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PURPOSE: Biallelic PIGN variants have been described in Fryns syndrome, multiple congenital anomalies-hypotonia-seizure syndrome (MCAHS), and neurologic phenotypes. The full spectrum of clinical manifestations in relation to the genotypes is yet to be reported.METHODS: Genotype and phenotype data were collated and analyzed for 61 biallelic PIGN cases: 21 new and 40 previously published cases. Functional analysis was performed for 2 recurrent variants (c.2679C>G p.Ser893Arg and c.932T>G p.Leu311Trp).RESULTS: Biallelic-truncating variants were detected in 16 patients-10 with Fryns syndrome, 1 with MCAHS1, 2 with Fryns syndrome/MCAHS1, and 3 with neurologic phenotype. There was an increased risk of prenatal or neonatal death within this group (6 deaths were in utero or within 2 months of life; 6 pregnancies were terminated). Incidence of polyhydramnios, congenital anomalies (eg, diaphragmatic hernia), and dysmorphism was significantly increased. Biallelic missense or mixed genotype were reported in the remaining 45 cases-32 showed a neurologic phenotype and 12 had MCAHS1. No cases of diaphragmatic hernia or abdominal wall defects were seen in this group except patient 1 in which we found the missense variant p.Ser893Arg to result in functionally null alleles, suggesting the possibility of an undescribed functionally important region in the final exon. For all genotypes, there was complete penetrance for developmental delay and near-complete penetrance for seizures and hypotonia in patients surviving the neonatal period.CONCLUSION: We have expanded the described spectrum of phenotypes and natural history associated with biallelic PIGN variants. Our study shows that biallelic-truncating variants usually result in the more severe Fryns syndrome phenotype, but neurologic problems, such as developmental delay, seizures, and hypotonia, present across all genotypes. Functional analysis should be considered when the genotypes do not correlate with the predicted phenotype because there may be other functionally important regions in PIGN that are yet to be discovered.

BACKGROUND: Dicarbonyls are major reactive precursors of advanced glycation endproducts (AGEs). Dicarbonyls are formed endogenously, but also during food processing. Circulating dicarbonyls and AGEs are associated with inflammation and microvascular complications of diabetes, but for dicarbonyls from the diet these associations are currently unknown.OBJECTIVE: To examine the associations of dietary intake of dicarbonyls with low-grade inflammation and microvascular function.DESIGN: In 2792 participants (60 ± 8 years, 50% men, 26% type 2 diabetes) of the population-based cohort The Maastricht Study, we estimated the habitual intake of the dicarbonyls methylglyoxal (MGO), glyoxal (GO), and 3-deoxyglucosone (3-DG) by linking Food Frequency Questionnaires to our food composition database of the MGO, GO, and 3-DG content of > 200 foods. Low-grade inflammation was assessed by six plasma biomarkers, compiled in a z-score. Microvascular function was assessed by a z-score of four plasma biomarkers, as flicker light-induced dilation and diameters in retinal micro vessels, as heat-induced skin hyperemic response, and as urinary albumin excretion. Cross-sectional associations of dietary dicarbonyls with low-grade inflammation and with microvascular function were investigated using linear regression adjusting for age, sex, potential confounders related to cardio-metabolic risk factors, lifestyle and dietary factors.RESULTS: Fully adjusted analyses revealed that higher intake of MGO was associated with a lower z-score for inflammation (std. β (95%CI) = -0.05 (-0.09, -0.01)) with strongest inverse associations for hsCRP and TNF-α (both -0.05 (-0.10, -0.01)). In contrast, higher dietary MGO intake was associated with impaired retinal venular dilation after full adjustment (std. β (95%CI) = -0.07 (-0.12, -0.01)), but not with the other features of microvascular function. GO and 3-DG intakes were not consistently associated with any of the outcomes.CONCLUSION: Higher habitual intake of MGO was associated with less low-grade inflammation. This novel, presumably beneficial, association is the first observation between MGO intake and health outcomes in humans, and warrants further investigation.

PURPOSE: The aim of this longitudinal study was to assess trabecular bone scores (TBS) in institutionalized adults with refractory epilepsy and intellectual disability and to study the association of TBS and incident fractures during seven years of follow-up.METHODS: In 2009 and 2016, all institutionalized adult patients of a long-stay care facility in the Netherlands (n=261) were invited to undergo a dual-energy X-ray absorptiometry (DXA) including vertebral fracture assessment (VFA) and assessment of TBS. Vertebrae T4-L4 were analyzed using quantitative morphometry. New and worsening vertebral fractures (VFs) were considered as incident VFs. Data regarding clinical fractures were extracted from the medical files. Patients were treated with anti-osteoporosis medication according to the Dutch guideline.RESULTS: Baseline and follow-up DXA, VFA and TBS could be obtained in 136 patients (83 male) aged between 18 and 79 years old (44.7±15.5). At baseline, 36 patients (26.5%) were diagnosed with osteoporosis, 68 (50.0%) with osteopenia and 32 patients (23.5%) had a normal bone mineral density (BMD). As for TBS, 26 patients (19.1%) had a partially degraded microarchitecture and 26 patients (19.1%) a degraded microarchitecture. During seven years of follow-up, 80 patients (59%) sustained at least one fracture, of which 28 patients (35%) had one or more major osteoporotic fractures. Thirty-four patients (25.0%) had at least one new or worsening morphometric VF. Compared to baseline, TBS significantly decreased over seven years of follow-up in non-treated patients (-0.039±0.064, pCONCLUSION: In this study, we found a high incidence of fractures and TBS decreased significantly over seven years of follow-up in non-treated institutionalized adult patients with refractory epilepsy and intellectual disability, but TBS was not associated with incident fractures.

BACKGROUND: Altered functional brain connectivity has been proposed as an intermediate phenotype between genetic risk loci and clinical expression of schizophrenia. Genetic high-risk groups of healthy subjects are particularly suited for the investigation of this proposition because they can be tested in the absence of medication or other secondary effects of schizophrenia. METHODS: Here, we applied dynamic functional connectivity analysis to functional magnetic resonance imaging data to reveal the reconfiguration of brain networks during a cognitive task. We recruited healthy carriers of common risk variants using the recall-by-genotype design. We assessed 197 individuals: 99 individuals (52 female, 47 male) with low polygenic risk scores (schizophrenia risk profile scores [SCZ-PRSs]) and 98 individuals (52 female, 46 male) with high SCZ-PRSs from both tails of the SCZ-PRS distribution from a genotyped population cohort, the Avon Longitudinal Study of Parents and Children (N = 8169). We compared groups both on conventional brain activation profiles, using the general linear model of the experiment, and on the neural flexibility index, which quantifies how frequent a brain region's community affiliation changes over experimental time. RESULTS: Behavioral performance and standard brain activation profiles did not differ significantly between groups. High SCZ-PRS was associated with reduced flexibility index and network modularity across n-back levels. The whole-brain flexibility index and that of the frontoparietal working memory network was associated with n-back performance. We identified a dynamic network phenotype related to high SCZ-PRS. CONCLUSIONS: Such neurophysiological markers can become important for the elucidation of biological mechanisms of schizophrenia and, particularly, the associated cognitive deficit.

A 29-year-old woman, known with polyostotic fibrous dysplasia, presented with facial palsy, vertigo, and ipsi-lateral neck pain. Radiology revealed a large temporal bone cyst, extruding intracranially, eroding the labyrinth and Fallopian canal. Histopathology of the cyst wall retrieved through transmastoidal biopsy showed a mutation in the Gs-alpha gene, confirming cystic degeneration of fibrous dysplasia, making this a unique case in which both the inner ear and facial canal are affected by this condition.

Cortical atrophy is an early feature of Alzheimers acute accent disease (AD). The biological processes associated with variability in cortical thickness remain largely unknown. We studied 220 cerebrospinal fluid (CSF) proteins to evaluate biological pathways associated with cortical thickness in 34 brain regions in 79 cognitively normal older individuals with normal (>192 ng/L, n = 47), and abnormal (

Background: Low-grade inflammation (LGI) and endothelial dysfunction (ED) might play a key role in the development of depression. We investigated the associations and mediation of LGI and ED with four-year incidence and course of depressive symptoms (remitted, recurrent or persistent). Design, setting, participants, measurements: In this prospective cohort study (mean age 59.6 +/- 8.2 years, 48.9% women, 26.6% diabetes by design), Cox and multinomial regression analyses, adjusted for age, sex, educational level and diabetes status were used to investigate the associations of LGI and ED with onset and course of depressive symptoms as assessed by the PHQ-9 questionnaire. Results: During 10,847 person-years of follow-up, 264 participants developed incident depression. Higher levels of LGI (OR [95%CI] per SD 1.32[1.16-1.49], p < 0.001) and ED (1.26[1.11-1.43], p < 0.001) were associated with incident depressive symptoms. In mediation analysis, 60% of the total effect of ED with incident depressive symptoms could be attributed to LGI. 76 out of 2637 participants had a persistent course of depressive symptoms. Higher levels of LGI (1.75[1.40-2.19], p < 0.001) and ED (1.33[1.04-1.71], p = 0.021) were associated with a persistent course of depressive symptoms. Higher ED was more strongly associated with persistent depressive symptoms (1.33[1.04-1.71], p = 0.021), while LGI was associated with remission of depression symptoms. Conclusions: LGI and ED were both associated with incident depressive symptoms, where the latter association was substantially mediated by LGI. ED was further associated with a persistent course of depressive symptoms, while LGI was not. These results suggest a temporal, vascular contribution of both LGI and ED to the etiology and chronicity of depressive symptoms.

Background The pathological hallmarks of Parkinson's disease include intraneuronal Lewy bodies, neuronal loss, and gliosis. We aim to correlate Parkinson's disease neuropsychiatric symptoms, (e.g., depression, psychosis, and anxiety) with the severity of neuropathology in the substantia nigra and locus coeruleus. Methods The brains of 175 participants with a primary pathologic diagnosis of Parkinson's disease were analyzed semi-quantitatively to ascertain the burden of neuronal loss and gliosis and Lewy body pathology within the locus coeruleus and substantia nigra. Participants’ history of anxiety, depression, and psychosis were determined using a chart-extracted medical history or record of formal psychiatric evaluation. Results Of the sample, 56% (n = 98), 50% (n = 88), and 31.25% (n = 55) of subjects had a diagnosis of psychosis, depression, and anxiety, respectively. Psychosis (χ2 = 7.1, p = 0.008, df = 1) and depression (χ2 = 7.2, p = 0.007, df = 1) were associated with severe neuronal loss and gliosis in the substantia nigra but not in the locus coeruleus. No association was observed between anxiety and neuronal loss and gliosis in either region. No neuropsychiatric symptoms were associated with Lewy body score. After controlling for disease duration and dementia, psychosis (odds ratio [OR]: 3.1, 95% confidence interval [CI]: 1.5–6.4, χ2 = 9.4, p = 0.012, df = 1) and depression (OR: 2.6, 95% CI: 1.3–5.0, χ2 = 7.9, p = 0.005, df = 1) remained associated with severe neuronal loss and gliosis in the substantia nigra. Conclusion These results suggest that psychosis and depression in Parkinson's disease are associated with the underlying neurodegenerative process and demonstrate that cell loss and gliosis may be a better marker of neuropsychiatric symptoms than Lewy body pathology.

Background Cerebral small vessel disease (CSVD) and neurodegeneration may be involved in the development and persistence of late-life depressive symptoms, but longitudinal evidence is scarce. We investigated the longitudinal associations of markers of CSVD and brain atrophy with incident depressive symptoms and the course of depressive symptoms, above and below 60 years of age. Methods White matter hyperintensity volumes (WMH), presence of lacunar infarcts and cerebral microbleeds, and white matter, grey matter, and cerebral spinal fluid volumes were assessed at baseline by 3T MRI in The Maastricht Study (mean age 59.5±8.5 years, 49.6% women, n=4,347; 16,535 person-years of follow-up). Clinically relevant depressive symptoms (9-item Patient Health Questionnaire≥10) were assessed at baseline and annually over seven years. We used Cox regression and multinomial logistic regression analyses adjusted for demographic, cardiovascular, and lifestyle risk factors. Results Above 60 years of age, larger WMH volumes were associated with an increased risk for incident depressive symptoms (HR[95%CI]:1.24[1.04;1.48] per SD) and a persistent course of depressive symptoms (OR:1.44[1.04;2.00] per SD). Total CSVD burden was associated with persistent depressive symptoms irrespective of age (adjusted OR:1.58[1.03;2.43]), while no associations were found for general markers of brain atrophy. Limitationss Our findings need replication in other large-scale population-based studies. Conclusions Our findings may suggest a temporal association of larger WMH volume with the incidence and persistence of late-life depression in the general population and may provide a potential target for the prevention of chronic late-life depression.

Advanced Alzheimer's disease (AD) is characterized by higher noradrenaline metabolite levels that may be associated with AD pathology. The locus coeruleus (LC) is the main site for cerebral noradrenaline synthesis and LC volume loss occurs as early as Braak stage 1. This study investigates the association between noradrenergic turnover and brain morphology, and the modifying effect of AD pathology. The study sample included 77 memory clinic patients (37 cognitively unimpaired and 40 cognitively impaired (mild cognitive impairment or AD dementia)). Cortical thickness and volumetric analyses were performed using FreeSurfer. Cerebrospinal fluid was analyzed for noradrenergic metabolite 3-methoxy-4hydroxyphenylethyleneglycol (MHPG), A beta 42 and phosphorylated tau. Higher MHPG was associated with lower cortical thickness and hippocampal volume at lower, but subthreshold, levels of A beta 42 and at higher p-tau levels. These associations remained significant after adding APOE-E4 or cognitive status as covariates. Our results suggest that greater MHPG together with worse AD pathology contributes to neurodegeneration, possibly before significant amyloidosis. The noradrenergic system may play an important role in early detection of AD-related processes. (C) 2021 The Authors. Published by Elsevier Inc.

INTRODUCTION: Vitamin K antagonists (VKA) and non-vitamin K oral antagonist anticoagulants (NOAC) are used in the clinic to reduce risk of thrombosis. However, they also exhibit vascular off-target effects. The aim of this study is to compare VKA and NOAC on atherosclerosis progression and calcification in an experimental setup.MATERIAL AND METHODS: Female Apoe-/- mice (age 12 weeks) were fed Western-type diet as control or supplemented with dabigatran etexilate or warfarin for 6 or 18 weeks. Vascular calcification was measured in whole aortic arches using µCT and [18 F]-NaF. Atherosclerotic burden was assessed by (immuno)histochemistry. Additionally, in vitro effects of warfarin, thrombin, and dabigatran on primary vascular smooth muscle cells (VSMC) were assessed.RESULTS: Short-term treatment with warfarin promoted formation of atherosclerotic lesions with a pro-inflammatory phenotype, and more rapid plaque progression compared with control and dabigatran. In contrast, dabigatran significantly reduced plaque progression compared with control. Long-term warfarin treatment significantly increased both presence and activity of plaque calcification compared with control and dabigatran. Calcification induced by warfarin treatment was accompanied by increased presence of uncarboxylated matrix Gla protein. In vitro, both warfarin and thrombin significantly increased VSMC oxidative stress and extracellular vesicle release, which was prevented by dabigatran.CONCLUSION: Warfarin aggravates atherosclerotic disease activity, increasing plaque inflammation, active calcification, and plaque progression. Dabigatran lacks undesired vascular side effects and reveals beneficial effects on atherosclerosis progression and calcification. The choice of anticoagulation impacts atherosclerotic disease by differential off target effect. Future clinical studies should test whether this beneficial effect also applies to patients.

It is unknown how smoking behavior polygenic scores (PRS) relate to psychosis and psychotic symptoms. To elucidate this, genotype and phenotype data were collected from patients with schizophrenia, their unaffected siblings, and healthy controls in a six-year follow-up prospective cohort study. Associations between smoking behaviors, PRS and schizophrenia symptoms were explored using linear mixed-effect models. The mean number of cigarettes smoked per day were 18 for patients, 13 for siblings and 12 for controls. In the overall sample, PRSs-smoking initiation (i.e., ever smoking as a binary phenotype, PRS-SI) were positively associated with positive symptoms, negative symptoms, and depressive symptoms, whereas PRSs-AI (age at regular smoking initiation) were negatively associated with all symptom dimensions, with similar effect sizes. When considering groups separately, PRS were only associated with psychotic symptoms in siblings and controls. In conclusion, unaffected siblings show smoking behaviors at an intermediate level between patients and healthy controls. Additionally, PRS-SI and PRS-AI are associated with all symptom dimensions only in unaffected siblings and healthy controls, possibly owing to the dominant role of other (genetic) risk factors in patients. Future studies may examine mechanisms via which genetic risk for smoking affects mental health symptoms.

Small fiber neuropathy (SFN) is a peripheral nerve condition causing neuropathic pain and autonomic complaints. Skin biopsy is an important diagnostic tool for diagnosing SFN. SFN is associated with conditions like diabetes mellitus and autoimmune diseases, but in 53% of the patients, the etiology remains unknown. Treating the underlying condition is the first-line treatment, but most patients will also need symptomatic treatment based on the biopsychosocial model. SFN can be managed by several health care professionals, including nurse practitioners, neurologists, pain specialists, and physiatrists. This article provides evidencebased information on the diagnostics of SFN and offers guidance for interdisciplinary treatment.(c) 2023 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction 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. Deep brain stimulation (DBS) is a treatment option for severe therapy-resistant OCD.Objective To provide a detailed clinical description and treatment outcome analysis in a cohort of eight refractory OCD patients receiving ventral capsule/ventral striatum (VC/VS) stimulation with the intention to validate discriminating fiber bundles previously associated with clinical response.Materials and Methods The primary outcome measure (the Yale-Brown Obsessive Compulsive Scale [Y-BOCS]) and secondary outcomes depressive symptoms, anxiety, and quality of life were retrospectively analyzed. DBS leads were warped into standard stereotactic space. A normative connectome was used to identify the neural network associated with clinical outcome.Results With a median stimulation duration of 26 months, patients exhibited a mean Y-BOCS reduction of 10.5 resulting in a response rate of 63%. Modulation of a fiber bundle traversing the anterior limb of the internal capsule (ALIC) was associated with Y-BOCS reduction. This fiber bundle connected the frontal regions to the subthalamic nucleus (STN) and was functionally identified as the hyperdirect pathway of the basal ganglia circuitry.Conclusion Our findings show that in VC/VS stimulation, the neural network associated with clinical outcome shows overlap with that of previously described for other targets namely the anterior limb of the internal capsula, the nucleus accumbens, or the STN, which supports the evolvement from the concept of an optimal gray matter target to conceiving the target as part of a symptom modulating network.

Background Moderate to vigorous physical activity (MVPA) can help to prevent depression, but identification of the most important psycho-biological pathways involved is unclear. The improvement of cardio-respiratory fitness (CRF) in response to MVPA can vary markedly, we therefore examined the association between CRF and the incidence of depressive symptoms. Methods We used data from The Maastricht Study, a large population-based prospective-cohort study. CRF was estimated at baseline from a graded submaximal exercise protocol and MVPA was measured with accelerometry. Depressive symptoms were assessed using the validated Dutch version of the 9-item Patient Health Questionnaire, both at baseline and during annual follow-up over five years. Cox proportional hazards models were used. Results A total of 1,730 individuals without depressive symptoms at baseline were included in the analysis. During the 5-year follow-up, n = 166 (9.6%) of individuals developed depressive symptoms. Compared to individuals with a low CRF, those with a moderate-to-high CRF had a significantly lower risk of developing depressive symptoms, independent of MVPA (medium CRF: HR = 0.49 (95%CI = 0.33–0.72); high CRF: HR = 0.48 (95% CI = 0.30–0.75). These associations were adjusted for age, sex, level of education, diabetes status, smoking status, alcohol use, energy intake, waist circumferences and antidepressant medications. Limitations PHQ-9 is a validated screening instrument, but it is not a diagnostic tool of depression. Conclusions Higher CRF was strongly associated with a lower risk of incident depressive symptoms over 5-year follow-up, independent of the level of MVPA at baseline, suggesting that interventions aimed at improving CRF could reduce the risk of depression.

Introduction Tourette syndrome (TS) is a complex neuropsychiatric disorder. A small percentage of individuals with TS will persist to experience severe, refractory, and impairing tics. Deep brain stimulation (DBS) has been increasingly used for symptom management especially in these settings. In this article, we aim to evaluate the rate and reasons for removal or explantation of DBS hardware in TS patients. Methods Data was analyzed from patients enrolled in the Tourette Association of America's International Tourette Syndrome Registry and Database. Results Fifteen of 269 (5.6%) patients required removal of their DBS systems. The mean age at explantation was 33.8 years. In these cases we observed a rate of 1.9 explantations per year of follow up from implantation. None of the removals took place in the immediate post-operative period. Infection was the most common cause (46.7%). Only one patient received explantation for tic resolution. There were no significant associations between explantation and the presence of specific psychiatric comorbidities, including OCD, depression, anxiety, or ADHD. Discussion The rate of removal of 5.6% was lower than the previously reported rate in the TS DBS literature. Infections account for nearly half of the TS DBS explantations. No relationship to psychiatric comorbidities has been established.

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.

Sleep spindles (8 - 16 Hz) are transient electrophysiological events during non-rapid eye movement sleep. While sleep spindles are routinely observed in the cortex using scalp electroencephalography (EEG), recordings of their thalamic counterparts have not been widely studied in humans. Based on a few existing studies, it has been hypothesized that spindles occur as largely local phenomena. We investigated intra-thalamic and thalamocortical spindle co-occurrence, which may underlie thalamocortical communication. We obtained scalp EEG and thalamic recordings from 7 patients that received bilateral deep brain stimulation (DBS) electrodes to the anterior thalamus for the treatment of drug resistant focal epilepsy. Spindles were categorized into subtypes based on their main frequency (i.e., slow (10±2 Hz) or fast (14±2 Hz)) and their level of thalamic involvement (spanning one channel, or spreading uni- or bilaterally within the thalamus). For the first time, we contrasted observed spindle patterns with permuted data to estimate random spindle co-occurrence. We found that multichannel spindle patterns were systematically coordinated at the thalamic and thalamocortical level. Importantly, distinct topographical patterns of thalamocortical spindle overlap were associated with slow and fast subtypes of spindles. These observations provide further evidence for coordinated spindle activity in thalamocortical networks.

Introduction: The brain is a frequent site of metastases in NSCLC, and screening for asymptomatic brain metastases (BM) is increasingly advised in NSCLC guidelines. An asymptomatic BM diagnosis may trigger anxiety for future neurologic problems and can negatively affect quality of life of patients and their relatives. Therefore, we performed this qualitative study.Methods: Three focus group discussions were organized with patients with NSCLC and asymptomatic BM (N = 3-4 per group) and separately with their relatives, to explore this psychosocial impact. Two researchers independently performed an inductive content analysis.Results: A total of 10 patients and 10 relatives participated in six focus groups. A diagnosis of BM caused feelings of distress and anxiety in both patients and relatives. These feelings diminished over time in case of a tumor responding to systemic therapy. The diagnosis of BM was not perceived as more distressful than other metastases, and scan-related anxiety was not experienced. Although magnetic resonance imaging screening and follow-up were thought of as burdensome, follow-up was valued. The coping strategies of both groups seemed related to personality and to the efficacy of the given systemic therapy. Relatives appreciated peer support of other relatives during the focus groups, and they seemed open for future psychological support.Conclusions: Asymptomatic BM diagnosis can cause anxiety and distress, but this diminishes over time with effective systemic treatment. Although patients perceive magnetic resonance imaging as burdensome, they value follow-up screening and imaging. Relatives highly appreciated peer support, and psychological distress of relatives should not be overlooked.

BACKGROUND AND AIMS: The easily accessible retinal vessels provide a unique opportunity to study a proxy for cerebral small vessels. Associations between retinal vessel diameters and macrostructural brain white matter changes have already been demonstrated. Alterations in microvascular function, likely precede these structural abnormalities. We examined whether retinal microvascular function is related to cerebral microvascular properties, assessed by the intravoxel incoherent motion (IVIM) effect in brain MRI.METHODS: Seventy participants (age 60 ± 8 years, 41% women) from the population-based Maastricht Study underwent brain IVIM diffusion imaging (3 Tesla) to determine the microvascular measures f (perfusion volume fraction) and D* (pseudo-diffusion of circulating blood). The retinal arteriolar and venular dilation response to flicker light stimulation were measured by a dynamic vessel analyzer. Linear regression analysis was used to investigate associations between retinal vasoreactivity and IVIM measures in white matter hyperintensities (WMH), normal-appearing white matter (NAWM) and cortical gray matter (CGM).RESULTS: More retinal arteriolar dilation was significantly associated with stronger pseudo-diffusion (D*) in the NAWM and CGM (β 0.280 [95% CI 0.084-0.475], and β 0.310 [95% CI 0.091-0.528], respectively), but not with the cerebral blood volume fraction (f). No associations were observed between retinal venular dilation response and cerebrovascular IVIM measures.CONCLUSIONS: Variations in retinal arteriolar microvascular function and microcirculatory properties in the brain are linked. The retina could serve as a proxy for early detection of brain microvascular dysfunction.

What drives the large differences across patients in terms of treatment efficacy of major depressive disorder (MDD) is unclear. A network approach to psychopathology may help to reveal underlying mechanisms determining patients' capacity for recovery. We used daily diary MDD symptom data and six-month follow-up data on depression to examine how dynamic associations between symptoms relate to the future course of MDD. Daily experiences of depressive symptoms of 69 participants were assessed by means of the SCL-90-R depression subscale, three days a week for a period of six weeks, as part of a larger intervention study. Multilevel vector autoregressive modelling was used to estimate networks of dynamic symptom connections. Long-term outcome was determined by the percentage change in Hamilton Depression Rating Scale (HDRS) score between pre-intervention and six-month follow-up. For patients with more persisting symptoms, the symptom 'feeling everything is an effort' most strongly predicted other symptoms. The networks of the two groups did not significantly differ in overall connectivity. Findings suggest that future research should not solely focus on the presence or intensity of individual symptoms when predicting long-term outcomes, but should also examine the role of a specific symptom in the larger network of dynamic symptom-to-symptom interactions.

Background: Recent studies have revealed the importance of the gut brain axis in the development of Parkinson's disease (PD). It has also been suggested that the cross-sectional area (CSA) of the vagus nerve can be used in the diagnosis of PD. Here, we hypothesize that the CSA of the vagus nerve is decreased in PD patients compared to control participants.Methods: In this study we measured the CSA of the vagus nerve on both sides in 31 patients with PD and 51 healthy controls at the level of the common carotid artery using high-resolution ultrasound.Results: The mean CSA of the left vagus nerve in the PD and the control group was respectively 2.10 and 1.90 and of the right respectively 2.54 and 2.24 mm2. There is no difference in CSA of the vagus nerve in PD patients compared to controls (p = .079). The mean CSA of the right vagus nerve was significantly larger than the left (p Conclusion: These findings show that the CSA of the vagus nerve using ultrasonography is not a reliable diagnostic tool in the diagnosis of PD.

Introduction: General practitioners (GPs) play a key role in early identification of dementia, yet diagnosis is often missed or delayed in primary care. As part of the multinational Models of Patient Engagement for Alzheimer’s Disease project, we assess GPs’ attitude toward early and pre-dementia diagnosis of AD and explore barriers to early diagnosis. Methods: Our survey covered general attitude toward early diagnosis, diagnostic procedures, resources, and opinion on present and future treatment options across five European countries. Results: In total 343 GPs completed the survey; 74% of GPs indicated that an early diagnosis is valuable. There were country-specific differences in GPs’ perceptions of reimbursement and time available for the patient. If a drug were available to slow down the progression of AD, 59% of the GPs would change their implementation of early diagnosis. Discussion: Our findings provide insight into GPs’ attitudes by exploring differences in perception and management of early diagnosis. (Less)

Background There is much debate on the use of angiotensin receptor blockers (ARBs) in severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2)-infected patients. Although it has been suggested that ARBs might lead to a higher susceptibility and severity of SARS-CoV-2 infection, experimental data suggest that ARBs may reduce acute lung injury via blocking angiotensin-II-mediated pulmonary permeability, inflammation, and fibrosis. However, despite these hypotheses, specific studies on ARBs in SARS-CoV-2 patients are lacking.Methods The PRAETORIAN-COVID trial is a multicenter, double-blind, placebo-controlled 1:1 randomized clinical trial in adult hospitalized SARS-CoV-2-infected patients (n = 651). The primary aim is to investigate the effect of the ARB valsartan compared to placebo on the composite end point of admission to an intensive care unit, mechanical ventilation, or death within 14 days of randomization. The active-treatment arm will receive valsartan in a dosage titrated to blood pressure up to a maximum of 160 mg bid, and the placebo arm will receive matching placebo. Treatment duration will be 14 days, or until the occurrence of the primary end point or until hospital discharge, if either of these occurs within 14 days. The trial is registered at clinicaltrials.gov (NCT04335786, 2020).Summary The PRAETORIAN-COVID trial is a double-blind, placebo-controlled 1:1 randomized trial to assess the effect of valsartan compared to placebo on the occurrence of ICU admission, mechanical ventilation, and death in hospitalized SARS-CoV-2-infected patients. The results of this study might impact the treatment of SARS-CoV-2 patients globally.

A patient presented severe combined immunodeficiency (SCID)-like symptoms. The presence of a substantial number of CD4+ T-cells in the peripheral blood was not explained by maternal engraftment. Genetic analysis revealed a novel RFXANK mutation, c.232C > T, resulting in a stop codon, with consequently defective transcription of MHC class II resulting in bare lymphocyte syndrome (BLS) type II. The initial unawareness of complete absence of MHC class II expression and normal T-cell receptor excision circles (TREC)-levels delayed the final diagnosis. After identification of the genetic defect the patient was scheduled for hematopoietic stem cell transplantation (HSCT). Here, we present and discuss the diagnostic and therapeutic approach of a novel case of BLS type II in relation to T-cell development.

Objectives A variety of health services delivered via the Internet, or “eHealth interventions,” to support caregivers of people with dementia have shown evidence of effectiveness, but only a small number are put into practice. This study aimed to investigate whether, how and why their implementation took place. Methods This qualitative study followed up on the 12 publications included in Boots et al.'s (2014) widely cited systematic review on eHealth interventions for informal caregivers of people with dementia, in order to explore further implementation into practice. Publicly available online information, implementation readiness (ImpRess checklist scores), and survey responses were assessed. Findings Two interventions were freely available online, two were available in a trial context, and one was exclusively available to clinical staff previously involved in the research project. The remaining seven were unavailable. All scores on the ImpRess checklist were at 50% or lower of the total, indicating that the interventions were not ready to implement at the time of the Boots et al. (2014) review, though some interventions were scored as more implementation-ready in subsequent follow-up publications. Responses to the survey were received from six out of twelve authors. Key learnings from the survey included the importance of the involvement of stakeholders at all stages of the process, as well as the flexible adaptation and commercialization of the intervention. Conclusions In general, low levels of implementation readiness were reported and often the information necessary to assess implementation readiness was unavailable. The only two freely available interventions had long-term funding from aging foundations. Authors pointed to the involvement of financial gatekeepers in the development process and the creation of a business model early on as important facilitators to implementation. Future research should focus on the factors enabling sustainable implementation., Highlights • Most interventionscouldno longer be found. • Most interventions reported low implementation readiness. • Available interventions made use of long-term funding. • They were not found to have developed self-sustaining business models. • More research is needed on business models and contextual factors.

Objective Self-monitoring is crucial to raise awareness for own behaviors and emotions, and thus facilitate self-management. The composition of self-monitoring within interventions, however, varies and guidelines are currently unavailable. This review aimed to provide a comprehensive overview of technology-based self-monitoring interventions that intend to improve health in middle-aged and older adults (>45 years). Methods Five online databases were systematically searched and articles were independently screened. A narrative synthesis of 26 studies with 21 unique interventions was conducted. Primary focus lay on the composition of self-monitoring within interventions, including technology used, health-aspects monitored, and type of feedback provided. Secondly, the usability of/adherence to the self-monitoring treatment, intervention effects, and their sustainability were examined. Findings Studies concentrated on middle-aged adults (mean of 51 years). Mobile technologies seem necessary to ensure flexible self-monitoring in everyday life. Social health aspects were rarely monitored. Mechanisms and the sustainability of intervention effect are understudied. Conclusion Digital self-monitoring technologies hold promise for future trials as they seem suitable to understand and support health-related self-management. Key elements including automatic and personal feedback following the blended care principle were highlighted and may guide study designs. Prospectively, research is especially needed to study sustained self-monitoring to support disease prevention and lasting lifestyle changes., Highlights • Digital self-monitoring interventions for middle-aged and older adults show great diversity. • Mobile technologies (e.g. smartphones) are needed for flexible self-monitoring. • Social health aspects (e.g. social networks/company) are rarely monitored. • Mechanisms and sustainability of intervention effects are understudied. • More research is needed on prevention and lasting lifestyle changes.

BACKGROUND: The incidence of cardiac arrest is high, with a poor survival rate of 8-14%. Currently, only limited evidence is available about long-term consequences of cardiac arrest on quality of life of caregivers.AIMS: First, to determine the level of daily functioning and quality of life in caregivers of cardiac arrest survivors two years after the cardiac arrest. Second, to study the long-term impact of witnessing the event of a cardiac arrest.METHODS: A longitudinal cohort study including caregivers of cardiac arrest survivors. Participants received a questionnaire at home. Outcome variables were instrumental daily activities(FAI), emotional functioning(HADS), fatigue(FSS), caregiver strain(CSI), impact of event(IES), and quality of life(SF36).RESULTS: 57 caregivers (89% female, age 56,9 ± 12 years) participated. Two years after the cardiac arrest, quality of life of caregivers equals that of the general population, although almost 30% still scored high on the Impact of Events Scale. Mean IES-, FSS-, CSI and FAI-scores were increased as compared to the general population (P CONCLUSIONS: Two years after the cardiac arrest, quality of life of caregivers is quite good, but almost one third of the caregivers still experience a high level of trauma-related stress, especially in those that witnessed the resuscitation. Future research will have to focus on the effectiveness of support programs for caregivers of survivors of cardiac arrest.

Chronic fatigue is highly prevalent in the general population as well as in multiple chronic diseases and psychiatric disorders. Its etiology however remains poorly understood and cannot be explained by biological factors alone. Occurring in a psychosocial context, the experience and communication of fatigue may be shaped by social interactions. In particular, interpersonal operant conditioning may strengthen and perpetuate fatigue complaints. In this experiment, individuals (N = 44) repeatedly rated their currently experienced fatigue while engaging in cognitive effort (working memory task). Subtle social reward was given when fatigue increased relative to the previous rating; or disapproval when fatigue decreased. In the control condition, only neutral feedback was given. Although all participants became more fatigued during cognitive effort, interpersonal operant conditioning led to increased fatigue reporting relative to neutral feedback. This effect occurred independently of conscious awareness. Interestingly, the experimental condition also performed worse on the working memory task. Results suggest that fatigue complaints (and cognitive performance) may become controlled by their consequences such as social reward, and not exclusively by their antecedents such as effort. Results have implications for treatment development and suggest that interpersonal operant conditioning may contribute to fatigue becoming a chronic symptom.

Objective Thalamic deep brain stimulation (DBS) is effective in reducing tics in patients with refractory Tourette syndrome at the short-term. Here, we report on the long-term outcome. Materials and Methods Seven patients underwent bilateral DBS between 2001 and 2008. The target was the centromedian nucleus, substantia periventricularis and nucleus ventro-oralis internus cross point of the thalamus. The effect on tics and side effects were evaluated with a variable follow-up duration of 12 to 78 months. Results Patient 1 and 2 showed good tic improvements of 81.6% (60 months) and 50% (36 months), respectively. However, side effects like reducing levels of energy and visual disturbances increased. In patient 1, the target was changed to the anterior part of the internal pallidum and patient 2 switched the stimulator permanently off. Patient 3 experiences still satisfying results with a tic improvement of 88.9% (78 months). Patient 4 and 7 showed minor tic improvements of 34% (16 months) and 9% (60 months), respectively. In both patients side effects became more severe and the target was changed to the anterior part of the internal pallidum. Patient 5 showed a tic improvement of 27.5% (12 months) and went abroad for stimulation of the external globus pallidus. Patient 6 developed cerebellar atrophy. He experienced several nonstimulation related side effects and turned the stimulator off. Conclusions There seems to be an increasing disbalance of therapeutic effects and side effects at long-term follow-up, often leading to either switching the stimulator off or new surgery with a different neuro-anatomic target.

Objective: Positive emotions and feelings of competence seem to play an important role in the well-being of caregivers of people with dementia. Both are likely to fluctuate constantly throughout the caretaking process. Unlike standard retrospective methods, momentary assessments in daily life can provide insight into these moment-to-moment fluctuations. Therefore, in this study both retrospective and momentary assessments were used to examine the relationship between caregivers' sense of competence and their experienced positive affect (PA) in daily life. Methods: Thirty Dutch caregivers provided momentary data on PA and daily sense of competence ratings for 6 consecutive days using the experience sampling methodology. Additionally, they reported retrospectively on their sense of competence with a traditional questionnaire. Results: A positive association was found between retrospective and daily measured sense of competence. Caregivers reported corresponding levels of sense of competence on both measures. Both daily and retrospective sense of competence were positively associated with the experienced levels of PA. However, daily sense of competence appeared to be the strongest predictor. Regarding the variability in PA, only daily sense of competence showed a significant association, with a higher daily sense of competence predicting a more stable PA pattern. Conclusion: This study provides support for redirecting caregiver support interventions toward enhancement of positive rather than negative experiences and focusing more on caregivers' momentary emotional experiences. Momentary assessments are a valuable addition to standard retrospective measures and provide a more comprehensive and dynamic view of caregiver functioning.

Depressive symptoms are common in multiple sclerosis (MS), and both depression and MS have been associated with a poor vitamin D status. As cytokine-mediated inflammatory processes play a role in the pathogenesis of both disorders, we hypothesized that vitamin D-3 supplementation reduces depressive symptoms in MS via its immunomodulatory properties. In this randomized pilot study relapsing remitting (RR) MS patients received either vitamin D-3 supplementation (n = 20; 14.000 IU/day) or placebo (n = 20) during 48 weeks. Pre- and post-supplementation depression scores, measured using the Hospital Anxiety Depression Scale (HADS) depression subscale (HADS-D), showed a significant decrease within the vitamin D-3 group (median HADS-D 4.0 to 3.0, p = 0.02), a trend towards a decrease within the placebo group (median HADS-D 3.0 to 2.0, p = 0.06), but no significantly different reductions between groups (p = 0.78). Furthermore, no reductions in pro- and anti-inflammatory cytokine balances, secreted by stimulated leukocytes and CD8(+) T cells, were found in the vitamin D-3 compared to the placebo arm. Therefore, we found no evidence for a reduction of depressive symptoms or related biomarkers upon vitamin D-3 supplementation in RRMS patients in this exploratory study. Whether vitamin D-3 supplementation is of benefit in manifest depression in MS needs to be assessed by additional studies. (C) 2017 Elsevier B.V. All rights reserved.

Background: In non-walking children with severe spasticity, daily care can be difficult and many patients suffer from pain. Selective dorsal rhizotomy (SDR) reduces spasticity in the legs, and therefore has the potential to improve daily care and comfort.Aim: To examine effects of SDR on daily care and comfort in non-walking children with severe spasticity due to different underlying neurological conditions.Methods: Medical history, changes in daily care and comfort and satisfaction with outcome were assessed retrospectively in non-walking children who underwent SDR in our center, with a mean follow-up of 1y 7m (range 11m-4y 3m). All eligible patients (n = 24, years 2009 2014) were included.Results: Mean age at SDR was 12y 4m (SD 4y 3m, range 2y 8m-19y 3m). Associated orthopaedic problems were frequent. Seven patients underwent scoliosis correction in the same session. Most improvements were reported in dressing (n = 16), washing (n = 12) and comfort (n = 10). Median score for satisfaction was 7 on a scale of 10 (range 1-9). SDR resulted in reduction of spasticity in leg muscles. In nine patients dystonia was recorded post-operatively, mainly in children with congenital malformations and syndromes.Interpretation: SDR is a single event intervention that can improve daily care and comfort in non-walking children with severe spasticity, and can safely be combined with scoliosis correction. Despite the improvements, satisfaction is variable. Careful attention is necessary for risk factors for dystonia, which may be unmasked after SDR. (C) 2016 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

OBJECTIVE: The aim of the current study was to investigate whether total intelligence scores (FSIQ) and/or a discrepancy in intelligence can predict behavioral or emotional problems in children with neurological deficiencies.METHOD: The population consists of children with neurological deficiencies (N = 610, ranging from 6 to 17 years), referred due to concerns on the (educational) development of the child to a tertiary outpatient clinic. All children were tested with the Dutch Wechsler Intelligence Scale for Children - third edition (WISC-III-NL). A VIQ-PIQ discrepancy score was calculated by subtracting the performance capacities of the verbal capacities. The effects of demographic variables, FSIQ, and the VIQ-PIQ discrepancy on two parent-rated questionnaires measuring behavior and emotions in children were analyzed with linear and logistic regression models.RESULTS AND CONCLUSION: The VIQ-PIQ discrepancy was not predictive of behavioral or emotional problems recorded on the above-mentioned parent-rated questionnaires. The FSIQ score, age, and sex were predictive to some extent: increases in age and FSIQ led to a decrease of reported problems, and boys showed more problems than girls. Children with neurological deficiencies had on average significantly higher verbal capacities than performance capacities, in line with the neuropsychological principle that language survives brain damage whereas performance capacities are more affected.

Introduction: Initial registration studies of perampanel (PMP), an AMPA receptor antagonist, have now been followed up by 'clinical' studies that confirmed its efficacy and safety in patients with refractory epilepsy. Publications on the use of PMP among patients with intellectual disability (ID) are still limited. This study extends our knowledge with respect to the relevance of PMP for patients with both ID and epilepsy, and furthermore specifies the behavioral side effects of PMP in this specific population.Methods: Retrospective evaluation of medical records at 3, 6 and 12 months of follow-up after the initial start of PMP.Results: 62 patients were included. 21 patients (33.9%) were female. All patients had complete data of 6 months follow-up and we were able to review 42 patients with a 1-year follow-up. Level of ID varied from borderline to profound, and mild ID was most common (43.5%). The mean maximum daily dosage of PMP was 5.6 mg (range 1-12 mg). Retention rates for PMP were 87.1% and 67.7% after three and six months. A trend indicated a longer mean retention time in patients with a more severe ID (borderline-mild-moderate ID: 205 days, severe-profound ID: 275 days). Seizure reduction was achieved in 53.2%. 36 patients (58.1%) experienced adverse effects, 80.6% of those within 3 months. 45.2% of the patients experienced somatic adverse effects. Most common were fatigue & sleep problems, motor problems & unsteadiness, and gastrointestinal problems. Behavioral adverse effects were present in 40.3%. Most common were aggression, agitated behavior, disruptive behavior, and mood symptoms. Reasons for discontinuation of PMP were lack of efficacy in 14.8%, intolerable adverse effects in 44.4%, and a combination of both in 40.7%.Altogether, 24.2% (15/62) of the patients achieved seizure reduction without experiencing adverse effects, though none reached seizure freedom.Conclusions: The use of PMP might lead to an effective seizure reduction without adverse effects in a minority of patients with both epilepsy and ID. Pre-existing behavioral problems or polypharmacy do not predict the occurrence of additional behavioral adverse effects, implying that these patients need not be excluded from the introduction of PMP when clinically indicated. Patients should, ideally, be monitored at a multidisciplinary clinic. (C) 2016 Elseyier Inc. All rights reserved.

BACKGROUND: Survivors of a cardiac arrest often have cognitive and emotional problems. As a cardiac arrest is also an obvious life-threatening event, other psychological sequelae associated with surviving such as spirituality may also affect quality of life.OBJECTIVES: To determine the relationship between spirituality, coping and quality of life in cardiac patients both with and without a cardiac arrest.METHODS: In this retrospective cohort study, participants received a questionnaire by post. The primary outcome measure was quality of life (LiSat-9). Secondary outcome measures were spiritual well-being (FACIT-Sp12), coping style (UPCC), emotional well-being (HADS, IES), fatigue (FSS) and daily activities (FAI). Statistical analyses included multiple regression analyses.RESULTS: Data were available from 72 (60% response rate) cardiac arrest survivors and 98 (47%) patients with a myocardial infarction. Against our hypothesis, there were no differences in spirituality or other variables between the groups, with the exception of more depressive symptoms in patients with myocardial infarction without arrest. Analysis of the total data set (170 participants) found that a better quality of life was associated with higher levels of meaning and peace in life, higher levels of social and leisure activities, and lower levels of fatigue.CONCLUSIONS: Quality of life after a cardiac arrest and after a myocardial infarction without arrest are not different; fatigue, a sense of meaning and peace, and level of extended daily activities are factors related to higher life satisfaction.

Deep brain stimulation of the anterior nucleus of the thalamus is an effective treatment for patients with refractory epilepsy who do not respond sufficiently to medical therapy. Optimal therapeutic effects of deep brain stimulation probably depend on accurate positioning of the stimulating electrodes. Microelectrode recordings show bursty firing neurons in the anterior nucleus of the thalamus region, which confirms the anatomical target determined by the surgeon. Deep brain stimulation electrodes in epilepsy patients are implanted under general anesthesia. The type and depth of anesthesia might interfere with microelectrode ecordings. Here, we describe our experience of a patient who underwent deep brain stimulation surgery under general anesthesia with sevoflurane, a volatile anesthetic, and its effect on the microelectrode recordings. Keywords: Thalamus, Deep brain stimulation, Sevoflurane

The clinical presentations of autoimmune encephalitides tend to be a mixture of neuropsychiatric and somatic symptoms. The focus of this chapter concerns these clinical problems: the clinical phenomenology, the prevalence, and the possible pathophysiologies of anti-NMDAR or the other types of autoimmune encephalitis. We also specifically address the psychopharmacologic and nonpsychopharmacologic treatments. Our main questions are: What are the most used and best justified drug treatments? What are the most frequent side effects? And which other treatment options, such as ECT, are available? We discuss the main findings, present limitations, and we conclude by giving recommendations and presenting two algorithms.

Summary Background Dysphonia, with or without laryngeal changes, has been reported as a complication following prolonged intubation. In contrast, it is unknown if laryngeal changes also occur following short-term airway instrumentation. The objectives of this study were to determine the prevalence of laryngeal changes in patients undergoing short-term routine general anesthesia using an endotracheal tube (ETT) or supraglottic airway (SGA), and to identify predictors to these changes. Methods Standardized voice assessments were performed preoperatively, postoperatively, and at follow-up on adults undergoing general anesthesia for an elective procedure of less than three hours requiring an ETT or a SGA. The standardized voice assessment protocol comprised a rigid videolaryngostroboscopy, the Voice Handicap Index (VHI), and acoustic voice analysis. The effects of demographic and anesthetic characteristics and type of airway instrumentation on the videolaryngostroboscopic variables were studied using multilevel logistic regression. Multilevel linear regression was used to reveal preoperative versus postoperative changes in VHI and acoustic voice scores. Results Overall, the prevalence of postoperative laryngeal changes was low. Significant postoperative laryngeal changes were found for the variables right-sided vocal fold redness in the ETT group (P = 0.048) and right-sided vocal fold blood vessels in both groups (ETT versus SGA). However, after adjustment for all demographic and anesthetic characteristics in the regression model, the effect of the type of airway instrumentation (ETT versus SGA) on the variable right-sided vocal fold redness was no longer significant. Conclusions ETT and SGA short-term airway instrumentation are vocal fold function sparing techniques with negligible laryngeal changes.

Highlights • Neurosurgeons are stable in STN targeting regardless of MRI field strength. • Neurosurgeons are stable in STN targeting regardless of MRI contrast. • The targeted STN electrode location is more ventral using 3 T versus 7 T scans., Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective surgical treatment for Parkinson’s disease (PD). Side-effects may, however, be induced when the DBS lead is placed suboptimally. Currently, lower field magnetic resonance imaging (MRI) at 1.5 or 3 Tesla (T) is used for targeting. Ultra-high-field MRI (7 T and above) can obtain superior anatomical information and might therefore be better suited for targeting. This study aims to test whether optimized 7 T imaging protocols result in less variable targeting of the STN for DBS compared to clinically utilized 3 T images. Three DBS-experienced neurosurgeons determined the optimal STN DBS target site on three repetitions of 3 T-T2, 7 T-T2*, 7 T-R2* and 7 T-QSM images for five PD patients. The distance in millimetres between the three repetitive coordinates was used as an index of targeting variability and was compared between field strength, MRI contrast and repetition with a Bayesian ANOVA. Further, the target coordinates were registered to MNI space, and anatomical coordinates were compared between field strength, MRI contrast and repetition using a Bayesian ANOVA. The results indicate that the neurosurgeons are stable in selecting the DBS target site across MRI field strength, MRI contrast and repetitions. The analysis of the coordinates in MNI space however revealed that the actual selected location of the electrode is seemingly more ventral when using the 3 T scan compared to the 7 T scans.

Several studies claim that listening to Mozart music affects cognition and can be used to treat neurological conditions like epilepsy. Research into this Mozart effect has not addressed how dynamic interactions between brain networks, i.e. effective connectivity, are affected. The Granger-causality analysis is often used to infer effective connectivity. First, we investigate if a new method, Bayesian topology identification, can be used as an alternative. Both methods are evaluated on simulation data, where the Bayesian method outperforms the Granger-causality analysis in the inference of connectivity graphs of dynamic networks, especially for short data lengths. In the second part, the Bayesian method is extended to enable the inference of changes in effective connectivity between groups of subjects. Next, we apply both methods to fMRI scans of 16 healthy subjects, who were scanned before and after the exposure to Mozart's sonata K448 at least 2 hours a day for 7 days. Here, we investigate if the effective connectivity of the subjects significantly changed after listening to Mozart music. The Bayesian method detected changes in effective connectivity between networks related to cognitive processing and control in the connection from the central executive to the superior sensori-motor network, in the connection from the posterior default mode to the fronto-parietal right network, and in the connection from the anterior default mode to the dorsal attention network. This last connection was only detected in a subgroup of subjects with a longer listening duration. Only in this last connection, an effect was found by the Granger-causality analysis.

Sex-steroids, corticosteroids and vitamin D-3-derived molecules have all been subject to experimental studies and clinical trials in a plethora of autoimmune diseases. These molecules are all derived from cholesterol metabolites and are ligands for nuclear receptors. Ligation of these receptors results in direct regulation of multiple gene transcription involved in general homeostatic and adaptation networks, including the immune system. Indeed, the distinct ligands affect the function of both myeloid and lymphoid cells, eventually resulting in a less pro inflammatory immune response which is considered beneficial in autoimmune diseases. Next to the immune system, also the central nervous system is prone to regulation by these nuclear receptor ligands. Understanding of the intricate interactions between sex-steroids, corticosteroids and vitamin D-3 metabolites, on the one hand, and the immune and central nervous system, on the other hand, may reveal novel approaches to utilize these nuclear receptor ligands to full extent as putative treatments in multiple sclerosis, the prototypic immune driven disease of the central nervous system.

OBJECTIVE: To evaluate the cost-effectiveness of an early intervention service for cardiac arrest survivors called 'Stand still…., and move on' from a societal perspective.INTERVENTION: This concise nursing intervention consists of screening for cognitive and emotional problems, information provision and support, self-management promotion, and further referral if necessary. Earlier research confirmed the feasibility of the intervention and its effectiveness in improving emotional functioning and quality of life.METHODS: In this multicentre randomized controlled trial with one year follow-up 185 patients were included between April 2007 and December 2010. The experimental group received the intervention, the control group received care-as-usual. Intervention costs, other direct healthcare costs (e.g. hospital care, rehabilitation, medication, home care) and indirect costs (productivity loss) were measured during ten months using monthly cost-diaries. The economic evaluation comprised a cost-utility analysis (SF-36) and a cost-effectiveness analysis (QOLIBRI) using bootstrapping (5000 replications) to quantify uncertainty concerning the Incremental Cost Effectiveness Ratio (ICER), and the probability of the intervention being cost-effective was estimated. To check the robustness of the findings, two sensitivity analyses were performed using the EQ-5D and the complete cases respectively.RESULTS: Of 136 (74%) participants sufficient data concerning costs were collected to be included in this economic evaluation. Intervention costs were on average €127 (SD 85). No significant differences between groups were found with regard to overall costs. The ICERs of the cost-utility and the cost-effectiveness analyses supported the cost-effectiveness of the intervention. The probability of the intervention being cost-effective was 54% - 76% for the SF-36 and 94% for the QOLIBRI. Findings were robust.CONCLUSION: The intervention 'Stand still…, and move on' has positive societal economic effects and has a high probability to be cost-effective. Implementation in regular healthcare is recommended.TRIAL REGISTRATION: ISRCTN74835019.

The Wada test is commonly used to evaluate language and memory lateralization in candidates for epilepsy surgery. The spatial Brain Symmetry Index (BSI) quantifies inter-hemispheric differences in the EEG. Its application has been shown to be feasible during Wada testing. We developed a method for the quantification of EEG asymmetry that matches visual assessments of the EEG better than BSI. Fifty-three patients' EEG data, with a total of 85 injections were analyzed. In a step-wise, data-driven manner, multiple electrode and frequency band combinations were evaluated. Eventually, BSI, calculated using only the frontal electrodes F 3 and F 4 , was combined with a temporal measure of delta power in the central electrodes, C 3 and C 4 , into a new measure: cBSI. Using the area under the ROC curve (AUC), we showed that cBSI performs significantly better relative to BSI (median AUC 0.98 versus 0.96, p = 0.0015, Wilcoxon signed rank test). Our results showed that asymmetry detection was significantly improved by combining temporal with spatial qEEG measures. In the future, our combined qEEG measure could allow for a more objective way of monitoring EEG asymmetry, thereby increasing the feasibility of using EEG as a monitoring tool during the Wada test. Future studies should, however, validate our cBSI method in real time in the operating room or radiology suite.

IntroductionIntrathecal baclofen (ITB) treatment is applied in patients with spastic cerebral palsy (SCP), dystonic cerebral palsy (DCP) and progressive neurological disease (PND). Our aim was to investigate whether ITB treatment has a different effect on activities of daily life (ADL) in these groups.MethodA retrospective and cross-sectional survey was conducted using a questionnaire to assess the qualitative effect of ITB (Likert scale) on different domains of functioning (mobility, personal care, communication, comfort) and satisfaction with the results. Groups were compared using non-parametric statistics.ResultsQuestionnaires were completed for 68 patients (39 SCP, 13 DCP, 16 PND). Satisfaction scores were relatively high in all groups (7–8) and the positive effect on personal care and communication was similar in all groups. The PND group had the shortest follow-up and scored significantly less favourably for the effect on mobility and comfort.DiscussionThis is the first study to show that ITB treatment has similar effects on personal care and communication in stable and progressive neurological disease. The decrease in mobility in the PND group is likely due to the progressive nature of the disease. The different effect on comfort between groups is mainly due to the smaller effect on startles in the PND group.

A long-standing concern has been whether epilepsy contributes to cognitive decline or so-called 'epileptic dementia'. Although global cognitive decline is generally reported in the context of chronic refractory epilepsy, it is largely unknown what percentage of patients is at risk for decline. This review is focused on the identification of risk factors and characterization of aberrant cognitive trajectories in epilepsy. Evidence is found that the cognitive trajectory of patients with epilepsy over time differs from processes of cognitive ageing in healthy people, especially in adulthood-onset epilepsy. Cognitive deterioration in these patients seems to develop in a 'second hit model' and occurs when epilepsy hits on a brain that is already vulnerable or vice versa when comorbid problems develop in a person with epilepsy. Processes of ageing may be accelerated due to loss of brain plasticity and cognitive reserve capacity for which we coin the term 'accelerated cognitive ageing'. We believe that the concept of accelerated cognitive ageing can be helpful in providing a framework understanding global cognitive deterioration in epilepsy.

Item does not contain fulltext Introduction: The Wechsler Memory Scale (WMS) is one of the most widely used test batteries to assess memory functions in patients with brain dysfunctions of different etiologies. This study examined the clinical validation of the Dutch Wechsler Memory Scale-Fourth Edition (WMS-IV-NL) in patients with temporal lobe epilepsy (TLE). Method: The sample consisted of 75 patients with intractable TLE, who were eligible for epilepsy surgery, and 77 demographically matched healthy controls. All participants were examined with the WMS-IV-NL. Results: Patients with TLE performed significantly worse than healthy controls on all WMS-IV-NL indices and subtests (p < .01), with the exception of the Visual Working Memory Index including its contributing subtests, as well as the subtests Logical Memory I, Verbal Paired Associates I, and Designs II. In addition, patients with mesiotemporal abnormalities performed significantly worse than patients with lateral temporal abnormalities on the subtests Logical Memory I and Designs II and all the indices (p < .05), with the exception of the Auditory Memory Index and Visual Working Memory Index. Patients with either a left or a right temporal focus performed equally on allWMS-IV-NL indices and subtests (F(15, 50) = .70, p = .78), as well as the Auditory-Visual discrepancy score (t(64) = -1.40, p = .17). Conclusion: The WMS-IV-NL is capable of detecting memory problems in patients with TLE, indicating that it is a sufficiently valid memory battery. Furthermore, the findings support previous research showing that the WMS-IV has limited value in identifying material-specific memory deficits in presurgical patients with TLE. 5 p.

Introduction Depression is considered a syndrome with a constellation of symptoms that are frequently categorized into 3 domains including affective, somatic and cognitive. There has been limited research into the domain specific magnitude or relative timing of treatment response in patients with Parkinson's disease (PD). In addition, antidepressant trials involving patients with PD have demonstrated a similar robust placebo response to that seen in other populations. However, the timing of the placebo response has not been carefully studied. Methods We studied differential responses to antidepressant treatment in affective, somatic and cognitive domains of depression. Patients were treated for twelve weeks with placebo, venlafaxine or paroxetine as part of the Study of Antidepressants in Parkinson's Disease (SAD-PD) randomized controlled trial. Depressive symptoms were evaluated with three commonly used rating scales. Results All symptom domains improved during the study period, There was a significant placebo effect, especially in the first two weeks that had diminished by week 12. Compared to placebo, the affective symptoms significantly improved during treatment as early as week 4, followed by the somatic symptoms of depression in week 6 and cognitive symptoms in week 8. The largest response was seen in the affective domain. Conclusion In depressed PD patients treated with venlafaxine or paroxetine, affective symptoms improved first, followed by somatic symptoms and cognitive symptoms. These findings could guide patient counselling and increase patient compliance by informing about the expected treatment responses. The substantial placebo effect underlines the importance of a sufficiently long study period in future studies.