One-year regional brain volume changes as potential predictors of cognitive function in multiple sclerosis: a pilot study.

BACKGROUND: The most reliable magnetic resonance imaging (MRI) marker of cognitive dysfunction in multiple sclerosis (MS) is brain atrophy. However, 1-year volumetric changes prior to cognitive assessment were never studied as potential predictors of cognition, which we aim to assess with this pilot work. METHODS: Twenty-two MS patients were submitted to a baseline measure of 83 regional brain volumes with MRI and re-evaluated 1 year later; they were also tested with the Brief International Cognitive Assessment for MS (BICAMS): sustained attention and processing speed were examined with the Symbol Digit Modalities Test (SDMT), verbal and visuo-spatial learning and memory with the learning trials from the California Verbal Learning Test-II (CVLT) and the Brief Visuo-spatial Memory Test-revised (BVMT), respectively. Controlling for age, sex, and years of education, a multivariate linear regression model was created for each cognitive score at 1-year follow-up in a backward elimination manner, considering cross-sectional regional volumes and 1-year volume changes as potential predictors. RESULTS: Decreases in the volumes of the left amygdala and the right lateral orbitofrontal cortex in the year prior to assessment were identified as possible predictors of worse performance in verbal memory (P = 0.009) and visuo-spatial memory (P = 0.001), respectively, independently of cross-sectional brain regional volumes at time of testing. CONCLUSION: Our work reveals novel 1-year regional brain volume changes as potential predictors of cognitive deficits in MS. This suggests a possible role of these regions in such deficits and might contribute to uncover cognitively deteriorating patients, whose detection is still unsatisfying in clinical practice.

Astrocytes Undergo Metabolic Reprogramming in the Multiple Sclerosis Animal Model.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system that presents a largely unknown etiopathology. The presence of reactive astrocytes in MS lesions has been described for a long time; however, the role that these cells play in the pathophysiology of MS is still not fully understood. Recently, we used an MS animal model to perform high-throughput sequencing of astrocytes' transcriptome during disease progression. Our data show that astrocytes isolated from the cerebellum (a brain region typically affected in MS) showed a strong alteration in the genes that encode for proteins related to several metabolic pathways. Specifically, we found a significant increase in glycogen degradation, glycolytic, and TCA cycle enzymes. Together with these alterations, we detected an upregulation of genes that characterize "astrocyte reactivity". Additionally, at each disease time point we also reconstructed the morphology of cerebellum astrocytes in non-induced controls and in EAE animals, near lesion regions and in the normal-appearing white mater (NAWM). We found that near lesions, astrocytes presented increased length and complexity compared to control astrocytes, while no significant alterations were observed in the NAWM. How these metabolic alterations are linked with disease progression is yet to be uncovered. Herein, we bring to the literature the hypothesis of performing metabolic reprogramming as a novel therapeutic approach in MS.

Comparative effectiveness of preventive treatment with dimethyl fumarate-loaded solid lipid nanoparticles and oral dimethyl fumarate in a mouse model of multiple sclerosis.

BACKGROUND: Orally administered dimethyl fumarate (DMF) presents gastrointestinal adverse effects, such as pain and diarrhea, in addition to flushing and lymphopenia. OBJECTIVE: Solid lipid nanoparticles (SLNs) with DMF were developed for subcutaneous administration. METHODS: DMF-incorporated SLNs and free DMF were tested in mice induced with experimental autoimmune encephalomyelitis (EAE). RESULTS: Preventive treatment of free or incorporated DMF were able to reduce the EAE clinical scores, increase the weight of the animals, reduce the lesion area (demyelination and infiltration), reduce microglial fluorescence intensity and reduce the number of microglial cells and astrocytes, when compared to untreated EAE animals. Groups that received DMF had reduced numbers of T cells, B cells and natural killer (NK) cells in the blood, when compared to the non-induced group. CONCLUSIONS: DMF incorporated in SLNs was as effective as free DMF in reducing the clinical scores of the animals, but with reduced administrations when given subcutaneously. In addition, SLN-DMF preventive treatment partially prevented a reduction in the percentages of T and B cells, in the blood, when compared to preventive treatment with free DMF (oral), which suggests reduction of lymphopenia.

Altered astrocytic function in experimental neuroinflammation and multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) that affects about 2.5 million people worldwide. In MS, the patients' immune system starts to attack the myelin sheath, leading to demyelination, neurodegeneration, and, ultimately, loss of vital neurological functions such as walking. There is currently no cure for MS and the available treatments only slow the initial phases of the disease. The later-disease mechanisms are poorly understood and do not directly correlate with the activity of immune system cells, the main target of the available treatments. Instead, evidence suggests that disease progression and disability are better correlated with the maintenance of a persistent low-grade inflammation inside the CNS, driven by local glial cells, like astrocytes and microglia. Depending on the context, astrocytes can (a) exacerbate inflammation or (b) promote immunosuppression and tissue repair. In this review, we will address the present knowledge that exists regarding the role of astrocytes in MS and experimental animal models of the disease.

Enhanced cognitive performance in experimental autoimmune encephalomyelitis mice treated with dimethyl fumarate after the appearance of disease symptoms.

In multiple sclerosis (MS), cognitive dysfunction is common but difficult to treat. We analyzed the impact of dimethyl fumarate, an MS drug with neuroprotective properties, in spatial memory performance in a mouse model of MS and looked for structural correlates in the hippocampus. Treated mice presented better cognitive performance which was not associated with structural hippocampal damage but with decreased demyelination in the fimbria. Dimethyl fumarate, even if initiated after hindlimb paralysis, ameliorated memory deficits in the MS mouse model due, at least in part, to its positive impact in the demyelination of the main hippocampal output pathway.

Structural and molecular correlates of cognitive aging in the rat.

Aging is associated with cognitive decline. Herein, we studied a large cohort of old age and young adult male rats and confirmed that, as a group, old  rats display poorer spatial learning and behavioral flexibility than younger adults. Surprisingly, when animals were clustered as good and bad performers, our data revealed that while in younger animals better cognitive performance was associated with longer dendritic trees and increased levels of synaptic markers in the hippocampus and prefrontal cortex, the opposite was found in the older group, in which better performance was associated with shorter dendrites and lower levels of synaptic markers. Additionally, in old, but not young individuals, worse performance correlated with increased levels of BDNF and the autophagy substrate p62, but decreased levels of the autophagy complex protein LC3. In summary, while for younger individuals "bigger is better", "smaller is better" is a more appropriate aphorism for older subjects.

Brain-machine interface of upper limb recovery in stroke patients rehabilitation: A systematic review.

BACKGROUND: Technologies such as brain-computer interfaces are able to guide mental practice, in particular motor imagery performance, to promote recovery in stroke patients, as a combined approach to conventional therapy. OBJECTIVE: The aim of this systematic review was to provide a status report regarding advances in brain-computer interface, focusing in particular in upper limb motor recovery. METHODS: The databases PubMed, Scopus, and PEDro were systematically searched for articles published between January 2010 and December 2017. The selected studies were randomized controlled trials involving brain-computer interface interventions in stroke patients, with upper limb assessment as primary outcome measures. Reviewers independently extracted data and assessed the methodological quality of the trials, using the PEDro methodologic rating scale. RESULTS: From 309 titles, we included nine studies with high quality (PEDro ≥ 6). We found that the most common interface used was non-invasive electroencephalography, and the main neurofeedback, in stroke rehabilitation, was usually visual abstract or a combination with the control of an orthosis/robotic limb. Moreover, the Fugl-Meyer Assessment Scale was a major outcome measure in eight out of nine studies. In addition, the benefits of functional electric stimulation associated to an interface were found in three studies. CONCLUSIONS: Neurofeedback training with brain-computer interface systems seem to promote clinical and neurophysiologic changes in stroke patients, in particular those with long-term efficacy.

Trait determinants of impulsive behavior: a comprehensive analysis of 188 rats.

Impulsivity is a naturally occurring behavior that, when accentuated, can be found in a variety of neuropsychiatric disorders. The expression of trait impulsivity has been shown to change with a variety of factors, such as age and sex, but the existing literature does not reflect widespread consensus regarding the influence of modulating effects. We designed the present study to investigate, in a cohort of significant size (188 rats), the impact of four specific parameters, namely sex, age, strain and phase of estrous cycle, using the variable delay-to-signal (VDS) task. This cohort included (i) control animals from previous experiments; (ii) animals specifically raised for this study; and (iii) animals previously used for breeding purposes. Aging was associated with a general decrease in action impulsivity and an increase in delay tolerance. Females generally performed more impulsive actions than males but no differences were observed regarding delay intolerance. In terms of estrous cycle, no differences in impulsive behavior were observed and regarding strain, Wistar Han animals were, in general, more impulsive than Sprague-Dawley. In addition to further confirming, in a substantial study cohort, the decrease in impulsivity with age, we have demonstrated that both the strain and sex influences modulate different aspects of impulsive behavior manifestations.

Relationships between neuropsychological and antisaccade measures in multiple sclerosis patients.

BACKGROUND: The Stroop test is frequently used to assess deficits in inhibitory control in people with multiple sclerosis (MS). This test has limitations and antisaccade eye movements, that also measure inhibitory control, may be an alternative to Stroop. OBJECTIVES: The aim of this study was twofold: (i) to investigate if the performance in the antisaccade task is altered in patients with MS and (ii) to investigate the correlation between performances in neuropsychological tests, the Stroop test and the antisaccade task. METHODS: We measured antisaccades (AS) parameters with an infrared eye tracker (SMIRED 250 Hz) using a standard AS paradigm. A total of 38 subjects diagnosed with MS and 38 age and gender matched controls participated in this study. Neuropsychological measures were obtained from the MS group. RESULTS: Patients with MS have higher error rates and prolonged latency than controls in the antisaccade task. There was a consistent association between the Stroop performance and AS latency. Stroop performance but not AS latency was associated with other neuropsychological measures in which the MS group showed deficits. CONCLUSIONS: Our findings suggest that AS may be a selective and independent measure to investigate inhibitory control in patients with MS. More studies are necessary to confirm our results and to describe brain correlates associated with impaired performance in the antisaccade task in people diagnosed with MS.

Physiotherapy based on problem-solving in upper limb function and neuroplasticity in chronic stroke patients: A case series.

RATIONALE, AIMS, AND OBJECTIVES: Upper limb recovery is one of the main concerns of stroke neurorehabilitation. Neuroplasticity might underlie such recovery, particularly in the chronic phase. The purpose of this study was to assess the effect of physiotherapy based on problem-solving in recovering arm function in chronic stroke patients and explore its neuroplastic changes. METHODS: A small sample research design with a n of 3 using a pre-post test design was carried out. Neuroplasticity and function were assessed by using functional magnetic resonance imaging (during motor imagery and performance), action research arm test, motor assessment scale, and Fugl-Meyer assessment scale, at 3 sequential time periods: baseline(m0-before a 4-week period without physiotherapy), pre-treatment(m1), and post-treatment(m2). Minimal clinical important differences and a recovery score were assessed. Assessors were blinded to moment assignment. Patients1 underwent physiotherapy sessions, 50 minutes, 5 days/week for 4 weeks. Four control subjects served as a reference for functional magnetic resonance imaging changes. RESULTS: All patients recovered more than 20% after intervention. Stroke patients had similar increased areas as healthy subjects during motor execution but not during imagination at baseline. Consequently, all patients increased activity in the contralateral precentral area after intervention. CONCLUSIONS: This study indicates that 4 weeks of physiotherapy promoted the recovery of arm function and neuroplasticity in all chronic stroke patients. Future research is recommended to determine the efficacy of this therapy.

Fifteen Years of Experience from a Medical School' Clinical Skills Laboratory.

INTRODUCTION: Medical Education has evolved being defined as a continuum of the medical training from the pre- to the post-graduate period and through a lifetime of medical practice that is mirrored in the competencies framework that several international institutions have established. This creates a challenge to educational institutions (pre- and post-graduate) that traditionally take separate pathways. MATERIAL AND METHODS: The present report is a description of the efforts carried by the School of Medicine of the University of Minho to implement a strategy of teaching/learning methods that follows modern standards towards constructive alignment of the medical curriculum, from the pre- to the post-graduate. The faculty members responsible for these activities make a narrative self-report of the activities developed and where available quantitative data from participant surveys are presented. RESULTS: In order to achieve a constructive alignment of educational/assessment strategies several steps were taken that focused on the revision of the learning goals, teaching methodologies and assessment strategies. This implicated the investment in the training/certification of faculty, acquisition of simulation tools and a dedicated infrastructure. Alumni were a fundamental cornerstone as voluntary faculty contributing to pre-graduate training, but also training their own scholar skills. Overall, courses are rate with a high rate of satisfaction among course participants. DISCUSSION: Setting up the present teaching/learning environment of the School of Medicine of the University of Minho required a collective effort of the faculty, as well a progressive investment in both acquisition of equipment and training of staff. These human and material efforts, however, lead to an excellent return in learning outcomes. CONCLUSION: The main conclusion is that the constructive alignment of educational and assessment strategies towards the medical education continuum needs reflective thinking on the learners' needs. The secondary gain of these initiatives is to provide opportunities for junior doctors to practice teaching.

Introdução: O conceito de Educação Médica tem evoluído sendo definido como um continuum do treino médico desde o pré- ao pós-graduado, prolongando-se por uma vida de prática médica que é espelhada na estrutura de competências que várias instituições internacionais estabeleceram. Isto cria um desafio às instituições de ensino (pre- e pós-graduado) que tradicionalmente funcionam separadamente. Material e Métodos: O presente trabalho reporta os esforços executados pela Escola de Medicina da Universidade do Minho para implementar uma estratégia de métodos de ensino/aprendizagem que seguem os níveis de exigência modernos por forma a se atingir o alinhamento construtivo do currículo médico, desde o pré- ao pós-graduado. Os docentes responsáveis por estas atividades fazem uma narrativa auto reportada das atividades desenvolvidas e quando disponíveis dados quantitativos de inquéritos de avaliação. Resultados: Por forma a atingir o alinhamento construtivo de estratégias educacionais/avaliação vários passos foram dados, que se focaram na revisão dos objetivos de aprendizagem, metodologias de ensino e estratégias de avaliação. Isto implicou o investimento no treino/cerificação dos docentes, aquisição de simuladores e estabelecimento de uma infraestrutura dedicada. Os alumni foram um pilar fundamental trabalhando como docentes voluntários e contribuindo para o treino dos alunos do pré-graduado, e adicionalmente treinando as suas próprias capacidades de ensino. Em geral, os cursos são avaliados com um elevado grau de satisfação entre os participantes dos cursos. Discussão: Montar o atual ambiente de ensino/aprendizagem presente na Escola de Medicina da Universidade do Minho requereu um esforço coletivo dos docentes bem como o investimento progressivo em equipamento e treino da equipa. Estes esforços humanos e materiais, contudo, produziram excelente retorno em termos de resultados de aprendizagem. Conclusão: A principal conclusão é que o alinhamento construtivo das estratégias educativas e de avaliação por forma a atingir as necessidades do continuum da educação médica exige um pensamento reflexivo nas necessidades dos estudantes. Um ganho secundário é que estas iniciativas providenciam oportunidades para médicos juniores praticarem o ensino.

An Objective Structured Clinical Exam to Assess Semiology Skills of Medical Students.

INTRODUCTION: Mastery of history taking and physical exam skills is a key competence of medical students. Objective Structured Clinical Examinations are the gold standard to assess these competencies, but their implementation in Portugal is poorly documented. We describe the implementation and our seven years experience with a high-stakes Objective Structured Clinical Examination to assess these skills in the School of Medicine, University of Minho. MATERIAL AND METHODS: Our Objective Structured Clinical Examination is in place since 2010 and has been subject to continuous improvements, including the adoption of a standard setting procedure and an increase in the number of stations. RESULTS: Grades in our exam are well distributed and discriminate among students. History taking grades are lower and have remained stable throughout the years while physical examination scores have risen. The exam is reliable, with internal consistency above 0.45 and a G-coefficient of 0.74. It is also feasible, with a total testing time of approximately 20 hours for 140 students, and the involvement of 18 standardized patients and 18 faculty assessors. More importantly, it was able to engage the students, who recognize its importance. DISCUSSION: The most important validity criterion of our, and any Objective Structured Clinical Examination, would be predictive validity,the ability to predict the performance of students in the clinical context. CONCLUSION: Our approach to a high-stakes Objective Structured Clinical Examination shows that it is feasible, reliable, valid and fair and can be implemented with success in the Portuguese setting.

Introdução: O domínio das aptidões de colheita de história e do exame físico é uma competência chave para os estudantes de medicina. Os Exames Clínicos Objetivos Estruturados são o padrão para avaliar estas competências, mas a sua implementação em Portugal está pouco documentada. Descrevemos a implementação e a nossa experiência de sete anos, com um Exame Clínico Objetivo Estruturado para avaliar estas aptidões na Escola de Medicina da Universidade do Minho. Material e Métodos: O nosso Exame Clínico Objetivo Estruturado existe desde 2010 e tem sido sujeito a melhorias contínuas, das quais se destacam a adoção de um procedimento de standard setting e o aumento do número de estações. Resultados: As notas no nosso exame estão bem distribuídas e discriminam entre estudantes. As notas da colheita da história são inferiores e têm permanecido estáveis ao longo do tempo, enquanto as do exame físico têm aumentado. O exame é fiável, tendo uma consistência interna acima de 0,45 e um coeficiente G de 0,74. Também é praticável, tendo um tempo total de teste de 20 horas para 140 alunos, envolvendo 18 pacientes estandardizados e 18 examinadores. Mais importante, o Exame Clínico Objetivo Estruturado foi capaz de cativar os estudantes, que reconhecem a sua importância para a sua formação. Discussão: O mais importante critério de valor do nosso, e de qualquer outro Exame Clínico Objetivo Estruturado, será o seu valor preditivo, que se traduz na faculdade de prever o desempenho dos estudantes em contexto clínico. Conclusão: A nossa abordagem para um Exame Clínico Objetivo Estruturado mostra que é praticável, fiável, válido e justo e que pode ser implementado com sucesso no contexto português.

S100B as a Potential Biomarker and Therapeutic Target in Multiple Sclerosis.

Multiple sclerosis (MS) pathology is characterized by neuroinflammation and demyelination. Recently, the inflammatory molecule S100B was identified in cerebrospinal fluid (CSF) and serum of MS patients. Although seen as an astrogliosis marker, lower/physiological levels of S100B are involved in oligodendrocyte differentiation/maturation. Nevertheless, increased S100B levels released upon injury may induce glial reactivity and oligodendrocyte demise, exacerbating tissue damage during an MS episode or delaying the following remyelination. Here, we aimed to unravel the functional role of S100B in the pathogenesis of MS. Elevated S100B levels were detected in the CSF of relapsing-remitting MS patients at diagnosis. Active demyelinating MS lesions showed increased expression of S100B and its receptor, the receptor for advanced glycation end products (RAGE), in the lesion area, while chronic active lesions displayed increased S100B in demyelinated areas with lower expression of RAGE in the rim. Interestingly, reactive astrocytes were identified as the predominant cellular source of S100B, whereas RAGE was expressed by activated microglia/macrophages. Using an ex vivo demyelinating model, cerebral organotypic slice cultures treated with lysophosphatidylcholine (LPC), we observed a marked elevation of S100B upon demyelination, which co-localized mostly with astrocytes. Inhibition of S100B action using a directed antibody reduced LPC-induced demyelination, prevented astrocyte reactivity and abrogated the expression of inflammatory and inflammasome-related molecules. Overall, high S100B expression in MS patient samples suggests its usefulness as a diagnostic biomarker for MS, while the beneficial outcome of its inhibition in our demyelinating model indicates S100B as an emerging therapeutic target in MS.

An efficient chronic unpredictable stress protocol to induce stress-related responses in C57BL/6 mice.

Exposure to chronic stress can have broad effects on health ranging from increased predisposition for neuropsychiatric disorders to deregulation of immune responses. The chronic unpredictable stress (CUS) protocol has been widely used to study the impact of stress exposure in several animal models and consists in the random, intermittent, and unpredictable exposure to a variety of stressors during several weeks. CUS has consistently been shown to induce behavioral and immunological alterations typical of the chronic stress-response. Unfortunately C57BL/6 mice, one of the most widely used mouse strains, due to the great variety of genetically modified lines, seem to be resistant to the commonly used 4-week-long CUS protocol. The definition of an alternative CUS protocol allowing the use of C57BL/6 mice in chronic stress experiments is a need. Here, we show that by extending the CUS protocol to 8 weeks is possible to induce a chronic stress-response in C57BL/6 mice, as revealed by abrogated body weight gain, increased adrenals weight, and an overactive hypothalamic-pituitary-adrenal axis with increased levels of serum corticosterone. Moreover, we also observed stress-associated behavioral alterations, including the potentiation of anxious-like and depressive-like behaviors and a reduction of exploratory behavior, as well as subtle stress-related changes in the cell population of the thymus and of the spleen. The present protocol for C57BL/6 mice consistently triggers the spectrum of CUS-induced changes observed in rats and, thus, will be highly useful to researchers that need to use this particular mouse strain as an animal model of neuropsychiatric disorders and/or immune deregulation related to CUS.

Estudio retrospectivo de la eficacia y seguridad del natalizumab en el tratamiento de la esclerosis múltiple en Portugal / The efficacy and safety of natalizumab for the treatment of multiple sclerosis in Portugal: a retrospective study

Introducción. Los estudios han demostrado que el natalizumab constituye un tratamiento eficaz contra la esclerosis múltiple remitente recurrente (EMRR). Hasta la fecha, no había datos de pacientes portugueses. Objetivo. Determinar la eficacia y la seguridad del natalizumab en pacientes con EMRR atendidos en la práctica clínica ordinaria en Portugal. Pacientes y métodos. Los datos clínicos de adultos con EMRR tratados con natalizumab en centros especializados de neurología en Portugal se introdujeron de forma retrospectiva en una base de datos para llevar a cabo un análisis entre octubre de 2010 y febrero de 2012. Se analizó el cambio en la tasa anualizada de brotes (TAB), en las puntuaciones de la escala ampliada de discapacidad (EDSS) y en el estado de discapacidad. Resultados. Se admitió un total de 383 pacientes atendidos en 20 centros. Antes de iniciar el tratamiento con natalizumab, la mediana inicial de la EDSS era de 4,0 y la TAB media, de 1,64. La mayor parte de los pacientes ya había recibido tratamiento contra la esclerosis múltiple (93,0%). La duración media del tratamiento con natalizumab era de 12 meses. El tratamiento propicio reducciones significativas (p < 0,001) de los valores iniciales de la TAB media y de las puntuaciones EDSS en los tratados con el anticuerpo durante ≥ 12 meses (n = 288) y durante ≥ 24 meses (n = 160). El natalizumab resulto mas eficaz en los pacientes que presentaban un menor grado de discapacidad (EDSS < 3,0) y en los que no habían recibido ningún tratamiento modificador de la enfermedad. Se notificaron dos casos de leuco encefalopatía multifocal progresiva. No hubo efectos adversos inesperados. Conclusión. El natalizumab presenta una tolerabilidad satisfactoria y se muestra eficaz en la reducción de las recidivas y la estabilización de la EMRR en el marco de la practica clínica ordinaria en Portugal. Conserva su eficacia con el tratamiento continuado y podría ser eficaz especialmente en los pacientes con menos discapacidad y en aquellos que no han recibido ningún tratamiento modificador de la enfermedad hasta el momento (AU)

Introduction. Studies have shown that natalizumab is an effective treatment for relapsing-remitting multiple sclerosis (RRMS). To date, no data are available in Portuguese patients. Aim. To determine the efficacy and safety of natalizumab in patients with RRMS in routine clinical practice in Portugal. Patients and methods. Clinical data for adult patients with RRMS treated with natalizumab at specialist neurology centres in Portugal were entered retrospectively into a database for analysis between October 2010 and February 2012. Changes in annualized relapse rates (ARR), Expanded Disability Status Scale (EDSS) scores and disability status were analysed. Results. A total of 383 patients from 20 centres were included. Prior to starting natalizumab, the baseline median EDSS score was 4 and the mean ARR was 1.64. Most patients had previously received multiple sclerosis treatment (93.0%). Median natalizumab treatment duration was 12 months. Natalizumab treatment was associated with significant (p < 0.001) reductions from baseline in the mean ARR and EDSS scores in patients treated with natalizumab for ≥ 12 months (n = 288) and for ≥ 24 months (n = 160). Natalizumab was more effective in patients with less disability (EDSS < 3) and in those who had not previously received disease-modifying treatments. Two cases of progressive multifocal leukoencephalopathy were reported. No new unexpected adverse events occurred. Conclusion. Natalizumab is well tolerated, and is effective in reducing relapse rate and stabilising disease in patients with RRMS in the clinical practice setting in Portugal. Its efficacy persists with continued treatment, and it may be particularly effective in patients with less disability and without prior disease modifying therapy (AU)

Asymmetric c-fos expression in the ventral orbital cortex is associated with impaired reversal learning in a right-sided neuropathy.

BACKGROUND: Recently we showed that unilateral peripheral neuropathic lesions impacted differentially on rat's emotional/cognitive behavior depending on its left/right location; importantly, this observation recapitulates clinical reports. The prefrontal cortex (PFC), a brain region morphofunctionally affected in chronic pain conditions, is involved in the modulation of both emotion and executive function and displays functional lateralization. To test whether the PFC is involved in the lateralization bias associated with left/right pain, c-fos expression in medial and orbital areas was analyzed in rats with an unilateral spared nerve injury neuropathy installed in the left or in the right side after performing an attentional set-shifting, a strongly PFC-dependent task. RESULTS: SNI-R animals required more trials to successfully terminate the reversal steps of the attentional set-shifting task. A generalized increase of c-fos density in medial and orbital PFC (mPFC/OFC), irrespectively of the hemisphere, was observed in both SNI-L and SNI-R. However, individual laterality indexes revealed that contrary to controls and SNI-L, SNI-R animals presented a leftward shift in c-fos density in the ventral OFC (VO). None of these effects were observed in the neighboring primary motor area. CONCLUSIONS: Our results demonstrate that chronic neuropathic pain is associated with a bilateral mPFC and OFC hyperactivation. We hypothesize that the impaired performance of SNI-R animals is associated with a left/right activity inversion in the VO, whose functional integrity is critical for reversal learning.

Stress Impact on Resting State Brain Networks.

Resting state brain networks (RSNs) are spatially distributed large-scale networks, evidenced by resting state functional magnetic resonance imaging (fMRI) studies. Importantly, RSNs are implicated in several relevant brain functions and present abnormal functional patterns in many neuropsychiatric disorders, for which stress exposure is an established risk factor. Yet, so far, little is known about the effect of stress in the architecture of RSNs, both in resting state conditions or during shift to task performance. Herein we assessed the architecture of the RSNs using functional magnetic resonance imaging (fMRI) in a cohort of participants exposed to prolonged stress (participants that had just finished their long period of preparation for the medical residence selection exam), and respective gender- and age-matched controls (medical students under normal academic activities). Analysis focused on the pattern of activity in resting state conditions and after deactivation. A volumetric estimation of the RSNs was also performed. Data shows that stressed participants displayed greater activation of the default mode (DMN), dorsal attention (DAN), ventral attention (VAN), sensorimotor (SMN), and primary visual (VN) networks than controls. Importantly, stressed participants also evidenced impairments in the deactivation of resting state-networks when compared to controls. These functional changes are paralleled by a constriction of the DMN that is in line with the pattern of brain atrophy observed after stress exposure. These results reveal that stress impacts on activation-deactivation pattern of RSNs, a finding that may underlie stress-induced changes in several dimensions of brain activity.

Perceived Stress in Obsessive-Compulsive Disorder is Related with Obsessive but Not Compulsive Symptoms.

Obsessive-compulsive disorder (OCD) is achronic psychiatric disorder characterized by recurrent intrusive thoughts and/or repetitive compulsory behaviors. This psychiatric disorder is known to be stress responsive, as symptoms increase during periods of stress but also because stressful events may precede the onset of OCD. However, only a few and inconsistent reports have been published about the stress perception and the stress-response in these patients. Herein, we have characterized the correlations of OCD symptoms with basal serum cortisol levels and scores in a stress perceived questionnaire (PSS-10). The present data reveals that cortisol levels and the stress scores in the PSS-10 were significantly higher in OCD patients that in controls. Moreover, stress levels self-reported by patients using the PSS-10 correlated positively with OCD severity in the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). Interestingly, PSS-10 scores correlated with the obsessive component, but not with the compulsive component, of Y-BOCS. These results confirm that stress is relevant in the context of OCD, particularly for the obsessive symptomatology.

Chronic stress disrupts neural coherence between cortico-limbic structures.

Chronic stress impairs cognitive function, namely on tasks that rely on the integrity of cortico-limbic networks. To unravel the functional impact of progressive stress in cortico-limbic networks we measured neural activity and spectral coherences between the ventral hippocampus (vHIP) and the medial prefrontal cortex (mPFC) in rats subjected to short term stress (STS) and chronic unpredictable stress (CUS). CUS exposure consistently disrupted the spectral coherence between both areas for a wide range of frequencies, whereas STS exposure failed to trigger such effect. The chronic stress-induced coherence decrease correlated inversely with the vHIP power spectrum, but not with the mPFC power spectrum, which supports the view that hippocampal dysfunction is the primary event after stress exposure. Importantly, we additionally show that the variations in vHIP-to-mPFC coherence and power spectrum in the vHIP correlated with stress-induced behavioral deficits in a spatial reference memory task. Altogether, these findings result in an innovative readout to measure, and follow, the functional events that underlie the stress-induced reference memory impairments.