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Aim The Rett Syndrome Gross Motor Scale (RSGMS) is an observational measurement, assessing gross motor skills in individuals with Rett syndrome. A Dutch version is lacking. The current study aims to translate and cross-culturally adapt the original RSMGS to Dutch and assess its inter-rater and intra-rater reliability. Design Translation and cross-cultural adaptation were performed in concordance with internationally accepted guidelines. A pretest was performed, and expert validation was assured. Video data of three girls with Rett syndrome was independently assessed by 27 physiotherapists via an online webinar to measure inter-rater reliability. Additionally, videos of 17 individuals with Rett syndrome were scored twice by two raters to assess intra-rater reliability. The reliability of the total score, the three subscale scores and the new items were analyzed using Intraclass Correlation Coefficients (ICC). Results Good comprehensibility and expert validation of the RSMGS-NL was achieved, and four items were added to the original scale. Inter-rater reliability for the total score was excellent (ICC 0.97, 95% CI 0.89-0.99), and good to perfect inter-rater reliability for the three subscales; Sitting, Standing & walking and Challenge was found (ICC values 1.0 (95% CI 0), 0.98 (95% CI 0.91-0.99) and 0.82 (95% CI 0.93-0.99) respectively). The intra-rater reliability was excellent for the total test score (ICC 0.98, 95% CI 0.97-0.99) and good to excellent for the subscale scores (ICC values 0.87 (95% CI 0.75-0.94), 0.99 (95% CI 0.98-1.0) and 0.97 (95% CI 0.95-0.99) respectively). The four new items (Standing to sitting, walking down a slope, ascending the stairs, descending the stairs) showed good to excellent intra-rater reliability. Conclusion The RSGMS-NL is a reliable measure of gross motor skills in Dutch individuals with Rett syndrome.

PURPOSE: This study evaluated the long-term effects of Brainz, a community-based treatment programme for adults with acquired brain injury in the chronic phase of the injury.MATERIALS AND METHODS: The treatment consisted of group modules and biweekly individual home training sessions. Of the 62 subjects who participated in the original effect study, 30 subjects were available for follow-up assessment. Selection bias analysis of baseline characteristics revealed no significant differences between the included and the excluded group. Baseline measurements were compared with follow-up measurements to assess effect consolidation after treatment cessation.RESULTS: The increased level of patient satisfaction with social participation found one year after baseline, was maintained at follow-up. The positive effects on the number of perceived difficulties in daily life and need of care that were found one year after baseline measurements were no longer present. However, an additional improvement in self-reported overall health was observed. The decreased level of self-esteem measured one year after baseline, was no longer present at follow-up.CONCLUSIONS: Overall, this study suggests consolidation of the effects of this community-based treatment programme. Further enhancement of treatment effects could be established by the implementation of booster sessions or peer support groups. Future controlled studies are needed. Implications for rehabilitation Acquired brain injury can lead to consequences in a variety of life domains that can persist after patients return to their homes. A low-intensity community-based rehabilitation programme called Brainz demonstrated to improve patient satisfaction with societal participation and reduce perceived difficulties in daily life and need of care. This study suggests the consolidation of these effects.

Background: The contribution of gene-environment interactions that lead to excessive aggression is poorly understood. Environmental stressors and mutations of the gene encoding tryptophan hydroxylase-2 (TPH2) are known to influence aggression. For example, TPH2 null mutant mice (Tph2−/−) are naturally highly aggressive, while heterozygous mice (Tph2+/−) lack a behavioral phenotype and are considered endophenotypically normal. Here we sought to discover whether an environmental stressor would affect the phenotype of the genetically ‘susceptible’ heterozygous mice (Tph2+/−). Methods: Tph2+/− male mice or Tph2+/+ controls were subjected to a five-day long rat exposure stress paradigm. Brain serotonin metabolism and the expression of selected genes encoding serotonin receptors, AMPA receptors, and stress markers were studied. Results: Stressed Tph2+/− mice displayed increased levels of aggression and social dominance, whereas Tph2+/+ animals became less aggressive and less dominant. Brain tissue concentrations of serotonin, its precursor hydroxytryptophan and its metabolite 5-hydroxyindoleacetic acid were significantly altered in all groups in the prefrontal cortex, striatum, amygdala, hippocampus and dorsal raphe after stress. Compared to non-stressed animals, the concentration of 5-hydroxytryptophan was elevated in the amygdala though decreased in the other brain structures. The overexpression of the AMPA receptor subunit, GluA2, and downregulation of 5-HT6 receptor, as well as overexpression of c-fos and glycogen-synthase-kinase-3β (GSK3-β), were found in most structures of the stressed Tph2+/− mice. Limitations: Rescue experiments would help to verify causal relationships of reported changes. Conclusions: The interaction of a partial TPH2 gene deficit with stress results in pathological aggression and molecular changes, and suggests that the presence of genetic susceptibility can augment aggression in seemingly resistant phenotypes. © 2020 The Authors 602805 Seventh Framework Programme, FP7 Deutsche Forschungsgemeinschaft, DFG: CRC TRR 58 A1/A5 Horizon 2020 Framework Programme, H2020: 728018 Russian Foundation for Basic Research, RFBR: 15-04-03602 Deutsche Forschungsgemeinschaft, DFG Russian Foundation for Basic Research, RFBR The authors’ work reported here was supported Deutsche Forschungsgemeinschaft (DFG: CRC TRR 58 A1/A5), the European Union's Seventh Framework Programme (FP7/2007–2013) under Grant No. 602805 (Aggressotype) and the Horizon 2020 Research and Innovation Programme under Grant No. 728018 (Eat2beNICE) (to KPL and TS), the “5-100” Russian Academic Excellence Project (to KPL and TS) and the Russian Foundation of Basic Research (RFBR Grant No. 15-04-03602 to TS). We appreciate the valuable technical help of Dr. Joao Costa-Nunes and Dolores Bonopartos with this project.

Objective: In long-term electroencephalogram (EEG) signals, automated classification of epileptic seizures is desirable in diagnosing epilepsy patients, as it otherwise depends on visual inspection. To the best of the author's knowledge, existing studies have validated their algorithms using cross-validation on the same database and less number of attempts have been made to extend their work on other databases to test the generalization capability of the developed algorithms. In this study, we present the algorithm for cross-database evaluation for classification of epileptic seizures using five EEG databases collected from different centers. The cross-database framework helps when sufficient epileptic seizures EEG data are not available to build automated seizure detection model.Methods: Two features, namely successive decomposition index and matrix determinant were extracted at a segmentation length of 4 s (50% overlap). Then, adaptive median feature baseline correction (AMFBC) was applied to overcome the inter-patient and inter-database variation in the feature distribution. The classification was performed using a support vector machine classifier with leave-one-database-out cross-validation. Different classification scenarios were considered using AM-FBC, smoothing of the train and test data, and post-processing of the classifier output.Results: Simulation results revealed the highest area under the curve-sensitivity-specificity-false detections (per hour) of 1-1-1-0.15, 0.89-0.99-0.82-2.5, 0.99-0.73-1-1, 0.95-0.97-0.85-1.7, 0.99-0.99-0.9 2-1.1 using the Ramaiah Medical College and Hospitals, Children's Hospital Boston-Massachusetts Institute of Technology, Temple University Hospital, Maastricht University Medical Centre, and University of Bonn databases respectively.Conclusions: We observe that the AM-FBC plays a significant role in improving seizure detection results by overcoming inter-database variation of feature distribution.Significance: To the best of the author's knowledge, this is the first study reporting on the cross-database evaluation of classification of epileptic seizures and proven to be better generalization capability when evaluated using five databases and can contribute to accurate and robust detection of epileptic seizures in real-time. (C) 2020 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

Objectives To assess the supraspinal working mechanisms of the burst spinal cord stimulation (SCS) mode, we used functional magnetic resonance imaging (fMRI) in chronic neuropathic rats. We hypothesized that active recharge burst SCS would induce a more profound blood oxygenation level-dependent (BOLD) signal increase in areas associated with cognitive-emotional aspects of pain, as compared to tonic SCS.Methods Sprague Dawley rats (n = 17) underwent a unilateral partial sciatic nerve ligation, which resulted in chronic neuropathic pain. Quadripolar SCS electrodes were epidurally positioned on top of the dorsal columns at Th13. Isoflurane-anesthetized (1.5%) rats received either tonic SCS (n = 8) or burst SCS (n = 9) at 66% of motor threshold. BOLD fMRI was conducted before, during, and after SCS using a 9.4-T horizontal bore scanner.Results Overall, both tonic and burst SCS induced a significant increase of BOLD signal levels in areas associated with the location and intensity of pain, and areas associated with cognitive-emotional aspects of pain. Additionally, burst SCS significantly increased BOLD signal levels in the raphe nuclei, nucleus accumbens, and caudate putamen. Tonic SCS did not induce a significant increase in BOLD signal levels in these areas.Conclusions In conclusion, active recharge burst and tonic SCS have different effects on the intensity and localization of SCS-induced activation responses in the brain. This work demonstrates that active recharge burst is another waveform that can engage brain areas associated with cognitive-emotional aspects of pain as well as areas associated with location and intensity of pain. Previous studies showing similar engagement used only passive recharge burst.

Disruption of persistent, stress-associated memories is relevant for treating posttraumatic stress disorder (PTSD) and related syndromes, which develop in a subset of individuals following a traumatic event. We previously developed a stress-enhanced fear learning (SEFL) paradigm in inbred mice that produces PTSD-like characteristics in a subset of mice, including persistently enhanced memory and heightened cFos in the basolateral amygdala complex (BLC) with retrieval of the remote (30-day-old) stress memory. Here, the contribution of BLC microRNAs (miRNAs) to stress-enhanced memory was investigated because of the molecular complexity they achieve through their ability to regulate multiple targets simultaneously. We performed small-RNA sequencing (smRNA-Seq) and quantitative proteomics on BLC tissue collected from mice 1 month after SEFL and identified persistently changed microRNAs, including mir-135b-5p, and proteins associated with PTSD-like heightened fear expression. Viral-mediated overexpression of mir-135b-5p in the BLC of stress-resilient animals enhanced remote fear memory expression and promoted spontaneous renewal 14 days after extinction. Conversely, inhibition of BLC mir-135b-5p in stress-susceptible animals had the opposite effect, promoting a resilient-like phenotype. mir-135b-5p is highly conserved across mammals and was detected in post mortem human amygdala, as well as human serum samples. The mir-135b passenger strand, mir-135b-3p, was significantly elevated in serum from PTSD military veterans, relative to combat-exposed control subjects. Thus, miR-135b-5p may be an important therapeutic target for dampening persistent, stress-enhanced memory and its passenger strand a potential biomarker for responsivity to a mir-135-based therapeutic.

BACKGROUND Diagnosing long QT syndrome (LQTS) remains challenging because of a considerable overlap in QT interval between patients with LQTS and healthy subjects. Characterizing T-wave morphology might improve LQTS diagnosis.OBJECTIVE The purpose of this study was to improve LQTS diagnosis by combining new polynomial-based T-wave morphology parameters with the corrected QT interval (QTc), age, and sex in a model.METHODS A retrospective cohort consisting of 333 patients with LQTS and 345 genotype-negative family members was used in this study. For each patient, a linear combination of the first 2 Hermite-Gauss (HG) polynomials was fitted to the STT segments of an average complex of all precordial leads and limb leads I and II. The weight coefficients as well as the error of the best fit were used to characterize T-wave morphology. Subjects were classified as patients with LQTS or controls by clinical QTc cutoffs and 3 support vector machine models fed with different features. An external cohort consisting of 72 patients and 45 controls was finally used to check the robustness of the models.RESULTS Baseline QTc cutoffs were specific but had low sensitivity in diagnosing LQTS. The model with T-wave morphology features, QTc, age, and sex had the best overall accuracy (84%), followed by a model with QTc, age, and sex (79%). The model with T-wave morphology features especially performed better in LQTS type 3 patients (69%).CONCLUSION T-wave morphologies can be characterized by fitting a linear combination of the first 2 Hermite-Gauss polynomials. Adding T-wave morphology characterization to age, sex, and QTc in a support vector machine model improves LQTS diagnosis.

OBJECTIVE: To test whether polygenic risk score for schizophrenia (PRS-S) interacts with childhood adversity and daily-life stressors to influence momentary mental state domains (negative affect, positive affect, and subtle psychosis expression) and stress-sensitivity measures. METHODS: The data were retrieved from a general population twin cohort including 593 adolescents and young adults. Childhood adversity was assessed using the Childhood Trauma Questionnaire. Daily-life stressors and momentary mental state domains were measured using ecological momentary assessment. PRS-S was trained on the latest Psychiatric Genetics Consortium schizophrenia meta-analysis. The analyses were conducted using multilevel mixed-effects tobit regression models. RESULTS: Both childhood adversity and daily-life stressors were associated with increased negative affect, decreased positive affect, and increased subtle psychosis expression, while PRS-S was only associated with increased positive affect. No gene-environment correlation was detected. There is novel evidence for interaction effects between PRS-S and childhood adversity to influence momentary mental states [negative affect (b = 0.07, P = 0.013), positive affect (b = -0.05, P = 0.043), and subtle psychosis expression (b = 0.11, P = 0.007)] and stress-sensitivity measures. CONCLUSION: Exposure to childhood adversities, particularly in individuals with high PRS-S, is pleiotropically associated with emotion dysregulation and psychosis proneness. ispartof: ACTA PSYCHIATRICA SCANDINAVICA vol:141 issue:5 pages:465-475 ispartof: location:United States status: published

Aims: Mutations in DNA/RNA-binding factor (fused-in-sarcoma) FUS and superoxide dismutase-1 (SOD-1) cause amyotrophic lateral sclerosis (ALS). They were reproduced in SOD-1-G93A (SOD-1) and new FUS[1-359]-transgenic (FUS-tg) mice, where inflammation contributes to disease progression. The effects of standard disease therapy and anti-inflammatory treatments were investigated using these mutants. Methods: FUS-tg mice or controls received either vehicle, or standard ALS treatment riluzole (8 mg/kg/day), or anti-inflammatory drug a selective blocker of cyclooxygenase-2 celecoxib (30 mg/kg/day) for six weeks, or a single intracerebroventricular (i.c.v.) infusion of Neuro-Cells (a preparation of 1.39 × 106 mesenchymal and hemopoietic human stem cells, containing 5 × 105 of CD34+ cells), which showed anti-inflammatory properties. SOD-1 mice received i.c.v.-administration of Neuro-Cells or vehicle. Results: All FUS-tg-treated animals displayed less marked reductions in weight gain, food/water intake, and motor deficits than FUS-tg-vehicle-treated mice. Neuro-Cell-treated mutants had reduced muscle atrophy and lumbar motor neuron degeneration. This group but not celecoxib-FUS-tg-treated mice had ameliorated motor performance and lumbar expression of microglial activation marker, ionized calcium-binding adapter molecule-1 (Iba-1), and glycogen-synthase-kinase-3ß (GSK-3ß). The Neuro-Cells-treated-SOD-1 mice showed better motor functions than vehicle-treated-SOD-1 group. Conclusion: The neuropathology in FUS-tg mice is sensitive to standard ALS treatments and Neuro-Cells infusion. The latter improves motor outcomes in two ALS models possibly by suppressing microglial activation. © 2019 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd We thank ?5-100? Russian Excellence Program, Prof. Daniel C. Anthony, Diana Babayevskaya, and Arina Kosakova for their highly valuable contribution. ?Neuro-Cells? preparation was provided by Neuroplast BV, Maastricht, Netherlands.

OBJECTIVE Prediabetes and type 2 diabetes are associated with structural brain abnormalities, often observed in cognitive disorders. Besides visible lesions, (pre)diabetes might also be associated with alterations of the intrinsic organization of the white matter. In this population-based cohort study, the association of prediabetes and type 2 diabetes with white matter network organization was assessed. RESEARCH DESIGN AND METHODS In the Maastricht Study, a type 2 diabetes–enriched population-based cohort study (1,361 subjects with normal glucose metabolism, 348 with prediabetes, and 510 with type 2 diabetes assessed by oral glucose tolerance test; 52% men; aged 59 ± 8 years), 3 Tesla structural and diffusion MRI was performed. Whole-brain white matter tractography was used to assess the number of connections (node degree) between 94 brain regions and the topology (graph measures). Multivariable linear regression analyses were used to investigate the associations of glucose metabolism status with network measures. Associations were adjusted for age, sex, education, and cardiovascular risk factors. RESULTS Prediabetes and type 2 diabetes were associated with lower node degree after full adjustment (standardized [st]βPrediabetes = −0.055 [95% CI −0.172, 0.062], stβType2diabetes = −0.256 [−0.379, −0.133], Ptrend < 0.001). Prediabetes was associated with lower local efficiency (stβ = −0.084 [95% CI −0.159, −0.008], P = 0.033) and lower clustering coefficient (stβ = −0.097 [95% CI −0.189, −0.005], P = 0.049), whereas type 2 diabetes was not. Type 2 diabetes was associated with higher communicability (stβ = 0.148 [95% CI 0.042, 0.253], P = 0.008). CONCLUSIONS These findings indicate that prediabetes and type 2 diabetes are associated with fewer white matter connections and weaker organization of white matter networks. Type 2 diabetes was associated with higher communicability, which was not yet observed in prediabetes and may reflect the use of alternative white matter connections.

Objective: To identify determinants within 3 different domains (ie, somatic comorbidities, cognitive functioning, and neuropsychiatric symptoms [NPS]) of health-related quality of life (HRQoL) over time in memory clinic patients without dementia. Methods: This longitudinal multicenter cohort study with a 3-year observation period recruited 315 individuals (age: 69.8 ± 8.6, 64.4% males, Mini-Mental State Examination score 26.9 ± 2.6). A multivariable explanatory model was built using linear mixed effects models (forward selection per domain) to select determinants for self-perceived HRQoL over time, as measured by the EuroQoL-5D visual analogue scale (EQ VAS). Results: Mean HRQoL at study entry was 69.4 ± 15.6. The presence of agitation, appetite and eating abnormalities, and eyes/ears/nose (ie, sensory impairment) comorbidities were associated with a change in HRQoL over time. Agitation was most strongly associated with HRQoL over time. Conclusions: The association of somatic comorbidities and NPS in memory clinic patients with course of HRQoL shows that these should receive more awareness, detection, and monitoring by clinicians.

Objectives:The aim of this study was to investigate survival time and life-expectancy in people with young-onset dementia (YOD) and to examine the relationship with age, sex, dementia subtype and comorbidity.Design, Setting and Participants:Survival was examined in 198 participants in the Needs in Young-onset Dementia study, including participants with Alzheimer’s dementia (AD), vascular dementia (VaD) and frontotemporal dementia (FTD).Measures:The primary outcomes were survival time after symptom onset and after date of diagnosis. Cox proportional hazards models were used to explore the relationship between survival and age, sex, dementia subtype and comorbidity. Additionally, the impact on remaining life expectancy was explored.Results:During the six-year follow-up, 77 of the participants died (38.9%), 78 participants survived (39.4%) and 43 were lost to follow-up (21.7%). The mean survival time after symptom onset and diagnosis was 209 months (95% CI 185-233) and 120 months (95% CI 110-130) respectively. Participants with AD had a statistically significant shorter survival compared with VaD participants, both regarding survival after symptom onset (p = 0.047) as well as regarding survival after diagnosis (p = 0.049). Younger age at symptom onset or at diagnosis was associated with longer survival times. The remaining life expectancy, after diagnosis, was reduced with 51% for males and 59% for females compared to the life expectancy of the general population in the same age groups.Conclusion/Implications:It is important to consider the dementia subtype when persons with YOD and their families are informed about the prognosis of survival. Our study suggests longer survival times compared to other studies on YOD, and survival is prolonged compared to studies on LOD. Younger age at symptom onset or at diagnosis was positively related to survival but diagnosis at younger ages, nevertheless, still diminishes life expectancy dramatically.

Introduction: Clinical trials involving patients with Alzheimer’s disease (AD) continue to try to identify disease-modifying treatments. Although trials are designed to meet regulatory and registration requirements, many do not measure outcomes of the disease most relevant to key stakeholders. Methods: A systematic review sought research that elicited information from people with AD, their caregivers, and health-care professionals on which outcomes of the disease were important. Studies published in any language between 2008 and 2017 were included. Results: Participants in 34 studies described 32 outcomes of AD. These included clinical (memory, mental health), practical (ability to undertake activities of daily living, access to health information), and personal (desire for patient autonomy, maintenance of identity) outcomes of the disease. Discussion: Evidence elicited directly from the people most affected by AD reveals a range of disease outcomes that are relevant to them but are not commonly captured in clinical trials of new treatments.

Previous research in patients with psychotic disorder has shown widespread abnormalities in brain activation during reward anticipation. Research at the level of subclinical psychotic experiences in individuals unexposed to antipsychotic medication is limited with inconclusive results. Therefore, brain activation during reward anticipation was examined in a larger sample of individuals with subclinical psychotic experiences (PE). Participants in the PE-group were included based on CAPE scores. A sample of emerging adults aged 16-26 years (n = 47) with PE and healthy controls (HC) (n = 40) underwent fMRI scanning. The Monetary Incentive Delay task was conducted with cues related to win, loss or neutral conditions. fMRI nonparametric tests were used to examine the reward versus neutral cue contrast. A significant main effect of the large win ((sic)3.00) > neutral contrast was found in both groups showing activation in many brain areas, including classic reward regions. Whole brain analysis on the group comparison regarding the large win > neutral contrast showed significantly decreased activation in the right insula, putamen and supramarginal gyrus in the PE-group compared to controls. There was no group difference in the hypothesized reward-related region. Decreased activation in the right insula, putamen and supramarginal gyrus during reward anticipation in individuals with PE may be consistent with altered processing of sensory information, related to decreased emotional valuing and motivational tendencies and/or altered motor-cognitive processes. The absence of group differences in striatal activation suggests that activation here is intact in the earliest stages of psychosis and may exhibit progressive deterioration in as the disease develops. (C) 2019 Elsevier B.V. and ECNP. All rights reserved.

Peripheral Neuropathy outcome measure Standardization (PeriNomS) studies the outcome measures for nerve conditions (polyneuropathy). Objective results require an objective measure (outcome). This method can be used to determine how a patient feels and the effects of a certain treatment. Unfortunately, no objective measures exist for most chronic disorders. This study led to the development of a measure that was internationally recognised as the best way to determine the effects of a treatment. This will make it easier to compare studies in the future and can be used for multiple diseases.

This dissertation examines whether a ketogenic diet (KD) is an effective treatment option for children, teens and adults with refractory epilepsy. KD consists of a high-fat, low-carb diet. The breakdown of fats releases ketones that the brain uses as a source of energy instead of carbohydrates.Based on the research results, it can be concluded that KD is an effective treatment that can decrease the total number of attacks, the number of cluster attacks and the severity of the attacks. Gastrointestinal issues are the most troubling symptom and tend to occur during the early stages of treatment. KD is well-tolerated with prolonged use. However, adults find it more difficult to follow the diet strictly. Incidentally, an EEG in individual patients is not an accurate predictor of who will benefit from this diet.

Achtergrond: Farmacotherapie bij ouderen met persoonlijkheidsstoornissen (PS) vormt een nieuw en belangrijk aandachtsgebied. Vooralsnog wordt de symptoomgerichte farmacotherapeutische behandeling van ouderen met PS vormgegeven aan de hand van de multidisciplinaire richtlijn Persoonlijkheidsstoornissen, die gebaseerd is op onderzoeken bij patiënten met PS tot circa 50 jaar oud. Het ontbreekt aan een richtlijn specifiek voor ouderen.Doel: Het leveren van een beschrijving van patiëntkenmerken: aantal comorbide psychiatrische stoornissen, medicatiegebruik, inclusief polyfarmacie, bij ouderen (≥ 65 jaar) met persoonlijkheidsstoornissen.Methode: Een retrospectieve cross-sectionele dossierstudie (n = 50) binnen een topklinisch centrum voor ouderen met persoonlijkheidsstoornissen (ambulante setting).Resultaten: Uit de dossierstudie blijkt 1) de ongespecificeerde/andere gespecificeerde persoonlijkheidsstoornis en de borderline persoonlijkheidsstoornis (BPS) het meest voor te komen, 2) er een trend (geen statistisch significant verschil) te zijn dat patiënten met BPS meer somatische medicatie en psychofarmaca gebruiken en 3) er een trend (geen statistisch significant verschil) te zijn dat polyfarmacie het meest voorkomt bij oudere patiënten met BPS.Conclusie: Het medicatiegebruik in bepaalde subgroepen van ouderen met PS lijkt hoog te zijn. Vervolgonderzoek is essentieel om farmacotherapie bij ouderen met PS te verbeteren.

Absence epilepsy (AE) has been associated with lower than average cognitive functioning, which are clinically relevant in some and may predispose to problems later in life. This study aimed to assess cognitive development during long-term follow-up in children with AE. Thirty-one children with AE, who had undergone two neuropsychological assessments between 2010 and 2017 were analyzed retrospectively. Cognitive measurements were 1.7 +/- 0.95 years apart. The difference in neurocognitive test scores was assessed on a group level and on an individual level using reliable change methodology. Results show that sustained attention was lower at the first measurement compared to the normative mean. Sustained attention improved during follow-up and 7 out of 14 children showed improvement after correction for practice effects. Receptive vocabulary showed a decline over time, but did not differ from the normative mean. Significant lower mean group scores were present for performance IQ, perceptual organization, processing speed, simple reaction times, and visual motor integration, while being stable over time in the majority of children. Cognitive development was not associated with seizure freedom. Mild-to-severe academic underachievement was present in 65% and comorbidities that might affect learning in 38%. This study in children with AE showed improvement in sustained attention during long-term follow-up while other cognitive weaknesses persisted over time, regardless of seizure freedom.

BackgroundIndividuals with autism spectrum disorder (ASD) appear to be at increased risk of non-affective psychotic disorder (NAPD) and bipolar disorder (BD). However, most previous studies examined the co-occurrence of ASD and NAPD or BD, ignoring possible diagnostic bias and selection bias. We used longitudinal data from Dutch psychiatric case registers to assess the risk of NAPD or BD among individuals with ASD, and compared the results to those obtained for the Dutch population in earlier studies.MethodsIndividuals with ASD (n = 17 234) were followed up between 16 and 35 years of age. Kaplan–Meier estimates were used to calculate the risk of NAPD or BD. We conducted separate analyses to reduce possible bias, including an analysis among individuals diagnosed with ASD before age 16 years (n = 8337).ResultsOf the individuals with ASD, 23.50% (95% confidence interval 21.87–25.22) were diagnosed with NAPD and 3.79% (3.06–4.69) with BD before age 35 years. The corresponding figures for the general population were 0.91% (0.63–1.28) and 0.13% (0.08–0.20). Risk estimates were substantially lower, but still higher than general population estimates, when we restricted our analyses to individuals diagnosed with ASD before age 16, with 1.87% (1.33–2.61) being diagnosed with NAPD and 0.57% (0.21–1.53) with BD before age 25 years. The corresponding figures for the general population were 0.63% (0.44–0.86) and 0.08% (0.05–0.12).ConclusionsIndividuals with ASD are at increased risk of NAPD or BD. This is likely not the result of diagnostic or selection bias.

OBJECTIVES: The examination of retinal microvascular abnormalities through fundus photography is currently the best available non-invasive technique for assessment of cerebral vascular status. Several studies in the last decade have reported higher incidences of adverse cerebrovascular events in Schizophrenia (SCZ) and bipolar disorder (BD). However, retinal microvasculature abnormalities in SCZ and BD have remained under-explored, and no study has compared this aspect of SCZ and BD till date.METHODS: Retinal Images of 100 SCZ patients, BD patients, and healthy volunteers each were acquired by trained individuals using a non-mydriatic camera with a 40-degree field of view. The retinal images were quantified using a valid semi-automated method. The average of left and right eye diameters of the venules and arterioles passing through the extended zone between 0.5 and 2 disc diameters from the optic disc were calculated.RESULTS: The groups differed significantly with respect to average diameters of both retinal venules (P < 0.001) and retinal arterioles (P < 0.001), after controlling for age and sex. Both SCZ and BD patients had significantly narrower arterioles and wider venules compared to HV. There were also significant differences between SCZ and BD patients; patients with BD had narrower arterioles and wider venules.CONCLUSION: Considering the affordability and easy accessibility of the investigative procedure, retinal microvascular examination could serve as a potential screening tool to identify individuals at risk for adverse cerebrovascular events. The findings of the current study also provide a strong rationale for further systematic examination of retinal vascular abnormalities in SCZ and BD.

Plasma proteins have been widely studied as candidate biomarkers to predict brain amyloid deposition to increase recruitment efficiency in secondary prevention clinical trials for Alzheimer's disease. Most such biomarker studies are targeted to specific proteins or are biased toward high abundant proteins. 4001 plasma proteins were measured in two groups of participants (discovery group = 516, replication group = 365) selected from the European Medical Information Framework for Alzheimer's disease Multimodal Biomarker Discovery study, all of whom had measures of amyloid. A panel of proteins (n = 44), along with age and apolipoprotein E (APOE) ε4, predicted brain amyloid deposition with good performance in both the discovery group (area under the curve = 0.78) and the replication group (area under the curve = 0.68). Furthermore, a causal relationship between amyloid and tau was confirmed by Mendelian randomization. The results suggest that high-dimensional plasma protein testing could be a useful and reproducible approach for measuring brain amyloid deposition. This research was conducted as part of the EMIF-AD project, which has received support from the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement no. 115372, resources of which are composed of financial contribution from the European Union’s Seventh Framework Program (FP7/2007-2013), and EFPIA companies’ in-kind contribution. The DESCRIPA study was funded by the European Commission within the 5th framework program (QLRT-2001-2455). The EDAR study was funded by the European Commission within the 5th framework program (contract # 37670). The Leuven cohort was funded by the Stichting voor Alzheimer Onderzoek (grant numbers #11020, #13007, and #15005). R.V. is a senior clinical investigator of the Flemish Research Foundation (FWO). J.S. is currently an employee of UCB, Braine-l’Alleud, Belgium. The San Sebastian GAP study is partially funded by the Department of Health of the Basque Government (allocation 17.0.1.08.12.0000.2.454.01.41142.001.H). The authors acknowledge the contribution of the personnel of the Genomic Service Facility at the VIB-U Antwerp Center for Molecular Neurology. The research at VIBCMN is funded in part by the University of Antwerp Research Fund. F.B. is supported by the NIHR biomedical research centre at UCLH. L.S. is funded by DPUK through MRC (grant no. MR/L023784/2) and the UK Medical Research Council Award to the University of Oxford (grant no. MC_PC_17215).

Objectives: The aim of the present study was to investigate the association between trait gratitude and loneliness in a Dutch population sample of adults over 40 years. In addition, the mediating role of psychological flexibility and engaged living between trait gratitude and loneliness was assessed. Method: A total sample of 163 adults of which 65 men (40%) and 98 women (60%) between 41 and 92 years (Mage = 66, SDage = 12) participated in this study. Data from the Loneliness Questionnaire, Flexibility Index Test, Engaged Living Scale and the Short Gratitude, Resentment, and Appreciation Test were used. Mediation analysis was performed.Results: Analysis showed a negative association between trait gratitude and loneliness. In addition, after adjusting for the demographic variables age, gender and educational level, the association between trait gratitude and loneliness was fully mediated by psychological flexibility, and partially mediated by engaged living.Conclusion: This study endorses the importance of trait gratitude and psychological flexibility in relation to experiencing loneliness. Further research is needed to replicate these findings in a more diverse sample and to investigate the causal relationships between these constructs. It would also be interesting to further investigate the role of different age groups and goal (dis)engagement strategies in this relation.

Inflammatory Rasch-built overall disability scale (I-RODS) seems to be a valid activity measure for use in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Our aim was to translate and validate the I-RODS for use in CIDP patients from Serbia. Study comprised 83 patients diagnosed with CIDP. I-RODS was translated and cross-culturally validated using the standard guidelines. Following scales were also administered: Medical Research Council (MRC) sum score, Inflammatory Neuropathy Cause and Treatment (INCAT) sensory and disability scores, Krupp's Fatigue Severity Scale, Beck Depression Inventory, Visual Analogue Scale for pain, and health survey-36 (SF-36) as a quality of life measure. According to the I-RODS, significant proportion of our patients reported that "running" (51%), "dancing" (41%), and "standing for hours" (40%) were impossible tasks to perform, while "teeth brushing" (94%), "eating" (88%), and "reading a newspaper/book" (82%) were noted as the easiest items. Patients with more muscle weakness (lower MRC sum score) and more severe INCAT sensory score had lower I-RODS score (P 1 (P

As patient/survivor movements continue to challenge reductionist biological views of mental health and psychosis, there is rising skepticism toward psychiatric medications and growing interest in withdrawal and alternatives. This new perspective also calls for a rethinking of reductionist assumptions about psychiatric medications themselves. General medical patient experience with collaborative decision making for other conditions has broad implications for psychiatric drug withdrawal, and by recognizing psychiatric medications as psychoactive substances, addiction science also suggests a central role for social context and therapeutic common factors in medication withdrawal response. New understandings of madness and medications support an emerging reconsideration of what constitutes the very definition of “health,” where measuring the absence of disease symptoms gives way to a systems-based focus on self-management, social relationships, and adaptability.

Introduction With increasing life expectancy, comorbidities become overt in Duchenne muscular dystrophy (DMD). Although micturition problems are common, bladder function is poorly understood in DMD. We studied dystrophin expression and multiple isoform involvement in the bladder during maturation to gain insights into their roles in micturition. Methods Dystrophin distribution was evaluated in rat bladders by immunohistochemical colocalization with smooth muscle, interstitial, urothelial, and neuronal markers. Protein levels of Dp140, Dp71, and smooth muscle were quantitated by Western blotting of neonatal to adult rat bladders. Results Dystrophin colocalized with smooth muscle cells and afferent nerve fibers. Dp71 was expressed two‐ to threefold higher compared with Dp140, independently of age. Age‐related muscle mass changes did not influence isoform expression levels. Discussion Dystrophin is expressed in smooth muscle cells and afferent nerve fibers in the urinary bladder, which underscores that micturition problems in DMD may have not solely a myogenic but also a neurogenic origin. Muscle Nerve 60: 202–210, 2019

BackgroundEvidence suggests that cannabis use, childhood adversity, and urbanicity, in interaction with proxy measures of genetic risk, may facilitate onset of psychosis in the sense of early affective dysregulation becoming ‘complicated’ by, first, attenuated psychosis and, eventually, full-blown psychotic symptoms.MethodsData were derived from three waves of the second Netherlands Mental Health Survey and Incidence Study (NEMESIS-2). The impact of environmental risk factors (cannabis use, childhood adversity, and urbanicity) was analyzed across severity levels of psychopathology defined by the degree to which affective dysregulation was ‘complicated’ by low-grade psychotic experiences (‘attenuated psychosis’ – moderately severe) and, overt psychotic symptoms leading to help-seeking (‘clinical psychosis’ – most severe). Familial and non-familial strata were defined based on family history of (mostly) affective disorder and used as a proxy for genetic risk in models of family history × environmental risk interaction.ResultsIn proxy gene–environment interaction analysis, childhood adversity and cannabis use, and to a lesser extent urbanicity, displayed greater-than-additive risk if there was also evidence of familial affective liability. In addition, the interaction contrast ratio grew progressively greater across severity levels of psychosis admixture (none, attenuated psychosis, clinical psychosis) complicating affective dysregulation.ConclusionKnown environmental risks interact with familial evidence of affective liability in driving the level of psychosis admixture in states of early affective dysregulation in the general population, constituting an affective pathway to psychosis. There is interest in decomposing family history of affective liability into the environmental and genetic components that underlie the interactions as shown here.

Objectives: To define ultrastructural features accompanying to antitumor effects of gemcitabine, vinorelbine and cyclooxygenase inhibitors in C6 glioma cells in vitro. Vinorelbine is a semisynthetic vinca alkaloid and recent studies showed its antitumor activity in pediatric optic and pontine gliomas. Vinorelbine infusion induces a severe tumor site-pain in systemic cancers, but it is unknown whether algesia and inflammation contribute to its antitumor effects. Gemcitabine is a nucleoside-chemotherapeutic which was recently shown to act as a radiosensitizer in high-grade glioma. Some studies showed synergism of anti-inflammatory cyclooxygenase-inhibitors with microtubule inhibitors and gemcitabine. DMSO is a solvent and blocks both cylooxygenase and ribonucleotide reductase, another target of gemcitabine. Rofecoxib is withdrawn from the market, yet we used it for investigational purposes, since it blocks cylooxygenase-2 1000-times more potently than cylooxygenase-1 and is also a selective inhibitor of crinophagy.Methods: Plating efficacy, 3D-spheroid S-phase analysis with BrdU labelling and transmission electron micro-scopical analyses were performed.Results: Vinorelbine induced frequent mitotic slippage/apoptosis and autophagy. Despite both DMSO and rofecoxib induced autophagy alone and in synergy, they reduced mitotic catastrophe and autophagy triggered by vinorelbine, which was also reflected by reduced inhibition of spheroid S-phase. Gemcitabine induced karyolysis and margination of coarse chromatin towards the nuclear membrane, abundant autophagy, gutta adipis formation and decrease in mitochondria, which were enhanced by DMSO and rofecoxib.Conclusions: Detailed ultrastructural analysis of the effects of chemotherapeutic drugs may provide a broader insight about their actions and pave to develop better strategies in treatment of glioblastoma.

BackgroundThe jumping to conclusions (JTC) reasoning bias and decreased working memory performance (WMP) are associated with psychosis, but associations with affective disturbances (i.e. depression, anxiety, mania) remain inconclusive. Recent findings also suggest a transdiagnostic phenotype of co-occurring affective disturbances and psychotic experiences (PEs). This study investigated whether JTC bias and decreased WMP are associated with co-occurring affective disturbances and PEs.MethodsData were derived from the second Netherlands Mental Health Survey and Incidence Study (NEMESIS-2). Trained interviewers administered the Composite International Diagnostic Interview (CIDI) at three time points in a general population sample (N = 4618). The beads and digit-span task were completed to assess JTC bias and WMP, respectively. CIDI was used to measure affective disturbances and an add-on instrument to measure PEs.ResultsCompared to individuals with neither affective disturbances nor PEs, the JTC bias was more likely to occur in individuals with co-occurring affective disturbances and PEs [moderate psychosis (1–2 PEs): adjusted relative risk ratio (RRR) 1.17, 95% CI 0.98–1.41; and high psychosis (3 or more PEs or psychosis-related help-seeking behaviour): adjusted RRR 1.57, 95% CI 1.19–2.08], but not with affective disturbances and PEs alone, whereas decreased WMP was more likely in all groups. There was some evidence of a dose–response relationship, as JTC bias and decreased WMP were more likely in individuals with affective disturbances as the level of PEs increased or help-seeking behaviour was reported.ConclusionThe findings suggest that JTC bias and decreased WMP may contribute to a transdiagnostic phenotype of co-occurring affective disturbances and PEs.

Contains fulltext : 205886.pdf (Publisher’s version ) (Open Access) Objectives: Memory clinics (MCs) have been established to improve diagnosis and treatment of cognitive disorders, including dementia. The aim of this study was to determine the characteristics and working methods of MCs in the Netherlands in 2016. More insight into different working methods can be used to improve the quality of care in Dutch MCs. Additionally, the findings will be compared with earlier results to investigate the development of MCs since 1998. Methods: A survey was sent in 1998, 2004, 2009, and 2017 to all operational Dutch MCs with questions about organization, collaboration, patients, and diagnostic procedures. Results: From 1998 to 2016, the number of MCs increased substantially from 12 to 91. The capacity increased from 1,560 patients to 24,388. In 1998, most patients received a dementia diagnosis (85%), while in 2016, half of the patients were diagnosed with milder cognitive problems. MCs are more often part of regional care chains and are better embedded within regional care organizations. Diagnostic tools, such as blood tests (97%), neuropsychological assessment (NPA) (95%) and neuroimaging (92%), were used in nearly all MCs. The number of patients in whom these tools were used differed greatly between MCs (NPA: 5-100%, neuroimaging: 10-100%, CSF: 0.5-80%). There was an increase in the use of NPA, while the use of neuroimaging, CSF, and EEG/ECG decreased by 8 to 15% since 2009. Conclusions: Since 1998, MCs have developed substantially and outgrown the primarily research-based university settings. They are now accepted as regular care facilities for people with cognitive problems. 8 p.

Objective: An epileptic seizure is recognized as a neurological disorder caused by transient and unexpected disturbance resulting from the excessive synchronous activity of the neurons in the brain. Analysis of epileptic seizures derived from long-term recordings of electroencephalogram (EEG) is cumbersome and time consuming for a neurologist. Therefore, introducing an automated detection system surrogate the neurologist involvement all time and speed up the treatment procedure.Methods: This study introduces a matrix determinant of EEG as a significant feature for recognition of epileptic seizures. Initially, artifact-free filtered EEG time series was arranged sequentially to form a square matrix of order, namely 13, 16, 23, and 32 and determinant was estimated. Assumed that the total elements in the square matrix represent a typical segmentation length. The experiment was conducted using EEG database obtained from the University of Bonn and Ramaiah Medical College and Hospital (RMCH). In total, eleven classification problems among non-epileptic group and epileptic EEG were composed to examine temporal dynamics of brain activity in different states of the epileptic activity. Next, the extracted feature was classified using support vector machine (SVM), K-nearest neighbor (K-NN), multilayer perceptron (MLP) classifiers with 10-fold cross-validation.Results: Experimental results revealed the highest classification accuracy of 99.45% (using University of Bonn) and 97.56% (using RMCH). between normal and epileptic EEG. In addition, other classification problems and matrix orders showed better results using all the classifiers. Further, descriptive analysis, histogram plot in polar coordinates and the bivariate histogram analysis was performed. In conclusion, matrix determinant found to be a potential biomarker for the real-time detection of epileptic seizure with minimal computational complexity. (C) 2019 Elsevier Ltd. All rights reserved.

The continuous monitoring of Parkinsons's disease (PD) symptoms would allow to automatically adjust medication or deep brain stimulation parameters to a patient's momentary condition. Wearable sensors have been proposed to monitor PD symptoms and have been validated in a number of lab and hospital settings. However, taking these sensors into the daily life of patients introduces a number of difficulties, most notably the absence of an observable ground truth of what the user is currently doing. In this pilot study, we investigate PD symptoms by combining wearable sensors on both wrist and the chest with a questionnaire based evaluation of PD symptoms, in the form of experience sampling method. For a tremor dominant patient, we show that experienced tremor severity can be predicted from the sensor data with correlations of up to r = 0.43. We evaluated different window lengths to calculate the features in and see better results for longer window lengths. Our results show that continuous monitoring of PD symptoms in daily life is feasible using wearable sensors.

The electroencephalogram (EEG) signal contains useful information on physiological states of the brain and has proven to be a potential biomarker to realize the complex dynamic behavior of the brain. Epilepsy is a brain disorder described by recurrent and unpredictable interruption of healthy brain function. Diagnosis of patients with epilepsy requires monitoring and visual inspection of long-term EEG by the neurologist, which is found to be a time-consuming procedure. Therefore, this study proposes an automated seizure detection model using a novel computationally efficient feature named sigmoid entropy derived from discrete wavelet transforms. The sigmoid entropy was estimated from the wavelet coefficients in each sub-band and classified using a non-linear support vector machine classifier with leave-one-subject-out cross-validation. The performance of the proposed method was tested with the Ramaiah Medical College and Hospital (RMCH) database, which consists of the 58 Hours of EEG from 115 subjects, the University of Bonn (UBonn), and CHB-MIT databases. Results showed that sigmoid entropy exhibits lower values for epileptic EEG in contrary to other existing entropy methods. We observe a seizure detection rate of 96.34%, a false detection rate of 0.5/h and a mean detection delay of 1.2 s for the RMCH database. The highest sensitivity of 100% and 94.21% were achieved for UBonn and CHB-MIT databases respectively. The performance comparison confirms that sigmoid entropy was found to be better and computationally efficient as compared to other entropy methods. It can be concluded that the proposed sigmoid entropy could be used as a potential biomarker for recognition and detection of epileptic seizures.

Background/Aims: The available episodic memory tests are not specifically constructed to examine older subjects. Their use in outpatient memory clinics may result in aborted test administration. We used a strict adherence to the test protocol in cognitively healthy, amnestic mild cognitive impairment (aMCI), and Alzheimer’s disease dementia subjects to assess the possibility of preventing this. Methods: This is a cross-sectional study in memory outpatient subjects with a mean age of 74.5 years. Primary study outcomes were: number of missing values and test results in the Visual Association Test (VAT) and the 15 Word Test (15WT). Results: A strict adherence to the test protocol resulted in a 10-fold decrease in the number of missing values in the VAT. For the 15WT this could not be realized mostly because the test was deemed too demanding for 1 in 6 patients. Conclusions: This study is one of the few examining the applicability of well-known episodic memory tests in older subjects. A strict adherence to the test protocol reduced the number of missing values. Floor effects were stronger for the 15WT than for the VAT. Results favor the use of the VAT in senior subjects and show the unsuitability of the 15WT in this group.

Background Success rates of up to 80% have been reported for the SNM screening period in the treatment of fecal incontinence (FI). Some patients who have an unsuccessful index implantation are successfully treated with SNM after a lead revision. There is a lack of studies comparing the outcomes of successful index implantations and successful lead revision. Therefore, the results of index implantations were compared with lead revisions in a single-center cohort.Methods Patients treated with SNM for FI between 2008 and 2016 were retrospectively reviewed. Patients with a successful index implantation were compared with patients who underwent lead revision after SNM screening. Primary outcome was a decrease in episodes of fecal incontinence of >= 50% documented by a 3-week bowel habit diary.Results Two hundred sixty-one patients (232 index group, 29 revision group) were eligible for SNM. Two hundred thirty-one patients (208 index group, 23 revision group) received permanent SNM. Follow-up was 68.8 months for the index group and 62.2 months for the revision group. The number of episodes of FI decreased from 20.6 (SD 19.3) to 3.4 (SD 4.2) in the index group and from 12.6 (SD 5.8) to 2.0 (SD 2.3) in the revision group. This effect was maintained up to 5 and 2 years in the index and revision group, respectively. Adverse events such as loss of efficacy which required surgical intervention did not differ between the two groups.Conclusion Lead revision during the test phase is a valid option in patients with FI treated by SNM who suffer from loss of efficacy of the index electrode.

Hyperactivity of the dopaminergic pathway is thought to contribute to clinical symptoms in the early stages of Huntington's disease (HD). It is suggested to be result of a reduced dopaminergic inhibition by degeneration of medium spiny neurons in the striatum.Previously, we have shown that the number of dopaminergic cells is increased in the dorsal raphe nucleus (DRN) of HD patients and transgenic HD (tgHD) rats during the manifestation phase of the disease; as well as in the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) of tgHD rats. To address whether these changes are secondary to neurodegeneration or take place in the pre-manifest phase of the disease, we examined the expression of genes controlling neuronal cell fate and genes that define dopaminergic cell phenotype.In the SNc-VTA of tgHD rats, Msx1 was upregulated, which correlated with an altered expression of transcription factors Zbtb16 and Tcf12. Zbtb16 was upregulated in the DRN and it was the only gene that showed a correlated expression in the tgHD rats between SNc-VTA and DRN. Zbtb16 may be a candidate for regionally tuning its cell populations, resulting in the increase in dopaminergic cells observed in our previous studies.Here, we demonstrated an altered expression of genes related to dopaminergic cell fate regulation in the brainstem of 6 months-old tgHD rats. This suggests that changes in dopaminergic system in HD precede the manifestation of clinical symptoms, contradicting the theory that hyperdopaminergic status in HD is a consequence of neurodegeneration in the striatum.

Purpose: To use the extent of retinal immaturity at the first visit to predict progression to any stage and treatment-requiring retinopathy of prematurity (ROP). Methods: Retrospective, multicenter, nonrandomized, observational, clinical, validation study. In all, 601 Asian Indian preterm infants born

There is ample evidence that phosphodiesterase 4 (PDE4) inhibition can improve memory performance in animal studies. In the present study, we examined the acute effects of the PDE4 inhibitor roflumilast on memory performance in healthy individuals (60-80 years of age). We tested the effects of acute roflumilast administration (100, 250, 1000 μg) in a double-blind, placebo-controlled, 4-way crossover design. Participants were first screened for their verbal word memory performance to ensure normal memory performance (within 0.5 standard deviation from norm score; n = 20) Drug effects on memory performance were tested in a verbal memory test and a spatial memory test. Reported side effects of drug treatment were registered. Roflumilast (100 μg) improved the delayed recall performance of the participants (Cohen's d, 0.69). No effects were observed in the spatial memory task. Roflumilast was well tolerated at this low dose. Although no clear adverse side effects were reported at the low dose, mild adverse events (including headache, dizziness, insomnia, and diarrhea) were reported after the 1000 μg dose. The present study provides first evidence that the PDE4 inhibitor roflumilast improves verbal memory performance in old participants. The current data encourage further development of PDE4 inhibitors for improving memory.

Background: Childhood maltreatment is a transdiagnostic risk factor for later psychopathology and has been associated with altered brain circuitry involved in the processing of threat and safety. Examining threat generalization mechanisms in young adults with childhood maltreatment and psychiatric symptoms may elucidate a pathway linking early-life adversities to the presence of subclinical psychopathology Methods: We recruited youth aged 16–25 years with subclinical psychiatric symptomatology and healthy controls. They were dichotomized into 2 groups: 1 with a high level of childhood maltreatment (n = 58) and 1 with no or a low level of childhood maltreatment (n = 55). Participants underwent a functional MRI threat generalization paradigm, measuring self-reported fear, expectancy of an unconditioned stimulus (US) and neural responses. Results: We observed interactions between childhood maltreatment and threat generalization indices on subclinical symptom load. In individuals reporting high levels of childhood maltreatment, enhanced generalization in self-reported fear and US expectancy was related to higher levels of psychopathology. Imaging results revealed that in the group with high levels of childhood maltreatment, lower activation in the left hippocampus during threat generalization was associated with a higher symptom load. Associations between threat generalization and psychopathology were nonsignificant overall in the group with no or low levels of childhood maltreatment. Limitations: The data were acquired in a cross-sectional manner, precluding definitive insight into the causality of childhood maltreatment, threat generalization and psychopathology. Conclusion: Our results suggest that threat generalization mechanisms may moderate the link between childhood maltreatment and subclinical psychopathology during emerging adulthood. Threat generalization could represent a vulnerability factor for developing later psychopathology in individuals being exposed to childhood maltreatment.

Purpose To evaluate the cost-effectiveness of ultrathin Descemet stripping automated endothelial keratoplasty (UT-DSAEK) versus standard DSAEK. Methods A cost-effectiveness analysis using data from a multicentre randomized clinical trial was performed. The time horizon was 12 months postoperatively. Sixty-four eyes of 64 patients with Fuchs' endothelial dystrophy were included and randomized to UT-DSAEK (n = 33) or DSAEK (n = 31). Relevant resources from healthcare and societal perspectives were included in the cost analysis. Quality-adjusted life years (QALYs) were determined using the Health Utilities Index Mark 3 questionnaire. The main outcome was the incremental cost-effectiveness ratio (ICER; incremental societal costs per QALY). Results Societal costs were euro9431 (US$11 586) for UT-DSAEK and euro9110 (US$11 192) for DSAEK. Quality-adjusted life years (QALYs) were 0.74 in both groups. The ICER indicated inferiority of UT-DSAEK. The cost-effectiveness probability ranged from 37% to 42%, assuming the maximum acceptable ICER ranged from euro2500-euro80 000 (US$3071-US$98 280) per QALY. Additional analyses were performed omitting one UT-DSAEK patient who required a regraft [ICER euro9057 (US$11 127) per QALY, cost-effectiveness probability: 44-62%] and correcting QALYs for an imbalance in baseline utilities [ICER euro23 827 (US$29 271) per QALY, cost-effectiveness probability: 36-59%]. Furthermore, the ICER was euro2101 (US$2581) per patient with clinical improvement in best spectacle-corrected visual acuity (>= 0.2 logMAR) and euro3274 (US$4022) per patient with clinical improvement in National Eye Institute Visual Functioning Questionnaire-25 composite score (>= 10 points). Conclusion The base case analysis favoured DSAEK, since costs of UT-DSAEK were higher while QALYs were comparable. However, additional analyses revealed no preference for UT-DSAEK or DSAEK. Further cost-effectiveness studies are required to reduce uncertainty.

The objective was to use various somatic parameters as basis for investigating the physical health of older adults with severe mental illnesses (SMI). A cross-sectional study design is performed by using baseline data from the Physical Health in SMI-elderly (PHiSMI-E) study. Data were collected using the Nursing Monitoring of Somatic Status and Lifestyle - Mental Health instrument in adults aged over 60 with SMI in a large Dutch mental health institute. Ninety-nine elderly SMI patients were included. Somatic comorbidity (84.8%), use of somatic medication (77.7%) and polypharmacy (67.7%) were prevalent. Extrapyramidal symptoms were experienced by 51% of patients, mainly in the subgroup with psychotic disorders (75.6%). Unhealthy diet was reported in 16.2%, obesity in 27.3%, and physical inactivity in 57.6%. Fatigue (67.7%) and dry mouth (66.6%) were the commonest reported physical symptoms. Mean VAS score (scale 0-10) indicating participants' self-perceived physical health was 6.7 (SD +/- 1.6). After division of the total patient group into tertiles based on the VAS scores, the lowest tertile was characterized by less physical activity, unhealthier diet, more use of medication, more fatigue, somnolence, and inner agitation. In conclusion, impaired physical health status was common in these older patients with SMI. Although they had more psychiatric and somatic comorbidity than adult SMI patients described in the literature, they had a healthier lifestyle. To reduce morbidity and premature mortality in these frail patients, it is essential that healthcare providers are aware of the high prevalence of somatic comorbidity and symptoms, and of their interactions with the psychiatric disorders. This study improves our understanding of differences in vulnerability factors of older patients with SMI. The (early) detection of somatic comorbidities may improve long-term health outcomes of these patients.

Purpose/Aim: Many genes have been associated with primary open-angle glaucoma (POAG). Knowing exactly where they are expressed in the eye helps to unravel POAG pathology and to select optimal targets for intervention. We investigated whether RNA in situ hybridization (RNA-ISH) is a convenient technique to obtain detailed pan-ocular expression data of these genes. We tested this for four diverse candidate POAG genes, selected because of unclear ocular distribution (F5 and Dusp1) and relevance for potential new therapies (Tnf, Tgf beta r3). Optn, a POAG gene with well-known ocular expression pattern served as control. Methods: We made a list of candidate glaucoma genes reported in genetic studies. A table of their ocular expression at the tissue level was compiled using publicly available microarray data (the ocular tissue database). To add cellular detail we performed RNA-ISH for Optn, Tnf, Tgf beta r3, F5, and Dusp1 on eyes of healthy, 2-month-old, pigmented, and albino mice. Results: Expression of the Optn control matched with published immunohistochemistry data. Ocular expression of Tnf was generally low, with patches of higher Tnf expression, superficially in the corneal epithelium. F5 had a restricted expression pattern with high expression in the nonpigmented ciliary body epithelium and moderate expression in the peripapillary region. Tgf beta r3 and Dusp1 showed ubiquitous expression. Conclusions: RNA-ISH is a suitable technique to determine the ocular expression pattern of POAG genes, adding meaningful cellular detail to existing microarray expression data. For instance, the high expression of F5 in the nonpigmented ciliary body epithelium suggests a role of this gene in aqueous humor dynamics and intraocular pressure. In addition, the ubiquitous expression of Tgf beta r3 has implications for designing TGF-beta-related glaucoma therapies, with respect to side effects. Creating pan-ocular expression maps of POAG genes with RNA-ISH will help to identify POAG pathways in specific cell types and to select targets for drug development.

Deep brain stimulation of the central auditory pathway is emerging as a promising treatment modality for tinnitus. Within this pathway, the dorsal cochlear nucleus (DCN) plays a key role in the pathophysiology of tinnitus and is believed to be a tinnitus generator. We hypothesized that high-frequency stimulation (HFS) of the DCN would influence tinnitus-related abnormal neuronal activity within the auditory pathway and hereby suppress tinnitus. To this end, we assessed the effect of HFS of the DCN in a noise-induced rat model of tinnitus. The presence of tinnitus was verified using the gap prepulse inhibition of the acoustic startle response paradigm. Hearing thresholds were determined before and after noise trauma by measuring the auditory brainstem responses. In addition, changes in neuronal activity induced by noise trauma and HFS were assessed using c-Fos immunohistochemistry in related structures. Results showed tinnitus development after noise trauma and hearing loss ipsilateral to the side exposed to noise trauma. During HFS of the DCN, tinnitus was suppressed. There was no change in c-Fos expression within the central auditory pathway after HFS. These findings suggest that DCN-HFS changes patterns of activity and results in information lesioning within the network and hereby blocking the relay of abnormal tinnitus-related neuronal activity.

Objective Quality of life of people with dementia and their family carers is strongly influenced by interpersonal issues and personal resources. In this context, relationship quality (RQ) and sense of coherence (SOC) potentially protect and promote health. We aimed to identify what influences RQ in dyads of people with dementia and their carers and to examine differences in their perspectives. Methods Cross‐sectional data were used from the Actifcare cohort study of 451 community‐dwelling people with dementia and their primary carers in eight European countries. Comprehensive assessments included the Positive Affect Index (RQ) and the Orientation to Life Questionnaire (SOC). Results Regression analyses revealed that RQ as perceived by people with dementia was associated with carer education, stress, and spouse caregiving. RQ as perceived by carers was associated with carer stress, depression, being a spouse, social support, reported neuropsychiatric symptoms of dementia, and carer SOC. Neuropsychiatric symptoms and carer stress contributed to discrepancies in RQ ratings within the dyad. The only factor associated with both individual RQ ratings and discrepancies was carer stress (negative feelings subscore). No significant differences in the overall perception of RQ were evident between spouses and adult children carers, but RQ determinants differed between the two. Conclusions In this European sample, carer SOC was associated with carer‐reported RQ. RQ determinants differed according to the perspective considered (person with dementia or carer) and carer subgroup. A deeper understanding of RQ and its determinants will help to tailor interventions that address these distinct perspectives and potentially improve dementia outcomes.

Purpose: To study the retinal vascular oxygen saturation in amblyopic eyes and compare them to unaffected fellow eyes and eyes of normal subjects. Methods: A total of 32 amblyopic, 24 normal and 13 fellow eyes of patients below age of 18 were enrolled in this prospective observation study. Retinal oximetry was performed using the Oxymap T1 retinal oximeter. Retinal vascular oxygen saturations and diameters were compared between amblyopic eyes, normal eyes and unaffected fellow eyes. Results: The average age was 8.6 years in the amblyopia group (M:F 16:16) and 10.9 years in the normal group (M:F 7:5; p = 0.024). Median corrected distance visual acuity in the amblyopia group was 20/50; it was 20/20 in the other groups (p

Fornix deep brain stimulation (DBS) has the ability to refurbish memory functions in animal models with experimental dementia. One of the possible underlying mechanisms is the acute increase of acetylcholine in the hippocampus. Another suggested hypothesis is neuroplasticity. Recent work in rats has shown that acute fornix DBS can modulate neurotrophic factors as well as synaptic plasticity markers on the short-term. Here, we want to test the hypothesis that acute fornix DBS can also lead to long-term effects on neuroplasticity. Rats received DBS at 100 Hz, 100 mu A and 100 mu s pulse width for 4 h with electrodes placed bilaterally in the fornix. Seven weeks after stimulation, rats were sacrificed. BDNF, p-CREB, SV2 and synaptophysin immunohistochemistry was performed for their brains. No differences were found in the number of BDNF, p-CREB or SV2 positive cells for fornix DBS rats when compared to sham. Surprisingly, the density of synaptophysin immunoreactive presynaptic boutons was significantly decreased in the CA1 and CA3 subregion of the hippocampus for DBS rats. Therefore, fornix DBS might induce long-term depression related mechanisms.

Deep brain stimulation (DBS) has shown to have antidepressant effects in both human trials and animal studies. However, the optimal target and the underlying therapeutic mechanisms remain to be determined. In this study, we investigated if high frequency (HF) DBS in the dorsal peduncular cortex (DPC) alleviates depressive-like behavior in an experimental model of depression. Surprisingly, HF DBS in the DPC caused acute induction of seizures in similar to 40% of animals stimulated with clinically relevant stimulation parameters. Reducing the stimulation's amplitude by 50% did not alter seizure occurrence. Electroencephalographic (EEG) recordings showed seizures up to Racine stage IV lasting up to 4 min after cessation of stimulation. We conclude that HF DBS in the DPC is not suitable for mood-related experiments in rats but could be a potential model for seizure induction. (C) 2019 Elsevier Inc. All rights reserved.

BackgroundAlthough equally efficacious in the acute phase, it is not known how cognitive therapy (CT) and interpersonal psychotherapy (IPT) for major depressive disorder (MDD) compare in the long run. This study examined the long-term outcomes of CT v. IPT for MDD.MethodsOne hundred thirty-four adult (18–65) depressed outpatients who were treated with CT (n = 69) or IPT (n = 65) in a large open-label randomized controlled trial (parallel group design; computer-generated block randomization) were monitored across a 17-month follow-up phase. Mixed regression was used to determine the course of self-reported depressive symptom severity (Beck Depression Inventory II; BDI-II) after treatment termination, and to test whether CT and IPT differed throughout the follow-up phase. Analyses were conducted for the total sample (n = 134) and for the subsample of treatment responders (n = 85). Furthermore, for treatment responders, rates of relapse and sustained response were examined for self-reported (BDI-II) and clinician-rated (Longitudinal Interval Follow-up Evaluation; LIFE) depression using Cox regression.ResultsOn average, the symptom reduction achieved during the 7-month treatment phase was maintained across follow-up (7–24 months) for CT and IPT, both in the total sample and in the responder sample. Two-thirds (67%) of the treatment responders did not relapse across the follow-up period on the BDI-II. Relapse rates assessed with the LIFE were somewhat lower. No differential effects between conditions were found.ConclusionsPatients who responded to IPT were no more likely to relapse following treatment termination than patients who responded to CT. Given that CT appears to have a prophylactic effect following successful treatment, our findings suggest that IPT might have a prophylactic effect as well.

Background and Purpose— Cerebral amyloid angiopathy (CAA) is a common small vessel disease that independently effects cognition in older individuals. The pathophysiology of CAA and CAA-related bleeding remains poorly understood. In this postmortem study, we explored whether blood-brain barrier leakage is associated with CAA and microvascular lesions. Methods— Eleven CAA cases (median [IQR] age=69 years [65–79 years], 8 males) and 7 cases without neurological disease or brain lesions (median [IQR] age=77 years [68–92 years], 4 males) were analyzed. Cortical sections were sampled from each lobe, and IgG and fibrin extravasation (markers of blood-brain barrier leakage) were assessed with immunohistochemistry. We hypothesized that IgG and fibrin extravasation would be increased in CAA cases compared with controls, that this would be more pronounced in parietooccipital brain regions compared with frontotemporal brain regions in parallel with the posterior predilection of CAA, and would be associated with CAA severity and number of cerebral microbleeds and cerebral microinfarcts counted on ex vivo magnetic resonance imaging of the intact brain hemisphere. Results— Our results demonstrated increased IgG positivity in the frontotemporal ( P =0.044) and parietooccipital ( P =0.001) cortex in CAA cases compared with controls. Within CAA cases, both fibrin and IgG positivity were increased in parietooccipital brain regions compared with frontotemporal brain regions ( P =0.005 and P =0.006, respectively). The percentage of positive vessels for fibrin and IgG was associated with the percentage of amyloid-β–positive vessels (Spearman ρ=0.71, P =0.015 and Spearman ρ=0.73, P =0.011, respectively). Moreover, the percentage of fibrin and IgG-positive vessels, but not amyloid-β–positive vessels, was associated with the number of cerebral microbleeds on magnetic resonance imaging (Spearman ρ=0.77, P =0.005 and Spearman ρ=0.70, P =0.017, respectively). Finally, we observed fibrin deposition in walls of vessels involved in cerebral microbleeds. Conclusions— Our results raise the possibility that blood-brain barrier leakage may be a contributory mechanism for CAA-related brain injury.

Background: Acute and chronic stress can lead to a dysregulation of the immune response. Growing evidence suggests peripheral immune dysregulation and low-grade systemic inflammation in posttraumatic stress disorder (PTSD), with numerous reports of elevated plasma interleukin-6 (IL-6) levels. However, only a few studies have assessed IL-6 levels in the cerebrospinal fluid (CSF). Most of those have used single time-point measurements, and thus cannot take circadian level variability and CSF-plasma IL-6 correlations into account.Methods: This study used time-matched, sequential 24-h plasma and CSF measurements to investigate the effects of combat stress and PTSD on physiologic levels and biorhythmicity of IL-6 in 35 male study volunteers, divided in 3 groups: (PTSD = 12, combat controls, CC = 12, and non-deployed healthy controls, HC = 11).Results: Our findings show no differences in diurnal mean concentrations of plasma and CSF IL-6 across the three comparison groups. However, a significantly blunted circadian rhythm of plasma IL-6 across 24 h was observed in all combat-zone deployed participants, with or without PTSD, in comparison to HC. CSF IL-6 rhythmicity was unaffected by combat deployment or PTSD.Conclusions: Although no significant group differences in mean IL-6 concentration in either CSF or plasma over a 24-h timeframe was observed, we provide first evidence for a disrupted peripheral IL-6 circadian rhythm as a sequel of combat deployment, with this disruption occurring in both PTSD and CC groups. The plasma IL-6 circadian blunting remains to be replicated and its cause elucidated in future research.

WOS: 000486326100009 PubMed: 30806475 AIM: To investigate the effect of using microelectrode recording (MER) on the length of time required to carry out a deep brain stimulation (DBS) procedure of the subthalamic nucleus in patients with Parkinson's disease (PD). MATERIAL and METHODS: The time required to include MER in the DBS operation was calculated for the first and second sides in 24 patients with PD. The number of microelectrodes used on each trajectory for the first and second sides, and the percentage of permanent electrodes implanted on each trajectory for the first and second sides, were quantified. RESULTS: The average times taken to use MER were 23.4 +/- 6.2 minutes, 17.4 +/- 6.5 minutes, and 41.2 +/- 6.3 minutes for the first side, second side and total procedure, respectively. In 75% of patients, the permanent electrode was implanted at the planned target site for the first side, and in 61% of patients for the second side. CONCLUSION: MER extends the time required to carry out the DBS procedure. However, during surgery, it provides real-time information on the electrodes' neurophysiological locations and helps the surgical team choose an alternative target if the planned target does not produce satisfying results.