilot prospective control study.

Background: Mild traumatic brain injury (mTBI) often results in post-concussion symptoms, chronic pain, and sleepiness. Genetic factors are thought to play an important role in poor prognosis. Aims: The aims of this study are to (1) document the prevalence of pain and post-concussion symptoms in mTBI patients in acute and chronic phases (2) determine whether candidate genes predispose to post-concussive symptoms and pain. Methods: Posttraumatic symptoms, evaluated using the Rivermead Post-Concussion Symptoms Questionnaire, and pain were assessed in 94 mTBI patients in the acute phase as well as in 22 healthy controls. Assessment was repeated in 36 patients after one year who agreed to participate in the follow-up visit. Gene polymorphisms and expression were assessed in mTBI patients and healthy controls. Results: In the acute phase, mTBI patients with pain (69%) presented more psychological symptoms and sleepiness and were less able to return to work than those without pain. At one year, 19% of mTBI patients had persistent pain and psychological distress. Two haplotypes (H2 and H3) in the brain-derived neurotrophic factor (BDNF) gene were shown to be respectively deleterious and protective against post-concussion symptoms and pain in both acute and chronic phases. Protective haplotype H3 was associated with a decreased expression of the anti-sense of BDNF (BDNF-AS). Deleterious haplotype H2 predicted the development of chronic pain at one year, whereas H3 was protective. Conclusions: This pilot study suggests a protective mechanism of a multilocus effect in BDNF, through BDNF-AS, against post-concussion symptoms and pain in the acute phase and possibly chronic pain at one year post-mTBI. The role of antisense RNA should be validated in larger cohorts.

Contexte: Le traumatisme cranio-cérébral léger (TCCL) donne souvent lieu à des symptômes post-commotionnels, de la douleur chronique et de la somnolence. On croit que des facteurs génétiques jouent un rôle important dans le pronostic défavorable.Buts: Les buts de cette étude sont : 1) documenter la prévalence de la douleur et des symptômes post-commotionnels chez les patients ayant subi un TCCL, au cours des phases aigue et chronique; ii) déterminer si des gènes du candidat le prédisposent à la douleur et aux symptômes post-commotionnels.Méthodes: La douleur et les symptômes post-traumatiques, évalués à l'aide du questionnaire Rivermead sur les symptômes post-commotionnels, ont été évalués chez 94 patients ayant subi un TCCL au cours de la phase aigue, ainsi que chez 22 sujets témoins. Après un an, 36 patients qui avaient accepté de participer à une visite de suivi ont à nouveau été évalués. Les polymorphismes et l'expression des gènes ont été évalués chez les patients ayant subi un TCCL et chez les sujets témoins.Résultats: Au cours de la phase aigue, les patients ayant subi un TCCL avec douleur (69 %) présentaient davantage de symptômes psychologiques et de somnolence et étaient moins aptes à retourner au travail que les patients sans douleur. Après un an, 19 % des patients ayant subi un TCCL souffraient d'une douleur persistante et de détresse psychologique. Deux haplotypes (H2 et H3) dans le gène BDNF se sont montrés respectivement délétère et protecteur contre les symptômes post-commotionnels et contre la douleur, tant au cours de la phase aigue que de la phase chronique. Le haplotype protecteur H3 a été associé à une diminution de l'expression de l'anti-sens de BDNF (BDNF-AS). Le haplotype délétère H2 a prédit le développement de la douleur chronique un an plus tard, tandis que H3 a été protecteur.Conclusions: Cette étude pilote suggère l'existence d'un mécanisme protecteur d'un effet multilocus dans BDNF à travers BDNF-AS, contre les symptômes post-commotionnels et la douleur au cours de la phase aigue et possiblement au cours de la phase chronique, un an après le TCCL. Le rôle de la RNA anti-sens devrait être validé avec de plus grandes cohortes.

Embrained drives to perform extraordinary roles predict schizotypal traits in the general population.

Some personal drives correspond to extraordinary social roles. Given that behavioral strategies associated with such drives may conflict with those associated with ordinary roles, they could cause behavioral disorganization. To test whether they do so independent of the factors responsible for full-blown schizotypy and schizophrenia, these drives were assessed in the general population. Two hundred and nine healthy volunteers were individually presented with hundreds of names of social roles in experimental psychology conditions. The task of the participant was to decide whether or not (s)he would consider performing the role at any moment of his/her life. Schizotypal traits were measured with the schizotypal personality questionnaire (SPQ), and delusion-like ideations were assessed by the Peters et al. Delusion Inventory. Demographics and social desirability were controlled for. Participants accepting a greater percentage of extraordinary roles had higher SPQ scores. Among the three factors of the SPQ, disorganization was the one best predicted by those percentages. This correlation (r=0.40, P=7.2E-09) was significantly greater (Fisher Z-transform, P=0.003) than the correlation between the percentages of ordinary roles accepted and the SPQ scores (r=0.145, P=0.044). Reaction times revealed no suboptimal cognitive functioning in high accepters of extraordinary roles and further strengthened the drive hypothesis. Their acceptances of roles were done faster and their rejections took longer than those of low accepters (P=5E-12). Culturally embrained drives to do extraordinary roles could thus be an independent factor of the symptoms measured in the normality to schizophrenia continuum.

Decisional role preferences, risk knowledge and information interests in patients with multiple sclerosis.

OBJECTIVE: Shared decision making is increasingly recognized as the ideal model of patient-physician communication especially in chronic diseases with partially effective treatments as multiple sclerosis (MS). To evaluate prerequisite factors for this kind of decision making we studied patients' decisional role preferences in medical decision making, knowledge on risks, information interests and the relations between these factors in MS. METHODS: After conducting focus groups to generate hypotheses, 219 randomly selected patients from the MS Outpatient Clinic register (n = 1374) of the University Hospital Hamburg received mailed questionnaires on their knowledge of risks in MS, their perception of their own level of knowledge, information interests and role preferences. RESULTS: Most patients (79%) indicated that they preferred an active role in treatment decisions giving the shared decision and the informed choice model the highest priority. MS risk knowledge was low but questionnaire results depended on disease course, disease duration and ongoing immune therapy. Measured knowledge as well as perceived knowledge was only weakly correlated with preferences of active roles. Major information interests were related to symptom alleviation, diagnostic procedures and prognosis. CONCLUSION: Patients with MS claimed autonomous roles in their health care decisions. The weak correlation between knowledge and preferences for active roles implicates that other factors largely influence role preferences.