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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.

Background Amyloid-beta (Aβ) has a dose-response relationship with cognition in healthy adults. Additionally, the levels of functional connectivity within and between brain networks have been associated with cognitive performance in healthy adults. Aiming to explore potential synergistic effects, we investigated the relationship of inter-network functional connectivity, Aβ burden, and memory decline among healthy individuals and individuals with preclinical, prodromal, or clinical Alzheimer’s disease. Methods In this longitudinal cohort study (ADNI2), participants (55–88 years) were followed for a maximum of 5 years. We included cognitively healthy participants and patients with mild cognitive impairment (with or without elevated Aβ) or Alzheimer’s disease. Associations between memory decline, Aβ burden, and connectivity between networks across the groups were investigated using linear and curvilinear mixed-effects models. Results We found a synergistic relationships between inter-network functional connectivity and Aβ burden on memory decline. Dose-response relationships between Aβ and memory decline varied as a function of directionality of inter-network connectivity across groups. When inter-network correlations were negative, the curvilinear mixed-effects models revealed that higher Aβ burden was associated with greater memory decline in cognitively normal participants, but when inter-network correlations were positive, there was no association between the magnitude of Aβ burden and memory decline. Opposite patterns were observed in patients with mild cognitive impairment. Combining negative inter-network correlations with Aβ burden can reduce the required sample size by 88% for clinical trials aiming to slow down memory decline. Conclusions The direction of inter-network connectivity provides additional information about Aβ burden on the rate of expected memory decline, especially in the preclinical phase. These results may be valuable for optimizing patient selection and decreasing study times to assess efficacy in clinical trials. Electronic supplementary material The online version of this article (10.1186/s13195-018-0420-9) contains supplementary material, which is available to authorized users.

Objective: To compare the surgical outcomes of the Minimally Invasive Ponto Surgery (MIPS) technique with those of the linear incision technique with soft-tissue preservation for bone-anchored hearing systems (BAHS). Design: Sponsor-initiated multicenter, open, randomized, controlled clinical trial. Setting: Maastricht University Medical Centre, Ziekenhuisgroep Twente and Medisch Centrum Leeuwarden, all situated in The Netherlands. Participants: Sixty-four adult patients eligible for unilateral BAHS surgery. Interventions Single-stage BAHS surgery with 1:1 randomization to the linear incision technique with soft-tissue preservation (control) or the MIPS (test) group. Primary and Secondary Outcome Measurements: Primary objective: compare the incidence of inflammation (Holgers Index ≥ 2) during 12 weeks’ follow-up after surgery. Secondary objectives: skin dehiscence, pain scores, loss of sensibility around the implant, soft-tissue overgrowth, skin sagging, implant extrusion, cosmetic results, surgical time, wound healing and Implant Stability Quotient measurements. Results: Sixty-three subjects were analyzed in the intention-to-treat population. No significant difference was found for the incidence of inflammation between groups. Loss of skin sensibility, cosmetic outcomes, skin sagging, and surgical time were significantly better in the test group. No statistically significant differences were found for dehiscence, pain, and soft-tissue overgrowth. A nonsignificant difference in extrusion was found for the test group. The Implant Stability Quotient was statistically influenced by the surgical technique, abutment length, and time. Conclusion: No significant differences between the MIPS and the linear incision techniques were observed regarding skin inflammation. MIPS results in a statistically significant reduction in the loss of skin sensibility, less skin sagging, improved cosmetic results, and reduced surgical time. Although nonsignificant, the implant extrusion rate warrants further research.

Background: The observed link between positive psychotic experiences (PE) and psychosis spectrum disorder (PSD) may be stronger depending on concomitant presence of PE with other dimensions of psychopathology. We examined whether the effect of common risk factors for PSD on PE is additive and whether the impact of risk factors on the occurrence of PE depends on the co-occurrence of other symptom dimensions (affective dysregulation, negative symptoms, and cognitive alteration).Method: Data from the Netherlands Mental Health Survey and Incidence Study 2 were used. Risk factors included childhood adversity, cannabis use, urbanicity, foreign born, hearing impairment, and family history of affective disorders. Logistic regression models were applied to test (1) the additive effect of risk factors (4 levels) on PE and (2) the moderating effects of symptom dimensions on the association between risk factors (present/absent) and PE, using additive interaction, expressed as the interaction contrast ratio.Results: Risk factors were additive: the greater the number of risk factors, the greater the odds of PE. Furthermore, concomitant presence of the other symptom dimensions all increased the impact of risk factors on PE. After controlling for age, sex, and education, only affective dysregulation and negative symptoms remained significant moderators; only affective dysregulation remained a significant moderator if all dimensions were adjusted for each other.Conclusions: Risk factors may not be directly associated with PE but additively give rise to a multidimensional subthreshold state anticipating the multidimensional clinical syndrome. Early motivational and cognitive impairments in the context of PE may be reducible to affective dysregulation.

AIM: For those patients who suffer unfavourable outcome after survival of cardiac arrest, it is important to know whether this can be predicted at an early stage. Support can subsequently be provided. This study aimed to identify early prognostic factors of quality of life (QOL) and societal participation at one year post-cardiac arrest.METHODS: The design was a prospective longitudinal cohort study following cardiac arrest survivors up to one year. Prognostic personal, injury-related, function-related and subjective outcome factors were selected and entered into a hierarchical regression model to assess whether they were predictive of QOL and societal participation at one year post-cardiac arrest.RESULTS: Hundred and ten cardiac arrest survivors were included. Not having a partner, more functional limitations (at two weeks) and cognitive complaints were significantly predictive of lower physical QOL, while higher levels of anxiety and depression symptoms (at three months) were significant predictors of mental QOL. A neurological history and higher levels of anxiety and depression symptoms were significantly predictive of lower brain injury-specific QOL. Societal participation was only predicted by premorbid functioning.CONCLUSION: This study identified prognostic factors of QOL and societal participation one year after survival of cardiac arrest. Screening of these factors in early stages can identify those survivors with possibly unfavourable QOL at one year post cardiac arrest. For those survivors, preventive and targeted interventions may be offered.

In all aspects of research it is vital to develop the researchers and academics of the future by ensuring that there are suitable career paths and career development opportunities. To demonstrate i...

We report here the sequence and functional characterization of a recombinantly expressed autoantibody (mAb 131) previously isolated from a myasthenia gravis patient by immortalization of thymic B cells using Epstein-Barr virus and TLR9 activation. The antibody is characterized by a high degree of somatic mutations as well as a 6 amino acid insertion within the VHCDR2. The recombinant mAb 131 is specific for the γ-subunit of the fetal AChR to which it bound with sub-nanomolar apparent affinity, and detected the presence of fetal AChR on a number of rhabdomyosarcoma cell lines. Mab 131 blocked one of the two α-bungarotoxin binding sites on the fetal AChR, and partially blocked the binding of an antibody (mAb 637) to the α-subunit of the AChR, suggesting that both antibodies bind at or near one ACh binding site at the α/γ subunit interface. However, mAb 131 did not reduce fetal AChR ion channel currents in electrophysiological experiments. These results indicate that mAb 131, although generated from an MG patient, is unlikely to be pathogenic and may make it a potentially useful reagent for studies of myasthenia gravis, rhabdomyosarcoma and arthrogryposis multiplex congenita which can be caused by fetal-specific AChR-blocking autoantibodies.

Background Spinal cord stimulation (SCS) has been shown to provide pain relief in painful diabetic polyneuropathy (PDPN). As the vasculature system plays a great role in the pathophysiology of PDPN, a potential beneficial side-effect of SCS is peripheral vasodilation, with high frequency (HF) SCS in particular. We hypothesize that HF-SCS (500 Hz), compared with conventional (CON) or low frequency (LF)-SCS will result in increased alleviation of mechanical hypersensitivity in chronic experimental PDPN. Methods Diabetes was induced in 8-week-old female Sprague–Dawley rats with an intraperitoneal injection of 65 mg/kg of streptozotocin (n = 44). Rats with a significant decrease in mechanical withdrawal response to von Frey filaments over a period of 20 weeks were implanted with SCS electrodes (n = 18). Rats were assigned to a cross-over design with a random order of LF-, CON-, HF- and sham SCS and mechanical withdrawal thresholds were assessed with von Frey testing. Results Compared with sham treatment, the average 50% WT score for 5 Hz was 4.88 g higher during stimulation (p = 0.156), and 1.77 g higher post-stimulation (p = 0.008). CON-SCS resulted in 50% WT scores 5.7 g, and 2.51 g higher during (p = 0.064) and after stimulation (p

Objective: This study investigated the hypotheses that (1) prelingually deafened CI users do not have perfect electrode discrimination ability and (2) the deactivation of non-discriminable electrodes can improve auditory performance. Design: Electrode discrimination difference limens were determined for all electrodes of the array. The subjects' basic map was subsequently compared to an experimental map, which contained only discriminable electrodes, with respect to speech understanding in quiet and in noise, listening effort, spectral ripple discrimination and subjective appreciation. Study Sample: Subjects were six prelingually deafened, late implanted adults using the Nucleus cochlear implant. Results: Electrode discrimination difference limens across all subjects and electrodes ranged from 0.5 to 7.125, with significantly larger limens for basal electrodes. No significant differences were found between the basic map and the experimental map on auditory tests. Subjective appreciation was found to be significantly poorer for the experimental map. Conclusions: Prelingually deafened CI users were unable to discriminate between all adjacent electrodes. There was no difference in auditory performance between the basic and experimental map. Potential factors contributing to the absence of improvement with the experimental map include the reduced number of maxima, incomplete adaptation to the new frequency allocation, and the mainly basal location of deactivated electrodes.

Objective: Cognitive impairment is frequently observed in patients with temporal lobe epilepsy. It is hypothesized that cumulative seizure exposure causes accelerated cognitive decline in patients with epilepsy. We investigated the influence of seizure frequency on cognitive decline in a rodent model for temporal lobe epilepsy.Methods: Neurobehavioral assessment was performed before and after surgery, after the induction of self-sustaining limbic status epilepticus (SSLSE), and in the chronic phase in which rats experienced recurrent seizures. Furthermore, we assessed potential confounders of memory performance.Results: Rats showed a deficit in spatial working memory after the induction of the SSLSE, which endured in the chronic phase. A progressive decline in recognition memory developed in SSLSE rats. Confounding factors were absent. Seizure frequency and also the severity of the status epilepticus were not correlated with the severity of cognitive deficits.Significance: The effect of the seizure frequency on cognitive comorbidity in epilepsy has long been debated, possibly because of confounders such as antiepileptic medication and the heterogeneity of epileptic etiologies. In an animal model of temporal lobe epilepsy, we showed that a decrease in spatial working memory does not relate to the seizure frequency. This suggests for other mechanisms are responsible for memory decline and potentially a common pathophysiology of cognitive deterioration and the occurrence and development of epileptic seizures. Identifying this common denominator will allow development of more targeted interventions treating cognitive decline in patients with epilepsy. The treatment of interictal symptoms will increase the quality of life of many patients with epilepsy. (C) 2016 Elsevier Inc. All rights reserved.

Posttraumatic stress disorder (PTSD) is a psychiatric disorder that can develop upon exposure to a traumatic event. While most people are able to recover promptly, others are at increased risk of developing PTSD. However, the exact underlying biological mechanisms of differential susceptibility are unknown. Identifying biomarkers of PTSD could assist in its diagnosis and facilitate treatment planning. Here, we identified serum microRNAs (miRNAs) of subjects that underwent a traumatic event and aimed to assess their potential to serve as diagnostic biomarkers of PTSD. Next-generation sequencing was performed to examine circulating miRNA profiles of 24 members belonging to the Dutch military cohort Prospective Research in Stress-Related Military Operations (PRISMO). Three groups were selected: "susceptible" subjects who developed PTSD after combat exposure, "resilient" subjects without PTSD, and nonexposed control subjects (N = 8 per group). Differential expression analysis revealed 22 differentially expressed miRNAs in PTSD subjects compared to controls and 1 in PTSD subjects compared to resilient individuals (after multiple testing correction and a log2 fold-change cutoff of >=|1|). Weighted Gene Coexpression Network Analysis (WGCNA) identified a module of coexpressed miRNAs which could distinguish between the three groups. In addition, receiver operating characteristic curve analyses suggest that the miRNAs with the highest module memberships could have a strong diagnostic accuracy as reflected by high areas under the curves. Overall, the results of our pilot study suggest that serum miRNAs could potentially serve as diagnostic biomarkers of PTSD, both individually or grouped within a cluster of coexpressed miRNAs. Larger studies are now needed to validate and build upon these preliminary findings.

Lumbar spondylolisthesis is usually asymptomatic. However, symptomatic spondylolisthesis results in back and/or leg pain such as radicular syndrome or neurogenic claudication. Variation in symptoms is caused by different types of spondylolisthesis. Lytic spondylolisthesis, most common at L5S1, is caused by spondylolysis of the pars interarticularis. This results in foraminal nerve compression and radicular symptoms. Degenerative spondylolisthesis, most common at L4L5 in patients >50 years old, is caused by slippage of the vertebral body and lamina, resulting in lumbar spinal stenosis and neurogenic claudication. Iatrogenic spondylolisthesis develops in 1.6-32.0% of patients after decompression surgery, causing recurrent neurogenic symptoms. It is important to understand the main symptoms patients experience: back or leg pain. In both cases, the preferred treatment is conservative. Surgery is only an option if patients have persistent/progressive leg pain. Shared decision-making is necessary to select the most accurate surgery for each individual patient while also taking into account age, comorbidities and symptoms. Further research is necessary to determine the advantages of each surgery in order to improve advice to patients.

Background: Theoretical models have implicated classical fear conditioning, fear generalization, and extinction learning in the development of anxiety disorders. To date, it is largely unknown to what extent these mechanisms and the underlying neurobiology may be altered in specific phobia, a disorder characterized by focal fears. The current study systematically examined fear conditioning, fear generalization, extinction learning, and extinction recall in a sample of individuals with a specific phobia.Methods: Participants with a specific phobia (SP) of spiders (n = 46) and healthy controls (HC) (n = 48) underwent a 3-day fMRI cue-conditioning protocol, including a fear acquisition and a fear generalization phase (day 1), an extinction learning phase (day 2), and an extinction recall phase (day 3). Stimuli were phobia-irrelevant, as geometrical shapes served as conditioned threat (CS + ) and safety stimuli (CS-), and an electrical shock as the unconditioned stimulus (US). Self-reported fear, US expectancy, and blood-oxygen-level dependent responses were measured.Results: Behavioral results only revealed enhanced CS + /CS-differentiation in fear scores during acquisition retention in SP. Some neural differences were observed during other task phases. During early fear acquisition, SP showed enhanced differential activation in the angular gyrus and lateral occipital cortex, and during extinction recall, more precuneus deactivation was found in SP compared to HC. There were no clear indications of altered neural fear generalization or extinction learning mechanisms in the SP group.Conclusions: Results indicate that spider phobia may be characterized by enhanced differential fear retention and altered brain activation patterns during fear acquisition and extinction recall. The findings provide insight into the nature of fear learning alterations in specific phobia, and how these may differ from those found in disorders characterized by broad anxious distress.

Introduction: Bilateral vestibulopathy (BV) is a chronic condition in which vestibular function is severely impaired or absent on both ears. Oscillopsia is one of the main symptoms of BV. Oscillopsia can be quantified objectively by functional vestibular tests, and subjectively by questionnaires. Recently, a new technique for testing functionally effective gaze stabilization was developed: the functional Head Impulse Test (fHIT). This study compared the fHIT with the Dynamic Visual Acuity assessed on a treadmill (DVA(treadmill)) and Oscillopsia Severity Questionnaire (OSQ) in the context of objectifying the experience of oscillopsia in patients with BV. Methods: Inclusion criteria comprised: (1) summated slow phase velocity of nystagmus of

Background Pain from skin penetrating procedures (procedural pain) during infancy in the neonatal intensive care unit (NICU) may result in changes of nociceptive sensitivity in later life. This supports the need for pain management during such vulnerable periods in life. This study, therefore, analyses the short- and long-term consequences of neonatal paracetamol (acetaminophen) treatment on pain behaviour in an experimental rat model of neonatal procedural pain. Methods A repetitive needle-prick model was used, in which neonatal rats received four needle pricks into the left hind paw per day from postnatal day 0 to day 7 (P0–P7). Paracetamol (50 mg/kg/day s.c.) was administered daily (P0–P7), and sensitivity to mechanical stimuli was compared with a needle-prick/saline-treated group and to a tactile control group. At 8 weeks of age, all animals underwent an ipsilateral paw-incision, modelling postoperative pain, and the duration of hypersensitivity was assessed. Results Neonatal paracetamol administration had no effect upon short-term mechanical hypersensitivity during the first postnatal week or upon long-term baseline sensitivity from 3 to 8 weeks. However, neonatal paracetamol administration significantly reduced the postoperative mechanical hypersensitivity in young adults, caused by repetitive needle pricking. Conclusion Paracetamol administration during neonatal procedural pain does not alter short-term or long-term effects on mechanical sensitivity, but does reduce the duration of increased postoperative mechanical hypersensitivity in a clinically relevant neonatal procedural pain model. What does this study add Paracetamol can be used safely in neonatal rats. Neonatal paracetamol treatment had no effect upon short-term mechanical hypersensitivity during the first postnatal week, nor upon long-term baseline sensitivity from 3 to 8 weeks. Paracetamol treatment during the first postnatal week significantly reduced the postoperative mechanical hypersensitivity in young adult rats.

Rationale Therapeutic agents for memory enhancement in psychiatric disorders, such as schizophrenia, are urgently needed. Objective The aim of this study is to characterize the preclinical profile of ITI-214, a potent inhibitor of phosphodiesterase 1 (PDE1). Methods ITI-214 was assayed for inhibition of PDE1 versus other PDE enzyme families using recombinant human PDE enzymes and for off-target binding to 70 substrates (General SEP II diversity panel; Caliper Life Sciences). Effects of ITI-214 (0.1–10 mg/kg, po) on memory performance were assayed in rats using the novel object recognition (NOR) paradigm, with drug given at specified time points prior to or following exposure to objects in an open field. ITI-214 was evaluated for potential drug-drug interaction with risperidone in rats using conditioned avoidance response (CAR) and pharmacokinetic assessments. Results ITI-214 inhibited PDE1A (Ki = 33 pmol) with >1000-fold selectivity for the nearest other PDE family (PDE4D) and displayed minimal off-target binding interactions in a 70-substrate selectivity profile. By using specific timing of oral ITI-214 administration, it was demonstrated in the NOR that ITI-214 is able to enhance acquisition, consolidation, and retrieval memory processes. All memory effects were in the absence of effects on exploratory behavior. ITI-214 did not disrupt the risperidone pharmacokinetic profile or effects in CAR. Conclusions ITI-214 improved the memory processes of acquisition, consolidation, and retrieval across a broad dose range (0.1–10 mg/kg, po) without disrupting the antipsychotic-like activity of a clinical antipsychotic medication, specifically risperidone. Clinical development of ITI-214 is currently in progress.

Objective Social support interventions for caregivers of persons with dementia (PwD) are important because informal carers often rely on their social networks for support. This systematic review synthesises findings from research on social support interventions, and examines their methodological quality and effectiveness on caregiver social support and well-being variables. Methods A systematic literature search utilised five databases. Papers were selected when the primary aim of the intervention was to improve social support. Quality of papers was assessed by the Level of Evidence grade and the criteria list from the Cochrane Back Review Group. Results 39 papers were identified and classified into 4 social support intervention categories: befriending and peer support, family support and social network interventions, support groups, and remote interventions using the internet or telephone. Content, intensity, uptake, effectiveness and quality of interventions varied widely. In general, the level of evidence was low. Most studies measured effect on well-being variables, while few examined social support outcomes. Multi-component social support interventions were most effective. Evidence suggested, also a caregiver benefit from remote interventions. Generally, results were inconsistent; some papers demonstrated beneficial results, while others demonstrated no improvement on social support and well-being variables. Social support outcomes were more positively evaluated when qualitative outcome measures rather than quantitative measures were used. Conclusions Although multi-component social support interventionsmay improve caregiver well-being, there is insufficient evidence to conclude whether a change in social support is the underlying mediating factor. The inclusion, validation and operationalization of caregiver social support measures deserve more attention.

To develop a tool for use in hearing screening and to evaluate the patient journey towards hearing rehabilitation, responses to the hearing aid rehabilitation questionnaire scales aid stigma, pressure, and aid unwanted addressing respectively hearing aid stigma, experienced pressure from others; perceived hearing aid benefit were evaluated with item response theory. The sample was comprised of 212 persons aged 55 years or more; 63 were hearing aid users, 64 with and 85 persons without hearing impairment according to guidelines for hearing aid reimbursement in the Netherlands. Bias was investigated relative to hearing aid use and hearing impairment within the differential test functioning framework. Items compromising model fit or demonstrating differential item functioning were dropped. The aid stigma scale was reduced from 6 to 4, the pressure scale from 7 to 4, and the aid unwanted scale from 5 to 4 items. This procedure resulted in bias-free scales ready for screening purposes and application to further understand the help-seeking process of the hearing impaired.

Objective: To enable a direct comparison of participation levels in the first year post-stroke, assessed by different outcome measures internationally. Design Two prospective stroke cohort studies following persons from stroke onset to 12 months post-stroke. Setting: Community. Participants: Persons with stroke (N=495), not living at a nursing home, from Australia STroke imAging pRevention and Treatment-Prediction and Prevention to Achieve optimal Recovery Endpoints after stroke (START-PrePARE; n=100) and the Netherlands (Restore4stroke; n=395). Interventions: Not applicable. Main Outcome Measures: Activity Card Sort-Australia and Utrecht Scale for Evaluation of Rehabilitation-Participation. Activity domains were matched across measures to find common denominators and original scoring methods were recoded, hereby enabling a direct comparison of retained activities. Results: Ninety-one (START-PrePARE) and 218 (Restore4stroke) persons with stroke were included for analyses. No major differences in background characteristics were observed between the cohorts; the Dutch cohort suffered from slightly more severe stroke. A higher level of participation was observed (radar charts) in the first months post-stroke for the Australian cohort than in the Dutch cohort, especially for unpaid work (P.003).ConclusionsAn international comparison of actual activities that persons re-engage in in the first year post-stroke was achieved using a new method and recoding of data. High levels of participation were observed in both cohorts. Unpaid work showed different frequencies at 2-3 months, contributing to different trajectories over time across cultures. Important insights were gained. Although valuable information is inevitably lost with recoding, the approach may assist future studies on the harmonization of data across cohorts, particularly for 1 of the key outcomes of stroke: participation.

There is an urgent need for therapies that could reduce the disease burden of preterm hypoxic-ischemic encephalopathy. Here, we evaluate the long-term effects of multipotent adult progenitor cells (MAPC) on long-term behavioral outcomes in a preterm rat model of perinatal asphyxia. Rats of both sexes were treated with two doses of MAPCs within 24 h after the insult. Locomotor, cognitive and psychiatric impairments were evaluated starting at 1.5 (juvenile) and 6 months (adult). Hypoxia-ischemia affected locomotion, cognition, and anxiety in a sex-dependent manner, with higher vulnerability observed in males. The MAPC therapy partially attenuated deficits in object recognition memory in females of all tested ages, and in the adult males. The hypoxic insult caused delayed hyperactivity in adult males, which was corrected by MAPC therapy. These results suggest that MAPCs may have long-term benefits for neurodevelopmental outcome after preterm birth and global hypoxia-ischemia, which warrants further preclinical exploration.

BACKGROUND: Many persons with stroke experience physical, cognitive, and emotional problems that contribute to restrictions in social participation. There is, however, a lack of knowledge on the long-term course of participation over time post-stroke.OBJECTIVE: To describe the time course of participation up to 2 years post-stroke and to identify which demographic and stroke-related factors are associated with this time course.METHODS: This was a multicenter, prospective cohort study following 390 persons with stroke from hospital admission up to 2 years (at 2, 6, 12, and 24 months). Multilevel modeling with linear and quadratic time effects was used to examine the course of the frequency of vocational and social/leisure activities, experienced restrictions, and satisfaction with participation.RESULTS: The frequency of vocational activities increased up to 1 year post-stroke and leveled off thereafter. Older and lower-educated persons showed less favorable courses of participation than younger and higher-educated persons, respectively. The frequency of social/leisure activities decreased post-stroke. Participation restrictions declined up to 1 year post-stroke and leveled off thereafter. Persons dependent in activities of daily living (ADL) kept experiencing more restrictions throughout time than independent persons. Satisfaction with participation increased slightly over time.CONCLUSIONS: Changes in participation occurred mostly in the first year post-stroke. Particularly older and lower-educated persons, and those dependent in ADL showed less favorable courses of participation up to 2 years post-stroke. Clinicians can apply these findings in identifying persons most at risk of long-term unfavorable participation outcome and, thus, target rehabilitation programs accordingly.

In this historical study we present an overview of lumbar interbody fusion surgery, which is one of the most commonly performed instrumented spinal fusion surgeries. The present article focuses on the history of lumbar interbody fusion surgery, starting from the foundation which was laid in the 19th and 20th century until today. The development of material and techniques evolved from simple wiring to the combination of transforaminal interbody fusion with polyether ether ketone cages and pedicle screw fixation with poly axial screws. The possibilities of instrumented spinal fusion grew during the past 100 years, and a considerable increase in instrumented spinal surgery was seen over the past decades. Today, gain lies in perfection of techniques and deliberate indication and development of guidelines. Therefore, more standardized studies on instrumented spinal surgery are needed to be done and techniques should be personalized on the patients' specific needs.

Objectives This study utilizes a model of long-term spinal cord stimulation (SCS) in experimental painful diabetic polyneuropathy (PDPN) to investigate the behavioral response during and after four weeks of SCS (12 hours/day). Second, we investigated the effect of long-term SCS on peripheral cutaneous blood perfusion in experimental PDPN. Methods Mechanical sensitivity was assessed in streptozotocin induced diabetic rats (n = 50) with von Frey analysis. Hypersensitive rats (n = 24) were implanted with an internal SCS battery, coupled to an SCS electrode covering spinal levels L2-L5. The effects of four weeks of daily conventional SCS for 12 hours (n = 12) or Sham SCS (n = 12) were evaluated with von Frey assessment, and laser Doppler imaging (LDI). Results Average paw withdrawal thresholds (PWT) increased during long-term SCS in the SCS group, in contrast to a decrease in the Sham group (Sham vs. SCS; p = 0.029). Twenty-four hours after long-term SCS average PWT remained higher in the SCS group. Furthermore, the SCS group showed a higher cutaneous blood perfusion during long-term SCS compared to the Sham group (Sham vs. SCS; p = 0.048). Forty-eight hours after long-term SCS, no differences in skin perfusion were observed. Discussion We demonstrated that long-term SCS results in decreased baseline mechanical hypersensitivity and results in increased peripheral blood perfusion during stimulation in a rat model of PDPN. Together, these findings indicate that long-term SCS results in modulation of the physiological circuitry related to the nociceptive system in addition to symptomatic treatment of painful symptoms.

Objective: Antiglutamate decarboxylase (anti-GAD) antibodies are associated with several neurological manifestations, like epilepsy and movement disorders. However, in daily neurological practice, it remains hard to define when to test for anti-GAD antibodies in patients with neurologic and/or psychiatric symptoms. Therefore, here, we report the patient characteristics of a large retrospective cohort of patients tested for anti-GAD antibodies in clinical practice and compare the characteristics of anti-GAD positive and anti-GAD negative patients.Methods: We blindly assessed relevant clinical symptoms and comorbidities and functional outcome with the modified Rankin Scale (mRS) in a retrospective observational cohort of all patients in which the decision to assess anti-GAD levels had been made based solely on the presence of possible associated neurological and/or psychiatric symptoms (N = 119).Results: Out of 119 patients, 17 (143%) were anti-GAD positive. The anti-GAD positive patients had a median age of 30 years (range: 3-64; 2 children). They all had epilepsy, with 8 (47%) patients reporting cognitive complaints. Psychiatric symptoms were less prevalent in anti-GAD positive patients, only 1 anti-GAD positive patient (6%) versus 34 anti-GAD negative patients (33%) reported psychiatric symptoms (p = 0.021). The most frequent comorbidity of anti-GAD positive patients was diabetes mellitus type 1 (n = 8). Twelve (71%) and 13 (78%) of the anti-GAD positive patients were functionally independent at the time of diagnosis and after one year, respectively (mRS score: 0 to 2). There was no significant difference in functional status at any time during follow-up compared with the anti-GAD negative group.Conclusion: Antiglutamate decarboxylase (anti-GAD) antibodies relate to epilepsy with or without cognitive complaints. However, psychiatric symptoms were almost absent in anti-GAD positive patients, and the presence of anti-GAD antibodies contributed little to the prognosis in our cohort. (C) 2018 Elsevier Inc. All rights reserved.

Objective: To determine the influence of daily use of spectacles to correct a refractive error, on the vestibulo-ocular reflex (VOR) gain measured with the video head impulse test (vHIT). Study design: This prospective study enrolled subjects between 18 and 80 years old with and without a refractive error. Subjects were classified into three groups: (1) contact lenses, (2) spectacles, and (3) control group without visual impairment. Exclusion criteria comprised ophthalmic pathology, history of vestibular disorders, and alternated use of spectacles and contact lenses in daily life. Corrective spectacles were removed seconds before testing. One examiner performed all vHIT's under standardized circumstances using the EyeSeeCam system. This system calculated the horizontal VOR gain for rightward and leftward head rotations separately. Results: No statistically significant difference was found in VOR gain between the control group (n = 16), spectacles group (n = 48), and contact lenses group (n = 15) (p = 0.111). Both the spectacles group and contact lenses group showed no statistically significant correlation between VOR gain and amount of refractive error, for rightwards (p = 0.071) and leftwards (p = 0.716) head rotations. There was no statistical significant difference in VOR gain between testing monocularly or binocularly (p = 0.132) and between testing with or without wearing contact lenses (p = 0.800). Conclusion: In this study, VOR gain was not influenced by wearing corrective spectacles or contact lenses on a daily basis. Based on this study, no corrective measures are necessary when performing the vHIT on subjects with a refractive error, regardless of the way of correction.

Objectives: Previous studies show that intracochlear electrical stimulation independent of environmental sounds appears to suppress tinnitus, even long-term. In order to assess the viability of this potential treatment option it is essential to study the effects of this tinnitus specific electrical stimulation on speech perception. Design: A randomised, prospective crossover design. Study sample: Ten patients with unilateral or asymmetric hearing loss and severe tinnitus complaints. Results: The audiological effects of standard clinical CI, formal auditory training and tinnitus specific electrical stimulation were investigated. Results show that standard clinical CI in unilateral or asymmetric hearing loss is shown to be beneficial for speech perception in quiet, speech perception in noise and subjective hearing ability. Formal auditory training does not appear to improve speech perception performance. However, CI-related discomfort reduces significantly more rapidly during CI rehabilitation in subjects receiving formal auditory training. Furthermore, tinnitus specific electrical stimulation has neither positive nor negative effects on speech perception. Conclusions: In combination with the findings from previous studies on tinnitus suppression using intracochlear electrical stimulation independent of environmental sounds, the results of this study contribute to the viability of cochlear implantation based on tinnitus complaints.

Recent neuro-imaging studies have implicated the cerebellum in several higher-order functions. Its role in human fear conditioning has, however, received limited attention. The current meta-analysis examines the loci of cerebellar contributions to fear conditioning in healthy subjects, thus mapping, for the first time, the neural response to conditioned aversive stimuli onto the cerebellum. By using the activation likelihood estimation (ALE) technique for analyses, we identified several distinct regions in the cerebellum that activate in response to the presentation of the conditioned stimulus: the cerebellar tonsils, lobules HIV-VI, and the culmen. These regions have separately been implicated in fear acquisition, consolidation of fear memories and expression of conditioned fear responses. Their specific role in these processes may be attributed to the general contribution of cerebellar cortical networks to timing and prediction. Our meta-analysis highlights the potential role of the cerebellum in human cognition and emotion in general, and addresses the possibility how deficits in associative cerebellar learning may play a role in the pathogenesis of anxiety disorders. Future studies are needed to further clarify the mechanistic role of the cerebellum in higher order functions and neuropsychiatric disorders. (C) 2015 Published by Elsevier Ltd.

Background Dysconnectivity in schizophrenia can be understood in terms of dysfunctional integration of a distributed network of brain regions. Here we propose a new methodology to analyze complex networks based on semi-metric behavior, whereby higher levels of semi-metricity may represent a higher level of redundancy and dispersed communication. It was hypothesized that individuals with (increased risk for) psychotic disorder would have more semi-metric paths compared to controls and that this would be associated with symptoms. Methods Resting-state functional MRI scans were obtained from 73 patients with psychotic disorder, 83 unaffected siblings and 72 controls. Semi-metric percentages (SMP) at the whole brain, hemispheric and lobar level were the dependent variables in a multilevel random regression analysis to investigate group differences. SMP was further examined in relation to symptomatology (i.e., psychotic/cognitive symptoms). Results At the whole brain and hemispheric level, patients had a significantly higher SMP compared to siblings and controls, with no difference between the latter. In the combined sibling and control group, individuals with high schizotypy had intermediate SMP values in the left hemisphere with respect to patients and individuals with low schizotypy. Exploratory analyses in patients revealed higher SMP in 12 out of 42 lobar divisions compared to controls, of which some were associated with worse PANSS symptomatology (i.e., positive symptoms, excitement and emotional distress) and worse cognitive performance on attention and emotion processing tasks. In the combined group of patients and controls, working memory, attention and social cognition were associated with higher SMP. Discussion The results are suggestive of more dispersed network communication in patients with psychotic disorder, with some evidence for trait-based network alterations in high-schizotypy individuals. Dispersed communication may contribute to the clinical phenotype in psychotic disorder. In addition, higher SMP may contribute to neuro- and social cognition, independent of psychosis risk., Highlights • Higher SMP was observed at whole brain and hemispheric level in psychotic disorder. • In patients, lobar SMP was associated with psychotic and cognitive symptoms. • Trait-based SMP alterations were observed in high schizotypy individuals.

Duchenne muscular dystrophy (DMD) is a recessive hereditary form of muscular dystrophy caused by a mutation in the dystrophin gene on the X chromosome. Clinical observations show that in addition to progressive muscular degeneration, DMD is more often accompanied by neurocognitive symptoms and learning disabilities, especially in automatisation of reading, attention processes, and expressive language skills. Additionally, three studies reported a higher prevalence of epilepsy in DMD, suggesting that the absence of dystrophin might be related to increased CNS excitability. In this article, we aim to review current clinical and experimental evidence for a potential role of brain dystrophin in seizure generation.

BackgroundAltered dopaminergic neurotransmission in the mesocorticolimbic (MCL) system may mediate psychotic symptoms. In addition, pharmacological dopaminergic manipulation may coincide with altered functional connectivity (fc) ‘in rest’. We set out to test whether MCL-fc is conditional on (familial risk for) psychotic disorder and/or interactions with environmental exposures.MethodResting-state functional magnetic resonance imaging data were obtained from 63 patients with psychotic disorder, 73 non-psychotic siblings of patients with psychotic disorder and 59 healthy controls. With the nucleus accumbens (NAcc) as seed region, fc within the MCL system was estimated. Regression analyses adjusting for a priori hypothesized confounders were used to assess group differences in MCL connectivity as well as gene (group) × environmental exposure interactions (G × E) (i.e. to cannabis, developmental trauma and urbanicity).ResultsCompared with controls, patients and siblings had decreased fc between the right NAcc seed and the right orbitofrontal cortex (OFC) as well as the left middle cingulate cortex (MCC). Siblings showed decreased connectivity between the NAcc seed and lentiform nucleus compared with patients and controls. In addition, patients had decreased left NAcc connectivity compared with siblings in the left middle frontal gyrus. There was no evidence for a significant interaction between group and the three environmental exposures in the model of MCL-fc.ConclusionsReduced NAcc–OFC/MCC connectivity was seen in patients and siblings, suggesting that altered OFC connectivity and MCC connectivity are vulnerability markers for psychotic disorder. Differential exposure to environmental risk factors did not make an impact on the association between familial risk and MCL connectivity.

ispartof: Psychotherapy and Psychosomatics vol:85 issue:4 pages:238-240 ispartof: location:Switzerland status: published

The benefits of combining a cochlear implant (CI) and a hearing aid (HA) in opposite ears on speech perception were examined in 15 adult unilateral CI recipients who regularly use a contralateral HA. A within-subjects design was carried out to assess speech intelligibility testing, listening effort ratings, and a sound quality questionnaire for the conditions CI alone, CIHA together, and HA alone when applicable. The primary outcome of bimodal benefit, defined as the difference between CIHA and CI, was statistically significant for speech intelligibility in quiet as well as for intelligibility in noise across tested spatial conditions. A reduction in effort on top of intelligibility at the highest tested signal-to-noise ratio was found. Moreover, the bimodal listening situation was rated to sound more voluminous, less tinny, and less unpleasant than CI alone. Listening effort and sound quality emerged as feasible and relevant measures to demonstrate bimodal benefit across a clinically representative range of bimodal users. These extended dimensions of speech perception can shed more light on the array of benefits provided by complementing a CI with a contralateral HA.

Diepe hersenstimulatie van de voorste thalamuskern is mogelijk een effectieve therapie voor refractaire epilepsie. De effectiviteit is echter zeer wisselend. Een probleem dat nog opgelost moet worden is bijvoorbeeld de instelling van de stimulatieparameters voor een optimaal effect. Wij pleiten dan ook voor gedegen dierexperimenteel wetenschappelijk onderzoek naar de effecten van diverse stimulusparameters bij epilepsie.

Background: Promoter methylation of N-myc Downstream-Regulated Gene 4 (NDRG4) in fecal DNA is an established early detection marker for colorectal cancer (CRC). Despite its connection to CRC, NDRG4 is predominantly studied in brain and heart, with little to no knowledge about its expression or role in other organs. In this study, we aimed to determine the whole-body expression of NDRG4, with a focus on the intestinal tract.Methods: We investigated NDRG4 expression throughout the body by immunohistochemistry, Western Blotting and in situ mRNA hybridization using tissues from NDRG4 wild-type, heterozygous and knockout mice and humans. In addition, we explored cell-specific expression of NDRG4 in murine whole-mount gut preparations using immunofluorescence and confocal microscopy.Key Results: NDRG4 is specifically expressed within nervous system structures throughout the body. In the intestinal tract of both mouse and man, NDRG4 immunoreactivity was restricted to the enteric nervous system (ENS), where it labeled cell bodies of the myenteric and submucosal plexuses and interconnecting nerve fibers. More precisely, NDRG4 expression was limited to neurons, as NDRG4 always co-localized with HuC/D (pan-neuronal marker) but never with GFAP (an enteric glial cell marker). Furthermore, NDRG4 was expressed in various neuropeptide Y positive neurons, but was only found in a minority (similar to 10%) of neurons expressing neuronal nitric oxide synthase.Conclusions and Inferences :NDRG4 is exclusively expressed by central, peripheral and enteric neurons/nerves, suggesting a neuronal-specific role of this protein. Our findings raise the question whether NDRG4, via the ENS, an understudied component of the tumor microenvironment, supports CRC development and/or progression.

Background: Different psychological models of trauma-induced psychosis have been postulated, often based on the observation of specific associations between particular types of childhood trauma (CT) and particular psychotic symptoms or the co-occurrence of delusions and hallucinations. However, the actual specificity of these associations remains to be tested. Methods: In 2 population-based studies with comparable methodology (Netherlands Mental Health Survey and Incidence Study-1 [NEMESIS-1] and NEMESIS-2, N 13 722), trained interviewers assessed CT, psychotic symptoms, and other psychopathology. Specificity of associations was assessed with mixed-effects regression models with multiple outcomes, a statistical method suitable to examine specificity of associations in case of multiple correlated outcomes. Results: Associations with CT were strong and significant across the entire range of psychotic symptoms, without evidence for specificity in the relationship between particular trauma variables and particular psychotic experiences (PEs). Abuse and neglect were both associated with PEs (ORabuse: 2.12, P

OBJECTIVE To evaluate the long-term effects of percutaneous transluminal renal angioplasty (PTRA) on blood pressure and renal function in patients with fibromuscular dysplasia (FMD). METHODS Patients in whom FMD was diagnosed during renal angiography (n = 51) were compared with a matched group of hypertensive patients in whom angiography revealed normal renal arteries (n = 51). Blood pressure, intensity of antihypertensive medication and creatinine clearance were assessed at 0, 1, 6 and 12 months. In addition, we recorded the frequencies of cure, improvement and failure of treatment. RESULTS The two groups did not differ with regard to baseline characteristics. In the FMD group, average blood pressure fell from 172/97 to 155/90 mmHg (P

Background Alterations in bone mineral density (BMD) in patients with psychotic disorder may reflect the effect of treatment (disease effect observed in patients but not their siblings) or, as an intermediate marker of cumulative endogenous estrogen exposure, alterations in the neuroprotective effect of estrogen in the brain (vulnerability effect observed in patients and siblings). Methods Dual X-ray absorptiometry (DEXA) scans were acquired in 62 patients with a psychotic disorder, 67 non-psychotic siblings of patients with a psychotic disorder, and 48 controls. BMD (g/cm2), Z-scores and T-scores were measured in the lumbar spine and proximal femur. Associations between group and BMD were investigated with multilevel random regression analyses. Group × sex interactions and effects of antipsychotic medication (AP) on BMD were examined. Results Group was not associated with BMD outcome measures, although patients had consistently lower BMD measures compared to both siblings and controls. There were no significant group × sex interactions, but stratified analyses showed that BMD measures in female patients were significantly lower in comparison to female controls and siblings (e.g. total femoral BMD, P vs. C: B = − 0.100, p = 0.010; P vs. S: B = − 0.104, p = 0.008). After excluding female patients who used prolactin-raising AP, the effect was attenuated (e.g. total femoral BMD, P vs. C: B = − 0.073, p = 0.072; P vs. S: B = − 0.085, p = 0.051). In men, there were no significant BMD differences between patients and controls. Conclusion Familial risk of psychotic disorder was not associated with BMD. Instead, decreased BMD in the femur may reflect treatment effects or non-familial risk associated with low cumulative endogenous estrogen levels in women.

BackgroundReduced hippocampal size and increased stress sensitivity are associated with psychotic disorder and familial risk for psychosis. However, to what degree the hippocampus is implicated in daily life stress reactivity has not yet been examined. The current study investigated (i) whether familial risk (the contrast between controls, patients and siblings of patients) moderated the relationship between hippocampal volume (HV) and emotional daily stress reactivity and (ii) whether familial risk (the contrast between controls and siblings of patients) moderated the relationship between HV and cortisol daily stress reactivity.MethodT1-weighted magnetic resonance imaging (MRI) scans were acquired from 20 patients with schizophrenia, 37 healthy siblings with familial risk for schizophrenia and 32 controls. Freesurfer 5.0.0 was used to measure HV. The experience sampling method (ESM), a structured momentary assessment technique, was used to assess emotional stress reactivity, that is the effect of momentary stress on momentary negative affect (NA). In addition, in the control and sibling groups, cortisol stress reactivity was assessed using momentary cortisol levels extracted from saliva.ResultsMultilevel linear regression analyses revealed a significant three-way interaction between group, HV and momentary stress in both the model of NA and the model of cortisol. Increased emotional stress reactivity was associated with smaller left HV in patients and larger total HV in controls. In line with the results in patients, siblings with small HV demonstrated increased emotional and cortisol stress reactivity compared to those with large HV.ConclusionsHV may index risk and possibly disease-related mechanisms underlying daily life stress reactivity in psychotic disorder.

Background Over the last years, less invasive surgical techniques with soft tissue preservation for bone conduction hearing implants (BCHI) have been introduced such as the linear incision technique combined with a punch. Results using this technique seem favorable in terms of rate of peri-abutment dermatitis (PAD), esthetics, and preservation of skin sensibility. Recently, a new standardized surgical technique for BCHI placement, the Minimally Invasive Ponto Surgery (MIPS) technique has been developed by Oticon Medical AB (Askim, Sweden). This technique aims to standardize surgery by using a novel surgical instrumentation kit and minimize soft tissue trauma. Methods A multicenter randomized controlled trial is designed to compare the MIPS technique to the linear incision technique with soft tissue preservation. The primary investigation center is Maastricht University Medical Center. Sixty-two participants will be included with a 2-year follow-up period. Parameters are introduced to quantify factors such as loss of skin sensibility, dehiscence of the skin next to the abutment, skin overgrowth, and cosmetic results. A new type of sampling method is incorporated to aid in the estimation of complications. To gain further understanding of PAD, swabs and skin biopsies are collected during follow-up visits for evaluation of the bacterial profile and inflammatory cytokine expression. The primary objective of the study is to compare the incidence of PAD during the first 3 months after BCHI placement. Secondary objectives include the assessment of parameters related to surgery, wound healing, pain, loss of sensibility of the skin around the implant, implant extrusion rate, implant stability measurements, dehiscence of the skin next to the abutment, and esthetic appeal. Tertiary objectives include assessment of other factors related to PAD and a health economic evaluation. Discussion This is the first trial to compare the recently developed MIPS technique to the linear incision technique with soft tissue preservation for BCHI surgery. Newly introduced parameters and sampling method will aid in the prediction of results and complications after BCHI placement. Trial registration Registered at the CCMO register in the Netherlands on 24 November 2014: NL50072.068.14. Retrospectively registered on 21 April 2015 at ClinicalTrials.gov: NCT02438618. This trial is sponsored by Oticon Medical AB. Electronic supplementary material The online version of this article (doi:10.1186/s13063-016-1662-0) contains supplementary material, which is available to authorized users.

Objective The purpose of this exploratory study was to investigate whether a quantitative image analysis of the labyrinth in conventional MRI scans using a radiomics approach showed differences between patients with Meniere’s disease and the control group. Materials and methods In this retrospective study, MRI scans of the affected labyrinths of 24 patients with Meniere’s disease were compared to the MRI scans of labyrinths of 29 patients with an idiopathic asymmetrical sensorineural hearing loss. The 1,5T and 3T MRI scans had been previously made in a clinical setting between 2008 and 2015. 3D Slicer 4.4 was used to extract several substructures of the labyrinth. A quantitative analysis of the normalized radiomic image features was performed in Mathematica 10. The image features of the two groups were statistically compared. Results For numerous image features, there was a statistically significant difference (p-value

Tonic GABA(A) receptors are a subpopulation of receptors that generate long-lasting inhibition and thereby control network excitability. In recent years, these receptors have been implicated in various neurological and psychiatric disorders, including Parkinson's disease, schizophrenia, and epilepsy. Their distinct subunit composition and function, compared to phasic GABA(A) receptors, opens the possibility to specifically modulate network properties. In this review, the role of tonic GABA(A) receptors in epilepsy and as potential antiepileptic target will be discussed.

The current diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders are being challenged by the heterogeneity and the symptom overlap of psychiatric disorders. Therefore, a framework toward a more etiology-based classification has been initiated by the US National Institute of Mental Health, the research domain criteria project. The basic neurobiology of human psychiatric disorders is often studied in rodent models. However, the differences in outcome measurements hamper the translation of knowledge. Here, we aimed to present a translational panic model by using the same stimulus and by quantitatively comparing the same outcome measurements in rodents, healthy human subjects and panic disorder patients within one large project. We measured the behavioral–emotional and bodily response to CO2 exposure in all three samples, allowing for a reliable cross-species comparison. We show that CO2 exposure causes a robust fear response in terms of behavior in mice and panic symptom ratings in healthy volunteers and panic disorder patients. To improve comparability, we next assessed the respiratory and cardiovascular response to CO2, demonstrating corresponding respiratory and cardiovascular effects across both species. This project bridges the gap between basic and human research to improve the translation of knowledge between these disciplines. This will allow significant progress in unraveling the etiological basis of panic disorder and will be highly beneficial for refining the diagnostic categories as well as treatment strategies.

Background: We investigated to what degree environmental exposure (childhood trauma, urbanicity, cannabis use, and discrimination) impacts symptom connectivity using both continuous and categorical measures of psychopathology.Methods: Outcomes were continuous symptom dimensions of self-reported psychopathology using the Self-report Symptom Checklist-90-R in 3021 participants from The Early Developmental Stages of the Psychopathology (EDSP) study and binary DSM-III-R categories of mental disorders and a binary measure of psychotic symptoms in 7076 participants from The Netherlands Mental Health Survey and Incidence Study (NEMESIS-1). For each symptom dimension in the EDSP and mental disorder in the NEMESIS-1 as the dependent variable, regression analyses were carried out including each of the remaining symptom dimensions/mental disorders and its interaction with cumulative environmental risk load (the sum score of environmental exposures) as independent variables.Results: All symptom dimensions in the EDSP and related diagnostic categories in the NEMESIS-1 were strongly associated with each other, and environmental exposures increased the degree of symptom connectivity in the networks in both cohorts.Conclusions: Our findings showing strong connectivity across symptom dimensions and related binary diagnostic constructs in two independent population cohorts provide further evidence for the conceptualization of psychopathology as a contextually sensitive network of mutually interacting symptoms.

Objective: Dystrophin is part of a protein complex that connects the cytoskeleton to the extracellular matrix. In addition to its role in muscle tissue, it functions as an anchoring protein within the central nervous system such as in hippocampus and cerebellum. Its presence in the latter regions is illustrated by the cognitive problems seen in Duchenne Muscular Dystrophy (DMD). Since epilepsy is also supposed to constitute a comorbidity of DMD, it is hypothesized that dystrophin plays a role in neuronal excitability. Here, we aimed to study brain dystrophin distribution and expression in both, human and experimental temporal lobe epilepsy (TLE).Method: Regional and cellular dystrophin distribution was evaluated in both human and rat hippocampi and in rat cerebellar tissue by immunofluorescent colocalization with neuronal (NeuN and calbindin) and glial (GFAP) markers. In addition, hippocampal dystrophin levels were estimated by Western blot analysis in biopsies from TLE patients, post-mortem controls, amygdala kindled (AK)-, and control rats.Results: Dystrophin was expressed in all hippocampal pyramidal subfields and in the molecular-, Purkinje-, and granular cell layer of the cerebellum. In these regions it colocalized with GFAP, suggesting expression in astrocytes such as Bergmann glia (BG) and velate protoplasmic astrocytes. In rat hippocampus and cerebellum there were neither differences in dystrophin positive cell types, nor in the regional dystrophin distribution between AK and control animals. Quantitatively, hippocampal full-length dystrophin (Dp427) levels were about 60% higher in human TLE patients than in post-mortem controls (p Conclusion: Dystrophin is ubiquitously expressed by astrocytes in the human and rat hippocampus and in the rat cerebellum. Hippocampal full-length dystrophin (Dp427) levels are upregulated in human TLE, but not in AK rats, possibly indicating a compensatory mechanism in the chronic epileptic human brain.

Obsessive-compulsive disorder (OCD) is among the most disabling chronic psychiatric disorders and has a significant negative impact on multiple domains of quality of life. For patients suffering from severe refractory OCD, deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been applied. Reviewing the literature of the last years we believe that through its central position within the cortico-basal ganglia-thalamocortical circuits, the STN has a coordinating role in decision-making and action-selection mechanisms. Dysfunctional information-processing at the level of the STN is responsible for some of the core symptoms of OCD. Research confirms an electrophysiological dysfunction in the associative and limbic (non-motor) parts of the STN. Compared to Parkinson's disease patients, STN neurons in OCD exhibit a lower firing rate, less frequent but longer bursts, increased burst activity in the anterior ventromedial area, an asymmetrical left-sided burst distribution, and a predominant oscillatory activity in the 5-band. Moreover, there is direct evidence for the involvement of the STN in both checking behavior and OCD symptoms, which are both related to changes in electrophysiological activity in the non-motor STN. Through a combination of mechanisms, DBS of the STN seems to interrupt the disturbed information-processing, leading to a normalization of connectivity within the cortico-basal ganglia-thalamocortical circuits and consequently to a reduction in symptoms. In conclusion, based on the STN's strategic position within cortico-basal ganglia-thalamocortical circuits and its involvement in action-selection mechanisms that are responsible for some of the core symptoms of OCD, the STN is a mechanism-based target for DBS in OCD.

Background: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) in Parkinson disease (PD) is associated with postoperative cognitive decline. One of the proposed underlying mechanisms is the surgical procedure with the lead trajectory penetrating the caudate nucleus. Objective: To study whether penetration of the caudate nucleus affects neuropsychological outcome. Methods: Neuropsychological and imaging data of 30 PD patients who underwent bilateral STN DBS were analysed. Lead trajectories were evaluated leading to a group with (n = 10) and a group without penetration of the caudate nucleus (n = 20). The neuropsychological performance of each group was compared to baseline, both at 3 and 12 months postoperatively. Results: Only the Trail-Making Test part B (TMT-B) showed an interaction effect within the groups over time at 3 months postoperatively. At 12 months postoperatively, there was only a main effect of time with a decrease in performance in TMT-B for both groups. Also verbal fluency showed a significant decrease over time for both groups at 3 and 12 months postoperatively. Conclusion: Caudate nucleus penetration affects cognitive flexibility only in the short term after surgery.

Objective To evaluate monaural beamforming in bimodally aided cochlear implant (CI) users. Design The study enrolled twelve adult bimodal listeners with at least six months of CI-experience and using a contralateral hearing aid (HA) most of the daytime. Participants were uniformly fitted with the same CI speech processor and HA, giving access to an identical monaural beamformer in both ears. A within-subject repeated measures design evaluated three directional configurations [omnidirectional, asymmetric directivity (in CI alone) and symmetric directivity (in both CI and HA)] in two noise types [stationary and fluctuating]. Bimodal speech reception thresholds (SRT) as well as listening effort ratings were assessed in a diffuse noise field. Results Symmetric monaural beamforming provided a significant SRT improvement of 2.6 dB SNR, compared to 1.6 dB SNR for asymmetric monaural beamforming. Directional benefits were similarly observed in stationary and fluctuating noise. Directivity did not contribute to less listening effort in addition to improvement in speech intelligibility. Bimodal performance was about 7 dB SNR worse in fluctuating than in stationary noise. Conclusions Monaural beamforming provided substantial benefit for speech intelligibility in noise for bimodal listeners. The greatest benefit occurred when monaural beamforming was activated symmetrically in both CI and HA. Monaural beamforming does not bridge the gap between bimodal and normal hearing performance, especially in fluctuating noise. Results advocate further bimodal co-operation. Trial Registration This trial was registered in www.trialregister.nl under number NTR4901.

International audience; With the growing use of selective serotonin reuptake inhibitor medications (SSRIs) for the treatment of depression during the perinatal period, questions have been raised about the longterm impact of these medications on development. We aimed to investigate how developmental SSRI exposure may alter affect-related behaviors and associated molecular processes in offspring using a rodent model of maternal stress and depression. For this purpose, prenatally stressed or non-stressed male offspring were exposed to fluoxetine (5 mg/kg/day) or vehicle, via lactation, until weaning. Primary results show that postnatal fluoxetine exposure differentially altered anxiety-like behavior by increasing anxiety in non-stressed offspring and decreasing anxiety in prenatally stressed offspring. In the hippocampus, developmental fluoxetine exposure decreased BDNF IV and TrkB mRNA expression. Prenatal stress alone also decreased escape behaviors and decreased hippocampal BDNF IV mRNA expression. These data provide important evidence for the long-term programming effects of early-life exposure to SSRIs on brain and behavior.

Enhancement of central availability of the second messenger CAMP is a promising approach to improve cognitive function. Pharmacological inhibition of phosphodiesterase type 4 (PDE4), a group of cAMP hydrolyzing enzymes in the brain, has been shown to improve cognitive performances in rodents and monkeys. However, inhibition of PDE4 is generally associated with severe emetic side-effects. Roflumilast, an FDA-approved PDE4 inhibitor for treatment of chronic obstructive pulmonary disease (COPD), is yielding only mild emetic side effects. In the present study we investigate the potential of roflumilast as a cognition enhancer and to determine the potential coinciding emetic response in comparison to rolipram, a classic PDE4 inhibitor with pronounced emetic effects. Cognition enhancement was evaluated in mice and it was found that both roflumilast and rolipram enhanced memory in an object location task (0.03 mg/kg), whereas only roflumilast was effective in a spatial Y-maze (0.1 mg/kg). Emetic potential was measured using competition of PDE4 inhibition for alpha 2-adrenergic receptor antagonism in which recovery from xylazine/ketamine-mediated anesthesia is used as a surrogate marker. While rolipram displayed emetic properties at a dose 10 times the memory-enhancing dose, roflumilast only showed increased emetic-like properties at a dose 100 times the memory-enhancing dose. Moreover, combining sub-efficacious doses of the approved cognition enhancer donepezil and roflumilast, which did not improve memory when given alone, fully restored object recognition memory deficit in rats induced by the muscarinic receptor antagonist scopolamine. These findings suggest that roflumilast offers a more favorable window for treatment of cognitive deficits compared to rolipram. (C) 2016 Elsevier B.V. All rights reserved. Takeda (Deerfield, USA) funded the combination therapy study and participated in its design.

Environmental enrichment (EE) is a way to induce voluntary locomotor training that positively affects locomotor recovery after acute spinal cord injury (SCI). The beneficial effect on SCI outcome is thought to be based on enhanced plasticity in motor pathways, triggered by locomotor-specific sensory feedback to the spinal cord circuitry for locomotion (central pattern generators [CPGs]). In view of chronic SCI, we tested the hypothesis that EE improves motor outcome after SCI in the rat when started after a clinically relevant delay of 3 weeks. At the CPG level (i.e., the spinal L1-L2 level), where EE-related sensory feedback is processed, two key mechanisms of anatomical plasticity were examined: (1) serotonergic innervation, and (2) survival and differentiation of spinal cord progenitor cells. Delayed EE improved interlimb coordination, which was associated with an increased serotonergic innervation of the ventro-lateral grey matter within the L1-L2 segments. Although spinal cord progenitor cells were found to differentiate into both neurons and glial cells, EE did not affect their survival. These results show that EE induces a substantial improvement of motor outcome after SCI when commenced after a clinically-relevant delay. Increased serotonergic innervation of the lumbar CPG area is therefore suggested to play an important role in the EE-induced recovery of interlimb coordination.