Enhancing emotion regulation with an in situ socially assistive robot among LGBTQ+ youth with self-harm ideation: protocol for a randomised controlled trial.

INTRODUCTION: Purrble, a socially assistive robot, was codesigned with children to support in situ emotion regulation. Preliminary evidence has found that LGBTQ+ youth are receptive to Purrble and find it to be an acceptable intervention to assist with emotion dysregulation and their experiences of self-harm. The present study is designed to evaluate the impact of access to Purrble among LGBTQ+ youth who have self-harmful thoughts, when compared with waitlist controls. METHODS AND ANALYSIS: The study is a single-blind, randomised control trial comparing access to the Purrble robot with waitlist control. A total of 168 LGBTQ+ youth aged 16-25 years with current self-harmful ideation will be recruited, all based within the UK. The primary outcome is emotion dysregulation (Difficulties with Emotion Regulation Scale-8) measured weekly across a 13-week period, including three pre-deployment timepoints. Secondary outcomes include self-harm (Self-Harm Questionnaire), anxiety (Generalised Anxiety Disorder-7) and depression (Patient Health Questionnaire-9). We will conduct analyses using linear mixed models to assess primary and secondary hypotheses. Intervention participants will have unlimited access to Purrble over the deployment period, which can be used as much or as little as they like. After all assessments, control participants will receive their Purrble, with all participants keeping the robot after the end of the study. After the study has ended, a subset of participants will be invited to participate in semistructured interviews to explore engagement and appropriation of Purrble, considering the young people's own views of Purrble as an intervention device. ETHICS AND DISSEMINATION: Ethical approval was received from King's College London (RESCM-22/23-34570). Findings will be disseminated in peer review open access journals and at academic conferences. TRIAL REGISTRATION NUMBER: NCT06025942.

Brain connectivity-guided, Optimised theta burst transcranial magnetic stimulation to improve Central Pain Modulation in knee Osteoarthritis Pain (BoostCPM): protocol of a pilot randomised clinical trial in a secondary care setting in the UK.

INTRODUCTION: Chronic pain is a common health problem that is not efficiently managed by standard analgesic treatments. There is evidence that treatment resistance may result from maladaptive brain changes in areas that are fundamental to the perception of pain. Knee osteoarthritis is one of the most prevalent causes of chronic pain and commonly associated with negative affect. Chronic knee osteoarthritis pain is also associated with altered right anterior insula functional connectivity. We posit that reversal of these brain circuit alterations may be critical to alleviate chronic pain and associated negative affect, and that this can be achieved through non-invasive neuromodulation techniques. Despite growing interest in non-invasive neuromodulation for pain relief and proven efficacy in depression, results in chronic pain are mixed with limited high-quality evidence for clinical and mechanistic efficacy. Limitations include patient heterogeneity, imprecision of target selection, uncertain blinding and protocols that may deliver pulses at subclinical efficacy. METHODS AND ANALYSIS: We hence developed an optimised treatment protocol of connectivity-guided intermittent theta-burst stimulation (iTBS) targeting the left dorsolateral prefrontal cortex with accelerated delivery on four consecutive days (allowing 4 days within the same week as protocol variation) with five daily treatment sessions that will be piloted in a sham-controlled design in 45 participants with chronic knee pain. This pilot study protocol will assess feasibility, tolerability and explore mechanistic efficacy through serial functional/structural magnetic resonance imaging (MRI) and quantitative sensory testing. ETHICS AND DISSEMINATION: This pilot trial has been approved by the Ethics Committee Cornwall and Plymouth.Results of the pilot trial will be submitted to peer-reviewed journals, presented at research conferences and may be shared with participants and PPI/E advisors. TRIAL REGISTRATION NUMBER: ISRCTN15404076.

The central autonomic system revisited - Convergent evidence for a regulatory role of the insular and midcingulate cortex from neuroimaging meta-analyses.

The autonomic nervous system regulates dynamic body adaptations to internal and external environment changes. Capitalizing on two different algorithms (that differ in empirical assumptions), we scrutinized the meta-analytic convergence of human neuroimaging studies investigating the neural basis of peripheral autonomic signal processing. Among the selected studies, we identified 42 records reporting 44 different experiments and testing 758 healthy individuals. The results of the two different algorithms converge in identifying the bilateral dorsal anterior insula and midcingulate cortex as the critical areas of the central autonomic system (CAN). Applying an unbiased approach, we were able to identify a single condition-independent functional circuit that supports CAN activity. Partially overlapping with the salience network this functional circuit includes the bilateral insular cortex and midcingulate cortex as well as the bilateral inferior parietal lobules. Remarkably, the critical regions of the CAN observed in this meta-analysis overlapped with the salience network as well as regions commonly reported across different cognitive and affective neuroimaging paradigms and regions being dysregulated across different mental and neurological disorders.

Language systems from lesion-symptom mapping in aphasia: A meta-analysis of voxel-based lesion mapping studies.

BACKGROUND: Aphasia is one of the most common causes of post-stroke disabilities. As the symptoms and impact of post-stroke aphasia are heterogeneous, it is important to understand how topographical lesion heterogeneity in patients with aphasia is associated with different domains of language impairments. Here, we aim to provide a comprehensive overview of neuroanatomical basis in post-stroke aphasia through coordinate based meta-analysis of voxel-based lesion-symptom mapping studies. METHODS: We performed a meta-analysis of lesion-symptom mapping studies in post-stroke aphasia. We obtained coordinate-based structural neuroimaging data for 2,007 individuals with aphasia from 25 studies that met predefined inclusion criteria. RESULTS: Overall, our results revealed that the distinctive patterns of lesions in aphasia are associated with different language functions and tasks. Damage to the insular-motor areas impaired speech with preserved comprehension and a similar pattern was observed when the lesion covered the insular-motor and inferior parietal lobule. Lesions in the frontal area severely impaired speaking with relatively good comprehension. The repetition-selective deficits only arise from lesions involving the posterior superior temporal gyrus. Damage in the anterior-to-posterior temporal cortex was associated with semantic deficits. CONCLUSION: The association patterns of lesion topography and specific language deficits provide key insights into the specific underlying language pathways. Our meta-analysis results strongly support the dual pathway model of language processing, capturing the link between the different symptom complexes of aphasias and the different underlying location of damage.

Mapping brain activity of gut-brain signaling to appetite and satiety in healthy adults: A systematic review and functional neuroimaging meta-analysis.

Understanding how neurohormonal gut-brain signaling regulates appetite and satiety is vital for the development of therapies for obesity and altered eating behavior. However, reported brain areas associated with appetite or satiety regulators show inconsistency across functional neuroimaging studies. The aim of this study was to systematically assess the convergence of brain regions modulated by appetite and satiety regulators. Twenty-five studies were considered for qualitative synthesis, and 14 independent studies (20-experiments) found eligible for coordinate-based neuroimaging meta-analyses across 212 participants and 123 foci. We employed two different meta-analysis approaches. The results from the systematic review revealed the modulation of insula, amygdala, hippocampus, and orbitofrontal cortex (OFC) with appetite regulators, where satiety regulators were more associated with caudate nucleus, hypothalamus, thalamus, putamen, anterior cingulate cortex in addition to the insula and OFC. The two neuroimaging meta-analyses methods identified the caudate nucleus as a key area associated with satiety regulators. Our results provide quantitative brain activation maps of neurohormonal gut-brain signaling in heathy-weight adults that can be used to define alterations with eating behavior.

Dysregulated anterior insula reactivity as robust functional biomarker for chronic pain-Meta-analytic evidence from neuroimaging studies.

Neurobiological pain models propose that chronic pain is accompanied by neurofunctional changes that mediate pain processing dysfunctions. In contrast, meta-analyses of neuroimaging studies in chronic pain conditions have not revealed convergent evidence for robust alterations during experimental pain induction. Against this background, the present neuroimaging meta-analysis combined three different meta-analytic approaches with stringent study selection criteria for case-control functional magnetic resonance imaging experiments during acute pain processing with a focus on chronic pain disorders. Convergent neurofunctional dysregulations in chronic pain patients were observed in the left anterior insula cortex. Seed-based resting-state functional connectivity based on a large publicly available dataset combined with a meta-analytic task-based approach identified the anterior insular region as a key node of an extended bilateral insula-fronto-cingular network, resembling the salience network. Moreover, the meta-analytic decoding showed that this region presents a high probability to be specifically activated during pain-related processes, although we cannot exclude an involvement in autonomic processes. Together, the present findings indicate that dysregulated left anterior insular activity represents a robust neurofunctional maladaptation and potential treatment target in chronic pain disorders.

Pet Ownership and Multiple Sclerosis during COVID-19.

Background: Multiple sclerosis (MS) is associated with lower quality of life, reduced social participation, and decreased self-efficacy. The COVID-19 pandemic has had documented effects on the health and wellbeing of people with and without MS. Previous research has demonstrated the positive impact pets can have for people living with long-term conditions. Objectives: To explore the rates of pet ownership and pet attachment in people living with MS and pet ownership associations with quality of life, satisfaction with social roles, and self-efficacy scores; and to explore the effects of the COVID-19 outbreak on people's perceived relationships with their pets. Materials and Methods: A postal questionnaire was distributed to members of a local MS Register and a control group of people without MS. The questionnaire assessed quality of life, satisfaction with social roles, self-efficacy, the perceived roles of pets, and pet-related concerns experienced during the COVID-19 pandemic. Results: No apparent difference in attachment to pets was found between the patient and control groups. Pet ownership and level of attachment were not associated with differences in quality of life or self-efficacy scores in people living with MS. Using multiple regression analysis, pet ownership was associated with a decrease in satisfaction with participation in social roles, but with the estimated effect being small compared to having a diagnosis of MS or being unemployed. Most participants reported that pets had positive roles during the pandemic, and the most reported pet-related concern was access to veterinary treatment. Conclusion: Pet owners both with and without MS reported subjective benefits to their wellbeing from pet ownership during COVID-19, although analysis suggested that pet ownership was associated with a reduction in satisfaction with social roles. The study had several limitations and suggestions are made for future work.

Localised Grey Matter Atrophy in Multiple Sclerosis and Clinically Isolated Syndrome-A Coordinate-Based Meta-Analysis, Meta-Analysis of Networks, and Meta-Regression of Voxel-Based Morphometry Studies.

BACKGROUND: Atrophy of grey matter (GM) is observed in the earliest stages of multiple sclerosis (MS) and is associated with cognitive decline and physical disability. Localised GM atrophy in MS can be explored and better understood using magnetic resonance imaging and voxel-based morphometry (VBM). However, results are difficult to interpret due to methodological differences between studies. METHODS: Coordinate-based analysis is a way to find the reliably observable results across multiple independent VBM studies. This work uses coordinate-based meta-analysis, meta-analysis of networks, and meta-regression to summarise the evidence from voxel-based morphometry of regional GM hanges in patients with MS and clinically isolated syndrome (CIS), and whether these measured changes are relatable to clinical features. RESULTS: Thirty-four published articles reporting forty-four independent experiments using VBM for the assessment of GM atrophy between MS or CIS patients and healthy controls were identified. Analysis identified eight clusters of consistent cross-study reporting of localised GM atrophy involving both cortical and subcortical regions. Meta-network analysis identified a network-like pattern indicating that GM loss occurs with some symmetry between hemispheres. Meta-regression analysis indicates a relationship between disease duration or age and the magnitude of reported statistical effect in some deep GM structures. CONCLUSIONS: These results suggest consistency in MRI-detectible regional GM loss across multiple MS studies, and the estimated effect sizes and symmetries can help design prospective studies to test specific hypotheses.

Hookworm Treatment for Relapsing Multiple Sclerosis: A Randomized Double-Blinded Placebo-Controlled Trial.

Importance: Studies suggest gut worms induce immune responses that can protect against multiple sclerosis (MS). To our knowledge, there are no controlled treatment trials with helminth in MS. Objective: To determine whether hookworm treatment has effects on magnetic resonance imaging (MRI) activity and T regulatory cells in relapsing MS. Design, Setting, and Participants: This 9-month double-blind, randomized, placebo-controlled trial was conducted between September 2012 and March 2016 in a modified intention-to-treat population (the data were analyzed June 2018) at the University of Nottingham, Queen's Medical Centre, a single tertiary referral center. Patients aged 18 to 61 years with relapsing MS without disease-modifying treatment were recruited from the MS clinic. Seventy-three patients were screened; of these, 71 were recruited (2 ineligible/declined). Interventions: Patients were randomized (1:1) to receive either 25 Necator americanus larvae transcutaneously or placebo. The MRI scans were performed monthly during months 3 to 9 and 3 months posttreatment. Main Outcomes and Measures: The primary end point was the cumulative number of new/enlarging T2/new enhancing T1 lesions at month 9. The secondary end point was the percentage of cluster of differentiation (CD) 4+CD25highCD127negT regulatory cells in peripheral blood. Results: Patients (mean [SD] age, 45 [9.5] years; 50 women [71%]) were randomized to receive hookworm (35 [49.3%]) or placebo (36 [50.7%]). Sixty-six patients (93.0%) completed the trial. The median cumulative numbers of new/enlarging/enhancing lesions were not significantly different between the groups by preplanned Mann-Whitney U tests, which lose power with tied data (high number of zeroactivity MRIs in the hookworm group, 18/35 [51.4%] vs 10/36 [27.8%] in the placebo group). The percentage of CD4+CD25highCD127negT cells increased at month 9 in the hookworm group (hookworm, 32 [4.4%]; placebo, 34 [3.9%]; P = .01). No patients withdrew because of adverse effects. There were no differences in adverse events between groups except more application-site skin discomfort in the hookworm group (82% vs 28%). There were 5 relapses (14.3%) in the hookworm group vs 11 (30.6%) receiving placebo. Conclusions and Relevance: Treatment with hookworm was safe and well tolerated. The primary outcome did not reach significance, likely because of a low level of disease activity. Hookworm infection increased T regulatory cells, suggesting an immunobiological effect of hookworm. It appears that a living organism can precipitate immunoregulatory changes that may affect MS disease activity. Trial Registration: ClinicalTrials.gov Identifier: NCT01470521.

Reduced Myelin Signal in Normal-appearing White Matter in Neuromyelitis Optica Measured by 7T Magnetic Resonance Imaging.

Whether the integrity of normal-appearing white matter (NAWM) is preserved in neuromyelitis optica spectrum disorders (NMOSD) is open to debate. To examine whether the tissue integrity of NAWM in NMOSD is compromised compared to that in healthy controls and patients with multiple sclerosis (MS), we prospectively enrolled 14 patients with NMOSD, 12 patients with MS, and 10 controls for clinical functional assessments and quantitative imaging, including T1 relaxation time (T1) and magnetization transfer ratio (MTR) at 7 Tesla. Cognitive performance on the Paced Auditory Serial Addition Test with a 3-second interstimulus interval (PASAT-3) was significantly lower in the NMOSD compared to the MS group (mean number of correct answers, 34.1 vs. 47.6; p = 0.006), but there were no differences in disease duration or disability. Histograms of T1 and MTR maps of NAWM demonstrated a decreased peak height in patients with NMOSD compared to the healthy controls, but not compared to patients with MS. Using 7T quantitative magnetic resonance imaging (MRI), this study showed that the NAWM in patients with NMOSD is abnormal, with reduced myelin signal; this was not previously observed using MRI at a lower field strength.

Seven-Tesla Magnetization Transfer Imaging to Detect Multiple Sclerosis White Matter Lesions.

BACKGROUND AND PURPOSE: Fluid-attenuated inversion recovery (FLAIR) imaging at 3 Tesla (T) field strength is the most sensitive modality for detecting white matter lesions in multiple sclerosis. While 7T FLAIR is effective in detecting cortical lesions, it has not been fully optimized for visualization of white matter lesions and thus has not been used for delineating lesions in quantitative magnetic resonance imaging (MRI) studies of the normal appearing white matter in multiple sclerosis. Therefore, we aimed to evaluate the sensitivity of 7T magnetization-transfer-weighted (MTw ) images in the detection of white matter lesions compared with 3T-FLAIR. METHODS: Fifteen patients with clinically isolated syndrome, 6 with multiple sclerosis, and 10 healthy participants were scanned with 7T 3-dimensional (D) MTw and 3T-2D-FLAIR sequences on the same day. White matter lesions visible on either sequence were delineated. RESULTS: Of 662 lesions identified on 3T-2D-FLAIR images, 652 were detected on 7T-3D-MTw images (sensitivity, 98%; 95% confidence interval, 97% to 99%). The Spearman correlation coefficient between lesion loads estimated by the two sequences was .910. The intrarater and interrater reliability for 7T-3D-MTw images was good with an intraclass correlation coefficient (ICC) of 98.4% and 81.8%, which is similar to that for 3T-2D-FLAIR images (ICC 96.1% and 96.7%). CONCLUSION: Seven-Tesla MTw sequences detected most of the white matter lesions identified by FLAIR at 3T. This suggests that 7T-MTw imaging is a robust alternative for detecting demyelinating lesions in addition to 3T-FLAIR. Future studies need to compare the roles of optimized 7T-FLAIR and of 7T-MTw imaging.

Smoking Cessation and the Reduction of Disability Progression in Multiple Sclerosis: A Cohort Study.

Background: Smoking is associated with a more severe disease course in people with multiple sclerosis (MS). The magnitude of effect of smoking cessation on MS progression is unknown. The aim of this study was to quantify the impact of smoking cessation on reaching MS disability milestones. Aims and Methods: This is a cross-sectional study with retrospective reports. A comprehensive smoking questionnaire was sent to 1270 patients with MS registered between 1994 and 2013 in the Nottingham University Hospital MS Clinics database. Demographic and clinical data were extracted from the clinical database. Cox proportional hazard regression was used to estimate effects of smoke-free years on the time to Expanded Disability Status Scale (EDSS) scores 4.0 and 6.0. MS Impact Scale 29 and Patient Determined Disease Steps were used to assess the physical and psychological impact of smoking. Results: Each "smoke-free year" was associated with 0.96 (95% confidence interval: 0.95 to 0.97) times decreased risk of reaching EDSS 4.0 and 0.97 (95% confidence interval: 0.95 to 0.98) times decreased risk of reaching EDSS 6.0. Nonsmokers showed a significantly lower level of disability in all the self-reported outcomes compared with current smokers. Conclusions: The reduction in the risk of disability progression after smoking cessation is significant and time dependent. The earlier the patients quit, the stronger the reduction in the risk of reaching disability milestones. The quantitative estimates of the impact of smoking cessation on reaching disability milestones in MS can be used in interventional trials. Implications: This study provides for the first time quantitative estimates of the effects of smoking cessation in MS, essential for informing smoking cessation trials. The clear effect of smoking cessation on MS progression suggests the need to consider adjusting for smoking cessation when assessing for treatment effects in clinical trials of treatments for MS. Smoking cessation should be an early intervention in people with MS.

Ten simple rules for neuroimaging meta-analysis.

Neuroimaging has evolved into a widely used method to investigate the functional neuroanatomy, brain-behaviour relationships, and pathophysiology of brain disorders, yielding a literature of more than 30,000 papers. With such an explosion of data, it is increasingly difficult to sift through the literature and distinguish spurious from replicable findings. Furthermore, due to the large number of studies, it is challenging to keep track of the wealth of findings. A variety of meta-analytical methods (coordinate-based and image-based) have been developed to help summarise and integrate the vast amount of data arising from neuroimaging studies. However, the field lacks specific guidelines for the conduct of such meta-analyses. Based on our combined experience, we propose best-practice recommendations that researchers from multiple disciplines may find helpful. In addition, we provide specific guidelines and a checklist that will hopefully improve the transparency, traceability, replicability and reporting of meta-analytical results of neuroimaging data.

Imaging pain relief in osteoarthritis (IPRO): protocol of a double-blind randomised controlled mechanistic study assessing pain relief and prediction of duloxetine treatment outcome.

INTRODUCTION: Osteoarthritis (OA) pain is a major cause of long-term disability and chronic pain in the adult population. One in five patients does not receive satisfactory pain relief, which reflects the complexity of chronic pain and the current lack of understanding of mechanisms of chronic pain. Recently, duloxetine has demonstrated clinically relevant pain relief, but only in half of treated patients with OA. Here, the aim is to investigate the neural mechanisms of pain relief and neural signatures that may predict treatment response to duloxetine in chronic knee OA pain. METHODS AND ANALYSIS: This is an ongoing single-centre randomised placebo-controlled mechanistic study (2:1 (placebo) allocation), using a multimodal neuroimaging approach, together with psychophysiological (quantitative sensory testing), genetics and questionnaire assessments. Eighty-one subjects with chronic knee OA pain are planned to power for between-group comparisons (placebo, duloxetine responder and duloxetine non-responder). Participants have a baseline assessment and, following 6 weeks of duloxetine (30 mg for 2 weeks, then 60 mg for 4 weeks), a follow-up evaluation. Brain imaging is performed at 3T with blood-oxygen-level dependent functional MRI at rest and during pin-prick nociceptive stimulation for main outcome assessment; arterial spin labelling and structural imaging (T1-weighted) for secondary outcome assessment. Questionnaires evaluate pain, negative affect, quality of sleep and cognition. ETHICS AND DISSEMINATION: The study has been approved by the East Midlands, Nottingham and is being carried out under the principles of the Declaration of Helsinki (64th, 2013) and Good Clinical Practice standards. Results will be disseminated in peer-reviewed journals and at scientific conferences. TRIAL REGISTRATION NUMBER: This trial is registered at ClinicalTrials.gov (NCT02208778).This work was supported by Arthritis Research UK (Grant 18769).

Lesion Topography and Microscopic White Matter Tract Damage Contribute to Cognitive Impairment in Symptomatic Carotid Artery Disease.

Purpose To investigate associations between neuroimaging markers of cerebrovascular disease, including lesion topography and extent and severity of strategic and global cerebral tissue injury, and cognition in carotid artery disease (CAD). Materials and Methods All participants gave written informed consent to undergo brain magnetic resonance imaging and the Addenbrooke's Cognitive Examination-Revised. One hundred eight patients with symptomatic CAD but no dementia were included, and a score less than 82 represented cognitive impairment. Group comparison and interrelations between global cognitive and fluency performance, lesion topography, and ultrastructural damage were assessed with voxel-based statistics. Associations between cognition, medial temporal lobe atrophy (MTA), lesion volumes, and global white matter ultrastructural damage indexed as increased mean diffusivity were tested with regression analysis by controlling for age. Diagnostic accuracy of imaging markers selected from a multivariate prediction model was tested with receiver operating characteristic analysis. Results Cognitively impaired patients (n = 53 [49.1%], classified as having probable vascular cognitive disorder) were older than nonimpaired patients (P = .027) and had more frequent MTA (P < .001), more cortical infarctions (P = .016), and larger volumes of acute (P = .028) and chronic (P = .009) subcortical ischemic lesions. Lesion volumes did not correlate with global cognitive performance (lacunar infarctions, P = .060; acute lesions, P = .088; chronic subcortical ischemic lesions, P = .085). In contrast, cognitive performance correlated with presence of chronic ischemic lesions within the interhemispheric tracts and thalamic radiation (P < .05, false discovery rate corrected). Skeleton mean diffusivity showed the closest correlation with cognition (R2 = 0.311, P < .001) and promising diagnostic accuracy for vascular cognitive disorder (area under the curve, 0.82 [95% confidence interval: 0.75, 0.90]). Findings were confirmed in subjects with a low risk of preclinical Alzheimer disease indexed by the absence of MTA (n = 85). Conclusion Subcortical white matter ischemic lesion locations and severity of ultrastructural tract damage contribute to cognitive impairment in symptomatic CAD, which suggests that subcortical disconnection within large-scale cognitive neural networks is a key mechanism of vascular cognitive disorder. Online supplemental material is available for this article.

Potential pitfalls when denoising resting state fMRI data using nuisance regression.

In resting state fMRI, it is necessary to remove signal variance associated with noise sources, leaving cleaned fMRI time-series that more accurately reflect the underlying intrinsic brain fluctuations of interest. This is commonly achieved through nuisance regression, in which the fit is calculated of a noise model of head motion and physiological processes to the fMRI data in a General Linear Model, and the "cleaned" residuals of this fit are used in further analysis. We examine the statistical assumptions and requirements of the General Linear Model, and whether these are met during nuisance regression of resting state fMRI data. Using toy examples and real data we show how pre-whitening, temporal filtering and temporal shifting of regressors impact model fit. Based on our own observations, existing literature, and statistical theory, we make the following recommendations when employing nuisance regression: pre-whitening should be applied to achieve valid statistical inference of the noise model fit parameters; temporal filtering should be incorporated into the noise model to best account for changes in degrees of freedom; temporal shifting of regressors, although merited, should be achieved via optimisation and validation of a single temporal shift. We encourage all readers to make simple, practical changes to their fMRI denoising pipeline, and to regularly assess the appropriateness of the noise model used. By negotiating the potential pitfalls described in this paper, and by clearly reporting the details of nuisance regression in future manuscripts, we hope that the field will achieve more accurate and precise noise models for cleaning the resting state fMRI time-series.

Functional reorganisation in chronic pain and neural correlates of pain sensitisation: A coordinate based meta-analysis of 266 cutaneous pain fMRI studies.

Maladaptive mechanisms of pain processing in chronic pain conditions (CP) are poorly understood. We used coordinate based meta-analysis of 266 fMRI pain studies to study functional brain reorganisation in CP and experimental models of hyperalgesia. The pattern of nociceptive brain activation was similar in CP, hyperalgesia and normalgesia in controls. However, elevated likelihood of activation was detected in the left putamen, left frontal gyrus and right insula in CP comparing stimuli of the most painful vs. other site. Meta-analysis of contrast maps showed no difference between CP, controls, mood conditions. In contrast, experimental hyperalgesia induced stronger activation in the bilateral insula, left cingulate and right frontal gyrus. Activation likelihood maps support a shared neural pain signature of cutaneous nociception in CP and controls. We also present a double dissociation between neural correlates of transient and persistent pain sensitisation with general increased activation intensity but unchanged pattern in experimental hyperalgesia and, by contrast, focally increased activation likelihood, but unchanged intensity, in CP when stimulated at the most painful body part.

Mortality in multiple sclerosis: meta-analysis of standardised mortality ratios.

OBJECTIVE: There are inconsistent data on mortality in people with multiple sclerosis (MS). We performed a meta-analysis of all-cause, cause-specific and gender-specific crude mortality rates (CMRs), and standardised mortality ratios (SMRs) in MS, and estimated the rate of change of CMR and SMR over the past 50 years. METHODS: Medline, Embase and the Cochrane Library were searched. KEYWORDS: 'Multiple Sclerosis' and ('standardised mortality' or 'standardized mortality'). INCLUSION CRITERIA: availability of data on the number of deaths; mean or median patient follow-up or reports of SMRs; being a longitudinal study. 12 studies were included covering the period 1949-2012 (27 423 patients; 6628 deaths; 437 832 person-years follow-up). CMR was calculated. SMRs were extracted. CMRs and natural logarithm of SMRs were pooled by the method of the inverse of the variance. Meta-regression models were used to investigate the secular trends. RESULTS: Pooled CMR was 9.78/1000 person-years (95% CI 6.81 to 14.02). Pooled all-cause SMR was 2.80 (95% CI 2.74 to 2.87). All-cause SMR was 2.56 (95% CI 2.47 to 2.66) in males and 3.06 (95% CI 2.97 to 3.17) in females. SMR due to cancer was 0.89 (95% CI 0.83 to 0.97). SMRs due to cardiovascular diseases, suicide, infection and respiratory diseases were 1.29 (95% CI 1.20 to 1.38), 2.13 (95% CI 1.80 to 2.51) and 2.91 (95% CI 2.60 to 3.26). There was no trend in CMRs, all-cause, and gender-specific SMRs. CONCLUSIONS: The excess mortality in MS relative to the general population has not changed over the past 50 years. Female patients with MS have higher survival disadvantage compared to that of males. Death due to cardiovascular diseases, suicide and infection is higher in patients with MS compared to the general population.

Multiple sclerosis course and clinical outcomes in patients with comorbid asthma: a survey study.

OBJECTIVE: To determine if comorbid asthma is associated with accumulation of multiple sclerosis (MS)-related impairment and disability. METHOD: We sent a comprehensive questionnaire to a cohort of patients with MS and examined the association between comorbid asthma and reaching Expanded Disability Status Scale (EDSS) scores 4.0 and 6.0. Multiple Sclerosis Impact Scale (MSIS-29) scores were compared between patients with MS with and without comorbid asthma. RESULTS: 680 patients participated in our study of whom 88 (12.9%) had comorbid asthma. There was no difference in the prevalence of asthma between our MS cohort and the England general population (OR: 0.89, 95% CI 0.68 to 1.17). We did not observe a significant association between having asthma and the risk of reaching EDSS scores 4.0 and 6.0 (HR: 1.29, 95% CI 0.93 to 1.77, and HR: 1.33, 95% CI 0.93 to 1.89, respectively) after controlling for confounders. Patients with MS with asthma reported higher level of psychological impairments (coefficient: 2.29, 95% CI 0.1 to 4.49). CONCLUSIONS: Asthma is a prevalent condition among patients with MS and it may contribute to the psychological impairment in MS. Although we did not observe significant association between comorbid asthma and physical disability in MS, it seems that the two conditions influence one another.