Investigating light sensitivity in bipolar disorder (HELIOS-BD).

Many people with bipolar disorder have disrupted circadian rhythms. This means that the timing of sleep and wake activities becomes out-of-sync with the standard 24-hour cycle. Circadian rhythms are strongly influenced by light levels and previous research suggests that people with bipolar disorder might have a heightened sensitivity to light, causing more circadian rhythm disruption, increasing the potential for triggering a mood switch into mania or depression. Lithium has been in clinical use for over 70 years and is acknowledged to be the most effective long-term treatment for bipolar disorder. Lithium has many reported actions in the body but the precise mechanism of action in bipolar disorder remains an active area of research. Central to this project is recent evidence that lithium may work by stabilising circadian rhythms of mood, cognition and rest/activity. Our primary hypothesis is that people with bipolar disorder have some pathophysiological change at the level of the retina which makes them hypersensitive to the visual and non-visual effects of light, and therefore more susceptible to circadian rhythm dysfunction. We additionally hypothesise that the mood-stabilising medication lithium is effective in bipolar disorder because it reduces this hypersensitivity, making individuals less vulnerable to light-induced circadian disruption. We will recruit 180 participants into the HELIOS-BD study. Over an 18-month period, we will assess visual and non-visual responses to light, as well as retinal microstructure, in people with bipolar disorder compared to healthy controls. Further, we will assess whether individuals with bipolar disorder who are being treated with lithium have less pronounced light responses and attenuated retinal changes compared to individuals with bipolar disorder not being treated with lithium. This study represents a comprehensive investigation of visual and non-visual light responses in a large bipolar disorder population, with great translational potential for patient stratification and treatment innovation.

A randomised controlled feasibility trial of intermittent theta burst stimulation with an open longer-term follow-up for young people with persistent anorexia nervosa (RaISE): Study protocol.

OBJECTIVE: We present the protocol of a feasibility randomised controlled trial (RCT) of intermittent theta burst stimulation (iTBS) for young people with anorexia nervosa (AN). Effective first-line psychological therapies exist for young people with AN, but little is known about how to treat those who do not respond. Non-invasive neuromodulation, such as iTBS, could address unmet treatment needs by targeting neurocircuitry associated with the development and/or maintenance of AN. DESIGN: Sixty-six young people (aged 13-30 years) with persistent AN will be randomly allocated to receive 20 sessions of real or sham iTBS over the left dorsolateral prefrontal cortex in addition to their usual treatment. Outcomes will be measured at baseline, post-treatment (1-month post-randomisation) and 4-months post-randomisation (when unblinding will occur). Additional open follow-ups will be conducted at 12- and 24-months post-randomisation. The primary feasibility outcome is the proportion of participants retained in the study at 4-months. Secondary outcomes include AN symptomatology, other psychopathology, quality of life, service utilisation, neurocognitive processes, and neuroimaging measures. DISCUSSION: Findings will inform the development of a future large-scale RCT. They will also provide exploratory data on treatment efficacy, and neural and neurocognitive predictors and correlates of treatment response to iTBS in AN.

Interferon-α receptor antisense oligonucleotides reduce neuroinflammation and neuropathology in a mouse model of cerebral interferonopathy.

Chronic and elevated levels of the antiviral cytokine IFN-α in the brain are neurotoxic. This is best observed in patients with genetic cerebral interferonopathies such as Aicardi-Goutières syndrome. Cerebral interferonopathies typically manifest in early childhood and lead to debilitating disease and premature death. There is no cure for these diseases with existing treatments largely aimed at managing symptoms. Thus, an effective therapeutic strategy is urgently needed. Here, we investigated the effect of antisense oligonucleotides targeting the murine IFN-α receptor (Ifnar1 ASOs) in a transgenic mouse model of cerebral interferonopathy. Intracerebroventricular injection of Ifnar1 ASOs into transgenic mice with brain-targeted chronic IFN-α production resulted in a blunted cerebral interferon signature, reduced neuroinflammation, restoration of blood-brain barrier integrity, absence of tissue destruction, and lessened neuronal damage. Remarkably, Ifnar1 ASO treatment was also effective when given after the onset of neuropathological changes, as it reversed such disease-related features. We conclude that ASOs targeting the IFN-α receptor halt and reverse progression of IFN-α-mediated neuroinflammation and neurotoxicity, opening what we believe to be a new and promising approach for the treatment of patients with cerebral interferonopathies.

The metabolic overdrive hypothesis: hyperglycolysis and glutaminolysis in bipolar mania.

Evidence from diverse areas of research including chronobiology, metabolomics and magnetic resonance spectroscopy indicate that energy dysregulation is a central feature of bipolar disorder pathophysiology. In this paper, we propose that mania represents a condition of heightened cerebral energy metabolism facilitated by hyperglycolysis and glutaminolysis. When oxidative glucose metabolism becomes impaired in the brain, neurons can utilize glutamate as an alternative substrate to generate energy through oxidative phosphorylation. Glycolysis in astrocytes fuels the formation of denovo glutamate, which can be used as a mitochondrial fuel source in neurons via transamination to alpha-ketoglutarate and subsequent reductive carboxylation to replenish tricarboxylic acid cycle intermediates. Upregulation of glycolysis and glutaminolysis in this manner causes the brain to enter a state of heightened metabolism and excitatory activity which we propose to underlie the subjective experience of mania. Under normal conditions, this mechanism serves an adaptive function to transiently upregulate brain metabolism in response to acute energy demand. However, when recruited in the long term to counteract impaired oxidative metabolism it may become a pathological process. In this article, we develop these ideas in detail, present supporting evidence and propose this as a novel avenue of investigation to understand the biological basis for mania.

Pilot study of a ketogenic diet in bipolar disorder.

BACKGROUND: Recent evidence from case reports suggests that a ketogenic diet may be effective for bipolar disorder. However, no clinical trials have been conducted to date. AIMS: To assess the recruitment and feasibility of a ketogenic diet intervention in bipolar disorder. METHOD: Euthymic individuals with bipolar disorder were recruited to a 6-8 week trial of a modified ketogenic diet, and a range of clinical, economic and functional outcome measures were assessed. Study registration number: ISRCTN61613198. RESULTS: Of 27 recruited participants, 26 commenced and 20 completed the modified ketogenic diet for 6-8 weeks. The outcomes data-set was 95% complete for daily ketone measures, 95% complete for daily glucose measures and 95% complete for daily ecological momentary assessment of symptoms during the intervention period. Mean daily blood ketone readings were 1.3 mmol/L (s.d. = 0.77, median = 1.1) during the intervention period, and 91% of all readings indicated ketosis, suggesting a high degree of adherence to the diet. Over 91% of daily blood glucose readings were within normal range, with 9% indicating mild hypoglycaemia. Eleven minor adverse events were recorded, including fatigue, constipation, drowsiness and hunger. One serious adverse event was reported (euglycemic ketoacidosis in a participant taking SGLT2-inhibitor medication). CONCLUSIONS: The recruitment and retention of euthymic individuals with bipolar disorder to a 6-8 week ketogenic diet intervention was feasible, with high completion rates for outcome measures. The majority of participants reached and maintained ketosis, and adverse events were generally mild and modifiable. A future randomised controlled trial is now warranted.

Surgical stress: the muscle and cognitive demands of robotic and laparoscopic surgery.

Introduction: Surgeons are among the most at-risk professionals for work-related musculoskeletal decline and experience high mental demands. This study examined the electromyographic (EMG) and electroencephalographic (EEG) activities of surgeons during surgery. Methods: Surgeons who performed live laparoscopic (LS) and robotic (RS) surgeries underwent EMG and EEG measurements. Wireless EMG was used to measure muscle activation in four muscle groups bilaterally (biceps brachii, deltoid, upper trapezius, and latissimus dorsi), and an 8-channel wireless EEG device was used to measure cognitive demand. EMG and EEG recordings were completed simultaneously during (i) noncritical bowel dissection, (ii) critical vessel dissection, and (iii) dissection after vessel control. Robust ANOVA was used to compare the %MVCRMS and alpha power between LS and RS. Results: Thirteen male surgeons performed 26 laparoscopic surgeries (LS) and 28 robotic surgeries (RS). Muscle activation was significantly higher in the right deltoid (p = 0.006), upper trapezius (left, p = 0.041; right, p = 0.032), and latissimus dorsi (left, p = 0.003; right, p = 0.014) muscles in the LS group. There was greater muscle activation in the right biceps than in the left biceps in both surgical modalities (both p = 0.0001). There was a significant effect of the time of surgery on the EEG activity (p <0.0001). A significantly greater cognitive demand was observed in the RS than in the LS with alpha, beta, theta, delta, and gamma (p = 0.002 - p <0.0001). Conclusion: These data suggest greater muscle demands in laparoscopic surgery, but greater cognitive demands in robotic surgery.

A randomised controlled feasibility study of food-related computerised attention training versus mindfulness training and waiting-list control for adults with overweight or obesity: the FOCUS study.

BACKGROUND: In a feasibility randomised controlled trial in people with overweight/obesity with and without binge eating disorder (BED) symptoms, we assessed eight weekly sessions of attention bias modification training (ABMT) and mindfulness training (MT) versus waiting list (WL) and explored potential mechanisms. METHODS: 45 participants were randomly allocated to one of three trial arms. Primary outcomes were recruitment, retention and treatment adherence rates. Secondary outcomes included measures of eating behaviour, mood, attention and treatment acceptability. Assessments were conducted at baseline, post-intervention (week 8), and follow-up (week 12). RESULTS: Participant retention at follow-up was 84.5% across groups. Session completion rates in the laboratory were 87% for ABMT and 94% for MT, but home practice was much poorer for ABMT. Changes in BMI and body composition were small between groups and there was a medium size BMI reduction in the MT group at follow-up. Effect sizes of eating disorder symptom changes were not greater for either intervention group compared to WL, but favoured ABMT compared to MT. Hedonic hunger and mindful eating scores favoured MT compared to ABMT and WL. ABMT reduced attention biases towards high-calorie food cues, which correlated with lower objective binge eating days at post-intervention. No significant changes were observed in the MT, or WL conditions. CONCLUSIONS: Both ABMT and MT have potential value as adjuncts in the treatment of obesity and BED, and a larger clinical trial appears feasible and indicated. TRIAL REGISTRATION: ISRCTN Registry, ISRCTN15745838. Registered on 22 May 2018.

In this small research study, people who were classified as overweight or living with obesity (with or without symptoms of binge eating disorder) received either a mindfulness intervention, a "subconscious" attention-based intervention called attention bias modification training (ABMT) or were put on a waiting list for 8 weeks. People in the mindfulness group experienced improvements in emotional eating, mindful eating, and "impulsive" eating. Those who received the attention-based training paid less attention to highly caloric food after the intervention which correlated with fewer binge eating episodes. Results from this study suggest that both types of interventions have potential as add-on treatments for obesity and binge eating disorder, but larger studies are necessary to assess their clinical impact.

Effects of transcranial direct current stimulation in children and young people with psychiatric disorders: a systematic review.

Transcranial direct current stimulation (tDCS) has demonstrated benefits in adults with various psychiatric disorders, but its clinical utility in children and young people (CYP) remains unclear. This PRISMA systematic review used published and ongoing studies to examine the effects of tDCS on disorder-specific symptoms, mood and neurocognition in CYP with psychiatric disorders. We searched Medline via PubMed, Embase, PsychINFO via OVID, and Clinicaltrials.gov up to December 2022. Eligible studies involved multiple session (i.e., treatment) tDCS in CYP (≤ 25 years old) with psychiatric disorders. Two independent raters assessed the eligibility of studies and extracted data using a custom-built form. Of 33 eligible studies (participant N = 517), the majority (n = 27) reported an improvement in at least one outcome measure of disorder-specific symptoms. Few studies (n = 13) examined tDCS effects on mood and/or neurocognition, but findings were mainly positive. Overall, tDCS was well tolerated with minimal side effects. Of 11 eligible ongoing studies, many are sham-controlled RCTs (n = 9) with better blinding techniques and a larger estimated participant enrolment (M = 79.7; range 15-172) than published studies. Although encouraging, the evidence to date is insufficient to firmly conclude that tDCS can improve clinical symptoms, mood, or cognition in CYP with psychiatric disorders. Ongoing studies appear of improved methodological quality; however, future studies should broaden outcome measures to more comprehensively assess the effects of tDCS and develop dosage guidance (i.e., treatment regimens).

EDIFY (Eating Disorders: Delineating Illness and Recovery Trajectories to Inform Personalised Prevention and Early Intervention in Young People): project outline.

EDIFY (Eating Disorders: Delineating Illness and Recovery Trajectories to Inform Personalised Prevention and Early Intervention in Young People) is an ambitious research project aiming to revolutionise how eating disorders are perceived, prevented and treated. Six integrated workstreams will address key questions, including: What are young people's experiences of eating disorders and recovery? What are the unique and shared risk factors in different groups? What helps or hinders recovery? How do the brain and behaviour change from early- to later-stage illness? How can we intervene earlier, quicker and in a more personalised way? This 4-year project, involving over 1000 participants, integrates arts, design and humanities with advanced neurobiological, psychosocial and bioinformatics approaches. Young people with lived experience of eating disorders are at the heart of EDIFY, serving as advisors and co-producers throughout. Ultimately, this work will expand public and professional perceptions of eating disorders, uplift under-represented voices and stimulate much-needed advances in policy and practice.

Remote neuropsychological assessment: Acceptability and feasibility of direct-to-home teleneuropsychology methodology during the COVID-19 pandemic.

OBJECTIVE: To determine the acceptability and feasibility of telephone and video-conference calls to complete cognitive assessments during the COVID-19 pandemic. METHOD: In rapid response to the pandemic, evidence-based adaptations were made to routine face-to-face (FTF) practice, delivering teleneuropsychology (TNP) within a National Health Service (NHS) Scotland neuropsychology service. Caldicott guardian approval was obtained to complete a six month study (April to October 2020) from the early stages of the first United Kingdom (UK) lockdown. Assessments were completed with patients in their own homes (direct-to-home) via remote connections. Neuropsychology clinicians, service-users and referring agents were approached for structured feedback and qualitative comment. RESULTS: Data was captured for 212 referrals assessed by seven clinical psychologists; with responses from 70 (33%) service-users and 14 (58%) referring agents. 94% of referrals were assessed remotely and discharged. TNP reduced defaulted appointment discharge rates. Gender, socioeconomic deprivation and age did not affect access to information technology (IT) equipment.Clinicians agreed that remote assessment allowed them to complete initial interview (96%) and formulate (77%) cases appropriately. Service-users agreed they were comfortable with equipment (84%), the process was straightforward (74%), and would recommend TNP to others (68%). Referring agents were satisfied with the service provided (100%). Limitations included evidence-based remote test availability, technical issues and home distractions. CONCLUSIONS: Study findings evidence the acceptability and efficiency of TNP; increasing service accessibility, while reducing infection risk, defaulted appointments and travel. The results advocate for a post-pandemic mixed model of service delivery encompassing both FTF and TNP approaches.

Associations between bone mineral density, body composition and amenorrhoea in females with eating disorders: a systematic review and meta-analysis.

BACKGROUND: Lower bone mineral density (BMD) increases the risk of osteoporosis in individuals with eating disorders (EDs), particularly women with anorexia nervosa (AN), making them susceptible to pain and fractures throughout adulthood. In AN, low weight, hypothalamic amenorrhoea, and longer illness duration are established risk factors for low BMD, and in people with other EDs a history of AN seems to be an important risk factor for low BMD. PURPOSE: To conduct a systematic review and meta-analysis of BMD in individuals with EDs, including AN, bulimia nervosa (BN), binge-eating disorder (BED) and other specified feeding or eating disorders (OSFED) compared to healthy controls (HC). METHODS: Following PRISMA guidelines, electronic databases were reviewed and supplemented with a literature search until 2/2022 of publications measuring BMD (dual-energy X-ray absorptiometry or dual photon absorptiometry) in females with any current ED diagnosis and a HC group. Primary outcomes were spine, hip, femur and total body BMD. Explanatory variables were fat mass, lean mass and ED clinical characteristics (age, illness duration, body mass index (BMI), amenorrhoea occurrence and duration, and oral contraceptives use). RESULTS: Forty-three studies were identified (N = 4163 women, mean age 23.4 years, min: 14.0, max: 37.4). No study with individuals with BED met the inclusion criteria. BMD in individuals with AN (total body, spine, hip, and femur), with BN (total body and spine) and with OSFED (spine) was lower than in HC. Meta-regression analyses of women with any ED (AN, BN or OSFED) (N = 2058) showed low BMI, low fat mass, low lean mass and being amenorrhoeic significantly associated with lower total body and spine BMD. In AN, only low fat mass was significantly associated with low total body BMD. CONCLUSION: Predictors of low BMD were low BMI, low fat mass, low lean mass and amenorrhoea, but not age or illness duration. In people with EDs, body composition measurement and menstrual status, in addition to BMI, are likely to provide a more accurate assessment of individual risk to low BMD and osteoporosis.

Individuals with eating disorders (EDs) have an increased risk for developing osteoporosis and suffering fractures. To better understand this problem, we conducted a systematic review and meta-analysis comparing bone mineral density (BMD) of females with EDs with that of healthy people without an ED. We also tried to identify key factors linked with reduced bone mass in EDs. We included studies reporting BMD of individuals with anorexia nervosa (AN), bulimia nervosa (BN), binge-eating (BED) or other non-specified ED (OSFED), and of healthy controls. We found that people with AN had overall lower BMD than controls and also in the spine, hip, and femur. In people with BN, there was lower BMD overall and in the spine, but that must be only in those who previously had AN. In people with OSFED, BMD was lower in the spine. Having a low BMI, low fat mass, low lean mass and not having menstrual periods seem to negatively affect BMD. Therefore, this systematic review supports the idea that people with current or past AN, irrespective of their current ED diagnosis, should have their bone health assessed. For early identification of those most at risk, body composition measurements, current menstrual status, duration of amenorrhoea and presence or absence of a history of AN should be considered in clinical practice.

Microglia shield the murine brain from damage mediated by the cytokines IL-6 and IFN-α.

Sustained production of elevated levels of the cytokines interleukin (IL)-6 or interferon (IFN)-α in the central nervous system (CNS) is detrimental and directly contributes to the pathogenesis of neurological diseases such as neuromyelitis optica spectrum disorders or cerebral interferonopathies, respectively. Using transgenic mice with CNS-targeted production of IL-6 (GFAP-IL6) or IFN-α (GFAP-IFN), we have recently demonstrated that microglia are prominent target and effector cells and mount stimulus-specific responses to these cytokines. In order to further clarify the phenotype and function of these cells, we treated GFAP-IL6 and GFAP-IFN mice with the CSF1R inhibitor PLX5622 to deplete microglia. We examined their ability to recover from acute microglia depletion, as well as the impact of chronic microglia depletion on the progression of disease. Following acute depletion in the brains of GFAP-IL6 mice, microglia repopulation was enhanced, while in GFAP-IFN mice, microglia did not repopulate the brain. Furthermore, chronic CSF1R inhibition was detrimental to the brain of GFAP-IL6 and GFAP-IFN mice and gave rise to severe CNS calcification which strongly correlated with the absence of microglia. In addition, PLX5622-treated GFAP-IFN mice had markedly reduced survival. Our findings provide evidence for novel microglia functions to protect against IFN-α-mediated neurotoxicity and neuronal dysregulation, as well as restrain calcification as a result of both IL-6- and IFN-α-induced neuroinflammation. Taken together, we demonstrate that CSF1R inhibition may be an undesirable target for therapeutic treatment of neuroinflammatory diseases that are driven by elevated IL-6 and IFN-α production.

Insulin signaling as a therapeutic mechanism of lithium in bipolar disorder.

In this paper, we propose that lithium may exert its therapeutic effect in bipolar disorder by acting on insulin signaling pathways. Specifically, we assess the importance of the phosphatidylinositol 3-kinase/Protein Kinase B (PI3K/Akt) insulin signaling pathway and we assess how the action of lithium on both glycogen synthase kinase-3 (GSK3) and the phosphatidylinositol cycle may lead to mood stabilization mediated by PI3K/Akt insulin signaling. We also highlight evidence that several other actions of lithium (including effects on Akt, Protein kinase C (PKC), and sodium myo-inositol transporters) are putative mediators of insulin signaling. This novel mode of action of lithium is consistent with an emerging consensus that energy dysregulation represents a core deficit in bipolar disorder. It may also provide context for the significant co-morbidity between bipolar disorder, type 2 diabetes, and other forms of metabolic illness characterized by impaired glucose metabolism. It is suggested that developments in assessing neuronal insulin signaling using extracellular vesicles would allow for this hypothesis to be tested in bipolar disorder patients.

Does concurrent self-administered transcranial direct current stimulation and attention bias modification training improve symptoms of binge eating disorder? Protocol for the TANDEM feasibility randomized controlled trial.

Background: Binge eating disorder (BED) is a common and disabling problem associated with impaired cognitive control. Preliminary studies show that brain-directed treatments, including transcranial direct current stimulation (tDCS) and attention bias modification training (ABMT), improve cognitive control and alleviate symptoms of BED. When combined, tDCS may enhance the effects of ABMT, and vice versa, thereby improving treatment outcomes. Methods: This protocol describes a feasibility single-blind randomized sham-controlled trial of concurrent self-administered tDCS and ABMT in adults with BED (The TANDEM Trial). Eighty adults with BED will be randomly assigned to one of four groups: ABMT with real or sham self-administered tDCS, ABMT only, or waiting list control. In the treatment arms, participants will complete 10-sessions of their allocated intervention over 2-3 weeks. Outcomes will be assessed at baseline (T0), immediately post treatment (T1), and 6 weeks after end of treatment (T2), and at comparable timepoints for participants in the waitlist control group. Feasibility will be evaluated by assessing recruitment/retention rates and blinding success. Acceptability will be assessed quantitatively via participant ratings and qualitatively via semi-structured interviews. Episodes of binge eating at follow-up will be the primary clinical outcome and rate ratios from Poisson regression will be reported. Secondary outcomes will assess changes in ED and general psychopathology, attention bias toward high calorie foods, and executive function. Discussion: It is hoped that data from the trial will contribute to the development of neurobiologically informed treatments for BED, provide insights into the potential use of at-home variants of tDCS, and inform the design of future large scale trials.

Brain Structure in Acutely Underweight and Partially Weight-Restored Individuals With Anorexia Nervosa: A Coordinated Analysis by the ENIGMA Eating Disorders Working Group.

BACKGROUND: The pattern of structural brain abnormalities in anorexia nervosa (AN) is still not well understood. While several studies report substantial deficits in gray matter volume and cortical thickness in acutely underweight patients, others find no differences, or even increases in patients compared with healthy control subjects. Recent weight regain before scanning may explain some of this heterogeneity. To clarify the extent, magnitude, and dependencies of gray matter changes in AN, we conducted a prospective, coordinated meta-analysis of multicenter neuroimaging data. METHODS: We analyzed T1-weighted structural magnetic resonance imaging scans assessed with standardized methods from 685 female patients with AN and 963 female healthy control subjects across 22 sites worldwide. In addition to a case-control comparison, we conducted a 3-group analysis comparing healthy control subjects with acutely underweight AN patients (n = 466) and partially weight-restored patients in treatment (n = 251). RESULTS: In AN, reductions in cortical thickness, subcortical volumes, and, to a lesser extent, cortical surface area were sizable (Cohen's d up to 0.95), widespread, and colocalized with hub regions. Highlighting the effects of undernutrition, these deficits were associated with lower body mass index in the AN sample and were less pronounced in partially weight-restored patients. CONCLUSIONS: The effect sizes observed for cortical thickness deficits in acute AN are the largest of any psychiatric disorder investigated in the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Consortium to date. These results confirm the importance of considering weight loss and renutrition in biomedical research on AN and underscore the importance of treatment engagement to prevent potentially long-lasting structural brain changes in this population.

Strawberry notch homolog 2 regulates the response to interleukin-6 in the central nervous system.

BACKGROUND: The cytokine interleukin-6 (IL-6) modulates a variety of inflammatory processes and, context depending, can mediate either pro- or anti-inflammatory effects. Excessive IL-6 signalling in the brain is associated with chronic inflammation resulting in neurodegeneration. Strawberry notch homolog 2 (Sbno2) is an IL-6-regulated gene whose function is largely unknown. Here we aimed to address this issue by investigating the impact of Sbno2 disruption in mice with IL-6-mediated neuroinflammation. METHODS: Mice with germline disruption of Sbno2 (Sbno2-/-) were generated and crossed with transgenic mice with chronic astrocyte production of IL-6 (GFAP-IL6). Phenotypic, molecular and transcriptomic analyses were performed on tissues and primary cell cultures to clarify the role of SBNO2 in IL-6-mediated neuroinflammation. RESULTS: We found Sbno2-/- mice to be viable and overtly normal. By contrast GFAP-IL6 × Sbno2-/- mice had more severe disease compared with GFAP-IL6 mice. This was evidenced by exacerbated neuroinflammation and neurodegeneration and enhanced IL-6-responsive gene expression. Cell culture experiments on primary astrocytes from Sbno2-/- mice further showed elevated and sustained transcript levels of a number of IL-6 stimulated genes. Notably, despite enhanced disease in vivo and gene expression both in vivo and in vitro, IL-6-stimulated gp130 pathway activation was reduced when Sbno2 is disrupted. CONCLUSION: Based on these results, we propose a role for SBNO2 as a novel negative feedback regulator of IL-6 that restrains the excessive inflammatory actions of this cytokine in the brain.

The cytokines interleukin-6 and interferon-α induce distinct microglia phenotypes.

BACKGROUND: Elevated production of the cytokines interleukin (IL)-6 or interferon (IFN)-α in the central nervous system (CNS) is implicated in the pathogenesis of neurological diseases such as neuromyelitis optica spectrum disorders or cerebral interferonopathies, respectively. Transgenic mice with CNS-targeted chronic production of IL-6 (GFAP-IL6) or IFN-α (GFAP-IFN) recapitulate important clinical and pathological features of these human diseases. The activation of microglia is a prominent manifestation found both in the human diseases and in the transgenic mice, yet little is known about how this contributes to disease pathology. METHODS: Here, we used a combination of ex vivo and in situ techniques to characterize the molecular, cellular and transcriptomic phenotypes of microglia in GFAP-IL6 versus GFAP-IFN mice. In addition, a transcriptomic meta-analysis was performed to compare the microglia response from GFAP-IL6 and GFAP-IFN mice to the response of microglia in a range of neurodegenerative and neuroinflammatory disorders. RESULTS: We demonstrated that microglia show stimulus-specific responses to IL-6 versus IFN-α in the brain resulting in unique and extensive molecular and cellular adaptations. In GFAP-IL6 mice, microglia proliferated, had shortened, less branched processes and elicited transcriptomic and molecular changes associated with phagocytosis and lipid processing. In comparison, microglia in the brain of GFAP-IFN mice exhibited increased proliferation and apoptosis, had larger, hyper-ramified processes and showed transcriptomic and surface marker changes associated with antigen presentation and antiviral response. Further, a transcriptomic meta-analysis revealed that IL-6 and IFN-α both contribute to the formation of a core microglia response in animal models of neurodegenerative and neuroinflammatory disorders, such as Alzheimer's disease, tauopathy, multiple sclerosis and lipopolysaccharide-induced endotoxemia. CONCLUSIONS: Our findings demonstrate that microglia responses to IL-6 and IFN-α are highly stimulus-specific, wide-ranging and give rise to divergent phenotypes that modulate microglia responses in neuroinflammatory and neurodegenerative diseases.

PLX5622 Reduces Disease Severity in Lethal CNS Infection by Off-Target Inhibition of Peripheral Inflammatory Monocyte Production.

PLX5622 is a CSF-1R inhibitor and microglia-depleting reagent, widely used to investigate the biology of this central nervous system (CNS)-resident myeloid population, but the indirect or off-target effects of this agent remain largely unexplored. In a murine model of severe neuroinflammation induced by West Nile virus encephalitis (WNE), we showed PLX5622 efficiently depleted both microglia and a sub-population of border-associated macrophages in the CNS. However, PLX5622 also significantly depleted mature Ly6Chi monocytes in the bone marrow (BM), inhibiting their proliferation and lethal recruitment into the infected brain, reducing neuroinflammation and clinical disease scores. Notably, in addition, BM dendritic cell subsets, plasmacytoid DC and classical DC, were depleted differentially in infected and uninfected mice. Confirming its protective effect in WNE, cessation of PLX5622 treatment exacerbated disease scores and was associated with robust repopulation of microglia, rebound BM monopoiesis and markedly increased inflammatory monocyte infiltration into the CNS. Monoclonal anti-CSF-1R antibody blockade late in WNE also impeded BM monocyte proliferation and recruitment to the brain, suggesting that the protective effect of PLX5622 is via the inhibition of CSF-1R, rather than other kinase targets. Importantly, BrdU incorporation in PLX5622-treated mice, suggest remaining microglia proliferate independently of CSF-1 in WNE. Our study uncovers significantly broader effects of PLX5622 on the myeloid lineage beyond microglia depletion, advising caution in the interpretation of PLX5622 data as microglia-specific. However, this work also strikingly demonstrates the unexpected therapeutic potential of this molecule in CNS viral infection, as well as other monocyte-mediated diseases.

'My dad was like "it's your brain, what are you doing?"': Participant experiences of repetitive transcranial magnetic stimulation treatment in severe enduring anorexia nervosa.

OBJECTIVE: Repetitive transcranial magnetic stimulation (rTMS) is a promising emerging treatment for anorexia nervosa (AN). However, to date, patients' views and experiences of this treatment have not been fully explored. To assess these, we integrated a qualitative study into a feasibility randomised controlled trial of rTMS in individuals with severe enduring AN. METHOD: Twenty-nine (of 34) trial participants contributed to this study. Semi-structured interviews were conducted 3-months following the completion of rTMS treatment (4-months post-randomisation), prior to unblinding. Transcripts were analysed using content analysis. RESULTS: rTMS was deemed an acceptable but time-consuming treatment. Many emphasised how their lives had changed to some extent during, but mainly after treatment by making them more positive, open-minded, flexible and willing to try new things in relation to their AN and other aspects of their lives. CONCLUSIONS: These qualitative data will be valuable in shaping participant information, recruitment and planning of future large-scale trials of rTMS in AN. TRIAL REGISTRATION: ISRCTN14329415, registered 23rd July 2015, https://www.isrctn.com/ISRCTN14329415.

A novel phosphoproteomic landscape evoked in response to type I interferon in the brain and in glial cells.

BACKGROUND: Type I interferons (IFN-I) are key responders to central nervous system infection and injury and are also increased in common neurodegenerative diseases. Their effects are primarily mediated via transcriptional regulation of several hundred interferon-regulated genes. In addition, IFN-I activate several kinases including members of the MAPK and PI3K families. Yet, how changes to the global protein phosphoproteome contribute to the cellular response to IFN-I is unknown. METHODS: The cerebral phosphoproteome of mice with brain-targeted chronic production of the IFN-I, IFN-α, was obtained. Changes in phosphorylation were analyzed by ontology and pathway analysis and kinase enrichment predictions. These were verified by phenotypic analysis, immunohistochemistry and immunoblots. In addition, primary murine microglia and astrocytes, the brain's primary IFN-I-responding cells, were acutely treated with IFN-α and the global phosphoproteome was similarly analyzed. RESULTS: We identified widespread protein phosphorylation as a novel mechanism by which IFN-I mediate their effects. In our mouse model for IFN-I-induced neurodegeneration, protein phosphorylation, rather than the proteome, aligned with the clinical hallmarks and pathological outcome, including impaired development, motor dysfunction and seizures. In vitro experiments revealed extensive and rapid IFN-I-induced protein phosphorylation in microglia and astrocytes. Response to acute IFN-I stimulation was independent of gene expression and mediated by a small number of kinase families. The changes in the phosphoproteome affected a diverse range of cellular processes and functional analysis suggested that this response induced an immediate reactive state and prepared cells for subsequent transcriptional responses. CONCLUSIONS: Our studies reveal a hitherto unappreciated role for changes in the protein phosphorylation landscape in cellular responses to IFN-I and thus provide insights for novel diagnostic and therapeutic strategies for neurological diseases caused by IFN-I.