Introduction: Aging impairs the function of the central circadian clock in mammals, the suprachiasmatic nucleus (SCN), leading to a reduction in the output signal. The weaker timing signal from the... Show moreIntroduction: Aging impairs the function of the central circadian clock in mammals, the suprachiasmatic nucleus (SCN), leading to a reduction in the output signal. The weaker timing signal from the SCN results in a decline in rhythm strength in many physiological functions, including sleep–wake patterns. Accumulating evidence suggests that the reduced amplitude of the SCN signal is caused by a decreased synchrony among the SCN neurons. The present study was aimed to investigate the hypothesis that the excitation/inhibition (E/I) balance plays a role in synchronization within the network.Methods: Using calcium (Ca2+) imaging, the polarity of Ca2+ transients in response to GABA stimulation in SCN slices of old mice (20–24 months) and young controls was studied.Results: We found that the amount of GABAergic excitation was increased, and that concordantly the E/I balance was higher in SCN slices of old mice when compared to young controls. Moreover, we showed an effect of aging on the baseline intracellular Ca2+ concentration, with higher Ca2+ levels in SCN neurons of old mice, indicating an alteration in Ca2+ homeostasis in the aged SCN. We conclude that the change in GABAergic function, and possibly the Ca2+ homeostasis, in SCN neurons may contribute to the altered synchrony within the aged SCN network. Show less
Medical imaging techniques are widely used in preclinical research as diagnostic tools to detect physiological abnormalities and assess the progression of neurovascular disease in animal models.... Show moreMedical imaging techniques are widely used in preclinical research as diagnostic tools to detect physiological abnormalities and assess the progression of neurovascular disease in animal models. Despite the wealth of imaging options in magnetic resonance imaging (MRI), interpretation of imaging-derived parameters regarding underlying tissue properties is difficult due to technical limitations or lack of parameter specificity. To address the challenge of interpretation, we present an animal preparation protocol to achieve quantitative measures from both MRI and advanced optical techniques, including laser speckle contrast imaging and two-photon microscopy, in murine models. In this manner, non-translatable methods support and improve interpretation of less specific, translatable methods, i.e., MRI. Combining modalities for improved clinical interpretation involves satisfying the requirements of various methods. Furthermore, physiology unperturbed by anesthetics is a prerequisite for the strategy to succeed. Awake animal imaging with restraint provides an alternative to anesthesia and facilitates translatability of cerebral measurements. The method outlines design requirements for the setup and a corresponding reproducible surgical procedure for implanting a 3D printed head holder and cranial window to enable repeated multimodal imaging. We document the development, application, and validation of the method and provide examples confirming the usefulness of the design in acquiring high quality data from multiple modalities for quantification of a wide range of metrics of cerebral physiology in the same animal. The method contributes to preclinical small animal imaging, enabling sequential imaging of previously mutually exclusive techniques. Show less
Gool, J.K.; Fronczek, R.; Bosma, P.; Meer, J.N. van der; Werf, Y.D. van der; Lammers, G.J. 2022
The brain activation patterns related to sleep resistance remain to be discovered in health and disease. The maintenance of wakefulness test (MWT) is an objective neuropsychological assessment... Show moreThe brain activation patterns related to sleep resistance remain to be discovered in health and disease. The maintenance of wakefulness test (MWT) is an objective neuropsychological assessment often used to assess an individual's ability to resist sleep. It is frequently used in narcolepsy type 1, a disorder characterized by impaired sleep-wake control and the inability to resist daytime sleep. We investigated the neural correlates of active sleep resistance in 12 drug-free people with narcolepsy type 1 and 12 healthy controls. Simultaneous fMRI-EEG measurements were recorded during five cycles of two alternating conditions of active sleep resistance and waking rest. Cleaned EEG signals were used to verify wakefulness and task adherence. Pooling both subject groups, significantly higher fMRI activation when actively resisting sleep was seen in the brainstem, superior cerebellum, bilateral thalamus and visual cortices. In controls the activation clusters were generally smaller compared to patients and no significant activation was seen in the brainstem. Formal comparison between groups only found a significantly higher left primary visual cortex activation in patients during active sleep resistance. The active sleep resistance paradigm is a feasible fMRI task to study sleep resistance and induces evident arousal- and visual-related activity. Significantly higher left primary visual cortical activation in patients could be caused by an enhanced need of visual focus to resist sleep, or reflecting a more rapid descent in their level of alertness when resting. Show less
Multi-view data refers to a setting where features are divided into feature sets, for example because they correspond to different sources. Stacked penalized logistic regression (StaPLR) is a... Show moreMulti-view data refers to a setting where features are divided into feature sets, for example because they correspond to different sources. Stacked penalized logistic regression (StaPLR) is a recently introduced method that can be used for classification and automatically selecting the views that are most important for prediction. We introduce an extension of this method to a setting where the data has a hierarchical multi-view structure. We also introduce a new view importance measure for StaPLR, which allows us to compare the importance of views at any level of the hierarchy. We apply our extended StaPLR algorithm to Alzheimer's disease classification where different MRI measures have been calculated from three scan types: structural MRI, diffusion-weighted MRI, and resting-state fMRI. StaPLR can identify which scan types and which derived MRI measures are most important for classification, and it outperforms elastic net regression in classification performance. Show less
Inglese, F.; Kim, M.; Steup-Beekman, G.M.; Huizinga, T.W.J.; Buchem, M.A. van; Bresser, J. de; ... ; Ronen, I. 2022
Introduction/PurposeSystemic lupus erythematosus (SLE) is a chronic auto-immune disease with a broad spectrum of clinical presentations, including heterogeneous neuropsychiatric (NP) syndromes.... Show moreIntroduction/PurposeSystemic lupus erythematosus (SLE) is a chronic auto-immune disease with a broad spectrum of clinical presentations, including heterogeneous neuropsychiatric (NP) syndromes. Structural brain abnormalities are commonly found in SLE and NPSLE, but their role in diagnosis is limited, and their usefulness in distinguishing between NPSLE patients and patients in which the NP symptoms are not primarily attributed to SLE (non-NPSLE) is non-existent. Self-supervised contrastive learning algorithms proved to be useful in classification tasks in rare diseases with limited number of datasets. Our aim was to apply self-supervised contrastive learning on T-1-weighted images acquired from a well-defined cohort of SLE patients, aiming to distinguish between NPSLE and non-NPSLE patients. Subjects and MethodsWe used 3T MRI T-1-weighted images of 163 patients. The training set comprised 68 non-NPSLE and 34 NPSLE patients. We applied random geometric transformations between iterations to augment our data sets. The ML pipeline consisted of convolutional base encoder and linear projector. To test the classification task, the projector was removed and one linear layer was measured. Validation of the method consisted of 6 repeated random sub-samplings, each using a random selection of a small group of patients of both subtypes. ResultsIn the 6 trials, between 79% and 83% of the patients were correctly classified as NPSLE or non-NPSLE. For a qualitative evaluation of spatial distribution of the common features found in both groups, Gradient-weighted Class Activation Maps (Grad-CAM) were examined. Thresholded Grad-CAM maps show areas of common features identified for the NPSLE cohort, while no such communality was found for the non-NPSLE group. Discussion/ConclusionThe self-supervised contrastive learning model was effective in capturing common brain MRI features from a limited but well-defined cohort of SLE patients with NP symptoms. The interpretation of the Grad-CAM results is not straightforward, but indicates involvement of the lateral and third ventricles, periventricular white matter and basal cisterns. We believe that the common features found in the NPSLE population in this study indicate a combination of tissue loss, local atrophy and to some extent that of periventricular white matter lesions, which are commonly found in NPSLE patients and appear hypointense on T-1-weighted images. Show less
Background: An increased risk of stroke in patients with migraine has been primarily found for women. The sex-dependent mechanisms underlying the migraine-stroke association, however, remain... Show moreBackground: An increased risk of stroke in patients with migraine has been primarily found for women. The sex-dependent mechanisms underlying the migraine-stroke association, however, remain unknown. This study aims to explore these sex differences to improve our understanding of pathophysiological mechanisms behind the migraine-stroke association.Methods: We included 2,492 patients with ischemic stroke from the prospective multicenter Dutch Parelsnoer Institute Initiative study, 425 (17%) of whom had a history of migraine. Cardiovascular risk profile, stroke cause (TOAST classification), and outcome [modified Rankin scale (mRS) at 3 months] were compared with both sexes between patients with and without migraine.Results: A history of migraine was not associated with sex differences in the prevalence of conventional cardiovascular risk factors. Women with migraine had an increased risk of stroke at young age (onset < 50 years) compared with women without migraine (RR: 1.7; 95% CI: 1.3-2.3). Men with migraine tended to have more often stroke in the TOAST category other determined etiology (RR: 1.7; 95% CI: 1.0-2.7) in comparison with men without migraine, whereas this increase was not found in women with migraine. Stroke outcome was similar for women with or without migraine (mRS >= 3 RR 1.1; 95% CI 0.7-1.5), whereas men seemed to have a higher risk of poor outcome compared with their counterparts without migraine (mRS >= 3 RR: 1.5; 95% CI: 1.0-2.1).Conclusion: Our results indicate possible sex differences in the pathophysiology underlying the migraine-stroke association, which are unrelated to conventional cardiovascular risk factors. Further research in larger cohorts is needed to validate these findings. Show less
Keo, A.; Dzyubachyk, O.; Grond, J. van der; Hilten, J.J. van; Reinders, M.J.T.; Mahfouz, A. 2021
Cortical atrophy is a common manifestation in Parkinson's disease (PD), particularly in advanced stages of the disease. To elucidate the molecular underpinnings of cortical thickness changes in PD,... Show moreCortical atrophy is a common manifestation in Parkinson's disease (PD), particularly in advanced stages of the disease. To elucidate the molecular underpinnings of cortical thickness changes in PD, we performed an integrated analysis of brain-wide healthy transcriptomic data from the Allen Human Brain Atlas and patterns of cortical thickness based on T1-weighted anatomical MRI data of 149 PD patients and 369 controls. For this purpose, we used partial least squares regression to identify gene expression patterns correlated with cortical thickness changes. In addition, we identified gene expression patterns underlying the relationship between cortical thickness and clinical domains of PD. Our results show that genes whose expression in the healthy brain is associated with cortical thickness changes in PD are enriched in biological pathways related to sumoylation, regulation of mitotic cell cycle, mitochondrial translation, DNA damage responses, and ER-Golgi traffic. The associated pathways were highly related to each other and all belong to cellular maintenance mechanisms. The expression of genes within most pathways was negatively correlated with cortical thickness changes, showing higher expression in regions associated with decreased cortical thickness (atrophy). On the other hand, sumoylation pathways were positively correlated with cortical thickness changes, showing higher expression in regions with increased cortical thickness (hypertrophy). Our findings suggest that alterations in the balanced interplay of these mechanisms play a role in changes of cortical thickness in PD and possibly influence motor and cognitive functions. Show less
The circadian timing system optimizes health by temporally coordinating behavior and physiology. During mammalian gestation, fetal circadian rhythms are synchronized by the daily fluctuations in... Show moreThe circadian timing system optimizes health by temporally coordinating behavior and physiology. During mammalian gestation, fetal circadian rhythms are synchronized by the daily fluctuations in maternal body temperature, hormones and nutrients. Circadian disruption during pregnancy is associated with negative effects on developmental outcomes in the offspring, highlighting the importance of regular and robust 24-h rhythms over gestation. In the case of preterm birth (before 37 weeks of gestation), maternal cues no longer synchronize the neonate's circadian system, which may adversely affect the neonate. There is increasing evidence that introducing robust light-dark cycles in the Neonatal Intensive Care Unit has beneficial effects on clinical outcomes in preterm infants, such as weight gain and hospitalization time, compared to infants exposed to constant light or constant near-darkness. However, the biological basis for these effects and the relationship with the functional and anatomical development of the circadian system is not fully understood. In this review, we provide a concise overview of the effects of light-dark cycles on clinical outcomes of preterm neonates in the NICU and its alignment with the development of the circadian system. Show less
Chronic exposure to high circulating levels of glucocorticoids has detrimental effects on health, including metabolic abnormalities, as exemplified in Cushing's syndrome (CS). Magnetic resonance... Show moreChronic exposure to high circulating levels of glucocorticoids has detrimental effects on health, including metabolic abnormalities, as exemplified in Cushing's syndrome (CS). Magnetic resonance imaging (MRI) studies have found volumetric changes in gray and white matter of the brain in CS patients during the course of active disease, but also in remission. In order to explore this further, we performed MRI-based brain volumetric analyses in the AdKO mouse model for CS, which presents its key traits. AdKO mice had reduced relative volumes in several brain regions, including the corpus callosum and cortical areas. The medial amygdala, bed nucleus of the stria terminalis, and hypothalamus were increased in relative volume. Furthermore, we found a lower immunoreactivity of myelin basic protein (MBP, an oligodendrocyte marker) in several brain regions but a paradoxically increased MBP signal in the male cingulate cortex. We also observed a decrease in the expression of glial fibrillary acidic protein (GFAP, a marker for reactive astrocytes) and ionized calcium-binding adapter molecule 1 (IBA1, a marker for activated microglia) in the cingulate regions of the anterior corpus callosum and the hippocampus. We conclude that long-term hypercorticosteronemia induced brain region-specific changes that might include aberrant myelination and a degree of white matter damage, as both repair (GFAP) and immune (IBA1) responses are decreased. These findings suggest a cause for the changes observed in the brains of human patients and serve as a background for further exploration of their subcellular and molecular mechanisms. Show less
Frequent or chronic reduction in heart rate variability (HRV) is a powerful predictor of cardiovascular disease, and psychological stress has been suggested to be a co-determinant of this reduction... Show moreFrequent or chronic reduction in heart rate variability (HRV) is a powerful predictor of cardiovascular disease, and psychological stress has been suggested to be a co-determinant of this reduction. Recently, we evaluated various methods to measure additional HRV reduction in everyday life and to relate these reductions to psychological stress. In the current paper, we thoroughly evaluate these methods and add two new methods in both newly acquired and reanalyzed datasets. All of these methods use a subset of 24 h worth of HRV and movement data to do so: either the first 10 min of every hour, the full 24 h, a combination of 10 min from three consecutive hours, a classification of level of movement, the data from day n to detect episodes in day n + 1, or a range of activities during lab calibration. The method that used the full 24 h worth of data detected the largest percentage of episodes of reduced additional HRV that matched with self-reported stress levels, making this method the most promising, while using the first 10 min from three consecutive hours was a good runner-up. Show less
Gallego, C.; Goncalves, M.A.F.V.; Wijnholds, J. 2020
Inherited retinal diseases encompass a highly heterogenous group of disorders caused by a wide range of genetic variants and with diverse clinical symptoms that converge in the common trait of... Show moreInherited retinal diseases encompass a highly heterogenous group of disorders caused by a wide range of genetic variants and with diverse clinical symptoms that converge in the common trait of retinal degeneration. Indeed, mutations in over 270 genes have been associated with some form of retinal degenerative phenotype. Given the immune privileged status of the eye, cell replacement and gene augmentation therapies have been envisioned. While some of these approaches, such as delivery of genes through recombinant adeno-associated viral vectors, have been successfully tested in clinical trials, not all patients will benefit from current advancements due to their underlying genotype or phenotypic traits. Gene editing arises as an alternative therapeutic strategy seeking to correct mutations at the endogenous locus and rescue normal gene expression. Hence, gene editing technologies can in principle be tailored for treating retinal degeneration. Here we provide an overview of the different gene editing strategies that are being developed to overcome the challenges imposed by the post-mitotic nature of retinal cell types. We further discuss their advantages and drawbacks as well as the hurdles for their implementation in treating retinal diseases, which include the broad range of mutations and, in some instances, the size of the affected genes. Although therapeutic gene editing is at an early stage of development, it has the potential of enriching the portfolio of personalized molecular medicines directed at treating genetic diseases. Show less
Retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) are inherited degenerative retinal dystrophies with vision loss that ultimately lead to blindness. Several genes have been shown to be... Show moreRetinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) are inherited degenerative retinal dystrophies with vision loss that ultimately lead to blindness. Several genes have been shown to be involved in early onset retinal dystrophies, includingCRB1andRPE65. Gene therapy recently became available for young RP patients with variations in theRPE65gene. Current research programs test adeno-associated viral gene augmentation or editing therapy vectors on various disease models mimicking the disease in patients. These include several animal and emerging human-derived models, such as human-induced pluripotent stem cell (hiPSC)-derived retinal organoids or hiPSC-derived retinal pigment epithelium (RPE), and human donor retinal explants. Variations in theCRB1gene are a major cause for early onset autosomal recessive RP with patients suffering from visual impairment before their adolescence and for LCA with newborns experiencing severe visual impairment within the first months of life. These patients cannot benefit yet from an available gene therapy treatment. In this review, we will discuss the recent advances, advantages and disadvantages of differentCRB1human and animal retinal degeneration models. In addition, we will describe novel therapeutic tools that have been developed, which could potentially be used for retinal gene augmentation therapy for RP patients with variations in theCRB1gene. Show less
Panman, J.L.; Y.Y. to; Ende, E.L. van der; Poos, J.M.; Jiskoot, L.C.; Meeter, L.H.H.; ... ; Hafkemeijer, A. 2019
Neuroimaging MRI data in scientific research is increasingly pooled, but the reliability of such studies may be hampered by the use of different hardware elements. This might introduce bias, for... Show moreNeuroimaging MRI data in scientific research is increasingly pooled, but the reliability of such studies may be hampered by the use of different hardware elements. This might introduce bias, for example when cross-sectional studies pool data acquired with different head coils, or when longitudinal clinical studies change head coils halfway. In the present study, we aimed to estimate this possible bias introduced by using different head coils to create awareness and to avoid misinterpretation of results. We acquired, with both an 8 channel and 32 channel head coil, T1-weighted, diffusion tensor imaging and resting state fMRI images at 3T MRI (Philips Achieva) with stable acquisition parameters in a large group of cognitively healthy participants (n = 77). Standard analysis methods, i.e., voxel-based morphometry, tract-based spatial statistics and resting state functional network analyses, were used in a within-subject design to compare 8 and 32 channel head coil data. Signal-to-noise ratios (SNR) for both head coils showed similar ranges, although the 32 channel SNR profile was more homogeneous. Our data demonstrates specific patterns of gray and white matter volume differences between head coils (relative volume change of 6 to 9%), related to altered image contrast and therefore, altered tissue segmentation. White matter connectivity (fractional anisotropy and diffusivity measures) showed hemispherical dependent differences between head coils (relative connectivity change of 4 to 6%), and functional connectivity in resting state networks was higher using the 32 channel head coil in posterior cortical areas (relative change up to 27.5%). This study shows that, even when acquisition protocols are harmonized, the results of standardized analysis models can be severely affected by the use of different head coils. Researchers should be aware of this when combining multiple neuroimaging MRI datasets, to prevent coil-related bias and avoid misinterpretation of their findings. Show less
Panman, J.L.; To, Y.Y.; Ende, E.L. van der; Poos, J.M.; Jiskoot, L.C.; Meeter, L.H.H.; ... ; Hafkemeijer, A. 2019
Humans possess a robust speech-perception apparatus that is able to cope with variation in spoken language. However, linguists have often claimed that this coping ability must be limited, since... Show moreHumans possess a robust speech-perception apparatus that is able to cope with variation in spoken language. However, linguists have often claimed that this coping ability must be limited, since otherwise there is no way for such variation to lead to language change and regional accents. Previous research has shown that the presence or absence of perceptual compensation is indexed by the N400 and P600 components, where the N400 reflects the general awareness of accented speech input, and the P600 responds to phonological-rule violations. The present exploratory paper investigates the hypothesis that these same components are involved in the accommodation to sound change, and that their amplitudes reduce as a sound change becomes accepted by an individual. This is investigated on the basis of a vowel shift in Dutch that has occurred in the Netherlands but not in Flanders (the Dutch-speaking part of Belgium). Netherlandic and Flemish participants were presented auditorily with words containing either conservative or novel vowel realizations, plus two control conditions. Exploratory analyses found no significant differences in ERPs to these realizations, but did uncover two systematic differences. Over 9 months, the N400 response became less negative for both groups of participants, but this effect was significantly smaller for the Flemish participants, a finding in line with earlier results on accent processing. Additionally, in one control condition where a “novel” realization was produced based on vowel lengthening, which cannot be achieved by any rule of either Netherlandic or Flemish Dutch and changes the vowel's phonemic identity, a P600 was obtained in the Netherlandic participants, but not in the Flemish participants. This P600 corroborates a small number of other studies which found phonological P600s, and provides ERP validation of earlier behavioral results that adaptation to variation in speech is possible, until the variation crosses a phoneme boundary. The results of this exploratory study thus reveal two types of perceptual-compensation (dys)function: on-line accent processing, visible as N400 amplitude, and failure to recover from an ungrammatical realization that crosses a phoneme boundary, visible as a P600. These results provide further insight on how these two ERPs reflect the processing of variation. Show less
