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Supplementary data are available. This work was supported by a Brain & Behavior Research Foundation NARSAD Young Investigator Grant to GM (#21200, Lieber Investigator). GM is funded by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (202397/Z/16/Z).

Background: Multiple sclerosis (MS) typically affects young adults during their primary productive years. We assessed the magnitude of, and factors associated with, employment status and informal care in people with MS in Canada. Methods: Data were compiled from the nationally representative cross-sectional Survey on Living with Neurological Conditions in Canada (SLNCC), which included adolescents and adults (age ≥15 years). Employment status was categorized as currently working or not working. The frequency of informal care that people with MS received was categorized as none, less than daily, or daily. Logistic regression analyses were undertaken to identify factors associated with employment status and informal care requirements in people with MS. Results: Of 4409 SLNCC respondents, 631 had MS, of whom 530 were included in the analysis. Of 358 respondents aged 18 to 65 years, 47.8% were not working because of MS; 44.0% reported receiving informal care, with more than half requiring daily care. For caregivers' employment, 15.5% reduced work and 8.2% stopped working because of caregiving. Greater feelings of stigmatization were associated with not working (adjusted odds ratio, 7.42 [95% CI, 2.59–21.28]) and greater informal care (adjusted odds ratio, 3.83 [95% CI, 1.84–7.96]), adjusting for sex, age, education, health-related quality of life, time since MS diagnosis, and comorbidity. Conclusions: People who feel stigmatized because of their MS are more likely to be unemployed and to require more informal care. Further research is needed to understand the temporal nature of the association between stigma and employment, productivity loss, and informal care.

OBJECTIVES Stigma has been found to be associated with lower self-esteem, which increases the risk of difficulties across life domains including vulnerability to mental health problems. There are no previous studies of interventions for people experiencing low self-esteem in the context of different stigmatized characteristics. This study evaluated feasibility, acceptability, and preliminary outcomes of an intervention targeting low self-esteem in stigmatized people aged 16-24 years. DESIGN An uncontrolled study with repeated measures. METHOD People with a range of stigmatized characteristics, who had low self-esteem and associated impaired daily functioning, were recruited from the general population. The individual six-session cognitive behavioural intervention had modules chosen according to participants' formulations. The CBT included compassion-focussed therapy methods and was informed by stigma research. Feasibility was assessed in relation to recruitment, retention, and protocol adherence. Acceptability was assessed through participant feedback. Questionnaires assessing self-esteem, functioning impairments, depression, anxiety, self-criticism, self-compassion, and responses to prejudice and discrimination were administered at baseline, pre-, mid-, post-intervention, and two-month follow-up. RESULTS Forty-four people completed screening; 73% were eligible. Of these, 78% consented and 69% (N = 22) started the intervention. Eighteen (82%) participants completed, and four dropped out. Follow-up measures were completed by all treatment completers. Treatment completers reported the intervention was useful, improved their self-esteem and coping, and would recommend it. Ratings of usefulness and frequency of use of intervention components were high at post-treatment and follow-up. CONCLUSIONS The intervention was feasible and highly acceptable to treatment completers. This suggests the intervention warrants investigation in a randomized-controlled trial. PRACTITIONER POINTS Young people with low self-esteem whom have been negatively affected by stigma may wish to access support and be willing to engage in psychological interventions. Cognitive behavioural therapy may be helpful for young people with low self-esteem who have experienced stigma, prejudice, or discrimination. Cognitive behavioural techniques such as self-compassionate thought records and behavioural experiments were considered acceptable and helpful by young people whose self-esteem has been affected by stigma. Addressing responses to stigma in therapy, such as rumination, avoidance, and perfectionism, appears to be feasible and acceptable.

BackgroundCortical glutamatergic dysfunction is thought to be fundamental for psychosis development, and may lead to structural degeneration through excitotoxicity. Glutamate levels have been related to gray matter volume (GMV) alterations in people at ultra-high risk of psychosis, and we previously reported GMV changes in individuals with high schizotypy (HS), which refers to the expression of schizophrenia-like characteristics in healthy people. This study sought to examine whether GMV changes in HS subjects are related to glutamate levels.MethodsWe selected 22 healthy subjects with HS and 23 healthy subjects with low schizotypy (LS) based on their rating on a self-report questionnaire for psychotic-like experiences. Glutamate levels were measured in the bilateral anterior cingulate cortex (ACC) using proton magnetic resonance spectroscopy, and GMV was assessed using voxel-based morphometry.ResultsSubjects with HS showed GMV decreases in the rolandic operculum/superior temporal gyrus (pFWE = 0.045). Significant increases in GMV were also detected in HS, in the precuneus (pFWE = 0.043), thereby replicating our previous finding in a separate cohort, as well as in the ACC (pFWE = 0.041). While the HS and LS groups did not differ in ACC glutamate levels, in HS subjects ACC glutamate was negatively correlated with ACC GMV (pFWE = 0.026). Such association was absent in LS.ConclusionsOur study shows that GMV findings in schizotypy are related to glutamate levels, supporting the hypothesis that glutamatergic function may lead to structural changes associated with the expression of psychotic-like experiences.

Arterial spin labeling (ASL) provides absolute quantification of resting tissue cerebral blood flow (CBF) as an entirely noninvasive approach with good reproducibility. As a result of neurovascular coupling, ASL provides a useful marker of resting neuronal activity. Recent ASL studies in individuals at clinical high risk of psychosis (CHR) have reported increased resting hippocampal perfusion compared with healthy controls. Schizotypy refers to the presence of subclinical psychotic-like experiences in healthy individuals and represents a robust framework to study neurobiological mechanisms involved in the extended psychosis phenotype while avoiding potentially confounding effects of antipsychotic medications or disease comorbidity. Here we applied pseudo-continuous ASL to examine differences in resting CBF in 21 subjects with high positive schizotypy (HS) relative to 22 subjects with low positive schizotypy (LS), as determined by the Oxford and Liverpool Inventory of Feelings and Experiences. Based on preclinical evidence that hippocampal hyperactivity leads to increased activity in mesostriatal dopamine projections, CBF in hippocampus, midbrain, and striatum was assessed. Participants with HS showed higher CBF of the right hippocampus compared to those with LS (p 5 .031, family-wise error corrected). No differences were detected in the striatum or midbrain. The association between increased hippocampal CBF and HS supports the notion that hippocampal hyperactivity might be a central characteristic of the extended psychosis phenotype, while hyperactivity in subcortical dopamine pathways may only emerge at a higher intensity of psychotic experiences. Wellcome Trust and the Royal Society

Objective to develop a resource of systematically collected, longitudinal clinical data and biospecimens for assisting in the investigation into neuromyelitis optica spectrum disorder (NMOSD) epidemiology, pathogenesis, and treatment. Methods to illustrate its research-enabling purpose, epidemiologic patterns and disease phenotypes were assessed among enrolled subjects, including age at disease onset, annualized relapse rate (ARR), and time between the first and second attacks. Results as of December 2017, the Collaborative International Research in Clinical and Longitudinal Experience Study (CIRCLES) had enrolled more than 1,000 participants, of whom 77.5% of the NMOSD cases and 71.7% of the controls continue in active follow-up. Consanguineous relatives of patients with NMOSD represented 43.6% of the control cohort. Of the 599 active cases with complete data, 84% were female, and 76% were anti-AQP4 seropositive. The majority were white/Caucasian (52.6%), whereas blacks/African Americans accounted for 23.5%, Hispanics/Latinos 12.4%, and Asians accounted for 9.0%. The median age at disease onset was 38.4 years, with a median ARR of 0.5. Seropositive cases were older at disease onset, more likely to be black/African American or Hispanic/Latino, and more likely to be female. Conclusions collectively, the CIRCLES experience to date demonstrates this study to be a useful and readily accessible resource to facilitate accelerating solutions for patients with NMOSD., The Guthy-Jackson Charitable Foundation, The CIRCLES Project

Disrupted striatal functional connectivity is proposed to play a critical role in the development of psychotic symptoms. Previous resting-state functional magnetic resonance imaging (rs-fMRI) studies typically reported disrupted striatal connectivity in patients with psychosis and in individuals at clinical and genetic high risk of the disorder relative to healthy controls. This has not been widely studied in healthy individuals with subclinical psychotic-like experiences (schizotypy). Here we applied the emerging technology of multi-echo rs-fMRI to examine corticostriatal connectivity in this group, which is thought to drastically maximize physiological noise removal and increase BOLD contrast-to-noise ratio. Multi-echo rs-fMRI data (echo times, 12, 28, 44, 60 ms) were acquired from healthy individuals with low (LS, n = 20) and high (HS, n = 19) positive schizotypy as determined with the Oxford-Liverpool Inventory of Feelings and Experiences (O-LIFE). After preprocessing to ensure optimal contrast and removal of non-BOLD signal components, whole-brain functional connectivity from six striatal seeds was compared between the HS and LS groups. Effects were considered significant at cluster-level p, Highlights • Multi-echo fMRI was used to investigate resting-state connectivity in subjects with low and high psychometric schizotypy (HS). • High schizotypy subjects showed hypoconnectivity between ventral striatum and ventromedial prefrontal cortex. • These subjects also showed hypoconnectivity between dorsal striatum and temporooccipital regions.

Background The optic nerve is frequently injured in multiple sclerosis and neuromyelitis optica, resulting in visual dysfunction, which may be reflected by measures distant from the site of injury. Objective To determine how retinal nerve fiber layer as a measure of axonal health, and macular volume as a measure of neuronal health are related to changes in myelin water fraction in the optic radiations of multiple sclerosis and neuromyelitis optica participants with and without optic neuritis and compared to healthy controls. Methods 12 healthy controls, 42 multiple sclerosis (16 with optic neuritis), and 10 neuromyelitis optica participants (8 with optic neuritis) were included in this study. Optical coherence tomography assessment involved measurements of the segmented macular layers (total macular, ganglion cell layer, inner plexiform layer, and inner nuclear layer volume) and paripapillary retinal nerve fiber layer thickness. The MRI protocol included a 32-echo T2-relaxation GRASE sequence. Average myelin water fraction values were calculated within the optic radiations as a measure of myelin density. Results Multiple sclerosis and neuromyelitis optica eyes with optic neuritis history had lower retinal nerve fiber layer thickness, total macular, ganglion cell and inner plexiform layer volumes compared to eyes without optic neuritis history and controls. Inner nuclear layer volume increased in multiple sclerosis with optic neuritis history (mean = 0.99 mm3, SD = 0.06) compared to those without (mean = 0.97 mm3, SD = 0.06; p = 0.003). Mean myelin water fraction in the optic radiations was significantly lower in demyelinating diseases (neuromyelitis optica: mean = 0.098, SD = 0.01, multiple sclerosis with optic neuritis history: mean = 0.096, SD = 0.01, multiple sclerosis without optic neuritis history: mean = 0.098, SD = 0.02; F3,55 = 3.35, p = 0.03) compared to controls. Positive correlations between MRI and optical coherence tomography measures were also apparent (retinal nerve fiber layer thickness and ganglion cell layer thickness: r = 0.25, p = 0.05, total macular volume and inner plexiform layer volume: r = 0.27, p = 0.04). Conclusions The relationship between reductions in OCT measures of neuro-axonal health in the anterior visual pathway and MRI-based measures of myelin health in the posterior visual pathway suggests that these measures may be linked through bidirectional axonal degeneration., Highlights • First study to assess relationship between segmented retinal layers and MRI in NMO • First study to use optic radiation myelin water imaging in demyelinating diseases • Inner nuclear layer thickening in MS with ON may occur independently of microcystic macular edema. • Myelin density reduction in the optic radiation observed in demyelinating diseases • Myelin loss may be due to subclinical MS disease activity in subjects without ON. • ON may lead to retinal and optic radiation pathology via bidirectional degeneration.

Background The continuum approach to psychosis proposes a dimensional continuity between the neurobiology of subclinical psychotic-like experiences in healthy individuals (or schizotypy) and psychotic symptoms in clinically relevant psychosis (Linscott and van Os, 2013, Nelson et al., 2013). Preclinical models propose that cortical glutamate dysfunction related to cortico-limbic-striatal hyper-responsivity to stress may underlie both hippocampal and striatal overdrive as well as gray matter loss associated with schizophrenia-like behaviors (Berretta et al., 2001, Lodge and Grace, 2011). Our recent studies investigated whether changes in brain glutamate are present in healthy individuals with high psychometric schizotypy, and whether these are related to changes in (1) corticolimbic response to emotion and (2) gray matter volume (GMV). Methods Forty-eight healthy participants were recruited based on their score on the O-LIFE questionnaire (Mason et al., 2005), after pre-screening 250 respondents to online advertisement. Participants with high levels of unusual experiences (HS group; that is, scored >7 on the Unusual Experiences (UE) subscale of the O-LIFE), and participants with low UE (LS group; that is

A number of compounds aimed at improving cognition in schizophrenia have failed to demonstrate efficacy in Phase 2 clinical trials. Translational studies using biomarkers in surrogate populations, such as schizotypy, could be used to assess the efficacy of novel compounds. In this study, we aimed to validate the sensitivity and inter-site reliability of cognitive biomarkers (working memory (N-back), spatial working memory (SWM) and verbal fluency (VF) tasks) to detect the schizotypy phenotype and its reversal by psychotropic drugs. Healthy volunteers scoring high or average on a schizotypal personality measure (122 in each group) were randomized to receive a single dose of risperidone, amisulpride, nicotine or placebo in a double-blind, between-subject design. We found evidence for a poorer performance on N-back and VF tasks in the high schizotypy group, replicating previous research. This effect was counteracted by amisulpride on N-back: it improved working memory in high schizotypy group but impaired the controls. A similar pattern was seen in SWM and VF. We interpret this finding in the light of the dopamine enhancing action of amisulpride when given in low doses. In contrast, risperidone impaired both groups and nicotine had a beneficial effect for the low baseline performers only. These effects were consistent across sites. These data demonstrates the utility of biomarkers in detecting the effect of schizotypy and its reversal by drugs that enhance dopamine and cholinergic function. Studies using similar design could help the early assessment of potential of compounds designed to improve cognition in schizophrenia.

Background: Empirical evidence shows that healthy individuals with high schizotypy (HS), who show schizophrenia-like characteristics, present similar but attenuated social and emotional disturbances to patients with schizophrenia. Altered glutamatergic neurotransmission in several limbic areas including the anterior cingulate cortex (ACC) has been demonstrated in patients with schizophrenia and individuals at ultra-high risk for psychosis and is associated with abnormalities in brain activation during several cognitive tasks. However, despite animal models of psychosis suggesting an association between prefrontal glutamatergic function and corticolimbic response to stress/emotion, the interactions between these abnormalities in man remain unclear. We examined changes in brain glutamate in subjects with HS and whether any such changes are related to corticolimbic response to emotional processing.

The increasing demand to develop more efficient compounds to treat cognitive impairments in schizophrenia has led to the development of experimental model systems. One such model system combines the study of surrogate populations expressing high levels of schizotypy with oculomotor biomarkers.We aimed (1) to replicate oculomotor deficits in a psychometric schizotypy sample and (2) to investigate whether the expected deficits can be remedied by compounds shown to ameliorate impairments in schizophrenia.In this randomized double-blind, placebo-controlled study 233 healthy participants performed prosaccade (PS), antisaccade (AS) and smooth pursuit eye movement (SPEM) tasks after being randomly assigned to one of four drug groups (nicotine, risperidone, amisulpride, placebo). Participants were classified into medium- and high-schizotypy groups based on their scores on the Schizotypal Personality Questionnaire (SPQ, Raine (Schizophr Bull 17:555-564, 1991)).AS error rate showed a main effect of Drug (p 0.01), with nicotine improving performance, and a Drug by Schizotypy interaction (p = 0.04), indicating higher error rates in medium schizotypes (p = 0.01) but not high schizotypes under risperidone compared to placebo. High schizotypes had higher error rates than medium schizotypes under placebo (p = 0.03). There was a main effect of Drug for saccadic peak velocity and SPEM velocity gain (both p ≤ 0.01) indicating impaired performance with risperidone.We replicate the observation of AS impairments in high schizotypy under placebo and show that nicotine enhances performance irrespective of group status. Caution should be exerted in applying this model as no beneficial effects of antipsychotics were seen in high schizotypes.

Background The cognitive impairment associated with schizophrenia is a major target for drug development but none of the drugs designed to address this problem has shown consistent efficacy. The most common causes for failure in the registration trials could be preempted by testing novel agents in milder forms of the disorder, such as schizotypy and assessing the effect with validated biomarkers. In this study we aimed to test this approach by comparing the effects of risperidone, amisulpride, and nicotine in a double-blind placebo-controlled three-centre study on the cognitive performance in schizotypy. Methods We recruited healthy volunteers who scored high and average on the Schizotypal Personality Questionnaire (122 in each group). 244 participants were randomised to an acute dose of risperidone (n=62, capsule plus placebo patch), amisulpride (n=62, capsule plus placebo patch), nicotine (n=61, placebo capsule plus nicotine patch), or placebo (n=59, placebo capsule plus placebo patch) and proceeded to complete cognitive tests (n-back, verbal fluency, and spatial working memory tasks). Primary outcome measures were percentage correct, errors of commission, and response latencies (n-back), number of correct words and category transitions (verbal fluency), and between-search and within-search errors (spatial working memory tasks). This trial has not been registered. Findings We found evidence for worse performance in the high schizotypy group on the n-back and verbal fluency tasks (p 2 =0·059 and p 2 =0·064, respectively). Amisulpride had a differential effect on the two groups in respect to these two tasks (p=0·02 and p=0·04, respectively): it improved performance in the high schizotypy group but impaired the controls. By contrast, risperidone impaired both groups while nicotine had a beneficial effect for the low baseline performers. There was a statistically significant increase in the reaction time latency in the n-back task in the risperidone arm compared with all other arms. Interpretation We attribute the effects of amisulpride to its presynaptic dopamine enhancing action at low doses. The deterioration of performance with risperidone on the other hand was probably due to sedation while nicotine showed signs of general vigilance improvement. Our findings confirm that cognitive abnormalities in schizotypy are replicable in multisite studies and responsive to drug challenges. Importantly, these results underline the importance of dopamine agonism in the pathophysiology of the cognitive deficits in the schizophrenia spectrum disorders. Funding P1vital Ltd.