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Background Cognitive stimulation therapy appears to show promising results in the rehabilitation of impaired cognitive processes in attention deficit hyperactivity disorder. Objective Encouraged by this evidence and the ever-increasing use of technology and artificial intelligence for therapeutic purposes, we examined whether cognitive stimulation therapy implemented on a mobile device and controlled by an artificial intelligence engine can be effective in the neurocognitive rehabilitation of these patients. Methods In this randomized study, 29 child participants (25 males) underwent training with a smart, digital, cognitive stimulation program (KAD_SCL_01) or with 3 commercial video games for 12 weeks, 3 days a week, 15 minutes a day. Participants completed a neuropsychological assessment and a preintervention and postintervention magnetoencephalography study in a resting state with their eyes closed. In addition, information on clinical symptoms was collected from the child´s legal guardians. Results In line with our main hypothesis, we found evidence that smart, digital, cognitive treatment results in improvements in inhibitory control performance. Improvements were also found in visuospatial working memory performance and in the cognitive flexibility, working memory, and behavior and general executive functioning behavioral clinical indexes in this group of participants. Finally, the improvements found in inhibitory control were related to increases in alpha-band power in all participants in the posterior regions, including 2 default mode network regions of the interest: the bilateral precuneus and the bilateral posterior cingulate cortex. However, only the participants who underwent cognitive stimulation intervention (KAD_SCL_01) showed a significant increase in this relationship. Conclusions The results seem to indicate that smart, digital treatment can be effective in the inhibitory control and visuospatial working memory rehabilitation in patients with attention deficit hyperactivity disorder. Furthermore, the relation of the inhibitory control with alpha-band power changes could mean that these changes are a product of plasticity mechanisms or changes in the neuromodulatory dynamics. Trial Registration ISRCTN Registry ISRCTN71041318; https://www.isrctn.com/ISRCTN71041318

Adequately learning to read and write is indispensable in our technological societies; however, it is an effortful process that requires years of formal education. In transparent alphabetic orthographies, such as Dutch, the crucial building blocks for literacy skills are the correspondences between letters and speech sounds (LS pairs). Previously, we demonstrated that LS pairs reliably produce a congruency-sensitive fMRI response in the superior temporal cortex (STC) of Dutch fluent readers, but not in dyslexic readers. Here, we used fMRI to investigate whether a similar congruency-sensitivity exists in STC of readers of opaque orthographies, such as English, where the relation between letters and speech sounds is unreliable, and may therefore not provide a similarly important basis for literacy. Eighteen subjects passively perceived congruent and incongruent audiovisual pairs that have different transparencies in English: letters/speech sounds (LS; irregular), letters/letter names (LN; fairly transparent) and numerals/number names (NN; transparent). We detected a congruency by pair-type interaction in STC bilaterally, that was produced by a strong congruency effect for NN, a weaker one for LN, and an incongruency effect for LS. No congruency effects for LS pairs were found in the predicted direction (congruent > incongruent), in contrast to the previous results in Dutch readers. These results indicate that through education, the STC becomes tuned to the congruency of transparent audiovisual pairs, but suggest different neural processing of irregular pairs. This orthographic dependency of LS integration has important implications for remediation strategies for dyslexia in different languages.

Multimodal neuroimaging has become a mainstay of basic and cognitive neuroscience in humans and animals, despite challenges to consider when acquiring and combining non-redundant imaging data. Multimodal data integration can yield important insights into brain processes and structures in addition to spatiotemporal resolution complementarity, including: a comprehensive physiological view on brain processes and structures, quantification, generalization and normalization, and availability of biomarkers. In this review, we discuss data acquisition and fusion in multimodal neuroimaging in the context of each of these potential merits. However, limitations – due to differences in the neuronal and structural underpinnings of each method – have to be taken into account when modeling and interpreting multimodal data using generative models. We conclude that when these challenges are adequately met, multimodal data fusion can create substantial added value for neuroscience applications making it an indispensable approach for studying the brain.

It has been asserted that children with mathematics learning difficulties (MLD) constitute a heterogeneous group. To date, most researchers have investigated differences between predefined MLD subtypes. Specifically MLD children are frequently categorized a priori into groups based on the presence or absence of an additional disorder, such as a reading disorder, to examine cognitive differences between MLD subtypes. In the current study 226 third to six grade children (M age=131 months) with MLD completed a selection of number specific and general cognitive measures. The data driven approach was used to identify the extent to which performance of the MLD children on these measures could be clustered into distinct groups. In particular, after conducting a factor analysis, a 200 times repeated K-means clustering approach was used to classify the children's performance. Results revealed six distinguishable clusters of MLD children, specifically (a) a weak mental number line group, (b) weak ANS group, (c) spatial difficulties group, (d) access deficit group, (e) no numerical cognitive deficit group and (f) a garden-variety group. These findings imply that different cognitive subtypes of MLD exist and that these can be derived from data-driven approaches to classification. These findings strengthen the notion that MLD is a heterogeneous disorder, which has implications for the way in which intervention may be tailored for individuals within the different subtypes.

How a visual stimulus is initially categorized as a face by the cortical face-processing network remains largely unclear. In this study we used functional MRI to study the dynamics of face detection in visual scenes by using a paradigm in which scenes containing faces or cars are revealed progressively as they emerge from visual noise. Participants were asked to respond as soon as they detected a face or car during the noise sequence. Among the face-sensitive regions identified based on a standard localizer, a high-level face-sensitive area, the right fusiform face area (FFA), showed the earliest difference between face and car activation. Critically, differential activation in FFA was observed before differential activation in the more posteriorly located occipital face area (OFA). A whole brain analysis confirmed these findings, with a face-sensitive cluster in the right fusiform gyrus being the only cluster showing face preference before successful behavioral detection. Overall, these findings indicate that following generic low-level visual analysis, a face stimulus presented in a gradually revealed visual scene is first detected in the right middle fusiform gyrus, only after which further processing spreads to a network of cortical and subcortical face-sensitive areas (including the posteriorly located OFA). These results provide further evidence for a nonhierarchical organization of the cortical face-processing network.

Theories about auditory hallucinations in schizophrenia suggest that these experiences occur because patients fail to recognize thoughts and mental events as self-generated. Different theoretical models have been proposed about the cognitive mechanisms underlying auditory hallucinations. Regardless of the cognitive model being tested, however, experimental designs are almost identical in that they require a judgment regarding whether an action was self-originated or not. The aim of the current study was to integrate all available literature for a meta-analysis on this topic and reach conclusions about self-recognition performance in (1) patients with schizophrenia compared with healthy controls and (2) patients with auditory hallucinations compared with patients without these symptoms. A comprehensive literature review identified 23 studies that contrasted the performance of schizophrenia patients with healthy controls (1370 participants) and 9 studies that directly compared patients with and without auditory hallucinations (315 participants). We found significantly reduced self-recognition performance in schizophrenia patients, which was more pronounced in patients with auditory hallucinations compared with patients without. In patients with hallucinations, this pattern of performance was specific to self-recognition processes and not to the recognition of new external information. A striking finding was the homogeneity in results across studies regardless of the action modality, timing delay, and design used to measure self-recognition. In summary, this review of studies from the last 30 years substantiates the view that self-recognition is impaired in patients with schizophrenia and particularly those with auditory hallucinations. This suggests an association, perhaps a causal one, between such deficit and hallucinatory experiences in schizophrenia.

Contains fulltext : 144426.pdf (Publisher’s version ) (Closed access) Contains fulltext : 144426pre.pdf (Author’s version preprint ) (Open Access) The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 x 10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction. 6 p.

INTRODUCTION:\ud \ud The default mode network and the working memory network are known to be anti-correlated during sustained cognitive processing, in a load-dependent manner. We hypothesized that functional connectivity among nodes of the two networks could be dynamically modulated by task phases across time.\ud METHODS:\ud \ud To address the dynamic links between default mode network and the working memory network, we used a delayed visuo-spatial working memory paradigm, which allowed us to separate three different phases of working memory (encoding, maintenance, and retrieval), and analyzed the functional connectivity during each phase within and between the default mode network and the working memory network networks.\ud RESULTS:\ud \ud We found that the two networks are anti-correlated only during the maintenance phase of working memory, i.e. when attention is focused on a memorized stimulus in the absence of external input. Conversely, during the encoding and retrieval phases, when the external stimulation is present, the default mode network is positively coupled with the working memory network, suggesting the existence of a dynamically switching of functional connectivity between "task-positive" and "task-negative" brain networks.\ud CONCLUSIONS:\ud \ud Our results demonstrate that the well-established dichotomy of the human brain (anti-correlated networks during rest and balanced activation-deactivation during cognition) has a more nuanced organization than previously thought and engages in different patterns of correlation and anti-correlation during specific sub-phases of a cognitive task. This nuanced organization reinforces the hypothesis of a direct involvement of the default mode network in cognitive functions, as represented by a dynamic rather than static interaction with specific task-positive networks, such as the working memory network.

White matter abnormalities have been observed in patients with classic galactosemia, an inborn error of galactose metabolism. However, magnetic resonance imaging (MRI) data collected in the past were generally qualitative in nature. Our objective was to investigate white matter microstructure pathology and examine correlations with outcome and behaviour in this disease, by using multi-shell diffusion weighted imaging. In addition to standard diffusion tensor imaging (DTI), neurite orientation dispersion and density imaging (NODDI) was used to estimate density and orientation dispersion of neurites in a group of eight patients (aged 16-21 years) and eight healthy controls (aged 15-20 years). Extensive white matter abnormalities were found: neurite density index (NDI) was lower in the patient group in bilateral anterior areas, and orientation dispersion index (ODI) was increased mainly in the left hemisphere. These specific regional profiles are in agreement with the cognitive profile observed in galactosemia, showing higher order cognitive impairments, and language and motor impairments, respectively. Less favourable white matter properties correlated positively with age and age at onset of diet, and negatively with behavioural outcome (e.g. visual working memory). To conclude, this study provides evidence of white matter pathology regarding density and dispersion of neurites in these patients. The results are discussed in light of suggested pathophysiological mechanisms.

Older age is associated with worsened outcome after mild traumatic brain injury (mTBI) and a higher risk of developing persistent post-traumatic complaints. However, the effects of mTBI sequelae on brain connectivity at older age and their association with post-traumatic complaints remain understudied.We analyzed multi-echo resting-state functional magnetic resonance imaging data from 25 older adults with mTBI (mean age: 68 years, SD: 5 years) in the subacute phase (mean injury to scan interval: 38 days, SD: 9 days) and 20 age-matched controls. Severity of complaints (e.g. fatigue, dizziness) was assessed using self-reported questionnaires. Group independent component analysis was used to identify intrinsic connectivity networks (ICNs). The effects of group and severity of complaints on ICNs were assessed using spatial maps intensity (SMI) as a measure of within-network connectivity, and (static) functional network connectivity (FNC) as a measure of between-network connectivity.Patients indicated a higher total severity of complaints than controls. Regarding SMI measures, we observed hyperconnectivity in left-mid temporal gyrus (cognitive-language network) and hypoconnectivity in the right-fusiform gyrus (visual-cerebellar network) that were associated with group. Additionally, we found interaction effects for SMI between severity of complaints and group in the visual(-cerebellar) domain. Regarding FNC measures, no significant effects were found.In older adults, changes in cognitive-language and visual(-cerebellar) networks are related to mTBI. Additionally, group-dependent associations between connectivity within visual(-cerebellar) networks and severity of complaints might indicate post-injury (mal)adaptive mechanisms, which could partly explain post-traumatic complaints (such as dizziness and balance disorders) that are common in older adults during the subacute phase.

BACKGROUND: Isolated rapid eye movement sleep behavior disorder (iRBD) is prodromal for α-synucleinopathies.OBJECTIVE: The aim of this study was to determine whether pathological cardiac [123 I]meta-iodobenzylguanidine scintigraphy ([123 I]MIBG) is associated with progression of [18 F]fluorodeoxyglucose-positron emission tomography-based Parkinson's disease (PD)-related brain pattern (PDRP) expression in iRBD.METHODS: Seventeen subjects with iRBD underwent [18 F]fluorodeoxyglucose-positron emission tomography brain imaging twice ~3.6 years apart. In addition, [123 I]MIBG and [123 I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane single-photon emission computed tomography ([123 I]FP-CIT-SPECT) at baseline were performed. Olfactory, cognitive, and motor functions were tested annually.RESULTS: Twelve of 17 subjects had pathological [123 I]MIBG. At baseline, 6 of 12 of these expressed the PDRP (suprathreshold PDRP z score). At follow-up, 12 of 17 subjects had suprathreshold PDRP z scores, associated with pathological [123 I]MIBG in 92% and with pathological [123 I]FP-CIT-SPECT in 75%. Subjects with pathological [123 I]MIBG had higher PDRP z score change per year (P = 0.027). Three subjects phenoconverted to PD; all had pathological [123 I]MIBG and [123 I]FP-CIT-SPECT, suprathreshold baseline PDRP z scores, and hyposmia.CONCLUSIONS: Pathological [123 I]MIBG was associated with progressive and suprathreshold PDRP z scores at follow-up. Abnormal [123 I]MIBG likely identifies iRBD as prodromal PD earlier than pathological [123 I]FP-CIT-SPECT. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Purpose: To investigate the relationship between dry eye disease (DED) and vision-related quality of life (VR-QoL) at population level.Methods: DED and VR-QoL were assessed in 89,022 participants (18–96 years, 59% female) from the Dutch population-based Lifelines cohort using the Women's Health study (WHS) and Visual function 25 (VFQ25) questionnaires. The relationship between DED and compromised VR-QoL was assessed with logistic regression, corrected for age, sex, BMI, income, education, smoking, and 55 comorbidities.Results: 9.1% of participants had DED. The participants with DED had higher risk of compromised average of ten domains of VR-QoL (OR 3.12 (95% CI 2.98–3.27) corrected for age, sex, BMI, income, smoking, and 55 comorbidities). Increasing symptom frequency was highly associated with decreasing VR-QoL (P < 0.0005). In all VR-QoL domains, including measures of daily visual function and emotional well-being, DED was clearly associated with compromised VR-QoL. Compared to macular degeneration, glaucoma, retinal detachment, and allergic conjunctivitis, DED presented similar or higher risks for compromised score on all VR-QoL domains. The population-attributable fraction of DED for compromised general vision exceeded that of other eye diseases investigated, especially in the younger age groups.Conclusion: DED is associated with reductions in all domains of VR-QoL, also after correction for associated comorbidities. We found that DED imposes an extensive population burden regarding compromised VR-QoL due to its high prevalence and substantial impact on VR-QoL, higher than that for other common vision-affecting eye disorders. Our results emphasize the importance of recognizing DED as a serious disorder from both patient and public health perspectives.

Psychotic and autistic symptoms are related to social functioning in individuals with psychotic disorders (PD). The present study used a network approach to (1) evaluate the interactions between autistic symptoms, psychotic symptoms, and social functioning, and (2) investigate whether relations are similar in individuals with and without PD. We estimated an undirected network model in a sample of 504 PD, 572 familial risk for psychosis (FR), and 337 typical comparisons (TC), with a mean age of 34.9 years. Symptoms were assessed with the Autism Spectrum Quotient (AQ; 5 nodes) and the Community Assessment of Psychic Experiences (CAPE; 9 nodes). Social functioning was measured with the Social Functioning Scale (SFS; 7 nodes). We identified statistically significant differences between the FR and PD samples in global strength (P < .001) and network structure (P < .001). Our results show autistic symptoms (social interaction nodes) are negatively and more closely related to social functioning (withdrawal, interpersonal behavior) than psychotic symptoms. More and stronger connections between nodes were observed for the PD network than for FR and TC networks, while the latter 2 were similar in density (P = .11) and network structure (P = .19). The most central items in strength for PD were bizarre experiences, social skills, and paranoia. In conclusion, specific autistic symptoms are negatively associated with social functioning across the psychosis spectrum, but in the PD network symptoms may reinforce each other more easily. These findings emphasize the need for increased clinical awareness of comorbid autistic symptoms in psychotic individuals.

Oxford Mental Illness and Violence (OxMIV) addresses the need in mental health services for a scalable, transparent and valid tool to predict violent behaviour in patients with severe mental illness. However, external validations are lacking. Therefore, we have used a Dutch sample of general psychiatric patients with schizophrenia spectrum disorders (N = 637) to evaluate the performance of OxMIV in predicting interpersonal violence over 3 years. The predictors and outcome were measured with standardized instruments and multiple sources of information. Patients were mostly male (n = 493, 77%) and, on average, 27 (SD = 7) years old. The outcome rate was 9% (n = 59). Discrimination, as measured by the area under the curve, was moderate at 0.67 (95% confidence interval 0.61–0.73). Calibration-in-the-large was adequate, with a ratio between predicted and observed events of 1.2 and a Brier score of 0.09. At the individual level, risks were systematically underestimated in the original model, which was remedied by recalibrating the intercept and slope of the model. Probability scores generated by the recalibrated model can be used as an adjunct to clinical decision-making in Dutch mental health services.

Colitis is a common, but poorly understood, adverse event of immune checkpoint inhibitors that are standard-of-care for an expanding range of cancer types. This explorative study aimed to describe the immune infiltrates in the colon from individuals developing checkpoint inhibitor colitis and compare them to well-known immunophenotypes of acute graft-versus-host disease, ulcerative colitis, and Crohn’s disease. Colon biopsies (n = 20 per group) of patients with checkpoint inhibitor colitis, acute graft-versus-host disease, ulcerative colitis and Crohn’s disease, all colitis treatment-naïve, and of individuals with a normal colon were analyzed using immunohistochemistry: CD8 for cytotoxic T cells, CD4 for T helper cells, and CD68 to identify cells of macrophage lineage. CD8 + T cell, CD4 + T cell, and CD68 + cell counts were performed. Cell infiltration was scored as scattered/patchy or band-like in the superficial and deep gut mucosa. Checkpoint inhibitor colitis was found to be heavily infiltrated by CD8 + T cells. Comparative analysis between groups showed that both CD8 + T cell counts (P

Deep brain stimulation is a treatment for Parkinson's disease and other related disorders, involving the surgical placement of electrodes in the deeply situated basal ganglia or thalamic structures. Good clinical outcome requires accurate targeting. However, due to limited visibility of the target structures on routine clinical MR images, direct targeting of structures can be challenging. Non-clinical MR scanners with ultra-high magnetic field (7T or higher) have the potential to improve the quality of these images. This technology report provides an overview of the current possibilities of visualizing deep brain stimulation targets and their related structures with the aid of ultra-high field MRI. Reviewed studies showed improved resolution, contrast- and signal-to-noise ratios at ultra-high field. Sequences sensitive to magnetic susceptibility such as T2(*) and susceptibility weighted imaging and their maps in general showed the best visualization of target structures, including a separation between the subthalamic nucleus and the substantia nigra, the lamina pallidi medialis and lamina pallidi incompleta within the globus pallidus and substructures of the thalamus, including the ventral intermediate nucleus (Vim). This shows that the visibility, identification, and even subdivision of the small deep brain stimulation targets benefit from increased field strength. Although ultra-high field MR imaging is associated with increased risk of geometrical distortions, it has been shown that these distortions can be avoided or corrected to the extent where the effects are limited. The availability of ultra-high field MR scanners for humans seems to provide opportunities for a more accurate targeting for deep brain stimulation in patients with Parkinson's disease and related disorders.

The macaque brain serves as a model for the human brain, but its suitability is challenged by unique human features, including connectivity reconfigurations, which emerged during primate evolution. We perform a quantitative comparative analysis of the whole brain macroscale structural connectivity of the two species. Our findings suggest that the human and macaque brain as a whole are similarly wired. A region-wise analysis reveals many interspecies similarities of connectivity patterns, but also lack thereof, primarily involving cingulate regions. We unravel a common structural backbone in both species involving a highly overlapping set of regions. This structural backbone, important for mediating information across the brain, seems to constitute a feature of the primate brain persevering evolution. Our findings illustrate novel evolutionary aspects at the macroscale connectivity level and offer a quantitative translational bridge between macaque and human research., Author Summary What are the commonalities and differences of human brains when compared to the brains of other primates? The brain can be conceived as a complex network. Its topological properties constrain its function. Ethical and technical reasons necessitate the use of animal brains, like the macaque monkey, as models for the human brain. However, evolutionary changes, including “brain rewiring”, might result in unique human features. Hence, a detailed and quantitative comparative analysis of the connectivity of the brains of the two species is needed. Here, we undertake this task by adopting techniques analogous to those used in comparative studies in other scientific fields. Our approach reveals converging but also diverging wiring patterns. The brain of the two species as a whole is similarly wired. The majority of the brain regions appear to have evolutionary conserved connectivity patterns while for certain regions this appears not to be the case. We also uncover an evolutionary conserved “structural backbone” in the brain of the two species. Our findings highlight common and unique “wiring properties” of the brains of these two primate species and offer a quantitative basis for translating findings from macaque research to human research.

In a highly dynamic visual environment the human brain needs to rapidly differentiate complex visual patterns, such as faces. Here, we defined the temporal frequency tuning of cortical face-sensitive areas for face discrimination. Six observers were tested with functional magnetic resonance imaging (fMRI) when the same or different faces were presented in blocks at 11 frequency rates (ranging from 1 to 12 Hz). We observed a larger fMRI response for different than same faces – the repetition suppression/adaptation effect – across all stimulation frequency rates. Most importantly, the magnitude of the repetition suppression effect showed a typical Gaussian-shaped tuning function, peaking on average at 6 Hz for all face-sensitive areas of the ventral occipito-temporal cortex, including the fusiform and occipital “face areas” (FFA and OFA), as well as the superior temporal sulcus. This effect was due both to a maximal response to different faces in a range of 3 to 6 Hz and to a sharp drop of the blood oxygen level dependent (BOLD) signal from 6 Hz onward when the same face was repeated during a block. These observations complement recent scalp EEG observations (Alonso-Prieto et al., 2013), indicating that the cortical face network can discriminate each individual face when these successive faces are presented every 160–170 ms. They also suggest that a relatively fast 6 Hz rate may be needed to isolate the contribution of high-level face perception processes during behavioral discrimination tasks. Finally, these findings carry important practical implications, allowing investigators to optimize the stimulation frequency rates for observing the largest repetition suppression effects to faces and other visual forms in the occipito-temporal cortex.

Contains fulltext : 243957.pdf (Publisher’s version ) (Open Access) PURPOSE: Primary open-angle glaucoma (POAG) has been reported to occur more frequently in Africans, and to follow a more severe course compared to Europeans. We aimed to describe characteristics of POAG presentation and treatment across three ethnic groups from Africa and one from Europe. METHODS: We ascertained 151 POAG patients from South African Coloured (SAC) and 94 South African Black (SAB) ethnicity from a university hospital in South Africa. In Tanzania, 310 patients were recruited from a university hospital and a referral hospital. In the Netherlands, 241 patients of European ancestry were included. All patients were over 35 years old and had undergone an extensive ophthalmic examination. Patients were diagnosed according to the ISGEO criteria. A biogeographic ancestry analysis was performed to estimate the proportion of genetic African ancestry (GAA). RESULTS: The biogeographic ancestry analysis showed that the median proportion of GAA was 97.6% in Tanzanian, 100% in SAB, 34.2% in SAC and 1.5% in Dutch participants. Clinical characteristics at presentation for Tanzanians, SAB, SAC and Dutch participants, respectively: mean age: 63, 57, 66, 70 years (p

Purpose: To date, population-based studies reporting associations between dry eye disease and medications were hypothesis-driven, did not take into account underlying comorbidities, and did not investigate individual drugs. The purpose of this study was to clarify the association of dry eye symptoms with medication classes and in-dividual drugs, using a hypothesis-free approach. Methods: 79,606 participants (age 20-97 years, 59.2% female) from the population-based Lifelines cohort in the Netherlands were cross-sectionally assessed for dry eye symptoms using the Womens' Health Study dry eye questionnaire. All medications used were coded with the ATC classification system. Logistic regression was used to assess the risk of the 59 most-used therapeutic/pharmacological subgroups and the 99 most-used individual drugs (all n > 200) on dry eye symptoms, correcting for age, sex, body mass index, and 48 comorbidities associated with dry eye. Results: Thirty-eight (64%) medication subgroups and fifty-two (53%) individual drugs were associated with dry eye symptoms (P < 0.05), after correction for age and sex only. A multivariable model correcting for comor-bidities revealed highly significant associations between dry eye symptoms and drugs for peptic ulcer (partic-ularly proton pump inhibitors (PPIs)), antiglaucoma and anticholinergic medications. Conclusions: This study underlines that medication use is highly informative of risk of dry eye symptoms. Correction for underlying comorbidities is critical to avoid confounding effects. This study confirms suggested associations between medications and dry eye symptoms at a population level and shows several new associa-tions. The novel link between PPIs and dry eye symptoms deserves particular attention given how commonly they are prescribed.

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.

The attentional blink (AB) reflects a temporal restriction of selective attention and is generally regarded as a very robust phenomenon. However, previous studies have found large individual differences in AB performance, and under some training conditions the AB can be reduced significantly. One factor that may account for individual differences in AB magnitude is the ability to accurately time attention. In the current study, we focus on the sensitivity for temporal information on the ability to control attention. Following a visual AB task, a time estimation task was presented in either the visual or auditory modality, followed by another visual AB task. It was found that the time estimation training in both the auditory and visual modality reduced AB magnitude. Although a reduction in AB magnitude was also observed when individuals were trained on a control task (either an auditory frequency or visual line length estimation task), the effect was significantly larger following the time estimation tasks. In addition, it was found that individuals who showed most improvement on the visual time estimation task, also showed the largest reduction in AB magnitude, which was not the case for individuals who were trained on the control tasks. Finally, a negative correlation was observed between depression scores (tested by Beck Depression Inventory-Short Form (BDI-SF) scores and the improvement in the AB and time estimation tasks. Our findings demonstrate clear links between timing ability and mechanisms to control attention and emotion.

Recent evidence suggests that the Fusiform Face Area (FFA) is not exclusively dedicated to the interactive processing of face features, but also contains neurons sensitive to local features. This suggests the existence of both interactive and local processing modes, consistent with recent behavioral findings that the strength of interactive feature processing (IFP) engages most strongly when similar features need to be disambiguated.Here we address whether the engagement of the FFA into interactive versus featural representational modes is governed by local feature discriminability. We scanned human participants while they matched target features within face pairs, independently of the context of distracter features. IFP was operationalized as the failure to match the target without being distracted by distracter features. Picture-plane inversion was used to disrupt IFP while preserving input properties. We found that FFA activation was comparably strong, irrespective of whether similar target features were embedded in dissimilar contexts (i.e., inducing robust IFP) or dissimilar target features were embedded in the same context, (i.e., engaging local processing). Second, inversion decreased FFA activation to faces most robustly when similar target features were embedded in dissimilar contexts, indicating that FFA engages into IFP mainly when features cannot be disambiguated at a local level. Third, by means of Spearman rank correlation tests, we show that the local processing of feature differences in the FFA is supported to a large extent by the Occipital Face Area (OFA), the Lateral Occipital Complex (LOC), and early visual cortex (EVC), suggesting that these regions encode the local aspects of face information. The present findings confirm the co-existence of holistic and featural representations in the FFA. Furthermore, they establish FFA as the main contributor to the featural/holistic representational mode switches determined by local discriminability.

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.

BackgroundRecovery in schizophrenia is a complex process, involving clinical, societal and personal recovery. Until now, studies analysed these domains separately, without examining their mutual relations and changes over time.AimsThis study aimed to examine different states of recovery and transition rates between states.MethodThe Pharmacotherapy Monitoring and Outcome Survey (2006–2017) yearly assesses patients with schizophrenia in the Northern Netherlands. Data from 2327 patients with one up to 11 yearly measurements on clinical, societal and personal recovery were jointly analysed with a mixture latent Markov model (MLMM).ResultsThe selected MLMM had four states that differed in degree and pattern of recovery outcomes. Patients in state 1 were least recovered on any domain (16% of measurements), and partly recovered in states 2 (25%; featured by negative symptoms) and 3 (21%; featured by positive symptoms). Patients in state 4 (38%) were most recovered, except for work, study and housekeeping. At the subsequent measurement, the probability of remaining in the same state was 77–89%, transitioning to a better state was 4–12% and transitioning to a worse state was 4–6%; no transitions occurred between states 1 and 4. Female gender, shorter illness duration and less schizophrenia were more prevalent in better states.ConclusionsQuite a high recovery rate was present among a substantial part of the measurements (38%, state 4), with a high probability (89%) of remaining in this state. Transition rates in the other states might increase to a more favourable state by focusing on adequate treatment of negative and positive symptoms and societal problems.

Purpose To assess the association between dry eye disease (DED) and alcohol consumption using a large population-based cohort. Methods 77,145 participants (19–94 years, 59% female) from the Dutch Lifelines cohort were cross-sectionally assessed for DED using the Women's Health Study (WHS) dry eye questionnaire. Alcohol intake was assessed using self-reported food frequency questionnaires. The relationship between DED and alcohol use was analyzed using logistic regression, corrected for age, sex, BMI, smoking status, education, income, and 55 potentially confounding comorbidities. Results Overall, 30.0% of participants had symptomatic dry eye. Alcohol use significantly increased the risk of symptomatic dry eye in females (odds ratio [OR] 1.095, 95%CI 1.045–1.148), but not in males (OR 0.988, 95%CI 0.900–1.084). Contrarily, in male drinkers, increasing alcohol intake (in 10 g/day) had a protective effect on symptomatic dry eye (OR 0.962, 95%CI 0.934–0.992), which was not seen in females (OR 0.986, 95%CI 0.950–1.023). Alcohol use and intake had a sex-specific effect on all outcomes of DED assessed: symptomatic dry eye, highly symptomatic dry eye, clinical diagnosis, and WHS definition dry eye. Conclusions This large population-based study found alcohol use to have a clear sex-specific effect on DED, presenting as a risk-factor only in females. This adds to the evidence of sex-specific pathophysiological mechanisms of dry eye and illustrates the importance of sex stratification in studies investigating DED. The mild protective effect of increased alcohol intake in male drinkers is advised to be interpreted with caution, as alcohol's other health effects might be of greater clinical significance.

The authors report here the case of a patient with severe deficits in arousal and sustained attention, associated with hemispatial neglect. These impairments were secondary to acute disseminated encephalomyelitis, with bilateral involvement of the medial nuclei and pulvinar of the thalamus. Treatment with the noradrenergic agonist guanfacine, previously used for attention deficits in attention deficit/hyperactivity disorder and stroke, was associated with a significant amelioration of both the spatial and sustained attention impairments in neglect. Guanfacine may prove to be a useful tool in the treatment of disorders of attention associated with neurological conditions.

How a visual stimulus is initially categorized as a face in a network of human brain areas remains largely unclear. Hierarchical neuro-computational models of face perception assume that the visual stimulus is first decomposed in local parts in lower order visual areas. These parts would then be combined into a global representation in higher order face-sensitive areas of the occipito-temporal cortex. Here we tested this view in fMRI with visual stimuli that are categorized as faces based on their global configuration rather than their local parts (2-tones Mooney figures and Arcimboldo’s facelike paintings). Compared to the same inverted visual stimuli that are not categorized as faces, these stimuli activated the right middle fusiform gyrus (Fusiform face area, FFA) and superior temporal sulcus (pSTS), with no significant activation in the posteriorly located inferior occipital gyrus (i.e., no occipital face area, OFA). This observation is strengthened by behavioral and neural evidence for normal face categorization of these stimuli in a brain-damaged prosopagnosic patient (PS) whose intact right middle fusiform gyrus and superior temporal sulcus are devoid of any potential face-sensitive inputs from the lesioned right inferior occipital cortex. Together, these observations indicate that face-preferential activation may emerge in higher order visual areas of the right hemisphere without any face-preferential inputs from lower order visual areas, supporting a non-hierarchical view of face perception in the visual cortex.

The main objective of functional neuroimaging is to detect and characterise (in space and time) relevant changes in brain states and their relation to neuronal activity. Functional mri (fmri), electroencephalography (eeg) and magnetoencephalography (meg) are the most widespread noninvasive techniques that are available to experimental and clinical neuroscientists to achieve this objective starting from in vivo measures of brain electrical activity. Both fmri and eeg assume that a given brain state can be decoded from the precise anatomical localisation and the detailed temporal evolution of neuroelectrical brain activation signals, respectively. Starting from these common assumptions, fmri neuroscientists have developed many different approaches for mapping brain states at a spatial resolution of a few millimetres and testing many different neurophysiological and neuropathological hypotheses in normal and clinical populations, despite the limited temporal resolution of the available signals (see previous chapters). On the other hand, eeg neuroscientists have posed analogous questions and addressed similar problems by developing different approaches for the detailed temporal analysis of eeg recordings, despite the limited spatial detail in their findings. The previous chapter illustrated how fmri can be used by eeg neuroscientists to improve the quality of eeg results and to help with the problem of source localisation. The purpose of this chapter is to illustrate how the fmri neuroscientist can integrate detailed temporal information by incorporating simultaneously recorded eeg signals into standard as well as sophisticated fmri spatiotemporal modelling. We discuss how this can be achieved in such a way that new effects become detectable in the fmri domain even when the original event or state change causing possible fmri effects can only be characterised at very rapid temporal scales (e.g. Milliseconds) or frequency bands (above 1 hz). Our discussion occurs at a conceptual level, and we refer the reader to other chapters in part 2 for more details regarding problems such as eeg preprocessing.keywordsindependent component analysisfmri datafmri signalfmri experimentequivalent current dipolethese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Metadehumanisation (i.e., the perception of being considered as less than human by others) is proposed to be widespread in stigmatised populations, such as people with severe alcohol use disorder (SAUD). However, the relations between metadehumanisation, self-dehumanisation (i.e., the self-perception of being less than human), and stigmatisation (i.e., the negative taint applied to some groups) remain unexplored. The aim of this research is thus to investigate the relations between these processes. Metadehumanisation, self-dehumanisation, self-stigma (and its subdimensions) and environmental satisfaction were assessed in 120 inpatients with SAUD and analysed in a mediational model. Stigma awareness was positively associated with metadehumanisation, whereas environmental satisfaction was negatively associated with metadehumanisation. Stigma's application to the self was associated with increased self-dehumanisation. Self-stigma and self-dehumanisation are closely intertwined phenomena. Self-dehumanisation seems to follow a multi-step process suggesting that some steps, such as dehumanisation awareness, are missing from current models of dehumanisation.

Chronic mood disorders pose an important mental health problem. Individuals with these disorders experience a significant impairment, often fail to seek help, and their illnesses frequently do not respond to treatment. It is therefore important to develop innovative and attractive treatments for these disorders. Mindful yoga represents a promising treatment approach. This pilot study tested the feasibility of a 9-week manualized mindful yoga intervention for patients with chronic mood disorders. Eleven patients receiving standard treatment were recruited to complete a 9-week mindful yoga intervention. Qualitative methods were used to assess patients' experiences of the intervention and quantitative methods were used to assess psychological distress and mechanisms that play a role in chronic mood disorders. Eight patients completed the intervention and rated the overall quality of the intervention with a mean score of 8.8 (range of 8 to 9, using a scale of 1 to 10). All participants reported a reduction in psychological distress and no adverse events. Among the mechanisms that play a role in chronic mood disorders, the most potentially promising effects from the intervention were found for worry, fear of depression and anxiety, rumination, and areas related to body awareness, such as trusting bodily experiences and not distracting from sensations of discomfort. A 9-week mindful yoga intervention appears to be a feasible and attractive treatment when added to treatment as usual for a group of patients with chronic mood disorders. A randomized controlled trial to study the effects of mindful yoga is recommended.

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/).

BackgroundLesbian, bisexual, or gay individuals (LBGs) have an increased risk for mental health problems compared to heterosexuals, but this association has sparsely been investigated for psychotic disorders. The aim of this study was: (1) to examine whether LBG sexual orientation is more prevalent in individuals with a non-affective psychotic disorder (NAPD) than in people without a psychotic disorder; and if so, (2) to explore possible mediating pathways.MethodsSexual orientation was assessed in the 6-year follow-up assessment of the Dutch Genetic Risk and Outcome of Psychosis study (GROUP), a case–control study with 1547 participants (582 patients with psychotic disorder, 604 siblings, and 361 controls). Binary logistic regression analyses were used to calculate the risk of patients with a psychotic disorder being LBG, compared to siblings and controls. Perceived discrimination, history of bullying, childhood trauma (CT), and sexual identity disclosure were investigated as potential mediating variables.ResultsThe proportion of individuals with LBG orientation was 6.8% in patients (n = 40), 4.3% in siblings (n = 26), and 2.5% in controls (n = 10). The age- and gender-adjusted odds ratio of LBG for patients was 1.57 (95% CI 1.08–2.27; p = 0.019), compared to siblings and controls. Discrimination, bullying, and CT all partially mediated this association.ConclusionsAdverse social experiences related to sexual minority status may increase the risk for NAPD. Sexual identity, behavior, and difficulties need more attention in everyday clinical practice.

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.

Although it is generally acknowledged that familiar face recognition is fast, mandatory, and proceeds outside conscious control, it is still unclear whether processes leading to familiar face recognition occur in a linear (i.e., gradual) or a nonlinear (i.e., all-or-none) manner. To test these two alternative accounts, we recorded scalp ERPs while participants indicated whether they recognize as familiar the faces of famous and unfamiliar persons gradually revealed in a descending sequence of frames, from the noisier to the least noisy. This presentation procedure allowed us to characterize the changes in scalp ERP responses occurring prior to and up to overt recognition. Our main finding is that gradual and all-or-none processes are possibly involved during overt recognition of familiar faces. Although the N170 and the N250 face-sensitive responses displayed an abrupt activity change at the moment of overt recognition of famous faces, later ERPs encompassing the N400 and late positive component exhibited an incremental increase in amplitude as the point of recognition approached. In addition, famous faces that were not overtly recognized at one trial before recognition elicited larger ERP potentials than unfamiliar faces, probably reflecting a covert recognition process. Overall, these findings present evidence that recognition of familiar faces implicates spatio-temporally complex neural processes exhibiting differential pattern activity changes as a function of recognition state.

International audience; Baseline activity of resting state brain networks (RSN) in a resting subject has become one of the fastest growing research topics in neuroimaging. It has been shown that up to 12 RSNs can be differentiated using an independent component analysis (ICA) of blood oxygen level dependent (BOLD) resting state data. In this work we investigate how many RSN signal sources can be separated from the entire brain cortex using high dimension ICA analysis from a group dataset. Group data from 55 subjects were analysed using temporal concatenation and a probabilistic ICA (PICA) algorithm. PICA estimation suggested 73 components to be calculated. ICA repeatability testing (ICASSO) verified that 60 of the 70 computed components were robustly detectable. Forty-two independent signal sources were identifiable as RSN, and 28 were related to artifacts or other non-interest sources (non-RSN). The depicted RSNs bore a closer match to functional neuroanatomy than the previously reported RSN components. The non-RSN sources have significantly lower temporal inter-source connectivity than the RSN (p< 0.0003). We conclude that the high model order ICA of group BOLD data enables functional segmentation of the brain cortex. The method enables new analysis approaches to causality and connectivity with more specific anatomical details.

Purpose: To improve upon self-reported glaucoma status in population-based cohorts by developing a questionnaire-based proxy incorporating self-reported status in conjunction with glaucoma-specific visual complaints. Methods: A vision specific questionnaire, including questions from the National Eye Institute Visual Functioning Questionnaire-25 (NEI-VFQ-25) was administered to 79,866 Lifelines participants, a population-based cohort study in the Northern Netherlands. We compared NEI-VFQ-25 responses between ‘definite’ glaucoma cases (n = 90; self-reported surgical cases) and an age- and gender-matched subset of controls (n = 1,800) to uncover glaucoma-specific visual complaints, using a case–control logistic regression. We defined ‘probable glaucoma’ as both self-reported disease status and visual complaints, and ‘possible glaucoma’ as either. To evaluate the resulting proxy, we determined age-stratified glaucoma prevalences in the remaining cohort and compared the result to the literature. Results: Per unit increase in the vision subscales (range 0–100) distance, peripheral and low luminance, we observed significantly increased odds of definite glaucoma (2% [P = 0.03], 4% [P = 1.2 × 10−8] and 2% [P = 0.02], respectively); the associated area under the curve was 0.73. We identified 300 probable and 3,015 (1,434 by self-report) possible glaucoma cases. Standardised prevalences of definite, probable and possible glaucoma for 55+ were 0.4%, 1.1% and 7.3%, respectively. For self-reported glaucoma (combining definite, probable and possible by self-report), this was 5.2%. Conclusions: The combination of self-reported glaucoma status and visual complaints can be used to capture glaucoma cases in population-based settings. The resulting prevalence of combined definite and probable glaucoma (1.5%) appears to be more consistent with previous reports than the prevalence estimate of 5.2% based only on self-report.

The peripheral auditory and vestibular systems rely on sensorineural structures that are vulnerable to ototoxic agents that cause hearing loss and/or equilibrium deficits. Although attention has focused on hair cell loss as the primary pathology underlying ototoxicity, evidence from the peripheral vestibular system indicates that hair cell loss during chronic exposure is preceded by synaptic uncoupling from the neurons and is potentially reversible. To determine if synaptic pathology also occurs in the peripheral auditory system, we examined the extent, time course, and reversibility of functional and morphological alterations in cochleae from mice exposed to 3,3′-iminodipropionitrile (IDPN) in drinking water for 2, 4 or 6 weeks. Functionally, IDPN exposure caused progressive high- to low-frequency hearing loss assessed by measurement of auditory brainstem response wave I absolute thresholds and amplitudes. The extent of hearing loss scaled with the magnitude of vestibular dysfunction assessed behaviorally. Morphologically, IDPN exposure caused progressive loss of outer hair cells (OHCs) and synapses between the inner hair cells (IHCs) and primary auditory neurons. In contrast, IHCs were spared from ototoxic damage. Importantly, hearing loss consistent with cochlear synaptopathy preceded loss of OHCs and synapses and, moreover, recovered if IDPN exposure was stopped before morphological pathology occurred. Our observations suggest that synaptic uncoupling, perhaps as an early phase of cochlear synaptopathy, also occurs in the peripheral auditory system in response to IDPN exposure. These findings identify novel mechanisms that contribute to the earliest stages of hearing loss in response to ototoxic agents and possibly other forms of acquired hearing loss. Supplementary Information The online version contains supplementary material available at 10.1007/s00204-020-02962-5.

Background With increasing age, symptoms of depression may increasingly overlap with age-related physical frailty and cognitive decline. We aim to identify late-life-related subtypes of depression based on measures of depressive symptom dimensions, cognitive performance, and physical frailty. Methods A clinical cohort study of 375 depressed older patients with a DSM-IV depressive disorder (acronym NESDO). A latent profile analysis was applied on the three subscales of the Inventory of Depressive Symptomatology, as well as performance in five cognitive domains and two proxies for physical frailty. For each class, we investigated remission, dropout, and mortality at 2-year follow-up as well as change over time of depressive symptom severity, cognitive performance, and physical frailty. Results A latent profile analysis model with five classes best described the data, yielding two subgroups suffering from pure depression (“mild” and “severe” depression, 55% of all patients) and three subgroups characterized by a specific profile of cognitive and physical frailty features, labeled as “amnestic depression,” “frail-depressed, physically dominated,” and “frail-depressed, cognitively dominated.” The prospective analyses showed that patients in the subgroup of “mild depression” and “amnestic depression” had the highest remission rates, whereas patients in both frail-depressed subgroups had the highest mortality rates. Conclusions Late-life depression can be subtyped by specific combinations of age-related clinical features, which seems to have prospective relevance. Subtyping according to the cognitive profile and physical frailty may be relevant for studies examining underlying disease processes as well as to stratify treatment studies on the effectiveness of antidepressants, psychotherapy, and augmentation with geriatric rehabilitation.

International audience; Differences in speakers' voice characteristics, such as mean fundamental frequency (F0) and vocal-tract length (VTL), that primarily define speakers' so-called perceived voice gender facilitate the perception of speech in competing speech. Perceiving speech in competing speech is particularly challenging for children, which may relate to their lower sensitivity to differences in voice characteristics than adults. This study investigated the development of the benefit from F0 and VTL differences in school-age children (4–12 years) for separating two competing speakers while tasked with comprehending one of them and also the relationship between this benefit and their corresponding voice discrimination thresholds. Children benefited from differences in F0, VTL, or both cues at all ages tested. This benefit proportionally remained the same across age, although overall accuracy continued to differ from that of adults. Additionally, children's benefit from F0 and VTL differences and their overall accuracy were not related to their discrimination thresholds. Hence, although children's voice discrimination thresholds and speech in competing speech perception abilities develop throughout the school-age years, children already show a benefit from voice gender cue differences early on. Factors other than children's discrimination thresholds seem to relate more closely to their developing speech in competing speech perception abilities.

Objectives: Tourette syndrome (TS) is characterized by the presence of sudden, rapid movements and vocalizations (tics). The nature of tics suggests impairments in inhibitory control. However, findings of impaired inhibitory control have so far been inconsistent, possibly due to small sample sizes, wide age ranges, or not taking medication use or attention-deficit/hyperactivity disorder (ADHD) comorbidity into account. Methods: We investigated group differences in response inhibition using an fMRI-based stop-signal task in 103 8-12-year-old children (n = 51 with TS, of whom n = 28 without comorbid ADHD [TS–ADHD] and n = 23 with comorbid ADHD [TS + ADHD]; and n = 52 healthy controls), and related these measures to tic and ADHD severity. Results: We observed an impaired response inhibition performance in children with TS + ADHD, but not in those with TS–ADHD, relative to healthy controls, as evidenced by a slower stop-signal reaction time, slower mean reaction times, and larger variability of reaction times. Dimensional analyses implicated ADHD severity as the driving force in these findings. Neural activation during failed inhibition was stronger in the inferior frontal gyrus and temporal and parietal areas in TS + ADHD compared to healthy controls. Conclusions: Impaired inhibitory performance and increased neural activity in TS appear to manifest predominantly in relation to ADHD symptomatology.

Age-related hearing loss is the most prevalent sensory impairment in the older adult population and is related to noise-induced damage or age-related deterioration of the peripheral auditory system. Hearing loss may affect the central auditory pathway in the brain, which is a continuation of the peripheral auditory system located in the ear. A debilitating symptom that frequently co-occurs with hearing loss is tinnitus. Strikingly, investigations into the impact of acquired hearing loss, with and without tinnitus, on the human central auditory pathway are sparse. This study used diffusion-weighted imaging (DWI) to investigate changes in the largest central auditory tract, the acoustic radiation, related to hearing loss and tinnitus. Participants with hearing loss, with and without tinnitus, and a control group were included. Both conventional diffusion tensor analysis and higher-order fixel-based analysis were applied. The fixel-based analysis was used as a novel framework providing insight into the axonal density and macrostructural morphologic changes of the acoustic radiation in hearing loss and tinnitus. The results show tinnitus-related atrophy of the left acoustic radiation near the medial geniculate body. This finding may reflect a decrease in myelination of the auditory pathway, instigated by more profound peripheral deafferentation or reflecting a preexisting marker of tinnitus vulnerability. Furthermore, age was negatively correlated with the axonal density in the bilateral acoustic radiation. This loss of fiber density with age may contribute to poorer speech understanding observed in older adults.SIGNIFICANCE STATEMENTAge-related hearing loss is the most prevalent sensory impairment in the older adult population. Older individuals are subject to the cumulative effects of aging and noise exposure on the auditory system. A debilitating symptom that frequently co-occurs with hearing loss is tinnitus: the perception of a phantom sound. In this large DWI-study, we provide evidence that in hearing loss, the additional presence of tinnitus is related to degradation of the acoustic radiation. Additionally, older age was related to axonal loss in the acoustic radiation. It appears that older adults have the aggravating circumstances of age, hearing loss, and tinnitus on central auditory processing, which may partly be because of the observed deterioration of the acoustic radiation with age.

The impact of age-related hearing loss extends beyond the auditory pathway and impacts brain areas related to cognitive impairment and even dementia. The presence of tinnitus, a sensation of sound that frequently co-occurs with hearing loss, is additionally linked to cognitive decline. Interestingly, structural neuroimaging studies have reported that hearing loss may precede or modulate the onset of cognitive impairment. In this study, we aimed to disentangle the effects of age, hearing loss, and tinnitus on gray matter structure. In total, 39 participants with hearing loss and tinnitus, 21 with hearing loss but without tinnitus, and 39 controls were included in this voxel- and surface-based morphometry MRI study. Whole brain volume and surface thickness measures were compared between the groups. Age-related gray matter volume decline was observed in all groups. Several brain areas showed smaller gray matter volume and cortical surface thickness in hearing loss without tinnitus, relative to controls. This reduction was observed both within and outside of the auditory pathway. Interestingly, these reductions were not observed in participants with tinnitus, who had similar hearing loss and were of similar age. Since we have tools to improve hearing loss, hearing screening may aid in the battle against cognitive decline.

Vassiliadis P, Derosiere G, Grandjean J, Duque J. Motor training strengthens corticospinal suppression during movement preparation. J Neurophysiol 124: 1656-1666, 2020. First published September 30, 2020; doi:10.1152/jn.00378.2020.-Training can improve motor skills and modify neural activity at rest and during movement execution. Learning-related modulations may also concern motor preparation but the neural correlates and the potential behavioral relevance of such adjustments remain unclear. In humans, preparatory processes have been largely investigated using transcranial magnetic stimulation (TMS) with several studies reporting decreased corticospinal excitability (CSE) relative to a baseline measure at rest; a phenomenon called preparatory suppression. Here, we investigated the effect of motor training on such preparatory suppression, in relation to resting CSE, in humans. We trained participants to initiate quick movements in an instructed-delay reaction time (RT) task and used TMS to investigate changes in CSE over the practice blocks. Training on the task speeded up RTs, with no repercussion on error rates. Training also increased resting CSE. Most interestingly, we found that CSE during action preparation did not mirror the training-related increase observed at rest. Rather, compared with the rising baseline, the degree of preparatory suppression strengthened with practice. This training-related change in preparatory suppression (but not the changes in baseline CSE) predicted RT gains: the subjects showing a greater strengthening of preparatory suppression were also those exhibiting larger gains in RTs. Finally, such a relationship between RTs and preparatory suppression was also evident at the single-trial level, though only in the nonselected effector: RTs were generally faster in trials where preparatory suppression was deeper. These findings suggest that training induces changes in motor preparatory processes that are linked to an enhanced ability to initiate fast movements., NEW & NOTEWORTHY Movement preparation involves a broad suppression in the excitability of the corticospinal pathway, a phenomenon called preparatory suppression. Here, we show that motor training strengthens preparatory suppression and that this strengthening is associated with faster reaction times. Our findings highlight a key role of preparatory suppression in training-driven behavioral improvements.

Purpose This study explores the effect of glaucomatous visual field defects on several neuropsychological tests that are often used in research and in clinical settings. Methods Nineteen glaucoma patients and nineteen healthy participants, which are current drivers and older than 65 years old were included. All participants completed the Montreal Cognitive Assessment (MoCA), the Trail Making Test (TMT), the Benton Visual Retention Test (BVRT), the Snellgrove Maze Task (SMT) and the Digit Span Test (DST). All participants were also tested on contrast sensitivity and near and far visual acuity. For the glaucoma patients, visual field tests were downloaded from hospital servers. Results On the MoCA test, glaucoma patients scored lower than the healthy group, but not significantly. On the MoCA-Blind, the difference was statistically significant. Glaucoma patients also had lower percentile scores on the TMT, with a significant difference in the TMT-A, but this difference largely disappeared in the calculated TMT B-A index, which isolates the cognitive component. The BVRT and SMT showed no significant differences between both groups. In the only non-visual test, the DST, glaucoma patients outperformed the healthy group. Glaucoma severity did not influence results, except for the BVRT on which the moderate/severe group has better scores. Conclusion Using visual items might lead to conclusions about cognition when it should be one about vision. Therefore, careful selection of tests is needed when examining cognition in glaucoma patients.

It remains unclear whether the supportive imaging features described in the diagnostic criteria for progressive supranuclear palsy (PSP) are suitable for the full clinical spectrum. The aim of the current study was to define and cross-validate the pattern of glucose metabolism in the brain associated with a diagnosis of different PSP variants. A retrospective multicenter cohort study performed on 73 PSP patients who were referred for a fluorodeoxyglucose positron emission tomography PET scan: PSP-Richardson's syndrome, n = 47; PSP-parkinsonian variant, n = 18; and progressive gait freezing, n = 8. In addition, we included 55 healthy controls and 58 Parkinson's disease (PD) patients. Scans were normalized by global mean activity. We analyzed the regional differences in metabolism between the groups. Moreover, we applied a multivariate analysis to obtain a PSP-related pattern that was cross-validated in independent populations at the individual level. Group analysis showed relative hypometabolism in the midbrain, basal ganglia, thalamus, and frontoinsular cortices and hypermetabolism in the cerebellum and sensorimotor cortices in PSP patients compared with healthy controls and PD patients, the latter with more severe involvement in the basal ganglia and occipital cortices. The PSP-related pattern obtained confirmed the regions described above. At the individual level, the PSP-related pattern showed optimal diagnostic accuracy to distinguish between PSP and healthy controls (sensitivity, 80.4%; specificity, 96.9%)s and between PSP and PD (sensitivity, 80.4%; specificity, 90.7%). Moreover, PSP-Richardson's syndrome and PSP-parkinsonian variant patients showed significantly more PSP-related pattern expression than PD patients and healthy controls. The glucose metabolism assessed by fluorodeoxyglucose PET is a useful and reproducible supportive diagnostic tool for PSP-Richardson's syndrome and PSP-parkinsonian variant. © 2020 International Parkinson and Movement Disorder Society.

Large-scale studies spanning diverse project sites, populations, languages, and measurements are increasingly important to relate psychological to biological variables. National and international consortia already are collecting and executing mega-analyses on aggregated data from individuals, with different measures on each person. In this research, we show that Asparouhov and Muthén’s alignment method can be adapted to align data from disparate item sets and response formats. We argue that with these adaptations, the alignment method is well suited for combining data across multiple sites even when they use different measurement instruments. The approach is illustrated using data from the Whole Genome Sequencing in Psychiatric Disorders consortium and a real-data-based simulation is used to verify accurate parameter recovery. Factor alignment appears to increase precision of measurement and validity of scores with respect to external criteria. The resulting parameter estimates may further inform development of more effective and efficient methods to assess the same constructs in prospectively designed studies.

Impairments in social cognition have been documented in severe alcohol use disorder (SAUD) over the past two decades. They have been linked with lower social functioning and poor treatment outcomes, illustrating their key role in the disorder. However, studies investigating social cognition in SAUD have largely focused on emotional decoding and theory of mind abilities, neglecting other important processes. We expand this line of research by exploring the association between SAUD and hostile attributional biases (i.e., the tendency to attribute hostile intentions to others), another clinically relevant subcomponent of social cognition. Thirty-five patients with SAUD and thirty-five matched healthy controls completed the short version of the Ambiguous Intentions Hostility Questionnaire, a validated measure assessing participants' perceived hostility, blame attribution and aggression in relation to vignettes depicting social situations with negative outcomes and ambiguous intent. Patients with SAUD attributed more hostile intentions to others than did healthy controls. Moreover, this hostile attributional bias was associated with increased interpersonal problems in SAUD, as measured through the Inventory of Interpersonal Problems. We thus evidence hostile attributional bias in SAUD and extend the growing literature on social cognition impairments in this population. Furthermore, these findings corroborate the recent proposal that patients with SAUD exhibit biases toward socially threatening information. The association between hostile attributional bias and interpersonal problems suggests that targeting this bias in treatment may reduce the relapse risk resulting from interpersonal deficits. Recommendations are made to further explore the clinical relevance of hostile attributional bias in SAUD.

AIM: Early intervention programs for first-episode psychosis have led to the awareness that the period before onset of a first episode is important in light of early intervention. This has induced a focus on the so-called 'at risk mental state' (ARMS). Individuals with ARMS are at increased risk for later psychotic disorder, but also for other psychiatric disorders as well as poor psychosocial functioning. Thus, adequate detection and treatment of ARMS is essential.METHODS: Since 2018, screening for and treatment of ARMS is recommended standard care in the Netherlands. Implementation is still ongoing. We initiated a naturalistic long-term cohort study of ARMS individuals, the onset and transition of and recovery from adverse development (OnTheROAD) study, with the aim to monitor course and outcome of symptoms and psychosocial functioning over time, as well as patterns of comorbidity and associations with factors of risk and resilience. To this end, participants complete a broad battery of instruments at baseline and yearly follow-up assessments up to 3 years. Outcome is defined in terms of symptom severity level, functioning and quality of life. In particular, we aim to investigate the impact of negative symptoms as part of the ARMS concept. Results from this study can aid in refining the existing ARMS criteria, understanding the developmental course of ARMS and investigating the hypothesized pluripotentiality in outcome of ARMS. New knowledge may inform the further development of specialized early interventions.RESULTS AND CONCLUSIONS: In this article, we describe the rationale, outline and set-up of OnTheROAD.

AIM OF THE STUDY: The fast-track (FT) protocol consists of several measures to optimize physiologic response to the surgical stress and improve postoperative outcome. Our goal was to evaluate the compliance to our protocol and to analyze the effect of compliance to the FT protocol on postoperative outcome and postoperative hospital stay. We also aimed to identify isolated FT measures able to influence outcome. METHODS: This retrospective study involves a cohort of consecutive patients who underwent colorectal surgery within a FT protocol between 2007 and 2013. Beside basic demographics, adherence to protocol, postoperative complications, and postoperative hospital stay (POHS) were recorded. Both univariate and multivariate analyses were performed to determine the predictive value of the FT protocol compliance and of specific FT items on surgical outcome and POHS. RESULTS: There were 284 patients with a mean age of 58 years. Compliance to the FT protocol reached a median of 18 out of 19 items. The median hospital stay was 3 days (2-49). Overall complications rate was 34.9% and 7,4% when Dindo-Clavien classification > 2 was considered. Higher compliance to the FT protocol reduces the complication rate (p = 0.00004), severity of complication (p = 0.002), and POHS (p = < 0.00001). We have not been able to identify any specific isolated FT measure able to influence post-operative outcome. CONCLUSIONS: Greater adherence to the FT protocol decreases postoperative complications and POHS. Our data support a holistic effect of the FT protocol rather than specific isolated measures to improve the patient's postoperative outcome.