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Improving our understanding of post-stroke fatigue is crucial to develop more effective interventions. This effort may be hampered by the methods used to assess fatigue, which usually rely on retrospective memory reports. However, such reports are prone to memory bias and may not capture variability in fatigue in daily life; thereby failing to adequately represent symptom experience. This study aimed to assess the strength of the relationship between real-time experience of post-stroke fatigue and the commonly used retrospective Fatigue Severity Scale (FSS). Thirty individuals with stroke completed 10 daily questionnaires about momentary (here-and-now) fatigue for six consecutive days using the mHealth application PsyMateTM (Experience Sampling Method). From these real-time fatigue ratings (N = 1012), we calculated three indices: total average, peak fatigue, and fatigue on the final day. Afterwards, participants rated their fatigue retrospectively with the FSS. Results showed weak to moderate and strong correlations (range: .334, .667), with retrospective reports capturing up to 44% of the variance in the indices of momentary fatigue. Exploratory analyses also revealed that even individuals with similar total FSS scores demonstrated highly different day-to-day fatigue patterns. We conclude that retrospective measures may provide an incomplete view of post-stroke fatigue and diurnal variation therein

PURPOSE: (1) To explore the course of participation from two months up to four years after stroke, and (2) to examine if adaptive and maladaptive psychological factors and mood measured at two months after stroke are determinants of the course of participation during this period.MATERIALS AND METHODS: Prospective cohort study in which 369 individuals with stroke were assessed at stroke onset, two months, six months, one year, two years and three to four years after stroke. The Utrecht Scale for Evaluation of Rehabilitation-Participation (USER-Participation) restrictions subscale was used to measure participation. Psychological factors were clustered into adaptive (proactive coping, self-efficacy, extraversion and optimism) and maladaptive (passive coping, neuroticism and pessimism) psychological factors. The Hospital Anxiety and Depression Scale was used to assess mood.RESULTS: Although improvements in participation were observed up to one year after stroke, considerable long-term restrictions in social and physical domains persisted. More mood problems and less adaptive psychological factors were independent determinants of worse participation up to four years after stroke.CONCLUSIONS: Participation improves in the first 12 months after stroke and stabilizes afterwards. Mood problems and less adaptive psychological factors negatively influence the course of participation over time up to four years after stroke. Implications for rehabilitation Follow-up assessments after stroke should not only focus on cognitive and motor impairment, but also encompass screening on mood problems and adaptive psychological factors. Implementation of a routine follow-up assessment one year after stroke can be beneficial as restrictions in participation are unlikely to diminish spontaneously from then onwards.

Contains fulltext : 249066.pdf (Publisher’s version ) (Open Access) BACKGROUND: Frontotemporal dementia (FTD) has a profound impact on the spouse and other family caregivers involved. While caregivers have a need for support, it is difficult for healthcare providers to respond to their specific needs. This qualitative study explores the lived experiences and needs of caregivers of persons with FTD to facilitate the development of support. METHODS: Three focus group discussions were organized to explore the lived experiences of Dutch FTD caregivers. The included caregivers (n = 24) were aged 16 years or older and were involved in the care of a relative with FTD. Two researchers independently performed an inductive content analysis using open and axial coding. RESULTS: The main category emerging from the data was a lack of recognition, acknowledgment, and understanding experienced by caregivers. This was linked to caregivers' experiences with (1) complex emotional and behavioral symptoms in the person with FTD, (2) the trivializing responses of family and friends, (3) a perceived lack of knowledge and support from healthcare professionals, and (4) the bureaucratic procedures that accompany caregiving. As a result, caregivers felt lonely and solely responsible for the caregiving role. CONCLUSION: Caregivers of persons with FTD experience a lack of understanding in caring for their relative with FTD, which contributes to feelings of loneliness. A specialized support approach is needed to address the specific needs of caregivers of persons with FTD. Support should address strategies that caregivers can use to inform and involve family and friends in the caregiving situation to prevent loneliness in FTD caregivers.

Copy Number Variation (CNV) at the 1q21.1 locus is associated with a range of neurodevelopmental and psychiatric disorders in humans, including abnormalities in head size and motor deficits. Yet, the functional consequences of these CNVs (both deletion and duplication) on neuronal development remain unknown. To determine the impact of CNV at the 1q21.1 locus on neuronal development, we generated induced pluripotent stem cells from individuals harbouring 1q21.1 deletion or duplication and differentiated them into functional cortical neurons. We show that neurons with 1q21.1 deletion or duplication display reciprocal phenotype with respect to proliferation, differentiation potential, neuronal maturation, synaptic density and functional activity. Deletion of the 1q21.1 locus was also associated with an increased expression of lower cortical layer markers. This difference was conserved in the mouse model of 1q21.1 deletion, which displayed altered corticogenesis. Importantly, we show that neurons with 1q21.1 deletion and duplication are associated with differential expression of calcium channels and demonstrate that physiological deficits in neurons with 1q21.1 deletion or duplication can be pharmacologically modulated by targeting Ca2+ channel activity. These findings provide biological insight into the neuropathological mechanism underlying 1q21.1 associated brain disorder and indicate a potential target for therapeutic interventions.

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.

Intensive care medicine 47(10), 1115-1129 (2021). doi:10.1007/s00134-021-06484-1, Published by Springer, Berlin

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.

The burden of large and rare copy number genetic variants (CNVs) as well as certain specific CNVs increase the risk of developing schizophrenia. Several cognitive measures are purported schizophrenia endophenotypes and may represent an intermediate point between genetics and the illness. This paper investigates the influence of CNVs on cognition. We conducted a systematic review and meta-analysis of the literature exploring the effect of CNV burden on general intelligence. We included ten primary studies with a total of 18,847 participants and found no evidence of association. In a new psychosis family study, we investigated the effects of CNVs on specific cognitive abilities. We examined the burden of large and rare CNVs (>200 kb, This work was supported by the Medical Research Council (G0901310) and the Wellcome Trust (grants 085475/B/08/Z, 085475/Z/08/Z). This study was supported by the NIHR Biomedical Research Centre at University College London Hospitals NHS Foundation Trust and University College London and by the NIHR Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust at King’s College London. Further support to EB: Mental Health Research UK’s John Grace QC award, BMA Margaret Temple grants 2016 and 2006, MRC—Korean Health Industry Development Institute Partnering Award (MC_PC_16014), MRC New Investigator Award and a MRC Centenary Award (G0901310), National Institute of Health Research UK post-doctoral fellowship, the Psychiatry Research Trust, the Schizophrenia Research Fund, the Brain and Behaviour Research foundation’s NARSAD Young Investigator Awards 2005, 2008, Wellcome Trust Research Training Fellowship, the NIHR Biomedical Research Centre at UCLH, and the NIHR Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and Institute of Psychiatry King’s College London. Further support to co-authors: The Brain and Behaviour Research foundation’s (NARSAD’s) Young Investigator Award (Grant 22604, awarded to CI). The BMA Margaret Temple grant 2016 to JT. A 2014 European Research Council Marie Curie award to A Díez-Revuelta. HI has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 747429. A Medical Research Council doctoral studentship to JH-S, IA-Z and AB. A Mental Health Research UK studentship to RM. VB is supported by a Wellcome Trust Seed Award in Science (200589/Z/16/Z). FWO Senior Clinical Fellowship to RvW. The infrastructure for the GROUP consortium is funded through the Geestkracht programme of the Dutch Health Research Council (ZON-MW, grant number 10-000-1001), and matching funds from participating pharmaceutical companies (Lundbeck, AstraZeneca, Eli Lilly, Janssen Cilag) and universities and mental health care organisations (Amsterdam: Academic Psychiatric Centre of the Academic Medical Centre and the mental health institutions: GGZ Ingeest, Arkin, Dijk en Duin, GGZ Rivierduinen, Erasmus Medical Centre, GGZ Noord Holland Noord. Groningen: University Medical Centre Groningen and the mental health institutions: Lentis, GGZ Friesland, GGZ Drenthe, Dimence, Mediant, GGNet Warnsveld, Yulius Dordrecht and Parnassia psycho-medical centre The Hague. Maastricht: Maastricht University Medical Centre and the mental health institutions: GGZ Eindhoven en De Kempen, GGZ Breburg, GGZ Oost-Brabant, Vincent van Gogh voor Geestelijke Gezondheid, Mondriaan, Virenze riagg, Zuyderland GGZ, MET ggz, Universitair Centrum Sint-Jozef Kortenberg, CAPRI University of Antwerp, PC Ziekeren Sint-Truiden, PZ Sancta Maria Sint-Truiden, GGZ Overpelt, OPZ Rekem. Utrecht: University Medical Centre Utrecht and the mental health institutions Altrecht, GGZ Centraal and Delta). The Santander cohort was supported by Instituto de Salud Carlos III (PI020499, PI050427, PI060507), SENY Fundació (CI 2005-0308007), Fundacion Ramón Areces and Fundacion Marqués de Valdecilla (API07/011, API10/13). We thank Valdecilla Biobank for providing the biological PAFIP samples and associated data included in this study and for its help in the technical execution of this work; we also thank IDIVAL Neuroimaging Unit for its help in the acquisition and processing of imaging PAFIP data.

Small fiber neuropathy (SFN) is a common condition affecting thinly myelinated A delta and unmyelinated C fibers, often resulting in excruciating pain and dysautonomia. SFN has been associated with several conditions, but a significant number of cases have no discernible cause. Recent genetic studies have identified potentially pathogenic gain-of-function mutations in several poreforming voltage-gated sodium channel alpha subunits (Na-v) in a subset of patients with SFN, but the auxiliary sodium channel beta-subunits have been less implicated in the development of the disease. beta subunits modulate Na-v trafficking and gating, and several mutations have been linked to epilepsy and cardiac dysfunction. Recently, we provided the first evidence for the contribution of a mutation in the beta 2 subunit to pain in human painful diabetic neuropathy. Here, we provide the first evidence for the involvement of a sodium channel beta subunit mutation in the pathogenesis of SFN with no other known causes. We show, through current-clamp analysis, that the newly identified Y69H variant of the beta(2) subunit induces neuronal hyperexcitability in dorsal root ganglion neurons, lowering the threshold for action potential firing and allowing for increased repetitive action potential spiking. Underlying the hyperexcitability induced by the beta(2)-Y69H variant, we demonstrate an upregulation in tetrodotoxin-sensitive, but not tetrodotoxin-resistant sodium currents. This provides the first evidence for the involvement of beta(2) subunits in SFN and strengthens the link between sodium channel beta subunits and the development of neuropathic pain in humans.NEW & NOTEWORTHY Small fiber neuropathy (SFN) often has no discernible cause, although mutations in the voltage-gated sodium channel alpha subunits have been implicated in some cases. We identify a patient suffering from SFN with a mutation in the auxiliary beta 2 subunit and no other discernible causes for SFN. Functional assessment confirms this mutation renders dorsal root ganglion neurons hyperexcitable and upregulates tetrodotoxin-sensitive sodium currents. This study strengthens a newly emerging link between sodium channel beta 2 subunit mutations and human pain disorders.

BACKGROUND AND PURPOSE: Dynamic contrast-enhanced MRI (DCE-MRI) can be employed to assess the blood-brain barrier (BBB) integrity. Detection of BBB leakage at lower field strengths (≤3T) is cumbersome as the signal is noisy, while leakage can be subtle. Utilizing the increased signal-to-noise ratio at higher field strengths, we explored the application of 7T DCE-MRI for assessing BBB leakage.METHODS: A dual-time resolution DCE-MRI method was implemented at 7T and a slow injection rate (0.3 ml/s) and low dose (3 mmol) served to obtain signal changes linearly related to the gadolinium concentration, that is, minimized for T2 * degradation effects. With the Patlak graphical approach, the leakage rate (Ki ) and blood plasma volume fraction (vp ) were calculated. The method was evaluated in 10 controls, an ischemic stroke patient, and a patient with a transient ischemic attack.RESULTS: Ki and vp were significantly higher in gray matter compared to white matter of all participants. These Ki values were higher in both patients compared to the control subjects. Finally, for the lesion identified in the ischemic stroke patient, higher leakage values were observed compared to normal-appearing tissue.CONCLUSION: We demonstrate how a dual-time resolution DCE-MRI protocol at 7T, with administration of half the clinically used contrast agent dose, can be used for assessing subtle BBB leakage. Although the feasibility of DCE-MRI for assessing the BBB integrity at 3T is well known, we showed that a continuous sampling DCE-MRI method tailored for 7T is also capable of assessing leakage with a high sensitivity over a range of Ki values.

The neural correlates of subjective cognitive decline (SCD; i.e., without objectifiable deficit) remain to be elucidated. Possible causes of SCD include early neurodegeneration related to Alzheimer's disease or functional and structural changes related to sub-clinical depression. We investigated the relationship between episodic memory performance or memory complaints and structural or functional magnetic resonance imaging (MRI) measures in participants with SCD ( n = 18) but without psychiatric disorders and healthy controls ( n = 31). In SCD, memory complaints were not associated with memory performance but with sub-clinical depression and executive functions. SCD-associated memory complaints correlated with higher amygdala and parahippocampal gyrus (specifically subiculum) gray matter density. In controls, but not in SCD, mesiotemporal gray matter density and superior frontal gyrus functional connectivity predicted memory performance. In contrast, in SCD, only a trend toward a correlation between memory performance and gray matter density in the parietooccipital lobes was observed. In our memory-clinic sample of SCD, we did not observe incipient neurodegeneration (limited to structural and functional MRI) but rather sub-clinical depression underlying subjective cognitive complaints. (c) 2021 Elsevier Inc. All rights reserved.

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.

BackgroundIndividuals with depression often experience widespread and persistent cognitive deficits, which might be due to brain atrophy and cerebral small vessel disease (CSVD). We therefore studied the associations between depression, markers of brain atrophy and CSVD, and cognitive functioning.MethodsWe used cross-sectional data from the population-based Maastricht study (n = 4734; mean age 59.1 ± 8.6 years, 50.2% women), which focuses on type 2 diabetes. A current episode of major depressive disorder (MDD, n = 151) was assessed by the Mini-International Neuropsychiatric Interview. Volumes of cerebral spinal fluid, white matter, gray matter and white matter hyperintensities, presence of lacunar infarcts and cerebral microbleeds, and total CSVD burden were assessed by 3 T magnetic resonance imaging. Multiple linear and logistic regression analyses tested the associations between MDD, brain markers and cognitive functioning in memory, information processing speed, and executive functioning & attention, and presence of cognitive impairment. Structural equation modeling was used to test mediation.ResultsIn fully adjusted models, MDD was associated with lower scores in information processing speed [mean difference = −0.18(−0.28;−0.08)], executive functioning & attention [mean difference = −0.13(−0.25;−0.02)], and with higher odds of cognitive impairment [odds ratio (OR) = 1.60(1.06;2.40)]. MDD was associated with CSVD in participants without type 2 diabetes [OR = 1.65(1.06;2.56)], but CSVD or other markers of brain atrophy or CSVD did not mediate the association with cognitive functioning.ConclusionsMDD is associated with more impaired information processing speed and executive functioning & attention, and overall cognitive impairment. Furthermore, MDD was associated with CSVD in participants without type 2 diabetes, but this association did not explain an impaired cognitive profile.

BackgroundThis study examined the associations between accelerometer-derived sedentary time (ST), lower intensity physical activity (LPA), higher intensity physical activity (HPA) and the incidence of depressive symptoms over 4 years of follow-up.MethodsWe included 2082 participants from The Maastricht Study (mean ± s.d. age 60.1 ± 8.0 years; 51.2% men) without depressive symptoms at baseline. ST, LPA and HPA were measured with the ActivPAL3 activity monitor. Depressive symptoms were measured annually over 4 years of follow-up with the 9-item Patient Health Questionnaire (PHQ-9). Cox regression analysis was performed to examine the associations between ST, LPA, HPA and incident depressive symptoms (PHQ-9 ⩾ 10). Analyses were adjusted for total waking time per day, age, sex, education level, type 2 diabetes mellitus, body mass index, total energy intake, smoking status and alcohol use.ResultsDuring 7812.81 person-years of follow-up, 203 (9.8%) participants developed incident depressive symptoms. No significant associations [Hazard Ratio (95% confidence interval)] were found between sex-specific tertiles of ST (lowest v. highest tertile) [1.13 (0.76–1.66], or HPA (highest v. lowest tertile) [1.14 (0.78–1.69)] and incident depressive symptoms. LPA (highest v. lowest tertile) was statistically significantly associated with incident depressive symptoms in women [1.98 (1.19–3.29)], but not in men (p-interaction ConclusionsWe did not observe an association between ST or HPA and incident depressive symptoms. Lower levels of daily LPA were associated with an increased risk of incident depressive symptoms in women. Future research is needed to investigate accelerometer-derived measured physical activity and ST with incident depressive symptoms, preferably stratified by sex.

Improving research capacity is key to better understand dementia globally (Gonzalez et al., 2014) and it depends on the investment made on the career development of the early- and mid-career resear...

We investigated the effect of a multidomain lifestyle intervention on the risk of dementia estimated using the validated CAIDE risk score (post-hoc analysis). The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) is a 2-year randomized controlled trial among 1,260 at-risk older adults (60–77 years). Difference in the estimated mean change in CAIDE score at 2 years in the intervention compared to the control group was –0.16 (95 %CI –0.31 to 0.00) (p = 0.013), corresponding to a relative dementia risk reduction between 6.04–6.50%. This could be interpreted as a reflection of the prevention potential of the intervention.

Introduction Innovative patient engagement models are required to identify people with prodromal and mild Alzheimer's disease who are “hidden” in their communities and not normally found in a memory clinic setting. Methods A marketing campaign and a web‐based pre‐screening tool were used to identify individuals at risk of dementia in five European countries. Harmonized clinical evaluation of these patients was performed in participating memory clinics within the MOPEAD project. Results A total of 1487 individuals completed the pre‐screening, with 547 of them found to be at risk of dementia (36.8%). Among the subset of 91 patients with a positive pre‐screening result that underwent full clinical evaluation, 49 (53.8%) were diagnosed with either mild cognitive impairment or Alzheimer's disease. Conclusion This novel web‐based pre‐screening tool showed to be a valid strategy to identify undiagnosed people with cognitive impairment.

The European Community’s Seventh Framework Programme under grant agreement No. HEALTH-F2-2010-241909 (EUGEI); The Spanish sample was supported by the Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III (SAM16PE07CP1, PI16/02012, PI19/024) (...), Velthorst, E., Mollon, J., Murray, R.M., de Haan, L., Germeys, I.M., Glahn, D.C., Arango, C., van der Ven, E., Di Forti, M., Bernardo, M., Guloksuz, S., Delespaul, P., Mezquida, G., Amoretti, S., Bobes, J., Saiz, P.A., García-Portilla, M.P., Santos, J.L., Jiménez-López, E., Sanjuan, J., Aguilar, E.J., Arrojo, M., Carracedo, A., López, G., González-Peñas, J., Parellada, M., Atbaşoğlu, C., Saka, M.C., Üçok, A., Alptekin, K., Akdede, B., Binbay, T., Altınyazar, V., Ulaş, H., Yalınçetin, B., Gümüş-Akay, G., Beyaz, B.C., Soygür, H., Cankurtaran, E.Ş., Kaymak, S.U., Maric, N.P., Mihaljevic, M.M., Petrovic, S.A., Mirjanic, T., Del-Ben, C.M., Ferraro, L., Gayer-Anderson, C., Jones, P.B., Jongsma, H.E., Kirkbride, J.B., La Cascia, C., Lasalvia, A., Tosato, S., Llorca, P.-M., Menezes, P.R., Morgan, C., Quattrone, D., Menchetti, M., Selten, J.-P., Szöke, A., Tarricone, I., Tortelli, A., McGuire, P., Valmaggia, L., Kempton, M.J., van der Gaag, M., Riecher-Rössler, A., Bressan, R.A., Barrantes-Vidal, N., Nelson, B., McGorry, P., Pantelis, C., Krebs, M.-O., Ruhrmann, S., Sachs, G., Rutten, B.P.F., van Os, J., Alizadeh, B.Z., van Amelsvoort, T., Bartels-Velthuis, A.A., Bruggeman, R., van Beveren, N.J., Luykx, J.J., Cahn, W., Simons, C.J.P., Kahn, R.S., Schirmbeck, F., van Winkel, R., Calem, M., Tognin, S., Modinos, G., Pisani, S., Kraan, T.C., van Dam, D.S., Burger, N., Amminger, G.P., Politis, A., Goodall, J., Borgwardt, S., Studerus, E., Gadelha, A., Brietzke, E., Asevedo, G., Asevedo, E., Zugman, A., Domínguez-Martínez, T., Monsonet, M., Cristóbal-Narváez, P., Racioppi, A., Kwapil, T.R., Kazes, M., Daban, C., Bourgin, J., Gay, O., Mam-Lam-Fook, C., Nordholm, D., Rander, L., Krakauer, K., Glenthøj, L.B., Glenthøj, B., Gebhard, D., Arnhold, J., Klosterkötter, J., Lasser, I., Winklbaur, B., Reichenberg, A., EU-GEI High Risk Study

BackgroundCognitive alterations are a central and heterogeneous trait in psychotic disorders, driven by environmental, familial and illness-related factors. In this study, we aimed to prospectively investigate the impact of high familial risk for cognitive alterations, unconfounded by illness-related factors, on symptomatic outcomes in patients.MethodsIn total, 629 probands with non-affective psychosis and their sibling not affected by psychosis were assessed at baseline, 3- and 6-year follow-up. Familial cognitive risk was modeled by three cognitive subtypes (‘normal’, ‘mixed’ and ‘impaired’) in the unaffected siblings. Generalized linear mixed models assessed multi-cross-sectional associations between the sibling cognitive subtype and repeated measures of proband symptoms across all assessments. Between-group differences over time were assessed by adding an interaction effect of time and sibling cognitive subtype.ResultsProbands affected by psychosis with a sibling of the impaired cognitive subtype were less likely to be in symptomatic remission and showed more disorganization across all time points. When assessing differences over time, probands of siblings with the impaired cognitive subtype showed less remission and less improvement of disorganization after 3 and 6 years relative to the other subtypes. They also showed less reduction of positive, negative and excitement symptoms at 6-year follow-up compared to probands with a sibling of the normal cognitive subtype.ConclusionsCross-sibling pathways from higher levels of familial cognitive vulnerability to worse long-term outcomes may be informative in identifying cognition-related environmental and genetic risks that impact psychotic illness heterogeneity over time.

Objective Current diagnostic criteria for bilateral vestibulopathy (BV) primarily involve measurements of vestibular reflexes. Perceptual self-motion thresholds however, are not routinely measured and their clinical value in this specific population is not yet fully determined. Objectives of this study were (1) to compare perceptual self-motion thresholds between BV patients and control subjects, and (2) to explore patterns of self-motion perception performance and vestibular function in BV patients. Methods Thirty-seven BV patients and 34 control subjects were included in this study. Perceptual self-motion thresholds were measured in both groups using a CAREN platform (Motek Medical BV, Amsterdam, The Netherlands). Vestibular function was evaluated (only in BV patients) by the caloric test, torsion swing test, video head impulse test of all semicircular canals, and cervical- and ocular vestibular-evoked myogenic potentials. Differences in thresholds between both groups were analyzed. Hierarchical cluster analysis was performed to visualize patterns between self-motion perception and vestibular function within the group of BV patients. Results Perceptual self-motion thresholds were significantly higher in BV patients compared to control subjects, regarding nearly all rotations and translations (depending on the age group) (p ≤ 0.001). Cluster analysis showed that within the group of BV patients, higher perceptual self-motion thresholds were generally associated with lower vestibular test results (significant for yaw rotation, caloric test, torsion swing test, and video head impulse test (p ≤ 0.001)). Conclusion Self-motion perception is significantly decreased in BV patients compared to control subjects regarding nearly all rotations and translations. Furthermore, decreased self-motion perception is generally associated with lower residual vestibular function in BV patients. Trial registration Trial registration number NL52768.068.15/METC

Objective: To explore the course of quality of life (QoL) and possible resident-related predictors associated with this course in institutionalized people with young-onset dementia (YOD). Design: An observational longitudinal study. Setting and Participants: A total of 278 residents with YOD were recruited from 13 YOD special care units in the Netherlands. Methods: Secondary analyses were conducted with longitudinal data from the Behavior and Evolution in Young-ONset Dementia (BEYOND)-II study. QoL was assessed with proxy ratings, using the Quality of Life in Dementia (QUALIDEM) questionnaire at 4 assessment points over 18 months. Predictors included age, gender, dementia subtype, length of stay, dementia severity, neuropsychiatric symptoms, and psycho tropic drug use at baseline. Multilevel modeling was used to adjust for the correlation of measurements within residents and clustering of residents within nursing homes. Results: The total QUALIDEM score (range: 0-111) decreased over 18 months with a small change of 0.65 (95% confidence interval-1.27,-0.04) points per 6 months. An increase in several domains of QoL regarding care relationship, positive self-image, and feeling at home was seen over time, whereas a decline was observed in the subscales positive affect, social relations, and having something to do. Residents with higher levels of QoL and more advanced dementia at baseline showed a more progressive decline in QoL over time. Sensitivity analyses indicated a more progressive decline in QoL for residents who died during the follow-up. Conclusion and Implications: This study shows that although overall QoL in nursing home residents with YOD was relatively stable over 18 months, there were multidirectional changes in the QoL subscales that could be clinically relevant. Higher levels of QoL and more advanced stages of dementia at baseline predicted a more progressive decline in QoL over time. More longitudinal studies are needed to verify factors influencing QoL in YOD. (c) 2020 The Authors. Published by Elsevier Inc. on behalf of AMDA -The Society for Post-Acute and Long-Term Care Medicine. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).

BACKGROUND AND PURPOSE: To update the digital online atlas for organs at risk (OARs) delineation in neuro-oncology based on high-quality computed tomography (CT) and magnetic resonance (MR) imaging with new OARs. MATERIALS AND METHODS: In this planned update of the neurological contouring atlas published in 2018, ten new clinically relevant OARs were included, after thorough discussion between experienced neuro-radiation oncologists (RTOs) representing 30 European radiotherapy-oncology institutes. Inclusion was based on daily practice and research requirements. Consensus was reached for the delineation after critical review. Contouring was performed on registered CT with intravenous (IV) contrast (soft tissue & bone window setting) and 3 Tesla (T) MRI (T1 with gadolinium & T2 FLAIR) images of one patient (1 mm slices). For illustration purposes, delineation on a 7 T MRI without IV contrast from a healthy volunteer was added. OARs were delineated by three experienced RTOs and a neuroradiologist based on the relevant literature. RESULTS: The presented update of the neurological contouring atlas was reviewed and approved by 28 experts in the field. The atlas is available online and includes in total 25 OARs relevant to neuro-oncology, contoured on CT and MRI T1 and FLAIR (3 T & 7 T). Three-dimensional (3D) rendered films are also available online. CONCLUSION: In order to further decrease inter- and intra-observer OAR delineation variability in the field of neuro-oncology, we propose the use of this contouring atlas in photon and particle therapy, in clinical practice and in the research setting. The updated atlas is freely available on www.cancerdata.org. ispartof: RADIOTHERAPY AND ONCOLOGY vol:160 pages:259-265 ispartof: location:Ireland status: published

Prospective momentary psychological and biological measures of real-time daily life stress experiences have been examined in several psychiatric disorders, but not in adults with an autism spectrum disorder (ASD). The current electronic self-monitoring study examined associations between momentary daily life stressors and (i) negative affect (NA; emotional stress reactivity) and (ii) cortisol levels (biological stress reactivity) in males and females with ASD (N = 50) and without ASD (N = 51). The Experience Sampling Method, including saliva sampling, was used to measure three types of daily life stress (activity-related, event-related, and social stress), NA, and cortisol. Multilevel regression analyses demonstrated significant interactions between group and stress (i.e., activity-related and event-related stress) in the model of NA, indicating stronger emotional stress reactivity in the ASD than in the control group. In the model of cortisol, none of the group × stress interactions were significant. Male/female sex had no moderating effect on either emotional or biological stress reactivity. In conclusion, adults with ASD showed a stronger emotional stress (but not cortisol) reactivity in response to unpleasant daily life events and activities. The findings highlight the feasibility of electronic self-monitoring in individuals with ASD, which may contribute to the development of more personalized stress-management approaches. ispartof: SCIENTIFIC REPORTS vol:11 issue:1 ispartof: location:England status: published

Strategies to reduce dementia risk are needed to minimize the burden of this growing public health concern. Most individuals are not aware that dementia risk reduction is possible, let alone how this could be achieved. Health education, such as public awareness campaigns on the topic of dementia risk reduction, can meet this need. A public health campaign (including social media and offering an online individual risk assessment tool) was carried out over a 7-month period in Flanders, Belgium. Impact was assessed in two independent online surveys, before (n = 1003) and after the campaign (n = 1008), in representative samples of adults aged 40–75 years. Questions regarding personal needs, wishes and barriers were also included. After the campaign, more individuals (10.3%) were aware that dementia risk reduction is possible than before the campaign, and more individuals correctly identified 10 out of 12 surveyed modifiable dementia risk and protective factors. However, no differences were observed in low-educated individuals. Further, specific differences in potential needs, wishes and barriers for future campaigns or interventions were observed between demographic strata. The majority of the respondents (89%) indicated that they would welcome more information on improving their brain-health. More than half (54%) also believed that they lacked the necessary knowledge to make brain-healthy behavior changes. In conclusion, effective public awareness campaigns on the topic of dementia risk reduction are feasible and timely, given the state of the evidence. Special efforts need to be made to develop effective campaigns, tailored towards low-educated individuals.

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.

Background Post-stroke cognitive impairment (PSCI) occurs in approximately half of people in the first year after stroke. Infarct location is a potential determinant of PSCI, but a comprehensive map of strategic infarct locations predictive of PSCI is unavailable. We aimed to identify infarct locations most strongly predictive of PSCI after acute ischaemic stroke and use this information to develop a prediction model. Methods In this large-scale multicohort lesion-symptom mapping study, we pooled and harmonised individual patient data from 12 cohorts through the Meta-analyses on Strategic Lesion Locations for Vascular Cognitive Impairment using Lesion-Symptom Mapping (Meta VCI Map) consortium. The identified cohorts (as of Jan 1, 2019) comprised patients with acute symptomatic infarcts on CT or MRI (with available infarct segmentations) and a cognitive assessment up to 15 months after acute ischaemic stroke onset. PSCI was defined as performance lower than the fifth percentile of local normative data, on at least one cognitive domain on a multidomain neuropsychological assessment or on the Montreal Cognitive Assessment. Voxel-based lesion-symptom mapping (VLSM) was used to calculate voxel-wise odds ratios (ORs) for PSCI that were mapped onto a three-dimensional brain template to visualise PSCI risk per location. For the prediction model of PSCI risk, a location impact score on a 5-point scale was derived from the VLSM results on the basis of the mean voxel-wise coefficient (ln[OR]) within each patient's infarct. We did combined internal-external validation by leave-one-cohort-out cross-validation for all 12 cohorts using logistic regression. Predictive performance of a univariable model with only the location impact score was compared with a multivariable model with addition of other clinical PSCI predictors (age, sex, education, time interval between stroke onset and cognitive assessment, history of stroke, and total infarct volume). Testing of visual ratings was done by three clinicians, and accuracy, inter-rater reliability, and intra-rater reliability were assessed with Cohen's weighted kappa. Findings In our sample of 2950 patients (mean age 66 & middot;8 years [SD 11 & middot;6]; 1157 [39 & middot;2%] women), 1286 (43 & middot;6%) had PSCI. We achieved high lesion coverage of the brain in our analyses (86 & middot;9%). Infarcts in the left frontotemporal lobes, left thalamus, and right parietal lobe were strongly associated with PSCI (after false discovery rate correction, q20). On cross-validation, the location impact score showed good correspondence, based on visual assessment of goodness of fit, between predicted and observed risk of PSCI across cohorts after adjusting for cohort specific PSCI occurrence. Cross-validations showed that the location impact score by itself had similar performance to the combined model with other PSCI predictors, while allowing for easy visual assessment. Therefore the univariable model with only the location impact score was selected as the final model. Correspondence between visual ratings and actual location impact score (Cohen's weighted kappa: range 0 & middot;88-0 & middot;92), inter-rater agreement (0 & middot;85-0 & middot;87), and intra-rater agreement (for a single rater, 0 & middot;95) were all high. Interpretation To the best of our knowledge, this study provides the first comprehensive map of strategic infarct locations associated with risk of PSCI.A location impact score was derived from this map that robustly predicted PSCI across cohorts.Furthermore, we developed a quick and reliable visual rating scale that might in the future be applied by clinicians to identify individual patients at risk of PSCI.

Background Several methods have been proposed to measure cerebrovascular autoregulation (CA) in traumatic brain injury (TBI), but the lack of a gold standard and the absence of prospective clinical data on risks, impact on care and outcomes of implementation of CA-guided management lead to uncertainty. Aim To formulate statements using a Delphi consensus approach employing a group of expert clinicians, that reflect current knowledge of CA, aspects that can be implemented in TBI management and CA research priorities. Methods A group of 25 international academic experts with clinical expertise in the management of adult severe TBI patients participated in this consensus process. Seventy-seven statements and multiple-choice questions were submitted to the group in two online surveys, followed by a face-to-face meeting and a third online survey. Participants received feedback on average scores and the rationale for resubmission or rephrasing of statements. Consensus on a statement was defined as agreement of more than 75% of participants. Results Consensus amongst participants was achieved on the importance of CA status in adult severe TBI pathophysiology, the dynamic non-binary nature of CA impairment, its association with outcome and the inadvisability of employing universal and absolute cerebral perfusion pressure targets. Consensus could not be reached on the accuracy, reliability and validation of any current CA assessment method. There was also no consensus on how to implement CA information in clinical management protocols, reflecting insufficient clinical evidence. Conclusion The Delphi process resulted in 25 consensus statements addressing the pathophysiology of impaired CA, and its impact on cerebral perfusion pressure targets and outcome. A research agenda was proposed emphasizing the need for better validated CA assessment methods as well as the focused investigation of the application of CA-guided management in clinical care using prospective safety, feasibility and efficacy studies.

Approximately 20% of patients diagnosed with a phaeochromocytoma or paraganglioma carry a germline mutation in one of the succinate dehydrogenase (SDHx) genes (SDHA, SDHB, SDHC and SDHD), which encode the four subunits of the SDH enzyme. When a pathogenic SDHx mutation is identified in an affected patient, genetic counselling is proposed for first-degree relatives. Optimal initial evaluation and follow-up of people who are asymptomatic but might carry SDHx mutations have not yet been agreed. Thus, we established an international consensus algorithm of clinical, biochemical and imaging screening at diagnosis and during surveillance for both adults and children. An international panel of 29 experts from 12 countries was assembled, and the Delphi method was used to reach a consensus on 41 statements. This Consensus Statement covers a range of topics, including age of first genetic testing, appropriate biochemical and imaging tests for initial tumour screening and follow-up, screening for rare SDHx-related tumours and management of elderly people who have an SDHx mutation. This Consensus Statement focuses on the management of asymptomatic SDHx mutation carriers and provides clinicians with much-needed guidance. The standardization of practice will enable prospective studies in the near future.

Contains fulltext : 234953.pdf (Publisher’s version ) (Open Access) This study investigates whether there exist differences in facial emotion detection accuracy in patients suffering from Vestibular Schwannoma (VS) due to their facial paresis. Forty-four VS patients, half of them with, and half of them without a facial paresis, had to classify pictures of facial expressions as being emotional or non-emotional. The visual information of images was systematically manipulated by adding different levels of visual noise. The study had a mixed design with emotional expression (happy vs. angry) and visual noise level (10% to 80%) as repeated measures and facial paresis (present vs. absent) and degree of facial dysfunction as between subjects' factors. Emotion detection accuracy declined when visual information declined, an effect that was stronger for anger than for happy expressions. Overall, emotion detection accuracy for happy and angry faces did not differ between VS patients with or without a facial paresis, although exploratory analyses suggest that the ability to recognize emotions in angry facial expressions was slightly more impaired in patients with facial paresis. The findings are discussed in the context of the effects of facial paresis on emotion detection, and the role of facial mimicry, in particular, as an important mechanism for facial emotion processing and understanding.

Background and objectives Facioscapulohumeral muscular dystrophy (FHSD) is a debilitating inherited muscle disease for which various therapeutic strategies are being investigated. Thus far, little attention has been given in FSHD to the development of scientifically sound outcome measures fulfilling regulatory authority requirements. The aim of this study was to design a patient‐reported Rasch‐built interval scale on activity and participation for FSHD. Methods A pre‐phase FSHD‐Rasch‐built overall disability scale (pre‐FSHD‐RODS; consisting of 159 activity/participation items), based on the World Health Organization international classification of disease‐related functional consequences was completed by 762 FSHD patients (Netherlands: n = 171; UK: n = 287; United States: n = 221; France: n = 52; Australia: n = 32). A proportion of the patient cohort completed it twice (n = 230; interval 2–4 weeks; reliability studies). The pre‐FSHD‐RODS was subjected to Rasch analyses to create a model fulfilling its requirements. Validity studies were performed through correlation with the motor function measure. Results The pre‐FSHD‐RODS did not meet the Rasch model expectations. Based on determinants such as misfit statistics and misfit residuals, differential item functioning, and local dependency, we systematically removed items until a final 38‐inquiry (originating from 32 items; six items split) FSHD‐RODS was constructed achieving Rasch model expectations. Adequate test‐retest reliability and (cross‐cultural and external) validity scores were obtained. Conclusions The FSHD‐RODS is a disease‐specific interval measure suitable for detecting activity and participation restrictions in patients with FSHD with good item/person reliability and validity scores. The use of this scale is recommended in the near future, to determine the functional deterioration slope in FSHD per year as a preparation for the upcoming clinical intervention trials in FSHD., This paper presents the development and validation of a patient‐reported Rasch‐built interval scale on activity and participation for facioscapulohumeral muscular dystrophy (FSHD‐RODS). The final 38‐inquiry scale met Rasch model expectations and showed adequate discriminative power, test‐retest reliability and validity. The use of this scale is recommended in the near future to determine the functional deterioration slope in facioscapulohumeral muscular dystrophy (FSHD) per year as a preparation for the upcoming clinical intervention trials in FSHD.

Objective: Cognitive alterations putatively contribute to the risk for suicide in individuals with psychosis. Yet, a comprehensive assessment of social-and general-cognitive abilities in a large sample is lacking. Methods: Seven-hundred -fifteen individuals diagnosed with a psychotic disorder performed tasks of facial emotion recognition, Theory of Mind, and general cognitive functioning (sustained attention, set-shifting, IQ-tests and verbal learning) as part of the Genetic-Risk-and-Outcome-of-Psychosis (GROUP) study. Presence of past suicide attempt/s and/or current suicidal ideation was reported by 261 individuals and 454 individuals reported no suicide attempt or ideation. We used general linear models to investigate group differences in task performance. All analysis were controlled for age, sex, education, and psychotic symptom severity. Results: Individuals with suicide attempt and/or ideation showed better performance on the facial emotion recognition task and lower performance on tasks of sustained attention and verbal learning, compared to individuals without suicide attempt and/or ideation, without a clear effect of attempt or ideation. Theory of Mind performance was also better for individuals with suicide attempt and/or ideation, with largest differences between individuals who reported both attempts and ideation compared to individuals without suicide attempt and/or ideation. No effect of suicide attempt and/or ideation was found on misperception of facial emotions, IQ and set-shifting. Overall, effect sizes were small. Conclusion: Higher sensitivity to social-emotional cues together with weakened attentional control and learning capacity was observed in individuals with psychosis and suicide attempt and/or ideation. This may suggest that insufficient capacity for regulating perceived social stress contributes to suicidal thoughts and behavior. (c) 2021 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).

Objective The present work was undertaken to study the genetic contribution to the start of Alzheimer's disease (AD) with amyloid and tau biomarkers in cognitively intact older identical twins.Methods We studied in 96 monozygotic twin-pairs relationships between amyloid-beta (A beta) aggregation as measured by the A beta 1-42/1-40 ratio in cerebrospinal fluid (CSF; n = 126) and positron emission tomography (PET, n = 194), and CSF markers for A beta production (beta-secretase 1, A beta 1-40, and A beta 1-38) and CSF tau. Associations among markers were tested with generalized estimating equations including a random effect for twin status, adjusted for age, gender, and apolipoprotein E epsilon 4 genotype. We used twin analyses to determine relative contributions of genetic and/or environmental factors to AD pathophysiological processes.Results Twenty-seven individuals (14%) had an abnormal amyloid PET, and 14 twin-pairs (15%) showed discordant amyloid PET scans. Within twin-pairs, A beta production markers and total-tau (t-tau) levels strongly correlated (r range = 0.73-0.86, all p < 0.0001), and A beta aggregation markers and 181-phosphorylated-tau (p-tau) levels correlated moderately strongly (r range = 0.50-0.64, all p < 0.0001). Cross-twin cross-trait analysis showed that A beta 1-38 in one twin correlated with A beta 1-42/1-40 ratios, and t-tau and p-tau levels in their cotwins (r range = -0.28 to 0.58, all p < .007). Within-pair differences in A beta production markers related to differences in tau levels (r range = 0.49-0.61, all p < 0.0001). Twin discordance analyses suggest that A beta production and tau levels show coordinated increases in very early AD.Interpretation Our results suggest a substantial genetic/shared environmental background contributes to both A beta and tau increases, suggesting that modulation of environmental risk factors may aid in delaying the onset of AD pathophysiological processes. ANN NEUROL 2021

Objective: In this paper, we aim to provide a comprehensive description of the multicomponent self-management intervention for adults with epilepsy, ZMILE. Rationale or theory: Acquiring self-management skills has been shown to play a vital role in enabling patients with epilepsy overcoming (health-related) struggles in daily life and coping with limitations their condition poses on them. ZMILE is a course consisting of education (to increase concordance to treatment), goal-setting (proactive coping), and self-monitoring. Resources needed: The course is guided by two nurse practitioners and each patient is allowed to bring one family member or friend. Self-monitoring plays an important role and can be done through e-Health tools or written diaries. Processes involved: During and after the course, patients are required to work toward a personally defined goal using a five-step approach by means of pro-active coping. Moreover, patients are expected to use self-monitoring tools to reflect on their own behavior and identify ways to optimize medication intake when required. Quantification: ZMILE is provided in an outpatient setting over five weekly group sessions and one booster session. From the start, patients are encouraged to set individual goals. Each group session will have a different theme but part of every session is reflecting on personal goals and to learn from eachother. Conclusions: The ZMILE-intervention has been evaluated and may be a promising intervention in terms of effectiveness and feasibility for adults with epilepsy, relatives, and professionals. We present the adapted version which can be implemented in clinical practice.

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.

Introduction The syndromes of thrombotic microangiopathy (TMA) are diverse and represent severe endothelial damage caused by various mechanisms. The complement system plays a major role in a subset of patients with TMA, and its recognition is of clinical importance because it guides choice and duration of treatment. Methods We studied a well-defined cohort of patients with TMA and hypothesized that assessment of serum-induced ex vivo C5b9 formation on the endothelium and screening for rare variants in complement genes can better categorize TMA. Results Massive ex vivo C5b9 formation was found in all patients with primary atypical hemolytic uremic syndrome (n/N = 11/11) and in 59% of patients with TMA and coexisting conditions (n/N = 30/51). Massive ex vivo C5b9 formation was associated with rare genetic variants (45% [n/N = 20/44] vs. 0% [n/N = 0/21] patients with normal ex vivo C5b9 formation; P < 0.001). Massive ex vivo C5b9 formation was associated with favorable renal response to therapeutic complement inhibition in patients with TMA and coexisting conditions (86% [n/N = 12/14] vs. 31% [n/N = 5/16] of untreated patients; P < 0.001), indicating complement-mediated TMA rather than secondary disease. Among treated patients, the odds ratio for 1-year kidney survival was 12.0 (95% confidence interval 1.2-115.4). TMA recurrence was linked to rare genetic variants in all cases. Patients with normal ex vivo C5b9 formation had an acute, nonrelapsing form of TMA. Conclusions Ex vivo C5b9 formation and genetic testing appears to categorize TMAs into different groups because it identifies complement as a driving factor of disease, with potential therapeutic and prognostic implications., Graphical abstract

OBJECTIVE: Studies on the course of depression often ignore comorbid anxiety disorders or anxiety symptoms. We explored predictors of complete remission (no depression nor anxiety diagnoses at follow-up) and of the course of comorbid anxiety symptoms. We additionally tested the hypothesis that the course of anxiety disorders and symptoms in depressed patients is explained by negative life-events in the presence of high neuroticism or a low sense of mastery.METHODS: An observational study of 270 patients (≥60 years) diagnosed with major depressive disorder and 2-year follow-up data, who participated in the Netherlands Study of Depression in Older persons (NESDO). Sociodemographic, somatic, psychiatric, and treatment variables were first explored as possible predictors. A multiple logistic regression analysis was used to examine their predictive value concerning complete remission. Subsequently, negative life-events, personality and their interaction were tested as potential predictors. Linear Mixed Models were used to assess whether the personality traits modified the effect of early and recent life-events, and time and their interactions on the course of the anxiety symptoms.RESULTS: A total of 135 of 270 patients achieved complete remission. Depressed patients with a comorbid anxiety disorder at baseline less often achieved complete remission: 38 of 103 (37.0%) versus 97 of 167 (58.1%). The severity of depressive and anxiety symptomatology, the presence of a comorbid anxiety disorder, and a poorer physical health at baseline predicted nonremission. In line with our hypothesis, a less favorable course of self-reported anxiety symptoms was associated with more recent negative life-events, but only among patients with a high level of neuroticism or a low level of mastery.CONCLUSION: Comorbid anxiety in depression as a negative impact on complete remission at 2-year follow-up. The course of anxiety severity seems dependent on the interaction of personality traits and life-events.

Contains fulltext : 235277.pdf (Publisher’s version ) (Closed access) BACKGROUND: Balancing the risks of recurrent ischaemic stroke and intracranial haemorrhage is important for patients treated with antithrombotic therapy after ischaemic stroke or transient ischaemic attack. However, existing predictive models offer insufficient performance, particularly for assessing the risk of intracranial haemorrhage. We aimed to develop new risk scores incorporating clinical variables and cerebral microbleeds, an MRI biomarker of intracranial haemorrhage and ischaemic stroke risk. METHODS: We did a pooled analysis of individual-patient data from the Microbleeds International Collaborative Network (MICON), which includes 38 hospital-based prospective cohort studies from 18 countries. All studies recruited participants with previous ischaemic stroke or transient ischaemic attack, acquired baseline MRI allowing quantification of cerebral microbleeds, and followed-up participants for ischaemic stroke and intracranial haemorrhage. Participants not taking antithrombotic drugs were excluded. We developed Cox regression models to predict the 5-year risks of intracranial haemorrhage and ischaemic stroke, selecting candidate predictors on biological relevance and simplifying models using backward elimination. We derived integer risk scores for clinical use. We assessed model performance in internal validation, adjusted for optimism using bootstrapping. The study is registered on PROSPERO, CRD42016036602. FINDINGS: The included studies recruited participants between Aug 28, 2001, and Feb 4, 2018. 15 766 participants had follow-up for intracranial haemorrhage, and 15 784 for ischaemic stroke. Over a median follow-up of 2 years, 184 intracranial haemorrhages and 1048 ischaemic strokes were reported. The risk models we developed included cerebral microbleed burden and simple clinical variables. Optimism-adjusted c indices were 0·73 (95% CI 0·69-0·77) with a calibration slope of 0·94 (0·81-1·06) for the intracranial haemorrhage model and 0·63 (0·62-0·65) with a calibration slope of 0·97 (0·87-1·07) for the ischaemic stroke model. There was good agreement between predicted and observed risk for both models. INTERPRETATION: The MICON risk scores, incorporating clinical variables and cerebral microbleeds, offer predictive value for the long-term risks of intracranial haemorrhage and ischaemic stroke in patients prescribed antithrombotic therapy for secondary stroke prevention; external validation is warranted. FUNDING: British Heart Foundation and Stroke Association.

ObjectiveThis is the first double-blind randomized controlled trial evaluating the efficacy and safety of IV immunoglobulin (IVIG) vs placebo in patients with idiopathic small fiber neuropathy (I-SFN).MethodsBetween July 2016 and November 2018, 60 Dutch patients with skin biopsy–proven I-SFN randomly received a starting dose of IVIG (2 g/kg body weight) or matching placebo (0.9% saline). Subsequently, 3 additional infusions of IVIG (1 g/kg) or placebo were administered at 3-week intervals. The primary outcome was a 1-point change in Pain Intensity Numerical Rating Scale score at 12 weeks compared to baseline.ResultsThirty patients received IVIG, and 30 received placebo. In both groups, 29 patients completed the trial. In 40% of patients receiving IVIG, the mean average pain was decreased by at least 1 point compared to 30% of the patients receiving placebo (p = 0.588, odds ratio 1.56, 95% confidence interval 0.53–4.53). No significant differences were found on any of the other prespecified outcomes, including general well-being, autonomic symptoms, and overall functioning and disability.ConclusionsThis randomized controlled trial showed that IVIG treatment had no significant effect on pain in patients with painful I-SFN.Trial Registration InformationClinicalTrials.gov Identifier: NCT02637700, EudraCT 2015-002624-31.Classification of EvidenceThis study provides Class I evidence that for patients with painful I-SFN, IVIG did not significantly reduce pain compared to placebo.

ObjectiveTo investigate the 2-year change in parenchymal diffusivity, a quantitative marker of microstructural tissue condition, and the relationship with baseline blood-brain barrier (BBB) permeability, in tissue at risk, i.e., the perilesional zone surrounding white matter hyperintensities (WMH) in patients with cerebral small vessel disease (cSVD).MethodsPatients with sporadic cSVD (lacunar stroke or mild vascular cognitive impairment) underwent 3T MRI at baseline, including dynamic contrast-enhanced MRI to quantify BBB permeability (i.e., leakage volume and rate) and intravoxel incoherent motion imaging (IVIM), a diffusion technique that provides parenchymal diffusivity D. After 2 years, IVIM was repeated. We assessed the relation between BBB leakage measures at baseline and change in parenchymal diffusivity (∆D) over 2 years in the perilesional zones (divided in 2-mm contours) surrounding WMH.ResultsWe analyzed 43 patients (age 68 ± 12 years, 58% male). In the perilesional zones, ∆D increased 0.10% (confidence interval [CI] 0.07–0.013%) (p < 0.01) per 2 mm closer to the WMH. Furthermore, ∆D over 2 years showed a positive correlation with both baseline BBB leakage volume (r = 0.29 [CI 0.06–0.52], p = 0.013) and leakage rate (r = 0.24 [CI 0.02–0.47], p = 0.034).ConclusionBBB leakage at baseline is related to the 2-year change in parenchymal diffusivity in the perilesional zone of WMH. These results support the hypothesis that BBB impairment might play an early role in subsequent microstructural white matter degeneration as part of the pathophysiology of cSVD.

The locus coeruleus (LC) supplies norepinephrine to the brain, is one of the first sites of tau deposition in Alzheimer's disease (AD) and modulates a variety of behaviors and cognitive functions. Transgenic mouse models showed that norepinephrine dysregulation after LC lesions exacerbates inflammatory responses, blood-brain barrier leakage (BBB), and cognitive deficits. Here, we investigated relationships between central norepinephrine metabolism, tau and beta-amyloid (Aβ), inflammation, BBB-dysfunction, neuropsychiatric problems, and memory in-vivo in a memory clinic population (total n = 111, 60 subjective cognitive decline, 36 mild cognitively impaired, and 19 AD dementia). Cerebrospinal fluid (CSF) and blood samples were collected and analyzed for 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), CSF/plasma albumin ratio (Q-alb), Aβ, phosphorylated tau, and interleukins. The verbal word learning task and the neuropsychiatric inventory assessed memory functioning and neuropsychiatric symptoms. Structural equation models tested the relationships between all fluid markers, cognition and behavior, corrected for age, education, sex, and clinical dementia rating score. Our results showed that neuropsychiatric symptoms show strong links to both MHPG and p-tau, whereas memory deficits are linked to MHPG via a combination of p-tau and inflammation-driven amyloidosis (30-35% indirect effect contribution). These results suggest that the LC-norepinephrine may be pivotal to understand links between AD pathology and behavioral and cognitive deficits in AD.

The noradrenergic (NE) locus coeruleus (LC) is vulnerable to hyperphosphorylated tau, and dysregulated NE-metabolism is linked to greater tau and disease progression. We investigated whether elevated NE-metabolism alone predicts memory decline or whether concomitant presence of tau and amyloid-β is required. Among 114 memory clinic participants, time trends (max. six years) showed dose-response declines in learning across groups with elevated NE-metabolite 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) with no, one, or two Alzheimer’s disease biomarkers; and no decline in the low MHPG group. Elevated MHPG is required and sufficient to detect learning declines, supporting a pathophysiologic model including the LC-NE system contributing to initial Alzheimer’s disease-related processes.

Introduction: Depressive symptoms are highly prevalent and clinically relevant in schizophrenia spectrum disorder (SSD) patients. So far, little is known about to what extent the depressive symptom profile in SSD is comparable to that seen in major depressive disorder (MDD).Methods: Data were derived from the Genetic Risk and Outcome of Psychosis study (GROUP) and the Netherlands Study of Depression and Anxiety (NESDA). We examined differences in severity of depressive symptom profiles and distribution of mood/cognition and somatic/vegetative depressive symptoms using the Quick Inventory of Depressive Symptomatology - Self Report (QIDS-SR) within SSD patients (n = 449), MDD patients (n = 816) and healthy controls (n = 417), aged 18 to 50. Within SSD, associations between depression severity and clinical and demographic data were examined.Results: 60.4% of SSD patients showed substantial depressive symptomatology (QIDS-SR >= 6). The difference in mood/cognition symptoms between SSD and MDD was larger (higher symptoms in MDD, effect size = 1.13), than the differences in somatic/vegetative symptoms (effect size 0.74). In patients with SSD, multivariable regression analyses showed that lower social functioning, male gender, use of benzodiazepine and more severe positive symptoms were associated with higher overall depressive symptomatology. The use of antipsychotics or anti-depressants was associated with more somatic/vegetative symptoms.Conclusion: More than half of SSD patients have considerable depressive symptomatology, with a relative preponderance of somatic/vegetative symptoms compared to the profile seen in MDD. Future research could explore whether depressive symptom profile in SSD may also be associated with biological dysregulations like in MDD.

Background and purpose Natural killer (NK) cells may play a role in multiple sclerosis (MS). Ratios of NK cells to CD4+ T cells have been proposed as a biomarker for the therapeutic effect of stem cell transplantation in MS. The objectives here were to explore the relevance of this ratio in MS patients by analysing NK and T cell subsets, as well as their prognostic value for disease activity. Methods Baseline peripheral blood mononuclear cells of 50 relapsing–remitting MS patients, participating in our vitamin D supplementation study (SOLARIUM), were analysed with flow cytometry. Disease activity was measured as new magnetic resonance imaging lesions, relapses and mean plasma neurofilament light chain levels after 48 weeks of follow‐up. Results The proportion of NK cells correlated negatively with CD4+ T cells (R = −0.335, p = 0.001) and interleukin 17A (IL‐17A+) CD4+ T cells (R = −0.203, p = 0.043). Participants with magnetic resonance imaging activity or relapses displayed lower NK/IL‐17A+ CD4+ T cell ratios (p =0.025 and p = 0.006, respectively). The NK/IL‐17A+ CD4+ T cell ratio correlated negatively with neurofilament light chain levels (R = −0.320, p = 0.050). Vitamin D supplementation did not affect these ratios. Conclusions Our data suggest a protective role of an expanded NK cell compartment compared to the CD4+ T cell subset fractions in relapsing–remitting MS patients. NK/CD4+ T cell ratios may be a prognostic biomarker for disease activity in MS., Natural killer (NK) cells may control activation of pathogenic CD4+ T cell subsets in multiple sclerosis (MS). It is shown that circulating NK cell proportions not only correlate negatively with interleukin 17A (IL‐17A+) CD4+ T cell proportions but also that a higher abundancy of NK cells relative to IL‐17A+ CD4+ T cells is associated with the absence of new magnetic resonance imaging lesions, the absence of new relapses and lower circulating neurofilament light chain levels during 48 weeks of follow‐up in relapsing– remitting MS patients treated with interferon beta. Therefore, NK cell/CD4+ T cell ratios may be a prognostic biomarker for disease activity in MS.

Voltage-gated sodium channels (NavChs) are pore-forming membrane proteins that regulate the transport of sodium ions through the cell membrane. Understanding the structure and function of NavChs is of major biophysical, as well as clinical, importance given their key role in cellular pathophysiology. In this work, we provide a computational framework for modeling system-size-dependent, i.e., cumulative, atomic properties around a NavCh’s pore. We illustrate our methodologies on the bacterial NavAb channel captured in a closed-pore state where we demonstrate that the atomic environment around its pore exhibits a bi-phasic spatial organization dictated by the structural separation of the pore domains (PDs) from the voltage-sensing domains (VSDs). Accordingly, a mathematical model describing packing of atoms around NavAb’s pore is constructed that allows—under certain conservation conditions—for a power-law approximation of the cumulative hydropathic dipole field effect acting along NavAb’s pore. This verified the non-extensitivity hypothesis for the closed-pore NavAb channel and revealed a long-range hydropathic interactions law regulating atom-packing around the NavAb’s selectivity filter. Our model predicts a PDs-VSDs coupling energy of \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$\sim \!282.1$\end{document}∼282.1 kcal/mol corresponding to a global maximum of the atom-packing energy profile. Crucially, we demonstrate for the first time how critical phenomena can emerge in a single-channel structure as a consequence of the non-extensive character of its atomic porous environment. Supplementary Information The online version contains supplementary material available at 10.1007/s10867-021-09565-w.

Contains fulltext : 231715.pdf (Publisher’s version ) (Open Access) OBJECTIVES: Patients with a vestibular schwannoma (VS) experience a reduced quality of life (QoL). The main objective of this study was to determine the strongest predictors reducing physical and mental QoL from the disease-specific Penn Acoustic Neuroma Quality of Life (PANQOL) questionnaire in patients with VS. DESIGN: Observational study. SETTING: Radboudumc Skull Base Centre, Nijmegen. PARTICIPANTS: Patients newly diagnosed with VS between 2014 and 2017 managed with either observation, stereotactic radiosurgery or microsurgery. MAIN OUTCOME MEASURES: Quality of life was assessed using the disease-specific PANQOL and general Short-Form (36) Health Survey (SF-36). Multiple linear regression models with PANQOL domains as predictors were used to determine the strongest predictors for SF-36 QoL physical and mental health scores. Standardised beta coefficients (β) were used for ranking. RESULTS: A total of 174 patients (50% females, mean age 58.9 years) returned the questionnaires, providing a 69% response rate. Fifteen patients (9%) were treated with microsurgery, 29 (17%) with stereotactic radiosurgery and 130 patients (75%) were observed in a wait and scan strategy. A lack of energy (β = .28; P ≤ .001), lower general health (β = .22; P ≤ .001), headache (β = .16; P ≤ .001), anxiety (β = .15; P ≤ .001) and balance problems (β = .10; P ≤ .001) are the strongest predictors affecting physical health, while mental health is most affected by anxiety (β = .37; P ≤ .001), a lack of energy (β = .34; P ≤ .001), facial nerve dysfunction (β = .07; P ≤ .001), balance problems (β = .04; P ≤ .001) and headaches (β = .04; P ≤ .001). CONCLUSION: A lack of energy, anxiety, headache and balance problems are the strongest predictors of both SF-36 physical and mental QoL in patients with VS. More awareness and supportive care regarding energy, anxiety, headache and balance in informing, evaluating and treating patients with VS could improve QoL.

This paper describes the diagnostic criteria for “Vestibular Migraine of Childhood”, “probable Vestibular Migraine of Childhood” and “Recurrent Vertigo of Childhood” as put forth by the Committee for the Classification of Vestibular Disorders of the Bárány Society (ICVD) and the Migraine Classification subgroup of the International Headache Society. Migraine plays an important role in some subgroups of children with recurrent vertigo. In this classification paper a spectrum of three disorders is described in which the migraine component varies from definite to possibly absent. These three disorders are: Vestibular Migraine of Childhood, probable Vestibular Migraine of Childhood and Recurrent Vertigo of Childhood. The criteria for Vestibular Migraine of Childhood (VMC) include (A) at least five episodes with vestibular symptoms of moderate or severe intensity, lasting between five minutes and 72 hours, (B) a current or past history of migraine with or without aura, and (C) at least half of episodes are associated with at least one migraine feature. Probable Vestibular Migraine of Childhood (probable VMC) is considered when at least three episodes with vestibular symptoms of moderate or severe intensity, lasting between five minutes and 72 hours, are accompanied by at least criterion B or C from the VMC criteria. Recurrent Vertigo of Childhood (RVC) is diagnosed in case of at least three episodes with vestibular symptoms of moderate or severe intensity, lasting between 1 minute and 72 hours, and none of the criteria B and C for VMC are applicable. For all disorders, the age of the individual needs to be below 18 years old. It is recommended that future research should particularly focus on RVC, in order to investigate and identify possible subtypes and its links or its absence thereof with migraine.

Social cognitive impairments may play a role in participation restrictions after stroke. Understanding their relationship could inform treatment approaches to improve participation. We investigated the relationship between social cognition and participation in the long term after stroke. Of 395 patients participating in a large prospective cohort study, cross-sectional data were available at 3-4 years post-stroke of 118 patients on tests for emotion recognition, theory of mind, empathy, and behaviour regulation. Participation was assessed with the Utrecht Scale for Evaluation of Rehabilitation - Participation (USER-P). Bivariate and multivariate regression analysis were used to examine the relationship between social cognitive domains and participation. The majority suffered from minor stroke (83.1% scored NIHSS 0-4). Only behaviour regulation was related to participation restrictions in bivariate analysis, but social cognitive impairments did not predict participation restrictions in multivariate regression in this group. To conclude, in a sample of minor stroke patients with mild impairments in theory of mind, emotion recognition and behavioural control, there were no associations with restrictions in participation. Research should examine whether a relationship is present in patients with more severe stroke. In addition, measuring social aspects of participation is necessary to further unravel this relationship, to determine treatment targets for improving participation.

Contains fulltext : 227913.pdf (Publisher’s version ) (Open Access) Background: Neuropsychological feedback is an important part of the neuropsychological assessment process. However, patients have difficulties remembering this information. Objective: The aim of this study was to develop a web-based visual tool to improve the understanding of neuropsychological results, information retention, and psychologist-patient communication. Methods: The visual tool was developed and optimized using an iterative three-phase stepwise approach to determine its usability, technology acceptance, and feasibility in a memory clinic population. Feedback from different user perspectives (patients, family members, and psychologists) was obtained in each phase using a multimethod approach (e.g., a multidisciplinary brainstorm session, think-aloud sessions, focus groups). The prototype was subsequently tested in a pilot study. Results: The first phases offered insights that led to optimization of the prototype. On a scale ranging from 0 to 100, psychologists evaluated the usability as high [88.1±7.6,70-87]. During the pilot study, both patients and significant others gave positive feedback, but information retention in patients remained low. All participants thought the benefits of the visual tool included seeing cognitive strengths and weaknesses with a translation to daily life all at one glance and receiving feedback on paper to take home. Important barriers were mentioned by psychologists, such as a limited set of tests included and no integration with hospital systems. Conclusion: Overall, patients, family members, and psychologists reported that a visual display of the cognitive profile with insights into daily life had added value to clinical practice. Feedback from the pilot study was adopted in the tool for future implementation purposes. 14 p.

Objective: In this paper, we provide the rationale behind and a description of BrainLevel, a new cognitive rehabilitation intervention for children with acquired brain injury. Rationale: Children with acquired brain injury frequently report cognitive problems and consequently problems in participation, psychosocial functioning, family functioning and quality of life. Computerized repeated practice of specific cognitive tasks (so-called ‘brain training’) improves performance on those specific or highly similar tasks, but rarely leads to better daily life functioning. Adding strategy use instruction as an intervention component, with the aim to transfer task-specific effects to other contexts, may yield positive effects on cognitive and daily life functioning of children with acquired brain injury. Description of the new intervention: In BrainLevel, computerized repeated practice is offered via the online training programme BrainGymmer. For the strategy use instruction, we developed a protocol to provide and practice function-specific and metacognitive strategies. The intervention period is 6 weeks, during which children train five times per week for 30 minutes per day at home with BrainGymmer. Additionally, they attend a weekly 45-minute strategy use instruction session on the basis of our protocol with a cognitive rehabilitation specialist. Discussion: BrainLevel is innovative in combining computerized repeated practice with strategy use instruction as cognitive rehabilitation for children with acquired brain injury. Currently, we are investigating the effectiveness of BrainLevel. In this paper, possible adaptations to tailor BrainLevel to other games or contexts, or to incorporate novel scientific insights, for example regarding optimal intervention duration and intensity, are discussed.

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.