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Background : Multiple sclerosis (MS) has two main phenotypes: relapse-remitting MS (RRMS) and progressive MS (PMS), distinguished by disability profiles and treatment response. Differentiating them using conventional MRI is challenging. Objective : This study explores the use of scaled subprofile modelling using principal component analysis (SSM/PCA) on MRI data to distinguish between MS phenotypes. Methods : MRI scans were performed on patients with RRMS (n = 30) and patients with PMS (n = 20), using the standard sequences T 1 w, T 2 w, T 2 w-FLAIR, and the myelin-sensitive sequences magnetisation transfer (MT) ratio (MTR), quantitative MT (qMT), inhomogeneous MT ratio (ihMTR), and quantitative inhomogeneous MT (qihMT). Results : SSM/PCA analysis of qihMT images best differentiated PMS from RRMS, with the highest specificity (87%) and positive predictive value (PPV) (83%), but a lower sensitivity (67%) and negative predictive value (NPV) (72%). Conversely, T 1 w data analysis showed the highest sensitivity (93%) and NPV (89%), with a lower PPV (67%) and specificity (53%). Phenotype classification agreement between T 1 w and qihMT was observed in 57% of patients. In the subset with concordant classifications, the sensitivity, specificity, PPV, and NPV were 100%, 88%, 90%, and 100%, respectively. Conclusions : SSM/PCA on MRI data revealed distinctive patterns for MS phenotypes. Optimal discrimination occurred with qihMT and T 1 w sequences, with qihMT identifying PMS and T 1 w identifying RRMS. When qihMT and T 1 w analyses align, MS phenotype prediction improves.

Introduction: The Next Move in Movement Disorders (NEMO) study is an initiative aimed at advancing our understanding and the classification of hyperkinetic movement disorders, including tremor, myoclonus, dystonia, and myoclonus-dystonia. The study has two main objectives: (a) to develop a computer-aided tool for precise and consistent classification of these movement disorder phenotypes, and (b) to deepen our understanding of brain pathophysiology through advanced neuroimaging techniques. This protocol review details the neuroimaging data acquisition and preprocessing procedures employed by the NEMO team to achieve these goals., Methods and Analysis: To meet the study's objectives, NEMO utilizes multiple imaging techniques, including T1-weighted structural MRI, resting-state fMRI, motor task fMRI, and 18F-FDG PET scans. We will outline our efforts over the past 4 years to enhance the quality of our collected data, and address challenges such as head movements during image acquisition, choosing acquisition parameters and constructing data preprocessing pipelines. This study is the first to employ these neuroimaging modalities in a standardized approach contributing to more uniformity in the analyses of future studies comparing these patient groups. The data collected will contribute to the development of a machine learning-based classification tool and improve our understanding of disorder-specific neurobiological factors., Ethics and Dissemination: Ethical approval has been obtained from the relevant local ethics committee. The NEMO study is designed to pioneer the application of machine learning of movement disorders. We expect to publish articles in multiple related fields of research and patients will be informed of important results via patient associations and press releases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Dalenberg, Peretti, Marapin, van der Stouwe, Renken and Tijssen.)

Tinnitus is a common phantom auditory percept believed to be related to plastic changes in the brain due to hearing loss. However, tinnitus can also occur in the absence of any clinical hearing loss. In this case, since there is no hearing loss, the mechanisms that drive plastic changes remain largely enigmatic. Previous studies showed subtle differences in sound-evoked brain activity associated with tinnitus in subjects with tinnitus and otherwise normal hearing, but the results are not consistent across studies. Here, we aimed to investigate these differences using monaural rather than binaural stimuli. Sound-evoked responses were measured using functional magnetic resonance imaging (MRI) in participants with and without tinnitus. All participants had clinically normal audiograms. The stimuli were pure tones with frequencies between 353 and 8000 Hz, presented monaurally. A Principal Component Analysis (PCA) of the response in the auditory cortex revealed no difference in tonotopic organization, which confirmed earlier studies. A GLM analysis showed hyperactivity in the lateral areas of the bilateral auditory cortex. Consistent with the tonotopic map, this hyperactivity mainly occurred in response to low stimulus frequencies. This may be related to hyperacusis. Furthermore, there was an interaction between stimulation side and tinnitus in the parahippocampus. This may reflect an interference between tinnitus and spatial orientation.

In machine learning, data often comes from different sources, but combining them can introduce extraneous variation that affects both generalization and interpretability. For example, we investigate the classification of neurodegenerative diseases using FDG-PET data collected from multiple neuroimaging centers. However, data collected at different centers introduces unwanted variation due to differences in scanners, scanning protocols, and processing methods. To address this issue, we propose a two-step approach to limit the influence of center-dependent variation on the classification of healthy controls and early vs. late-stage Parkinson's disease patients. First, we train a Generalized Matrix Learning Vector Quantization (GMLVQ) model on healthy control data to identify a "relevance space" that distinguishes between centers. Second, we use this space to construct a correction matrix that restricts a second GMLVQ system's training on the diagnostic problem. We evaluate the effectiveness of this approach on the real-world multi-center datasets and simulated artificial dataset. Our results demonstrate that the approach produces machine learning systems with reduced bias - being more specific due to eliminating information related to center differences during the training process - and more informative relevance profiles that can be interpreted by medical experts. This method can be adapted to similar problems outside the neuroimaging domain, as long as an appropriate "relevance space" can be identified to construct the correction matrix., Competing Interests: Declaration of competing interest S.K. Meles, K.L. Leenders, R. van Veen reports financial support was provided by The Michael J Fox Foundation. D. Arnaldi, S. Morbelli reports financial support was provided by Italian Ministry of Health. R. van Veen reports financial support was provided by State of Upper Austria in the frame of SCCH competence center INTEGRATE. S.K. Meles, K.L. Leenders reports financial support was provided by Dutch Stichting Parkinson Fonds. S.K. Meles reports a relationship with The Michael J Fox Foundation that includes: funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Research has shown that maladaptive personality characteristics, such as Neuroticism, are associated with poor outcome after mild traumatic brain injury (mTBI). The current exploratory study investigated the neural underpinnings of this process using dynamic functional network connectivity (dFNC) analyses of resting-state (rs) fMRI, and diffusion MRI (dMRI). Twenty-seven mTBI patients and 21 healthy controls (HC) were included. After measuring the Big Five personality dimensions, principal component analysis (PCA) was used to obtain a superordinate factor representing emotional instability, consisting of high Neuroticism, moderate Openness, and low Extraversion, Agreeableness, and Conscientiousness. Persistent symptoms were measured using the head injury symptom checklist at six months post-injury; symptom severity (i.e., sum of all items) was used for further analyses. For patients, brain MRI was performed in the sub-acute phase (~1 month) post-injury. Following parcellation of rs-fMRI using independent component analysis, leading eigenvector dynamic analysis (LEiDA) was performed to compute dynamic phase-locking brain states. Main patterns of brain diffusion were computed using tract-based spatial statistics followed by PCA. No differences in phase-locking state measures were found between patients and HC. Regarding dMRI, a trend significant decrease in fractional anisotropy was found in patients relative to HC, particularly in the fornix, genu of the corpus callosum, anterior and posterior corona radiata. Visiting one specific phase-locking state was associated with lower symptom severity after mTBI. This state was characterized by two clearly delineated communities (each community consisting of areas with synchronized phases): one representing an executive/saliency system, with a strong contribution of the insulae and basal ganglia; the other representing the canonical default mode network. In patients who scored high on emotional instability, this relationship was even more pronounced. Dynamic phase-locking states were not related to findings on dMRI. Altogether, our results provide preliminary evidence for the coupling between personality and dFNC in the development of long-term symptoms after mTBI., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 van der Horn et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: We present a novel framework for the detection and continuous evaluation of 3D motion perception by deploying a virtual reality environment with built-in eye tracking., Methods: We created a biologically-motivated virtual scene that involved a ball moving in a restricted Gaussian random walk against a background of 1/f noise. Sixteen visually healthy participants were asked to follow the moving ball while their eye movements were monitored binocularly using the eye tracker. We calculated the convergence positions of their gaze in 3D using their fronto-parallel coordinates and linear least-squares optimization. Subsequently, to quantify 3D pursuit performance, we employed a first-order linear kernel analysis known as the Eye Movement Correlogram technique to separately analyze the horizontal, vertical and depth components of the eye movements. Finally, we checked the robustness of our method by adding systematic and variable noise to the gaze directions and re-evaluating 3D pursuit performance., Results: We found that the pursuit performance in the motion-through depth component was reduced significantly compared to that for fronto-parallel motion components. We found that our technique was robust in evaluating 3D motion perception, even when systematic and variable noise was added to the gaze directions., Conclusion: The proposed framework enables the assessment of 3D Motion perception by evaluating continuous pursuit performance through eye-tracking., Significance: Our framework paves the way for a rapid, standardized and intuitive assessment of 3D motion perception in patients with various eye disorders.

Human observers tend to naturally track moving stimuli. This tendency may be exploited towards an intuitive means of screening visual function as an impairment induced reduction in stimulus visibility will decrease tracking performance. Yet, to be able to detect subtle impairments, stimulus contrast is critical. If too high, the decrease in performance may remain undetected. Therefore, for this approach to become reliable and sensitive, we need a detailed understanding of how age, stimulus contrast, and the type of stimulus movement affect continuous tracking performance. To do so, we evaluated how well twenty younger and twenty older participants tracked a semi-randomly moving stimulus (Goldmann size III, 0.43 degrees of visual angle), presented at five contrast levels (5%-10%-20%-40%-80%). The stimulus could move smoothly only (smooth pursuit mode) or in alternation with displacements (saccadic pursuit mode). Additionally, we assessed static foveal and peripheral contrast thresholds. For all participants, tracking performance improved with increasing contrast in both pursuit modes. To reach threshold performance levels, older participants required about twice as much contrast (20% vs. 10% and 40% vs. 20% in smooth and saccadic modes respectively). Saccadic pursuit detection thresholds correlated significantly with static peripheral contrast thresholds (rho = 0.64). Smooth pursuit detection thresholds were uncorrelated with static foveal contrast thresholds (rho = 0.29). We conclude that continuous visual stimulus tracking is strongly affected by stimulus contrast, pursuit mode, and age. This provides essential insights that can be applied towards new and intuitive approaches of screening visual function., Competing Interests: Declaration of Competing Interest AG is the majority shareholder of Reperio B.V., a private company that develops ophthalmic and neurological tests based on eye movements. ECP is an employee of Reperio B.V.. AG and RJR are listed as inventors on the patent application WO2021096361A1 (Grillini, Renken, & Hernández-García, 2021). Method, system, and computer program product for mapping a visual field) on which the method used in this manuscript is partially based. Reperio B.V. had no control over the design, conduct, analysis, or publication of this research, nor did it contribute financially towards it., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: It has been theorized that hallucinations, a common symptom of schizophrenia, are caused by failures in reality monitoring. The paracingulate sulcus (PCS) has been implicated as a brain structure supporting reality monitoring with the absence or shorter length of PCS associated with an occurrence of hallucinations in schizophrenia. The absence or shorter length of PCS has been associated with an occurrence of hallucinations. There are inconsistent findings in the literature regarding the role of the asymmetry of this structure for hallucinations. Here, we investigated the length of the PCS and cortical thickness of surrounding structures in patients with a lifetime history of auditory verbal hallucinations (AVH)., Design: Seventy-seven patients and twenty-eight healthy controls (HC) underwent an anatomical MRI scan. PCS length and cortical thickness were estimated using Mango brain visualization and FreeSurfer, respectively. Patients with AVH (n = 45) and patients without AVH were compared (n = 32) to the controls., Results: PCS length significantly differed between HC and patient groups (F(2,102) = 3.57, P = .032) in the left but not in the right sulcus. We found significantly longer PCS between HC and AVH group but no difference between patient groups. Similarly, we found significant thinning of cortical structures including structures surrounding anterior parts of PCS between HC and patients either in general or per group, but no significant differences were observed between patient groups., Conclusions: PCS length in the left hemisphere is shorter in schizophrenia patients with hallucinations as compared to HC subjects. The patient group without hallucinations was in between those 2 groups. Cortical thickness of neighboring areas of PCS is diminished in patient groups relative to the healthy comparison subjects. The role of lateralization and functional involvement of the PCS region in processes underlying hallucinations, such as reality monitoring, needs further clarification., (The Author(s) 2023. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. 
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The degree to which the adult human visual cortex retains the ability to functionally adapt to damage at the level of the eye remains ill-understood. Previous studies on cortical neuroplasticity primarily focused on the consequences of foveal visual field defects (VFD), yet these findings may not generalize to peripheral defects such as occur in glaucoma. Moreover, recent findings on neuroplasticity are often based on population receptive field (pRF) mapping, but interpreting these results is complicated in the absence of appropriate control conditions. Here, we used fMRI-based neural modeling to assess putative changes in pRFs associated with glaucomatous VFD. We compared the fMRI-signals and pRF in glaucoma participants to those of controls with case-matched simulated VFD. We found that the amplitude of the fMRI-signal is reduced in glaucoma compared to control participants and correlated with disease severity. Furthermore, while coarse retinotopic structure is maintained in all participants with glaucoma, we observed local pRF shifts and enlargements in early visual areas, relative to control participants. These differences suggest that the adult brain retains some degree of local neuroplasticity. This finding has translational relevance, as it is consistent with VFD masking, which prevents glaucoma patients from noticing their VFD and seeking timely treatment., (© 2022. The Author(s).)

Patients with the genetic blistering skin condition epidermolysis bullosa (EB) report severe pain as a consequence of skin and mucous membrane lesions including blisters, wounds, and scars. Adequate symptom alleviation is not often achieved using conventional pharmacologic interventions. Finding novel approaches to pain care in EB is imperative to improve the quality of life of patients living with EB. There are several anecdotal reports on the use of cannabinoid-based medicines (CBMs) by EB patients to reduce the burden of symptoms. However, controlled clinical investigations assessing these reported effects are lacking. As the pain quality "unpleasantness" delineates EB pain, we hypothesize the modulation of affective pain processing in the brain by way of intervention with CBMs comprising the cannabinoids Δ-9-tetrahydrocannabinol and cannabidiol-objectified by functional magnetic resonance imaging (fMRI). The C4EB study is an investigator-initiated, single-centre, randomized, double-blind, placebo-controlled and crossover trial. Adult patients with the diagnosis epidermolysis bullosa, reporting chronic pain will be eligible to participate. Following baseline measurements, participants will be randomized to receive the sublingually administered interventions placebo and Transvamix® in forward or reversed orders, each for two weeks and separated by a washout. The primary outcome is the difference in numeric rating scale pain scores between grouped interventions, using affective descriptors within the Short-form McGill Pain Questionnaire-2. Secondary outcomes include pain self-efficacy, concomitant analgesic medication-use and adverse events. Additionally, fMRI will be employed to assess brain connectivity related to neuroanatomic pain circuits at baseline, placebo and Transvamix® interventions. The study was approved by the ethical committee at the University Medical Center of Groningen in the Netherlands. Results will be submitted for publication in a peer-reviewed journal. Trial registration number: Netherlands Trial Register: NL9347 (Acronym: C4EB)., Competing Interests: This is an investigator-initiated study at the University Medical Centre of Groningen, the Netherlands. This work was supported by the Dystrophic Epidermolysis Bullosa Research Association, United Kingdom (DEBRA-UK). The grant application was considered by the Care and Research Committee and External Peer Reviewers of DEBRA, consisting of academic experts within and outside the EB field, as well as people living with EB. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., (Copyright: © 2022 Schräder et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The majority of neurons in the human brain process signals from neurons elsewhere in the brain. Connective Field (CF) modelling is a biologically-grounded method to describe this essential aspect of the brain's circuitry. It allows characterizing the response of a population of neurons in terms of the activity in another part of the brain. CF modelling translates the concept of the receptive field (RF) into the domain of connectivity by assessing, at the voxel level, the spatial dependency between signals in distinct cortical visual field areas. Thus, the approach enables to characterize the functional cortical circuitry of the human cortex. While already very useful, the present CF modelling approach has some intrinsic limitations due to the fact that it only estimates the model's explained variance and not the probability distribution associated with the estimated parameters. If we could resolve this, CF modelling would lend itself much better for statistical comparisons at the level of single voxels and individuals. This is important when trying to gain a detailed understanding of the neurobiology and pathophysiology of the visual cortex, notably in rare cases. To enable this, we present a Bayesian approach to CF modeling (bCF). Using a Markov Chain Monte Carlo (MCMC) procedure, it estimates the posterior probability distribution underlying the CF parameters. Based on this, bCF quantifies, at the voxel level, the uncertainty associated with each parameter estimate. This information can be used in various ways to increase confidence in the CF model predictions. We applied bCF to BOLD responses recorded in the early human visual cortex using 3T fMRI. We estimated both the CF parameters and their associated uncertainties and show they are only weakly correlated. Moreover, we show how bCF facilitates the use of effect size (beta) as a data-driven parameter that can be used to select the most reliable voxels for further analysis. Finally, to further illustrate the functionality gained by bCF, we apply it to perform a voxel-level comparison of a single, circular symmetric, Gaussian versus a Difference-of-Gaussian model. We conclude that our bCF framework provides a comprehensive tool to study human functional cortical circuitry in health and disease., (Copyright © 2022. Published by Elsevier Inc.)

Neuronal damage is the primary cause of long-term disability of multiple sclerosis (MS) patients. Assessment of axonal integrity from diffusion MRI parameters might enable better disease characterisation. 16 diffusion derived measurements from diffusion tensor imaging (DTI), diffusion kurtosis imaging (DKI), and fixel-based analysis (FBA) in lesions, peri-lesion and normal appearing white matter were investigated. Diffusion MRI scans of 11 MS patients were processed to generate DTI, DKI, and FBA images. Fractional anisotropy (FA) and fibre density (FD) were used to assess axonal integrity across brain regions. Subsequently, 359 lesions were identified, and lesion and peri-lesion segmentation was performed using structural T 1 w, T 2 w, T 2 w-FLAIR, and T 1 w post-contrast MRI. The segmentations were then used to extract 16 diffusion MRI parameters from lesion, peri-lesion, and contralateral normal appearing white matter (NAWM). The measurements for axonal integrity, DTI-FA, DKI-FA, FBA-FD, produced similar results. All diffusion MRI parameters were affected in lesions as compared to NAWM (p < 0.001), confirming loss of axonal integrity in lesions. In peri-lesions, most parameters, except FBA-FD, were also significantly different from NAWM, although the effect size was smaller than in lesions. The reduction in axonal integrity in peri-lesions, despite unaffected fibre density estimates, suggests an effect of Wallerian degeneration.

Background and Objectives: 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET) combined with principal component analysis (PCA) has been applied to identify disease-related brain patterns in neurodegenerative disorders such as Parkinson's disease (PD), Dementia with Lewy Bodies (DLB) and Alzheimer's disease (AD). These patterns are used to quantify functional brain changes at the single subject level. This is especially relevant in determining disease progression in idiopathic REM sleep behavior disorder (iRBD), a prodromal stage of PD and DLB. However, the PCA method is limited in discriminating between neurodegenerative conditions. More advanced machine learning algorithms may provide a solution. In this study, we apply Generalized Matrix Learning Vector Quantization (GMLVQ) to FDG-PET scans of healthy controls, and patients with AD, PD and DLB. Scans of iRBD patients, scanned twice with an approximate 4 year interval, were projected into GMLVQ space to visualize their trajectory., Methods: We applied a combination of SSM/PCA and GMLVQ as a classifier on FDG-PET data of healthy controls, AD, DLB, and PD patients. We determined the diagnostic performance by performing a ten times repeated ten fold cross validation. We analyzed the validity of the classification system by inspecting the GMLVQ space. First by the projection of the patients into this space. Second by representing the axis, that span this decision space, into a voxel map. Furthermore, we projected a cohort of RBD patients, whom have been scanned twice (approximately 4 years apart), into the same decision space and visualized their trajectories., Results: The GMLVQ prototypes, relevance diagonal, and decision space voxel maps showed metabolic patterns that agree with previously identified disease-related brain patterns. The GMLVQ decision space showed a plausible quantification of FDG-PET data. Distance traveled by iRBD subjects through GMLVQ space per year (i.e. velocity) was correlated with the change in motor symptoms per year (Spearman's rho =0.62, P=0.004)., Conclusion: In this proof-of-concept study, we show that GMLVQ provides a classification of patients with neurodegenerative disorders, and may be useful in future studies investigating speed of progression in prodromal disease stages., Competing Interests: Declaration of Competing Interest The authors declare no competing or financial interest in this work., (Copyright © 2022. Published by Elsevier B.V.)

Studying individuals who recently experienced a romantic reltionship breakup allows us to investigate mood disturbances in otherwise healthy individuals. In our study, we aimed to identify distinct depressive symptom trajectories following breakup and investigate whether these trajectories relate to personality traits and cognitive control. Subjects (n = 87) filled out questionnaires (RRS-NL-EXT trait rumination and NEO-FFI neuroticism) and performed cognitive tasks (trail making test, Stroop task) during a period of 30 weeks. To identify distinct depressive symptom trajectories ('trajectory groups'), we performed K-means clustering on the consecutive (assessed every 2 weeks) Major Depression Inventory scores. This resulted in four trajectory groups; 'resilience', 'fast recovery', 'slow recovery' and 'chronic distress'. The 'slow recovery group' and the 'chronic distress group' were found to have higher neuroticism and trait rumination levels compared to the 'resilience group', and the 'chronic distress group' also had higher neuroticism levels than the 'fast recovery group'. Moreover, the 'chronic distress group' showed worse overall trail making test performance than the 'resilience group'. Taken together, our findings show that distinct patterns of depressive symptom severity can be observed following breakup and that personality traits and cognitive flexibility seem to play a role in these depressive symptom patterns., (© 2021 The Authors. Stress and Health published by John Wiley & Sons Ltd.)

Purpose: Chronic traumatic encephalopathy refers to a neurodegenerative disease resulting from repetitive head injury of participants in contact sports. Similar to other neurodegenerative diseases, neuroinflammation is thought to play a role in the onset and progression of the disease. Limited knowledge is available regarding the neuroinflammatory consequences of repetitive head injury in currently active contact sports athletes. PET imaging of the 18-kDa translocator protein (TSPO) allows quantification of microglial activation in vivo, a marker of neuroinflammation., Methods: Eleven rank A kickboxers and 11 age-matched controls underwent TSPO PET using [ 11 C]-PK11195, anatomical MRI, diffusion tensor imaging, and neuropsychological testing. Relevant imaging parameters were derived and correlated with the outcomes of the neuropsychological testing., Results: On a group level, no statistically significant differences were detected in non-displaceable binding potential (BP ND ) using PET. Individually, 3 kickboxers showed increased BP ND s in widespread regions of the brain without a correlation with other modalities. Increased FA was observed in the superior corona radiata bilaterally. DTI parameters in other regions did not differ between groups., Conclusion: Despite negative results on a group level, individual results suggest that neuroinflammation may be present as a consequence of repetitive head injury in active kickboxers. Future studies using a longitudinal design may determine whether the observed TSPO upregulation is related to the future development of neuropsychiatric symptoms., (© 2022. The Author(s).)

Background: 2-Deoxy-2-[ 18 F]fluoroglucose (FDG) PET is an important tool for the identification of Alzheimer's disease (AD) patients through the characteristic neurodegeneration pattern that these patients present. Regional cerebral blood flow (rCBF) images derived from dynamic 11 C-labelled Pittsburgh Compound B (PIB) have been shown to present a similar pattern as FDG. Moreover, multivariate analysis techniques, such as scaled subprofile modelling using principal component analysis (SSM/PCA), can be used to generate disease-specific patterns (DP) that may aid in the classification of subjects. Therefore, the aim of this study was to compare rCBF AD-DPs with FDG AD-DP and their respective performances. Therefore, 52 subjects were included in this study. Fifteen AD and 16 healthy control subjects were used to generate four AD-DP: one based on relative cerebral trace blood (R 1 ), two based on time-weighted average of initial frame intervals (ePIB), and one based on FDG images. Furthermore, 21 subjects diagnosed with mild cognitive impairment were tested against these AD-DPs., Results: In general, the rCBF and FDG AD-DPs were characterized by a reduction in cortical frontal, temporal, and parietal lobes. FDG and rCBF methods presented similar score distribution., Conclusion: rCBF images may provide an alternative for FDG PET scans for the identification of AD patients through SSM/PCA., (© 2022. The Author(s).)

Current understanding of human genital-brain interactions relates primarily to neuroendocrine and autonomic control, whereas interactions during sexual stimulation remain largely unexplored. Here we present a systematic approach towards identifying how the human brain encodes sensory genital information. Using a validated affective touch paradigm and functional magnetic resonance imaging, we found that hedonic responses to discriminatory versus affective tactile stimulation were distinctly different for both penile shaft and forearm. This suggests that, as with other body sites, genital skin contains small diameter mechanoreceptive nerve fibres that signal pleasant touch. In the brain, secondary somatosensory cortex (S2) distinguished between affective and discriminative touch for the penile shaft, but not for the forearm. Frenulum stimulation induced the greatest reports of subjective pleasure and led to the greatest deactivation of the default-mode network. This study represents a first pass at investigating, in humans, the relationship between innervation of genital surfaces, hedonic feelings, and brain mechanisms, in a systematic way., (© 2022. The Author(s).)

Background: Game-based learning appears to be a promising instructional method because of its engaging properties and positive effects on motivation and learning. There are numerous options to design game-based learning; however, there is little data-informed knowledge to guide the choice of the most effective game-based learning design for a given educational context. The effectiveness of game-based learning appears to be dependent on the degree to which players like the game. Hence, individual differences in game preferences should be taken into account when selecting a specific game-based learning design., Objective: We aimed to identify patterns in students' perceptions of play and games-player types and their most important characteristics., Methods: We used Q methodology to identify patterns in opinions on game preferences. We recruited undergraduate medical and dental students to participate in our study and asked participants to sort and rank 49 statements on game preferences. These statements were derived from a prior focus group study and literature on game preferences. We used by-person factor analysis and varimax rotation to identify common viewpoints. Both factors and participants' comments were used to interpret and describe patterns in game preferences., Results: From participants' (n=102) responses, we identified 5 distinct patterns in game preferences: the social achiever, the explorer, the socializer, the competitor, and the troll. These patterns revolved around 2 salient themes: sociability and achievement. The 5 patterns differed regarding cheating, playing alone, story-telling, and the complexity of winning., Conclusions: The patterns were clearly interpretable, distinct, and showed that medical and dental students ranged widely in how they perceive play. Such patterns may suggest that it is important to take students' game preferences into account when designing game-based learning and demonstrate that not every game-based learning-strategy fits all students. To the best of our knowledge, this study is the first to use a scientifically sound approach to identify player types. This can help future researchers and educators select effective game-based learning game elements purposefully and in a student-centered way., (©A E J Van Gaalen, J Schönrock-Adema, R J Renken, A D C Jaarsma, J R Georgiadis. Originally published in JMIR Serious Games (https://games.jmir.org), 04.04.2022.)

Background & Aims: Sarcopenia is a muscle disorder associated with loss of muscle mass, strength and function. Early screening, diagnosis and treatment may improve outcome in different disease conditions. A wide variety of tools for estimation of muscle mass is available and each tool has specific technical requirements. However, different investigational settings and lack of homogeneity of populations influence the definition of gold standards, proving it difficult to systematically adopt these tools. Recently, the European Working Group on Sarcopenia in Older People (EWGSOP) published a revised recommendation (EWGSOP-2) and algorithm for using tools for screening and diagnosing sarcopenia. However, agreement of the EWGSOP2 criteria with other classifications is poor and although an overview of available tools is valuable, for the purpose of clinical decision-making the reverse is useful; a given scenario asks for the most suitable tools., Results: Tools were identified for screening, diagnostics and longitudinal monitoring of muscle mass. For each of these clinical scenarios the most appropriate tools were listed and for each technique their usability is specified based on sensitivity and specificity. Based on this information a specific recommendation is made for each clinical scenario., Conclusion: This narrative review provides an overview of currently available tools and future developments for different clinical scenarios such as screening, diagnosis and longitudinal monitoring of alterations in muscle status. It supports clinical decision-making in choosing the right tools for muscle mass quantification depending on the need within a given clinical scenario as well as the local availability and expertise., Competing Interests: Declaration of competing interest There is no conflict of interest., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Graph theoretical network analysis with structural magnetic resonance imaging (MRI) of multiple sclerosis (MS) patients can be used to assess subtle changes in brain networks. However, the presence of multiple focal brain lesions might impair the accuracy of automatic tissue segmentation methods, and hamper the performance of graph theoretical network analysis. Applying "lesion filling" by substituting the voxel intensities of a lesion with the voxel intensities of nearby voxels, thus creating an image devoid of lesions, might improve segmentation and graph theoretical network analysis. This study aims to determine if brain networks are different between MS subtypes and healthy controls (HC) and if the assessment of these differences is affected by lesion filling., Methods: The study included 49 MS patients and 19 HC that underwent a T1w, and T2w-FLAIR MRI scan. Graph theoretical network analysis was performed from grey matter fractions extracted from the original T1w-images and T1w-images after lesion filling., Results: Artefacts in lesion-filled T1w images correlated positively with total lesion volume (r = 0.84, p < 0.001) and had a major impact on grey matter segmentation accuracy. Differences in sensitivity for network alterations were observed between original T1w data and after application of lesion filling: graph theoretical network analysis obtained from lesion-filled T1w images produced more differences in network organization in MS patients., Conclusion: Lesion filling might reduce variability across subjects resulting in an increased detection rate of network alterations in MS, but also induces significant artefacts, and therefore should be applied cautiously especially in individuals with higher lesions loads., (© 2022. The Author(s).)

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., (© 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

In glaucoma participants, both structural and functional brain changes have been observed, but we still have insufficient understanding of how these changes also affect the integrity of cortical functional networks, and how these changes relate to visual function. This is relevant, as functional network integrity may affect the applicability of future treatments, as well as the options for rehabilitation or training. Here, we compare global and local functional connectivity in local and global brain networks between glaucoma and control participants. Moreover, we study the relationship between functional connectivity and visual field (VF) loss. For our study, 20 subjects with primary open-angle glaucoma (POAG) and 24 age-similar healthy participants were recruited to undergo an ophthalmic assessment followed by two resting-state (RS) (f)MRI scans. For each scan and for each group, the ROIs with eigenvector centrality (EC) values higher than the 95th percentile were considered the most central brain regions ("hubs"). Hubs for which we found a significant difference in EC in both scans between glaucoma and healthy participants were considered to provide evidence for network changes. In addition, we tested the notion that a brain region's hub function in POAG might relate to the severity of a participant's VF defect, irrespective of which eye contributed mostly to this. To determine this, for each participant, eye-independent scores were derived for: (1) sensitivity of the worse eye - indicating disease severity, (2) sensitivity of both eyes combined - with one eye potentially compensating for loss in the other, or (3) difference in eye sensitivity - potentially requiring additional network interactions. By correlating each of these VF scores and the EC values, we assessed whether VF defects could be associated with centrality alterations in POAG. Our results show that no functional connectivity disruptions were found at the global brain level in POAG participants. This indicates that in glaucoma global brain network communication is preserved. Furthermore, for the Lingual Gyrus, identified as a brain hub, we found a positive correlation between the EC value and the VF sensitivity of both eyes combined. The fact that reduced local network functioning is associated with reduced binocular VF sensitivity suggests the presence of local brain reorganization that has a bearing on functional visual abilities., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Demaria, Invernizzi, Ombelet, Carvalho, Renken and Cornelissen.)

Spinocerebellar ataxia type 3 (SCA3) is a rare genetic neurodegenerative disease. The neurobiological basis of SCA3 is still poorly understood, and up until now resting-state fMRI (rs-fMRI) has not been used to study this disease. In the current study we investigated (multi-echo) rs-fMRI data from patients with genetically confirmed SCA3 (n = 17) and matched healthy subjects (n = 16). Using independent component analysis (ICA) and subsequent regression with bootstrap resampling, we identified a pattern of differences between patients and healthy subjects, which we coined the fMRI SCA3 related pattern (fSCA3-RP) comprising cerebellum, anterior striatum and various cortical regions. Individual fSCA3-RP scores were highly correlated with a previously published 18 F-FDG PET pattern found in the same sample (rho = 0.78, P = 0.0003). Also, a high correlation was found with the Scale for Assessment and Rating of Ataxia scores (r = 0.63, P = 0.007). No correlations were found with neuropsychological test scores, nor with levels of grey matter atrophy. Compared with the 18 F-FDG PET pattern, the fSCA3-RP included a more extensive contribution of the mediofrontal cortex, putatively representing changes in default network activity. This rs-fMRI identification of additional regions is proposed to reflect a consequence of the nature of the BOLD technique, enabling measurement of dynamic network activity, compared to the more static 18 F-FDG PET methodology. Altogether, our findings shed new light on the neural substrate of SCA3, and encourage further validation of the fSCA3-RP to assess its potential contribution as imaging biomarker for future research and clinical use., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The visual brain has the remarkable capacity to complete our percept of the world even when the information extracted from the visual scene is incomplete. This ability to predict missing information based on information from spatially adjacent regions is an intriguing attribute of healthy vision. Yet, it gains particular significance when it masks the perceptual consequences of a retinal lesion, leaving patients unaware of their partial loss of vision and ultimately delaying diagnosis and treatment. At present, our understanding of the neural basis of this masking process is limited which hinders both quantitative modeling as well as translational application. To overcome this, we asked the participants to view visual stimuli with and without superimposed artificial scotoma (AS). We used fMRI to record the associated cortical activity and applied model-based analyzes to track changes in cortical population receptive fields and connectivity in response to the introduction of the AS. We found that throughout the visual field and cortical hierarchy, pRFs shifted their preferred position towards the AS border. Moreover, extrastriate areas biased their sampling of V1 towards sections outside the AS projection zone, thereby effectively masking the AS with signals from spared portions of the visual field. We speculate that the signals that drive these system-wide population modifications originate in extrastriate visual areas and, through feedback, also reconfigure the neural populations in the earlier visual areas., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021. Published by Elsevier Inc.)

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 < 0.01) and immune cell infiltration patterns in checkpoint inhibitor colitis were most similar to those observed in ulcerative colitis, with a deep band-like CD4 + T cell infiltration pattern and a superficial band-like CD68 + cell infiltration pattern in both. In conclusion, this is the first immunohistopathological study comparing infiltrate characteristics of checkpoint inhibitor colitis, acute graft-versus-host disease, ulcerative colitis, and Crohn's disease. Checkpoint inhibitor colitis samples are heterogeneous, heavily infiltrated by CD8 + T cells, and show an immune cell infiltration pattern that is more similar to ulcerative colitis than to colonic acute graft-versus-host disease or colonic Crohn's disease., (© 2021. The Author(s).)

Different types of physical activity are thought to differentially affect children's brain activation, via physiological mechanisms, or by activating similar brain areas during physical and cognitive tasks. Despite many behavioral studies relying on these mechanisms, they have been rarely studied. This study looks at both mechanisms simultaneously, by examining effects of two physical activity interventions (aerobic vs. cognitively-engaging) on children's brain activation. Functional Magnetic Resonance Imaging (fMRI) data of 62 children (48.4% boys, mean age 9.2 years) was analyzed. Children's visuospatial working memory related brain activity patterns were tested using a Spatial Span Task before and after the 14-week interventions consisting of four physical education lessons per week. The control group followed their regular program of two lessons per week. Analyses of activation patterns in SPM 12.0 revealed no activation changes between pretest and posttest (p > .05), and no differences between the three conditions in pretest-posttest changes in brain activation (p > .05). Large inter-individual differences were found, suggesting that not every child benefited from the interventions in the same way. To get more insight into the assumed mechanisms, further research is needed to understand whether, when, for whom, and how physical activity results in changed brain activation patterns., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Although the presence of anosognosia in amnestic mild cognitive impairment (aMCI) may be predictive of conversion to Alzheimer's disease (AD), little is known about its neural correlates in AD and aMCI. Four different groups were compared using volumetric and diffusion magnetic resonance imaging metrics in regions of interest (hippocampus and cingulum cortex gray matter, cingulum bundle white matter): aMCI subjects with anosognosia ( n = 6), aMCI subjects without anosognosia ( n = 12), AD subjects with anosognosia ( n = 6), and AD subjects without anosognosia ( n = 9). aMCI subjects with anosognosia displayed a significantly lower gray matter density (GMD) in the bilateral hippocampus than aMCI subjects without anosognosia, which was accounted for by bilateral hippocampal differences. Furthermore, we identified that the mean hippocampal gray matter density of aMCI subjects with anosognosia was not statistically different than that of AD subjects. The groups of aMCI and AD subjects with anosognosia also displayed a lower GMD in the bilateral cingulum cortex compared to subjects without anosognosia, but these differences were not statistically significant. No statistically significant differences were found in the fractional anisotropy or mean diffusivity of the hippocampus or cingulum between subjects with and without anosognosia in aMCI or AD groups. While these findings are derived from a small population of subjects and are in need of replication, they suggest that anosognosia in aMCI might be a useful clinical marker to suspect brain changes associated with AD neuropathology., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Flores-Vázquez, Ramírez-García, Marrufo-Meléndez, Alcalá-Lozano, Lietz, Rodríguez-Agudelo, Acosta-Castillo, Renken, Aleman, Enriquez-Geppert and Sosa-Ortiz.)

Standard automated perimetry (SAP) is the gold standard for evaluating the presence of visual field defects (VFDs). Nevertheless, it has requirements such as prolonged attention, stable fixation, and a need for a motor response that limit application in various patient groups. Therefore, a novel approach using eye movements (EMs) - as a complementary technique to SAP - was developed and tested in clinical settings by our group. However, the original method uses a screen-based eye-tracker which still requires participants to keep their chin and head stable. Virtual reality (VR) has shown much promise in ophthalmic diagnostics - especially in terms of freedom of head movement and precise control over experimental settings, besides being portable. In this study, we set out to see if patients can be screened for VFDs based on their EM in a VR-based framework and if they are comparable to the screen-based eyetracker. Moreover, we wanted to know if this framework can provide an effective and enjoyable user experience (UX) compared to our previous approach and the conventional SAP. Therefore, we first modified our method and implemented it on a VR head-mounted device with built-in eye tracking. Subsequently, 15 controls naïve to SAP, 15 patients with a neuro-ophthalmological disorder, and 15 glaucoma patients performed three tasks in a counterbalanced manner: (1) a visual tracking task on the VR headset while their EM was recorded, (2) the preceding tracking task but on a conventional screen-based eye tracker, and (3) SAP. We then quantified the spatio-temporal properties (STP) of the EM of each group using a cross-correlogram analysis. Finally, we evaluated the human-computer interaction (HCI) aspects of the participants in the three methods using a user-experience questionnaire. We find that: (1) the VR framework can distinguish the participants according to their oculomotor characteristics; (2) the STP of the VR framework are similar to those from the screen-based eye tracker; and (3) participants from all the groups found the VR-screening test to be the most attractive. Thus, we conclude that the EM-based approach implemented in VR can be a user-friendly and portable companion to complement existing perimetric techniques in ophthalmic clinics., Competing Interests: RR is listed as an inventor on the European patent application “Grillini, A., Hernández-García, A., and Renken, J. R. (2019). Method, system and computer program product for mapping a visual field. EP19209204.7” filed by the UMCG. The patent application is partially based on some elements of the continuous tracking method described in this manuscript. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Soans, Renken, John, Bhongade, Raj, Saxena, Tandon, Gandhi and Cornelissen.)

Purpose: Taste and smell alterations (TAs and SAs) are often reported by patients with cancer receiving systemic antitumor therapy and can negatively impact food intake and quality of life. This study aimed to examine the occurrence of TAs and SAs and investigate the impact of TAs on overall liking of oral nutritional supplements (ONS) with warming and cooling sensations., Methods: Patients receiving systemic antitumor therapy completed a questionnaire on sensory alterations and evaluated overall liking of 5 prototype flavors of Nutridrink® Compact Protein (hot tropical ginger (HTG), hot mango (HM), cool red fruits (CRF), cool lemon (CL), and neutral (N)) on a 10-point scale via a sip test. Differences between patients with and without TAs were investigated using permutation analysis., Results: Fifty patients with various cancer types and treatments were included. Thirty patients (60%) reported TAs and 13 (26%) experienced SAs. Three flavors were rated highly with a liking score > 6 (CRF 6.8 ± 1.7; N 6.5 ± 1.9; HTG 6.0 ± 2.0). Larger variation in ONS liking scores was observed in patients with TAs with or without SAs (4.5-6.9 and 4.6-7.2, respectively) vs. patients without TAs (5.9-6.5). TAs were associated with increased liking of CRF (Δ = + 0.9) and N (Δ = + 1.0) flavors., Conclusions: TAs and SAs are common in patients with cancer undergoing systemic antitumor therapy. Patients with TAs were more discriminant in liking of ONS flavors compared to patients without TAs, and sensory-adapted flavors appeared to be appreciated. The presence of TAs should be considered when developing or selecting ONS for patients with cancer., Trial Registration: Registration at ClinicalTrials.gov (NCT03525236) on 26 April 2018., (© 2021. The Author(s).)

The measurement of retinal sensitivity at different visual field locations-perimetry-is a fundamental procedure in ophthalmology. The most common technique for this scope, the Standard Automated Perimetry, suffers from several issues that make it less suitable to test specific clinical populations: it can be tedious, it requires motor manual feedback, and requires from the patient high levels of compliance. Previous studies attempted to create user-friendlier alternatives to Standard Automated Perimetry by employing eye movements reaction times as a substitute for manual responses while keeping the fixed-grid stimuli presentation typical of Standard Automated Perimetry. This approach, however, does not take advantage of the high spatial and temporal resolution enabled by the use of eye-tracking. In this study, we introduce a novel eye-tracking method to perform high-resolution perimetry. This method is based on the continuous gaze-tracking of a stimulus moving along a pseudo-random walk interleaved with saccadic jumps. We then propose two computational methods to obtain visual field maps from the continuous gaze-tracking data: the first is based on the spatio-temporal integration of ocular positional deviations using the threshold free cluster enhancement (TFCE) algorithm; the second is based on using simulated visual field defects to train a deep recurrent neural network (RNN). These two methods have complementary qualities: the TFCE is neurophysiologically plausible and its output significantly correlates with Standard Automated Perimetry performed with the Humphrey Field Analyzer, while the RNN accuracy significantly outperformed the TFCE in reconstructing the simulated scotomas but did not translate as well to the clinical data from glaucoma patients. While both of these methods require further optimization, they show the potential for a more patient-friendly alternative to Standard Automated Perimetry., Competing Interests: AG, AH-G, and RR listed as inventors on the patent application (Grillini et al., 2019). AG majority shareholder of REPERIO, BV, a private company that develops ophthalmic and neurological tests based on eye-movements. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Grillini, Hernández-García, Renken, Demaria and Cornelissen.)

Experiencing stress can have a disadvantageous effect on mental well-being. Additional to the relation between suffering from chronic stress and depression, both stress (acute and chronic) and depression are associated with cognitive alterations, including working memory. The breakup of a relationship is considered to be a stressful event that can lead to symptoms of depression in otherwise healthy people. Additional to elevated depression scores, stress-related cognitive alterations may occur in this population as well. Therefore, in the present fMRI study we investigated whether experiencing a relationship breakup is associated with working memory alterations and whether this is related to depressive symptom severity. A three workload version of the n -back task (0-back, 1-back, 2-back) was used to measure working memory in subjects who experienced a breakup in the preceding 6 months ("heartbreak group", n = 70) and subjects in a romantic relationship ("relationship group", n = 46). Behavioral task performance was compared between the two groups. Functional MRI scans were analyzed using General Linear Model (GLM) activation analyses. Workload conditions were contrasted to each other and to baseline and group differences were assessed. To investigate whether brain networks are associated with depressive symptom severity within the heartbreak group specifically, a post hoc feature-based Independent Component Analysis was performed on the 2-back > 0-back contrast images to identify brain regions that covaried across subjects. Behaviorally, the heartbreak group performed similar at high workload (i.e., 2-back) and better at moderate workload (i.e., 1-back) than the relationship group. GLM analysis revealed an interaction between group and 2-back > 0-back, 2-back > 1-back and 2-back > baseline; the heartbreak group showed less precuneus activation compared to the relationship group. Furthermore, within the heartbreak group, we found a negative association between depressive symptom severity and a brain network representing mostly the precuneus, anterior cingulate gyrus and supplementary motor cortex. Our findings suggest that the effect of a breakup is accompanied by workload-dependent working memory alterations. Therefore, we propose that this population can potentially be used to investigate the interplay between stress, cognitive functioning and depression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Verhallen, Renken, Marsman and ter Horst.)

Auditory hallucinations, the perception of a sound without a corresponding source, are common in people with hearing impairment. Two forms can be distinguished: simple (i.e., tinnitus) and complex hallucinations (speech and music). Little is known about the precise mechanisms underlying these types of hallucinations. Here we tested the assumption that spontaneous activity in the auditory pathways, following deafferentation, underlies these hallucinations and is related to their phenomenology. By extracting (fractional) Amplitude of Low Frequency Fluctuation [(f)ALFF] scores from resting state fMRI of 18 hearing impaired patients with complex hallucinations (voices or music), 18 hearing impaired patients with simple hallucinations (tinnitus or murmuring), and 20 controls with normal hearing, we investigated differences in spontaneous brain activity between these groups. Spontaneous activity in the anterior and posterior cingulate cortex of hearing-impaired groups was significantly higher than in the controls. The group with complex hallucinations showed elevated activity in the bilateral temporal cortex including Wernicke's area, while spontaneous activity of the group with simple hallucinations was mainly located in the cerebellum. These results suggest a decrease in error monitoring in both hearing-impaired groups. Spontaneous activity of language-related areas only in complex hallucinations suggests that the manifestation of the spontaneous activity represents the phenomenology of the hallucination. The link between cerebellar activity and simple hallucinations, such as tinnitus, is new and may have consequences for treatment., Competing Interests: Declaration of Competing Interest No conflicts of interest., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Connective Field (CF) modeling estimates the local spatial integration between signals in distinct cortical visual field areas. As we have shown previously using 7T data, CF can reveal the visuotopic organization of visual cortical areas even when applied to BOLD activity recorded in the absence of external stimulation. This indicates that CF modeling can be used to evaluate cortical processing in participants in which the visual input may be compromised. Furthermore, by using Bayesian CF modeling it is possible to estimate the co-variability of the parameter estimates and therefore, apply CF modeling to single cases. However, no previous studies evaluated the (Bayesian) CF model using 3T resting-state fMRI data. This is important since 3T scanners are much more abundant and more often used in clinical research compared to 7T scanners. Therefore in this study, we investigate whether it is possible to obtain meaningful CF estimates from 3T resting state (RS) fMRI data. To do so, we applied the standard and Bayesian CF modeling approaches on two RS scans, which were separated by the acquisition of visual field mapping data in 12 healthy participants. Our results show good agreement between RS- and visual field (VF)- based maps using either the standard or Bayesian CF approach. In addition to quantify the uncertainty associated with each estimate in both RS and VF data, we applied our Bayesian CF framework to provide the underlying marginal distribution of the CF parameters. Finally, we show how an additional CF parameter, beta , can be used as a data-driven threshold on the RS data to further improve CF estimates. We conclude that Bayesian CF modeling can characterize local functional connectivity between visual cortical areas from RS data at 3T. Moreover, observations obtained using 3T scanners were qualitatively similar to those reported for 7T. In particular, we expect the ability to assess parameter uncertainty in individual participants will be important for future clinical studies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Invernizzi, Gravel, Haak, Renken and Cornelissen.)

Purpose: Assessing the presence of visual field defects (VFD) through procedures such as perimetry is an essential aspect of the management and diagnosis of ocular disorders. However, even the latest perimetric methods have shortcomings-a high cognitive demand and requiring prolonged stable fixation and feedback through a button response. Consequently, an approach using eye movements (EM)-as a natural response-has been proposed as an alternate way to evaluate the presence of VFD. This approach has given good results for computer-simulated VFD. However, its use in patients is not well documented yet. Here we use this new approach to quantify the spatiotemporal properties (STP) of EM of various patients suffering from glaucoma and neuro-ophthalmological VFD and controls., Methods: In total, 15 glaucoma patients, 37 patients with a neuro-ophthalmological disorder, and 21 controls performed a visual tracking task while their EM were being recorded. Subsequently, the STP of EM were quantified using a cross-correlogram analysis. Decision trees were used to identify the relevant STP and classify the populations., Results: We achieved a classification accuracy of 94.5% (TPR/sensitivity = 96%, TNR/specificity = 90%) between patients and controls. Individually, the algorithm achieved an accuracy of 86.3% (TPR for neuro-ophthalmology [97%], glaucoma [60%], and controls [86%]). The STP of EM were highly similar across two different control cohorts., Conclusions: In an ocular tracking task, patients with VFD due to different underlying pathology make EM with distinctive STP. These properties are interpretable based on different clinical characteristics of patients and can be used for patient classification., Translational Relevance: Our EM-based screening tool may complement existing perimetric techniques in clinical practice.

Purpose: To evaluate the accuracy and reliability of functional magnetic resonance imaging (fMRI)-based techniques to assess the integrity of the visual field (VF)., Methods: We combined 3T fMRI and neurocomputational models, that is, conventional population receptive field (pRF) mapping and a new advanced pRF framework "microprobing" (MP), to reconstruct the VF representations of different cortical areas. To demonstrate their scope, both approaches were applied in healthy participants with simulated scotomas and participants with glaucoma. For the latter group we compared the VFs obtained with standard automated perimetry (SAP) and via fMRI., Results: Using SS, we found that the fMRI-based techniques can detect absolute defects in VFs that are larger than 3°, in single participants, based on 12 minutes of fMRI scan time. Moreover, we found that the MP approach results in a less biased estimation of the preserved VF. In participants with glaucoma, we found that fMRI-based VF reconstruction detected VF defects with a correspondence to SAP that was decent, reflected by the positive correlation between fMRI-based sampling density and SAP-based contrast sensitivity loss (SAP) r 2 = 0.44, P = 0.0002. This correlation was higher for MP compared to that for the conventional pRF analysis., Conclusions: The fMRI-based reconstruction of the VF enables the evaluation of vision loss and provides useful details on the properties of the visual cortex., Translational Relevance: The fMRI-based VF reconstruction provides an objective alternative to detect VF defects. It may either complement SAP or could provide VF information in patients unable to perform SAP., Competing Interests: Disclosure: J. Carvalho, None; A. Invernizzi, None; J. Martins, None; N.M. Jansonius, None; R.J. Renken, None; F.W. Cornelissen, None, (Copyright 2021 The Authors.)

Scaled subprofile model using principal component analysis (SSM/PCA) is a multivariate analysis technique used, mainly in [ 18 F]-2-fluoro-2-deoxy-d-glucose (FDG) PET studies, for the generation of disease-specific metabolic patterns (DP) that may aid with the classification of subjects with neurological disorders, like Alzheimer's disease (AD). The aim of this study was to explore the feasibility of using quantitative parametric images for this type of analysis, with dynamic [ 11 C]-labelled Pittsburgh Compound B (PIB) PET data as an example. Therefore, 15 AD patients and 15 healthy control subjects were included in an SSM/PCA analysis to generate four AD-DPs using relative cerebral blood flow (R 1 ), binding potential (BP ND ) and SUVR images derived from dynamic PIB and static FDG-PET studies. Furthermore, 49 new subjects with a variety of neurodegenerative cognitive disorders were tested against these DPs. The AD-DP was characterized by a reduction in the frontal, parietal, and temporal lobes voxel values for R 1 and SUVR-FDG DPs; and by a general increase of values in cortical areas for BP ND and SUVR-PIB DPs. In conclusion, the results suggest that the combination of parametric images derived from a single dynamic scan might be a good alternative for subject classification instead of using 2 independent PET studies., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Isolated rapid eye movement sleep behavior disorder is known to be prodromal for alpha-synucleinopathies, such as Parkinson's disease (PD) and dementia with Lewy bodies. The [ 18 F]fluorodeoxyglucose-positron emission tomography (PET)-based PD-related brain pattern can be used to monitor disease progression., Objective: We longitudinally investigated PD-related brain pattern expression changes in 20 subjects with isolated rapid eye movement sleep behavior disorder to investigate whether this may be a suitable technique to study prodromal PD progression in these patients and to identify potential phenoconverters., Methods: Subjects underwent two [ 18 F]fluorodeoxyglucose-PET brain scans ~3.7 years apart, along with baseline and repeated motor, cognitive, and olfactory testing within roughly the same time frame., Results: At baseline, 8 of 20 (40%) subjects significantly expressed the PD-related brain pattern (with z scores above the receiver operating characteristic-determined threshold). At follow-up, six additional subjects exhibited significant PD-related brain pattern expression (70% in total). PD-related brain pattern expression increased in all subjects (P = 0.00008). Four subjects (20%), all with significant baseline PD-related brain pattern expression, phenoconverted to clinical PD., Conclusions: Suprathreshold PD-related brain pattern expression and greater score rate of change may signify greater shorter-term risk for phenoconversion. Our results support the use of serial PD-related brain pattern expression measurements as a prodromal PD progression biomarker in patients with isolated rapid eye movement sleep behavior disorder. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background and Objective: Neurodegenerative diseases like Parkinson's disease often take several years before they can be diagnosed reliably based on clinical grounds. Imaging techniques such as MRI are used to detect anatomical (structural) pathological changes. However, these kinds of changes are usually seen only late in the development. The measurement of functional brain activity by means of [ 18 F]fluorodeoxyglucose positron emission tomography (FDG-PET) can provide useful information, but its interpretation is more difficult. The scaled sub-profile model principal component analysis (SSM/PCA) was shown to provide more useful information than other statistical techniques. Our objective is to improve the performance further by combining SSM/PCA and prototype-based generalized matrix learning vector quantization (GMLVQ)., Methods: We apply a combination of SSM/PCA and GMLVQ as a classifier. In order to demonstrate the combination's validity, we analyze FDG-PET data of Parkinson's disease (PD) patients collected at three different neuroimaging centers in Europe. We determine the diagnostic performance by performing a ten times repeated ten fold cross validation. Additionally, discriminant visualizations of the data are included. The prototypes and relevance of GMLVQ are transformed back to the original voxel space by exploiting the linearity of SSM/PCA. The resulting prototypes and relevance profiles have then been assessed by three neurologists., Results: One important finding is that discriminative visualization can help to identify disease-related properties as well as differences which are due to center-specific factors. Secondly, the neurologist assessed the interpretability of the method and confirmed that prototypes are similar to known activity profiles of PD patients., Conclusion: We have shown that the presented combination of SSM/PCA and GMLVQ can provide useful means to assess and better understand characteristic differences in FDG-PET data from PD patients and HCs. Based on the assessments by medical experts and the results of our computational analysis we conclude that the first steps towards a diagnostic support system have been taken successfully., Competing Interests: Declaration of Competing Interest The authors declare no competing or financial interest in this work., (Copyright © 2020. Published by Elsevier B.V.)

Previous studies demonstrated that alterations in functional MRI derived receptive field (pRF) properties in cortical projection zones of retinal lesions can erroneously be mistaken for cortical large-scale reorganization in response to visual system pathologies. We tested, whether such confounds are also evident in the normal cortical projection zone of the fovea for simulated peripheral visual field defects. We applied fMRI-based visual field mapping of the central visual field at 3 T in eight controls to compare the pRF properties of the central visual field of a reference condition (stimulus radius: 14°) and two conditions with simulated peripheral visual field defect, i.e., with a peripheral gray mask, stimulating only the central 7° or 4° radius. We quantified, for the cortical representation of the actually stimulated visual field, the changes in the position and size of the pRFs associated with reduced peripheral stimulation using conventional and advanced pRF modeling. We found foveal pRF-positions (≤3°) to be significantly shifted towards the periphery (p<0.05, corrected). These pRF-shifts were largest for the 4° condition [visual area (mean eccentricity shift): V1 (0.9°), V2 (0.9°), V3 (1.0°)], but also evident for the 7° condition [V1 (0.5°), V2 (0.5°), V3 (0.9°)]. Further, an overall enlargement of pRF-sizes was observed. These findings indicate the dependence of foveal pRF parameters on the spatial extent of the stimulated visual field and are likely associated with methodological biases and/or physiological mechanisms. Consequently, our results imply that, previously reported similar findings in patients with actual peripheral scotomas need to be interpreted with caution and indicate the need for adequate control conditions in investigations of visual cortex reorganization., Competing Interests: Declaration of competing interest None, (Copyright © 2020. Published by Elsevier Inc.)

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%) 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., (© 2020 International Parkinson and Movement Disorder Society.)

It has recently been shown that large-scale propagation of blood-oxygen-level-dependent (BOLD) activity is constrained by anatomical connections and reflects transitions between behavioral states. It remains to be seen, however, if the propagation of BOLD activity can also relate to the brain's anatomical structure at a more local scale. Here, we hypothesized that BOLD propagation reflects structured neuronal activity across early visual field maps. To explore this hypothesis, we characterize the propagation of BOLD activity across V1, V2, and V3 using a modeling approach that aims to disentangle the contributions of local activity and directed interactions in shaping BOLD propagation. It does so by estimating the effective connectivity (EC) and the excitability of a noise-diffusion network to reproduce the spatiotemporal covariance structure of the data. We apply our approach to 7T fMRI recordings acquired during resting state (RS) and visual field mapping (VFM). Our results reveal different EC interactions and changes in cortical excitability in RS and VFM, and point to a reconfiguration of feedforward and feedback interactions across the visual system. We conclude that the propagation of BOLD activity has functional relevance, as it reveals directed interactions and changes in cortical excitability in a task-dependent manner., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Background: Cognitive insight is defined as the ability to reflect upon oneself (i.e. self-reflectiveness), and to not be overly confident of one's own (incorrect) beliefs (i.e. self-certainty). These abilities are impaired in several disorders, while they are essential for the evaluation and regulation of one's behavior. We hypothesized that cognitive insight is a dynamic process, and therefore examined how it relates to temporal dynamics of resting state functional connectivity (FC) and underlying structural network characteristics in 58 healthy individuals., Methods: Cognitive insight was measured with the Beck Cognitive Insight Scale. FC characteristics were calculated after obtaining four FC states with leading eigenvector dynamics analysis. Gray matter (GM) and DTI connectomes were based on GM similarity and probabilistic tractography. Structural graph characteristics, such as path length, clustering coefficient, and small-world coefficient, were calculated with the Brain Connectivity Toolbox. FC and structural graph characteristics were correlated with cognitive insight., Results: Individuals with lower cognitive insight switched more and spent less time in a globally synchronized state. Additionally, individuals with lower self-reflectiveness spent more time in, had a higher probability of, and had a higher chance of switching to a state entailing default mode network (DMN) areas. With lower self-reflectiveness, DTI-connectomes were segregated less (i.e. lower global clustering coefficient) with lower embeddedness of the left angular gyrus specifically (i.e. lower local clustering coefficient)., Conclusions: Our results suggest less stable functional and structural networks in individuals with poorer cognitive insight, specifically self-reflectiveness. An overly present DMN appears to play a key role in poorer self-reflectiveness., Competing Interests: Declarations of competing interest None., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Evaluating the state of the oculomotor system of a patient is one of the fundamental tests done in neuro-ophthalmology. However, up to date, very few quantitative standardized tests of eye movements' quality exist, limiting this assessment to confrontational tests reliant on subjective interpretation. Furthermore, quantitative tests relying on eye movement properties, such as pursuit gain and saccade dynamics are often insufficient to capture the complexity of the underlying disorders and are often (too) long and tiring. In this study, we present SONDA (Standardized Oculomotor and Neurological Disorder Assessment): this test is based on analyzing eye tracking recorded during a short and intuitive continuous tracking task. We tested patients affected by Multiple Sclerosis (MS) and Parkinson's Disease (PD) and find that: (1) the saccadic dynamics of the main sequence alone are not sufficient to separate patients from healthy controls; (2) the combination of spatio-temporal and statistical properties of saccades and saccadic dynamics enables an identification of oculomotor abnormalities in both MS and PD patients. We conclude that SONDA constitutes a powerful screening tool that allows an in-depth evaluation of (deviant) oculomotor behavior in a few minutes of non-invasive testing., (Copyright © 2020 Grillini, Renken, Vrijling, Heutink and Cornelissen.)