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Background Reducing radiation dose to the hippocampus with hippocampal avoidance prophylactic cranial irradiation (HA-PCI) is proposed to prevent cognitive decline. It has, however, not been investigated whether hippocampal atrophy is actually mitigated by this approach. Here, we determined whether HA-PCI reduces hippocampal atrophy. Additionally, we evaluated neurotoxicity of (HA-)PCI to other brain regions. Finally, we evaluated associations of hippocampal atrophy and brain neurotoxicity with memory decline. Methods High-quality research MRI scans were acquired in the multicenter, randomized phase 3 trial NCT01780675. Hippocampal atrophy was evaluated for 4 months (57 HA-PCI patients and 46 PCI patients) and 12 months (28 HA-PCI patients and 27 PCI patients) after (HA-)PCI. We additionally studied multimodal indices of brain injury. Memory was assessed with the Hopkins Verbal Learning Test–Revised (HVLT-R). Results HA-PCI reduced hippocampal atrophy at 4 months (1.8% for HA-PCI and 3.0% for PCI) and at 12 months (3.0% for HA-PCI and 5.8% for PCI). Both HA-PCI and PCI were associated with considerable reductions in gray matter and normal-appearing white matter, increases in white matter hyperintensities, and brain aging. There were no significant associations between hippocampal atrophy and memory. Conclusions HA-PCI reduces hippocampal atrophy at 4 and 12 months compared to regular PCI. Both types of radiotherapy are associated with considerable brain injury. We did not find evidence for excessive brain injury after HA-PCI relative to PCI. Hippocampal atrophy was not associated with memory decline in this population as measured with HVLT-R. The usefulness of HA-PCI is still subject to debate.

Purpose Multiple sclerosis (MS) is a disease characterized by inflammatory demyelinated lesions. New treatment strategies are being developed to stimulate myelin repair. Quantitative myelin imaging could facilitate these developments. This first-in-man study aimed to evaluate [11C]MeDAS as a PET tracer for myelin imaging in humans. Methods Six healthy controls and 11 MS patients underwent MRI and dynamic [11C]MeDAS PET scanning with arterial sampling. Lesion detection and classification were performed on MRI. [11C]MeDAS time-activity curves of brain regions and MS lesions were fitted with various compartment models for the identification of the best model to describe [11C]MeDAS kinetics. Several simplified methods were compared to the optimal compartment model. Results Visual analysis of the fits of [11C]MeDAS time-activity curves showed no preference for irreversible (2T3k) or reversible (2T4k) two-tissue compartment model. Both volume of distribution and binding potential estimates showed a high degree of variability. As this was not the case for 2T3k-derived net influx rate (Ki), the 2T3k model was selected as the model of choice. Simplified methods, such as SUV and MLAIR2 correlated well with 2T3k-derived Ki, but SUV showed subject-dependent bias when compared to 2T3k. Both the 2T3k model and the simplified methods were able to differentiate not only between gray and white matter, but also between lesions with different myelin densities. Conclusion [11C]MeDAS PET can be used for quantification of myelin density in MS patients and is able to distinguish differences in myelin density within MS lesions. The 2T3k model is the optimal compartment model and MLAIR2 is the best simplified method for quantification. Trial registration. NL7262. Registered 18 September 2018.

Purpose Rapid acquisition scheme and parameter estimation method are proposed to acquire distortion-free spin- and stimulated-echo signals and combine the signals with a physics-driven unsupervised network to estimate T-1, T-2, and proton density (M-0) parameter maps, along with B-0 and B-1 information from the acquired signals. Theory and Methods An imaging sequence with three 90 degrees RF pulses is utilized to acquire spin- and stimulated-echo signals. We utilize blip-up/-down acquisition to eliminate geometric distortion incurred by the effects of B-0 inhomogeneity on rapid EPI acquisitions. For multislice imaging, echo-shifting is applied to utilize dead time between the second and third RF pulses to encode information from additional slice positions. To estimate parameter maps from the spin- and stimulated-echo signals with high fidelity, 2 estimation methods, analytic fitting and a novel unsupervised deep neural network method, are developed. Results The proposed acquisition provided distortion-free T-1, T-2, relative proton density (M0), B-0, and B-1 maps with high fidelity both in phantom and in vivo brain experiments. From the rapidly acquired spin- and stimulated-echo signals, analytic fitting and the network-based method were able to estimate T-1, T-2, M-0, B-0, and B-1 maps with high accuracy. Network estimates demonstrated noise robustness owing to the fact that the convolutional layers take information into account from spatially adjacent voxels. Conclusion The proposed acquisition/reconstruction technique enabled whole-brain acquisition of coregistered, distortion-free, T-1, T-2, M-0, B-0, and B-1 maps at 1 x 1 x 5 mm(3) resolution in 50 s. The proposed unsupervised neural network provided noise-robust parameter estimates from this rapid acquisition.

Cerebral microvascular rarefaction, the reduction in number of functional or structural small blood vessels in the brain, is thought to play an important role in the early stages of microvascular related brain disorders. A better understanding of its underlying pathophysiological mechanisms, and methods to measure microvascular density in the human brain are needed to develop biomarkers for early diagnosis and to identify targets for disease modifying treatments. Therefore, we provide an overview of the assumed main pathophysiological processes underlying cerebral microvascular rarefaction and the evidence for rarefaction in several microvascular related brain disorders. A number of advanced physiological MRI techniques can be used to measure the pathological alterations associated with microvascular rarefaction. Although more research is needed to explore and validate these MRI techniques in microvascular rarefaction in brain disorders, they provide a set of promising future tools to assess various features relevant for rarefaction, such as cerebral blood flow and volume, vessel density and radius and blood-brain barrier leakage.

Perivascular spaces (PVS) are compartments surrounding cerebral blood vessels that become visible on MRI when enlarged. Enlarged PVS (EPVS) are commonly seen in patients with cerebral small vessel disease (CSVD) and have been suggested to reflect dysfunctional perivascular clearance of soluble waste products from the brain. In this study, we investigated histopathological correlates of EPVS and how they relate to vascular amyloid-beta (A beta) in cerebral amyloid angiopathy (CAA), a form of CSVD that commonly co-exists with Alzheimer's disease (AD) pathology. We used ex vivo MRI, semi-automatic segmentation and validated deep-learning-based models to quantify EPVS and associated histopathological abnormalities. Severity of MRI-visible PVS during life was significantly associated with severity of MRI-visible PVS on ex vivo MRI in formalin fixed intact hemispheres and corresponded with PVS enlargement on histopathology in the same areas. EPVS were located mainly around the white matter portion of perforating cortical arterioles and their burden was associated with CAA severity in the overlying cortex. Furthermore, we observed markedly reduced smooth muscle cells and increased vascular A beta accumulation, extending into the WM, in individually affected vessels with an EPVS. Overall, these findings are consistent with the notion that EPVS reflect impaired outward flow along arterioles and have implications for our understanding of perivascular clearance mechanisms, which play an important role in the pathophysiology of CAA and AD.

Aim: To investigate the clinical relevance of the radiotherapy (RT) dose bath in patients treated for lower grade glioma (LGG).Methods: Patients (n = 17) treated with RT for LGG were assessed with neurocognitive function (NCF) tests and structural Magnetic Resonance Imaging (MRI) and categorized in subgroups based on tumour lateralisation. RT dose, volumetric results and cerebral microbleed (CMB) number were extracted for contralateral cerebrum, contralateral hippocampus, and cerebellum. The RT clinical target volume (CTV) was included in the analysis as a surrogate for focal tumour and other treatment effects. The relationships between RT dose, CTV, NCF and radiological outcome were analysed per subgroup.Results: The subgroup with left-sided tumours (n = 10) performed significantly lower on verbal tests. The RT dose to the right cerebrum, as well as CTV, were related to poorer performance on tests for processing speed, attention, and visuospatial abilities, and more CMB.In the subgroup with right-sided tumours (n = 7), RT dose in the left cerebrum was related to lower verbal memory performance, (immediate and delayed recall, r = -0.821, p = 0.023 and r = -0.937, p = 0.002, respectively), and RT dose to the left hippocampus was related to hippocampal volume (r = -0.857, p = 0.014), without correlation between CTV and NCF.Conclusion: By using a novel approach, we were able to investigate the clinical relevance of the RT dose bath in patients with LGG more specifically. We used combined MRI-derived and NCF outcome measures to assess radiation-induced brain damage, and observed potential RT effects on the left-sided brain resulting in lower verbal memory performance and hippocampus volume.

Magnetic resonance spectroscopy is a powerful, non-invasive, quantitative imaging technique that allows for the measurement of brain metabolites that has demonstrated utility in diagnosing and characterizing a broad range of neurological diseases. Its impact, however, has been limited due to small sample sizes and methodological variability in addition to intrinsic limitations of the method itself such as its sensitivity to motion. The lack of standardization from a data acquisition and data processing perspective makes it difficult to pool multiple studies and/or conduct multisite studies that are necessary for supporting clinically relevant findings. Based on the experience of the ENIGMA MRS work group and a review of the literature, this manuscript provides an overview of the current state of MRS data harmonization. Key factors that need to be taken into consideration when conducting both retrospective and prospective studies are described. These include (1) MRS acquisition issues such as pulse sequence, RF and B0 calibrations, echo time, and SNR; (2) data processing issues such as pre-processing steps, modeling, and quantitation; and (3) biological factors such as voxel location, age, sex, and pathology. Various approaches to MRS data harmonization are then described including meta-analysis, mega-analysis, linear modeling, ComBat and artificial intelligence approaches. The goal is to provide both novice and experienced readers with the necessary knowledge for conducting MRS data harmonization studies.

Available online 22 March 2023 Cerebrovascular reactivity (CVR), defined as the cerebral blood flow response to a vasoactive stimulus, is an imag- ing biomarker with demonstrated utility in a range of diseases and in typical development and aging processes. A robust and widely implemented method to map CVR involves using a breath-hold task during a BOLD fMRI scan. Recording end-tidal CO 2 (P ET CO 2 ) changes during the breath-hold task is recommended to be used as a refer- ence signal for modeling CVR amplitude in standard units (%BOLD/mmHg) and CVR delay in seconds. However, obtaining reliable P ET CO 2 recordings requires equipment and task compliance that may not be achievable in all settings. To address this challenge, we investigated two alternative reference signals to map CVR amplitude and delay in a lagged general linear model (lagged-GLM) framework: respiration volume per time (RVT) and average gray matter BOLD response (GM-BOLD). In 8 healthy adults with multiple scan sessions, we compare spatial agreement of CVR maps from RVT and GM-BOLD to those generated with P ET CO 2 . We define a threshold to determine whether a P ET CO 2 recording has “sufficient ”quality for CVR mapping and perform these comparisons in 16 datasets with sufficient P ET CO 2 and 6 datasets with insufficient P ET CO 2 . When P ET CO 2 quality is sufficient, both RVT and GM-BOLD produce CVR amplitude maps that are nearly identical to those from P ET CO 2 (after accounting for differences in scale), with the caveat they are not in standard units to facilitate between-group comparisons. CVR delays are comparable to P ET CO 2 with an RVT regressor but may be underestimated with the average GM-BOLD regressor. Importantly, when P ET CO 2 quality is insufficient, RVT and GM-BOLD CVR recover reasonable CVR amplitude and delay maps, provided the participant attempted the breath-hold task. Therefore, our framework offers a solution for achieving high quality CVR maps in both retrospective and prospective stud- ies where sufficient P ET CO 2 recordings are not available and especially in populations where obtaining reliable measurements is a known challenge (e.g., children). Our results have the potential to improve the accessibility of CVR mapping and to increase the prevalence of this promising metric of vascular health. This research was supported by the European Union’s Horizon 2020 research and innovation program (Marie Sk ł odowska-Curie grant agreement No. 713673 ), a fellowship from La Caixa Foundation (ID 100010434 , fellowship code LCF/BQ/IN17/11620063 ), the Spanish Ministry of Economy and Competitiveness (Ramon y Cajal Fellowship, RYC-2017–21845 ), the Spanish State Research Agency (BCBL “Severo Ochoa ”excellence accreditation, SEV-2015–490 ), the Basque Govern- ment ( BERC 2018–2021 and PIBA_2019_104 ), the Spanish Ministry of Science, Innovation and Universities (MICINN; PID2019–105520GB- 100 and FJCI-2017–31814 ). K.M.Z. was supported by the National In- stitutes of Health under a training program ( T32EB025766 ) and by the National Heart, Lung, And Blood Institute under Award Number F31HL166079 . The content is solely the responsibility of the authors and does not necessarily represent the official views of the National In- stitutes of Health.

The spinal cord is an elongated nervous structure that together with the brain forms the central nervous system. It relays sensory and motor information between the brain and the body, thus controlling most somatic and autonomic body functions. In recent years, great progress has been made in creating digital atlases for the mouse brain, covering regions, cell composition and connectivity. For the spinal cord, however, such atlases do not yet exist. In this dissertation, I present the first versions of high-resolution 3D atlases of the spinal cords for five mammalian species: mouse, rat, marmoset, rhesus monkey, and human. First, I summarize the current state of the efforts to understand the spinal cord and its organization principles from anatomy (cytoarchitecture) to cell classifications and connectome principles. I then describe how the different properties of the spinal cord can help us in reconstructing the various spinal structures. Next, I present a workflow for data-driven reconstruction that can be used to create 3D models of the spinal cord of any species based on available annotated 2D microscopy images. I used data from Sengul, Watson, et al., 2012 to generate 3D reference volumes of the cytoarchitecture of the 5 mammalian species: mouse, rat, marmoset, rhesus monkey and human. Every 3D reference volume model comprises six levels of the spinal cytoarchitecture and defines their locations, shapes, and volumes. This allows us to compare the spinal cord of these 5 species. I find that all reconstructed spinal cords are remarkably similar, showing far fewer differences than the brains of the respective species. For the mouse spinal cord, I use data from the Allen Institute for Brain Science to generate a cell atlas for the three major spinal cell types: interneurons, motoneurons, and glial cells. The mouse spinal cell atlas comprises the densities and positions of 11,7 million cells in total with 2.7 million interneurons, about 31 thousand motoneurons, and 9.0 million glial cells. Next, I discuss how recent transcriptomic data can be used to assign a gene expression profile to each neuron in the spinal cell atlas. I present a preliminary analysis of RNA-sequencing and in situ RNA hybridization data aiming to develop a workflow for labeling of spinal cells with appropriate transcriptome profiles. Finally, I summarize the results of my dissertation as well as consequences and limitations of the underlying assumptions. This discussion ends with an outlook for how the atlas can be developed further in the future.

ObjectiveTo determine whether the timing of puberty associates with school performance.MethodsGrowth data on 13,183 children born between 1997 and 2002, were collected from child health clinics and school healthcare and school performance data from school records. Age at peak height velocity (PHV) marked pubertal timing. The relationships between age at PHV and average grades in mathematics, native language, English, and physical education from school years 6 (end of elementary school; age 11-12 years), 7 (start of middle school; 12-13 years), and 9 (end of middle school; 14-15 years) were modeled using generalized estimating equations and linear mixed models, adjusted for the month of birth and annual income and education levels in school catchment areas.ResultsThe mean (SD) age at PHV was 13.54 (1.17) years in boys and 11.43 (1.18) years in girls. In girls, age at PHV was associated with grades in mathematics (β=0.041–0.062, pConclusionsIn both sexes, the timing of puberty was associated with the grades in physical education, and in girls, with academic achievement. The decrease in boys’ mathematics grades and sex difference in academic achievement were unexplained by the timing of puberty.

Deriving reliable information about the structural and functional architecture of the brain in vivo is critical for the clinical and basic neurosciences. In the new era of large population‐based datasets, when multiple brain imaging modalities and contrasts are combined in order to reveal latent brain structural patterns and associations with genetic, demographic and clinical information, automated and stringent quality control (QC) procedures are important. Diffusion magnetic resonance imaging (dMRI) is a fertile imaging technique for probing and visualising brain tissue microstructure in vivo, and has been included in most standard imaging protocols in large‐scale studies. Due to its sensitivity to subject motion and technical artefacts, automated QC procedures prior to scalar diffusion metrics estimation are required in order to minimise the influence of noise and artefacts. However, the QC procedures performed on raw diffusion data cannot guarantee an absence of distorted maps among the derived diffusion metrics. Thus, robust and efficient QC methods for diffusion scalar metrics are needed. Here, we introduce Fast qualitY conTrol meThod foR derIved diffUsion Metrics (YTTRIUM), a computationally efficient QC method utilising structural similarity to evaluate diffusion map quality and mean diffusion metrics. As an example, we applied YTTRIUM in the context of tract‐based spatial statistics to assess associations between age and kurtosis imaging and white matter tract integrity maps in U.K. Biobank data (n = 18,608). To assess the influence of outliers on results obtained using machine learning (ML) approaches, we tested the effects of applying YTTRIUM on brain age prediction. We demonstrated that the proposed QC pipeline represents an efficient approach for identifying poor quality datasets and artefacts and increases the accuracy of ML based brain age prediction., Accurate quality control of diffusion scalar maps in big data. Influence of outliers on brain age gap estimation.

Primary education is the incubator for learning academic skills that help children to become a literate, communicative, and independent person. Over this learning period, nonlinear and regional changes in the brain occur, but how these changes relate to academic performance, such as reading ability, is still unclear. In the current study, we analyzed longitudinal T1 MRI data of 41 children in order to investigate typical cortical development during the early reading stage (end of kindergarten–end of grade 2) and advanced reading stage (end of grade 2–middle of grade 5), and to detect putative deviant trajectories in children with dyslexia. The structural brain change was quantified with a reliable measure that directly calculates the local morphological differences between brain images of two time points, while considering the global head growth. When applying this measure to investigate typical cortical development, we observed that left temporal and temporoparietal regions belonging to the reading network exhibited an increase during the early reading stage and stabilized during the advanced reading stage. This suggests that the natural plasticity window for reading is within the first years of primary school, hence earlier than the typical period for reading intervention. Concerning neurotrajectories in children with dyslexia compared to typical readers, we observed no differences in gray matter development of the left reading network, but we found different neurotrajectories in right IFG opercularis (during the early reading stage) and in right isthmus cingulate (during the advanced reading stage), which could reflect compensatory neural mechanisms., In this three‐time point longitudinal MRI study, we show that during the first 2 years of primary school gray matter regions of the reading network seem to mature while stabilizing during the later grades of primary school. Children with dyslexia show a deviant cortical development in regions outside of the reading network.

In the last 20 years, research on turn-taking and duetting has flourished in at least three, historically separate disciplines: animal behavior, language sciences, and music cognition. While different in scope and methods, all three ultimately share one goal—namely the understanding of timed interactions among conspecifics. In this perspective, we aim at connecting turn-taking and duetting across species from a neural perspective. While we are still far from a defined neuroethology of turn-taking, we argue that the human neuroscience of turn-taking and duetting can inform animal bioacoustics. For this, we focus on a particular concept, interhemispheric connectivity, and its main white-matter substrate, the corpus callosum. We provide an overview of the role of corpus callosum in human neuroscience and interactive music and speech. We hypothesize its mechanistic connection to turn-taking and duetting in our species, and a potential translational link to mammalian research. We conclude by illustrating empirical venues for neuroethological research of turn-taking and duetting in mammals.

N-acetylaspartate (NAA) is the second most abundant metabolite in the human brain; although it is assumed to be a proxy for a neuronal marker, its function is not fully elucidated. NAA is also detectable in plasma, but its relation to cerebral NAA levels, cognitive performance, or features of cerebral disease has not been investigated. To study whether circulating NAA tracks cerebral NAA levels, and whether circulating NAA correlates with cognitive function and features of cerebral small vessel disease (SVD). Two datasets were analyzed. In dataset 1, structural MRI was acquired in 533 subjects to assess four features of cerebral SVD. Cognitive function was evaluated with standardized test scores (N = 824). In dataset 2, brain 1H-MRS from the occipital region was acquired (N = 49). In all subjects, fasting circulating NAA was measured with mass spectrometry. Dataset 1: in univariate and adjusted for confounders models, we found no correlation between circulating NAA and the examined features of cerebral SVD. In univariate analysis, circulating NAA levels were associated inversely with the speed in information processing and the executive function score, however these associations were lost after accounting for confounders. In line with the negative findings of dataset 1, in dataset 2 there was no correlation between circulating and central NAA or total NAA levels. This study indicates that circulating NAA levels do not reflect central (occipital) NAA levels, cognitive function, or cerebral small vessel disease in man.

We conducted a cross-sectional pilot study to explore the biological substrate of the Motoric Cognitive Risk (MCR) syndrome in a Memory Clinic cohort, using a multimodal imaging approach. Twenty participants were recruited and classified as MCR+/−. Amyloid- and tau-PET uptakes, temporal atrophy, white matter hyperintensities, lateral ventricular volume (LVV), and diffusion tensor parameters were compared between groups. No significant differences were found in imaging features related to Alzheimer’s disease or gross vascular damage. MCR+ patients had increased LVV and altered diffusion parameters in the superior corona radiata. Ventricular enlargement and microstructural damage of the surrounding white matter tracts could contribute to MCR pathophysiology.

Background Diffusion tensor imaging is a widely used imaging method of brain white matter, but it is prone to imaging artifacts. The data corrections can affect the measured values. Objective To explore the impact of susceptibility correction on diffusion metrics. Materials and methods A cohort of 27 healthy adolescents (18 boys, 9 girls, mean age 12.7 years) underwent 3-T MRI, and we collected two diffusion data sets (anterior–posterior). The data were processed both with and without susceptibility artifact correction. We derived fractional anisotropy, mean diffusivity and histogram data of fiber length distribution from both the corrected and uncorrected data, which were collected from the corpus callosum, corticospinal tract and cingulum bilaterally. Results Fractional anisotropy and mean diffusivity values significantly differed when comparing the pathways in all measured tracts. The fractional anisotropy values were lower and the mean diffusivity values higher in the susceptibility-corrected data than in the uncorrected data. We found a significant difference in total tract length in the corpus callosum and the corticospinal tract. Conclusion This study indicates that susceptibility correction has a significant effect on measured fractional anisotropy, and on mean diffusivity values and tract lengths. To receive reliable and comparable results, the correction should be used systematically.

Proton therapy offers an attractive alternative to conventional photon-based radiotherapy in low grade glioma patients, delivering radiotherapy with equivalent efficacy to the tumour with less radiation exposure to the brain. In the Netherlands, patients with favourable prognosis based on tumour and patient characteristics can be offered proton therapy. Radiation-induced neurocognitive function decline is a major concern in these long surviving patients. Although level 1 evidence of superior clinical outcome with proton therapy is lacking, the Dutch National Health Care Institute concluded that there is scientific evidence to assume that proton therapy can have clinical benefit by reducing radiation-induced brain damage. Based on this decision, proton therapy is standard insured care for selected low grade glioma patients. Patients with other intracranial tumours can also qualify for proton therapy, based on the same criteria. In this paper, the evidence and considerations that led to this decision are summarised. Additionally, the eligibility criteria for proton therapy and the steps taken to obtain high-quality data on treatment outcome are discussed. (C) 2020 The Author(s). Published by Elsevier B.V.

Proton therapy offers an attractive alternative to conventional photon-based radiotherapy in low grade glioma patients, delivering radiotherapy with equivalent efficacy to the tumour with less radiation exposure to the brain. In the Netherlands, patients with favourable prognosis based on tumour and patient characteristics can be offered proton therapy. Radiation-induced neurocognitive function decline is a major concern in these long surviving patients. Although level 1 evidence of superior clinical outcome with proton therapy is lacking, the Dutch National Health Care Institute concluded that there is scientific evidence to assume that proton therapy can have clinical benefit by reducing radiation-induced brain damage. Based on this decision, proton therapy is standard insured care for selected low grade glioma patients. Patients with other intracranial tumours can also qualify for proton therapy, based on the same criteria. In this paper, the evidence and considerations that led to this decision are summarised. Additionally, the eligibility criteria for proton therapy and the steps taken to obtain high-quality data on treatment outcome are discussed. (C) 2020 The Author(s). Published by Elsevier B.V.

Over the past few decades, neuroimaging has become a ubiquitous tool in basic research and clinical studies of the human brain. However, no reference standards currently exist to quantify individual differences in neuroimaging metrics over time, in contrast to growth charts for anthropometric traits such as height and weight1. Here we assemble an interactive open resource to benchmark brain morphology derived from any current or future sample of MRI data ( http://www.brainchart.io/ ). With the goal of basing these reference charts on the largest and most inclusive dataset available, acknowledging limitations due to known biases of MRI studies relative to the diversity of the global population, we aggregated 123,984 MRI scans, across more than 100 primary studies, from 101,457 human participants between 115 days post-conception to 100 years of age. MRI metrics were quantified by centile scores, relative to non-linear trajectories2 of brain structural changes, and rates of change, over the lifespan. Brain charts identified previously unreported neurodevelopmental milestones3, showed high stability of individuals across longitudinal assessments, and demonstrated robustness to technical and methodological differences between primary studies. Centile scores showed increased heritability compared with non-centiled MRI phenotypes, and provided a standardized measure of atypical brain structure that revealed patterns of neuroanatomical variation across neurological and psychiatric disorders. In summary, brain charts are an essential step towards robust quantification of individual variation benchmarked to normative trajectories in multiple, commonly used neuroimaging phenotypes., R.A.I.B. was supported by a British Academy Postdoctoral fellowship and by the Autism Research Trust. J. Seidlitz was supported by NIMH T32MH019112-29 and K08MH120564. S.R.W. was funded by UKRI Medical Research Council MC_UU_00002/2 and was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). E.T.B. was supported by an NIHR Senior Investigator award and the Wellcome Trust collaborative award for the Neuroscience in Psychiatry Network. A.F.A.-B. was supported by NIMH K08MH120564. Data were curated and analysed using a computational facility funded by an MRC research infrastructure award (MR/M009041/1) to the School of Clinical Medicine, University of Cambridge and supported by the mental health theme of the NIHR Cambridge Biomedical Research Centre.

Regulatory T cells (Tregs) control inflammation and maintain immune homeostasis. The well-characterised circulatory population of CD4+Foxp3+ Tregs is effective at preventing autoimmunity and constraining the immune response, through direct and indirect restraint of conventional T cell activation. Recent advances in Treg cell biology have identified tissue-resident Tregs, with tissue-specific functions that contribute to the maintenance of tissue homeostasis and repair. A population of brain-resident Tregs, characterised as CD69+, has recently been identified in the healthy brain of mice and humans, with rapid population expansion observed under a number of neuroinflammatory conditions. During neuroinflammation, brain-resident Tregs have been proposed to control astrogliosis through the production of amphiregulin, polarize microglia into neuroprotective states, and restrain inflammatory responses by releasing IL-10. While protective effects for Tregs have been demonstrated in a number of neuroinflammatory pathologies, a clear demarcation between the role of circulatory and brain-resident Tregs has been difficult to achieve. Here we review the state-of-the-art for brain-resident Treg population, and describe their potential utilization as a therapeutic target across different neuroinflammatory conditions. ispartof: IMMUNOLOGY LETTERS vol:248 pages:26-30 ispartof: location:Netherlands status: published

A B S T R A C T The white matter structures of the human brain can be represented using diffusion-weighted MRI tractography. Unfortunately, tractography is prone to find false-positive streamlines causing a severe decline in its specificity and limiting its feasibility in accurate structural brain connectivity analyses. Filtering algorithms have been pro-posed to reduce the number of invalid streamlines but the currently available filtering algorithms are not suitable to process data that contains motion artefacts which are typical in clinical research. We augmented the Con-vex Optimization Modelling for Microstructure Informed Tractography (COMMIT) algorithm to adjust for these signals drop-out motion artefacts. We demonstrate with comprehensive Monte-Carlo whole brain simulations and in vivo infant data that our robust algorithm is capable of properly filtering tractography reconstructions despite these artefacts. We evaluated the results using parametric and non-parametric statistics and our results demonstrate that if not accounted for, motion artefacts can have severe adverse effects in human brain structural connectivity analyses as well as in microstructural property mappings. In conclusion, the usage of robust filtering methods to mitigate motion related errors in tractogram filtering is highly beneficial, especially in clinical stud-ies with uncooperative patient groups such as infants. With our presented robust augmentation and open-source implementation, robust tractogram filtering is readily available.

Highlights • Differences observed in all blood marker categories, from on-therapy until years later. • Differences observed in metabolic and blood cell markers, even pre-chemotherapy. • Blood markers were associated with cognition mainly years post-chemotherapy. • Structural brain metrics associated with cognition shortly and years post-treatment., Breast cancer treatment can induce alterations in blood- and neuroimaging-based markers. However, an overview of the predictive value of these markers for cognition is lacking for breast cancer survivors. This systematic review summarized studies of the last decade, using the PubMed database, evaluating blood markers, and the association between blood- or structural neuroimaging markers and cognition across the chemotherapy trajectory for primary breast cancer, following PRISMA guidelines. Forty-four studies were included. Differences were observed in all blood marker categories, from on-therapy until years post-chemotherapy. Associations were found between cognitive functioning and (1) blood markers (mainly inflammation-related) during, shortly-, or years post-chemotherapy and (2) white and gray matter metrics in frontal, temporal and parietal brain regions months up until years post-chemotherapy. Preliminary evidence exists for epigenetic and metabolic changes being associated with cognition, only after chemotherapy. This review demonstrated time-dependent associations between specific blood-based and structural neuroimaging markers with cognitive impairment in patients with breast cancer. Future studies are encouraged to include both neuroimaging- and blood markers (e.g. of neuronal integrity, epigenetics and metabolism) to predict long-term cognitive effects of chemotherapy.

Background Researchers have used direct electrical brain stimulation to treat a range of neurological and psychiatric disorders. However, for brain stimulation to be maximally effective, clinicians and researchers should optimize stimulation parameters according to desired outcomes. Objective The goal of our large-scale study was to comprehensively evaluate the effects of stimulation at different parameters and locations on neuronal activity across the human brain. Methods To examine how different kinds of stimulation affect human brain activity, we compared the changes in neuronal activity that resulted from stimulation at a range of frequencies, amplitudes, and locations with direct human brain recordings. We recorded human brain activity directly with electrodes that were implanted in widespread regions across 106 neurosurgical epilepsy patients while systematically stimulating across a range of parameters and locations. Results Overall, stimulation most often had an inhibitory effect on neuronal activity, consistent with earlier work. When stimulation excited neuronal activity, it most often occurred from high-frequency stimulation. These effects were modulated by the location of the stimulating electrode, with stimulation sites near white matter more likely to cause excitation and sites near gray matter more likely to inhibit neuronal activity. Conclusion By characterizing how different stimulation parameters produced specific neuronal activity patterns on a large scale, our results provide an electrophysiological framework that clinicians and researchers may consider when designing stimulation protocols to cause precisely targeted changes in human brain activity.

Rationale: Hypertension is a major risk factor for cerebral small vessel disease, the most prevalent cause of vascular cognitive impairment. As we have shown, hypertension induced by a prolonged Angiotensin II infusion is associated with increased permeability of the blood-brain barrier (BBB), chronic activation of microglia and myelin loss. In this study we therefore aim to determine the contribution of microglia to hypertension-induced cognitive impairment in an experimental hypertension model by a pharmacological depletion approach.Methods: For this study, adult Cx3Cr1gfp/wtxThy1yfp/0 reporter mice were infused for 12 weeks with Angiotensin II or saline and subgroups were treated with PLX5622, a highly selective CSF1R tyrosine kinase inhibitor. Systolic blood pressure (SBP) was measured via tail-cuff. Short- and long-term spatial memory was assessed during an Object Location task and a Morris Water Maze task (MWM). Microglia depletion efficacy was assessed by flow cytometry and immunohistochemistry. BBB leakages, microglia phenotype and myelin integrity were assessed by immunohistochemistry.Results: SBP, heart weight and carotid pulsatility were increased by Ang II and were not affected by PLX5622. Short-term memory was significantly impaired in Ang II hypertensive mice, and partly prevented in Ang II mice treated with PLX5622. Histological and flow cytometry analysis revealed almost complete ablation of microglia and a 60% depletion of brain resident perivascular macrophages upon CSF1R inhibition. Number and size of BBB leakages were increased in Ang II hypertensive mice, but not altered by PLX5622 treatment. Microglia acquired a pro-inflammatory phenotype at the site of BBB leakages in both Saline and Ang II mice and were successfully depleted by PLX5622. There was however no significant change in myelin integrity at the site of leakages.Conclusion: Our results show that depletion of microglia and PVMs, by CSF1R inhibition prevents short-term memory impairment in Ang II induced hypertensive mice. We suggest this beneficial effect is mediated by the major decrease of pro-inflammatory microglia within BBB leakages. This novel finding supports the critical role of brain immune cells in the pathogenesis of hypertension-related cognitive impairment. An adequate modulation of microglia/PVM density and phenotype may constitute a relevant approach to prevent and/or limit the progression of vascular cognitive impairment.

Impaired cognitive functioning is a core feature of schizophrenia, and is hypothesized to be due to myelination as well as interneuron defects during adolescent prefrontal cortex (PFC) development. Here we report that in the apomorphine-susceptible (APO-SUS) rat model, which has schizophrenia-like features, a myelination defect occurred specifically in parvalbumin interneurons. The adult rats displayed medial PFC (mPFC)-dependent cognitive inflexibility, and a reduced number of mature oligodendrocytes and myelinated parvalbumin inhibitory axons in the mPFC. In the developing mPFC, we observed decreased myelin-related gene expression that persisted into adulthood. Environmental enrichment applied during adolescence restored parvalbumin interneuron hypomyelination as well as cognitive inflexibility. Collectively, these findings highlight that impairment of parvalbumin interneuron myelination is related to schizophrenia-relevant cognitive deficits., Dysfunction of GABAergic neurons in the prefrontal cortex has been reported in schizophrenia. Here, the authors use the apomorphine-susceptible rat, which displays some schizophrenia-like behaviors, and show that interneurons in the medial prefrontal cortex are hypomyelinated, which may contribute to this behavioral phenotype.

BACKGROUND AND PURPOSE: The process of myelination starts in utero around 20 weeks of gestation and continues through adulthood. We first set out to characterize the maturation of the tract-specific myelin content in healthy subjects from childhood (7-12 years) into adulthood (18-32 years). Second, we apply the resulting development graph to children with childhood absence epilepsy (CAE), a pediatric epilepsy that was previously characterized by changes in myelin content.METHODS: In a prospective cross-sectional study, 15 healthy children (7-12 years), 14 healthy adult participants (18-32 years) and 17 children with a clinical diagnosis of CAE (6-12 years) were included. For each participant, diffusion weighted images were acquired to reconstruct bundles of white matter tracts and multi-echo multi-slice GRASE images were acquired for myelin-water estimation. Subsequently, a tract-specific myelin development graph was constructed using the percentual difference in myelin-water content from childhood (12 year) to adulthood (25 year).RESULTS: The graph revealed myelination patterns, where tracts in the central regions myelinate prior to peripheral tracts and intra-hemispheric tracts as well as tracts in the left hemisphere myelinate prior to inter-hemispheric tracts and tracts in the right hemisphere, respectively. No significant differences were found in myelin-water content between children with CAE and healthy children for neither the early developing tracts, nor the tracts that develop in a later stage. However, the difference between the myelin-water of late and early developing tracts is significantly smaller in the children with CAE.CONCLUSION: These results indicate that CAE is associated with widespread neurodevelopmental myelin differences.

Patients with acquired brain injury (ABI) suffer from cognitive deficits that interfere significantly with their daily lives. These deficits are long-lasting and no treatment options are available. A better understanding of the mechanistic basis for these cognitive deficits is needed to develop novel treatments. Intracellular cyclic adenosine monophosphate (cAMP) levels are decreased in ABI. Herein, we focus on augmentation of cAMP by PDE4 inhibitors and the potentially synergistic mechanisms in traumatic brain injury. A major acute pathophysiological event in ABI is the breakdown of the blood-brain-barrier (BBB). Intracellular cAMP pathways are involved in the subsequent emergence of edema, inflammation and hyperexcitability. We propose that PDE4 inhibitors such as roflumilast can improve cognition by modulation of the activity in the cAMPPhosphokinase A-Ras-related C3 botulinum toxin substrate (RAC1) inflammation pathway. In addition, PDE4 inhibitors can also directly enhance network plasticity and attenuate degenerative processes and cognitive dysfunction by increasing activity of the canonical cAMP/phosphokinase- A/cAMP Responsive Element Binding protein (cAMP/PKA/CREB) plasticity pathway. Doublecourtin and microtubule-associated protein 2 are generated following activation of the cAMP/PKA/CREB pathway and are decreased or even absent after injury. Both proteins are involved in neuronal plasticity and may consist of viable markers to track these processes. It is concluded that PDE4 inhibitors may consist of a novel class of drugs for the treatment of residual symptoms in ABI attenuating the pathophysiological consequences of a BBB breakdown by their anti-inflammatory actions via the cAMP/PKA/RAC1 pathway and by increasing synaptic plasticity via the cAMP/PKA/CREB pathway. Roflumilast improves cognition in young and elderly humans and would be an excellent candidate for a proof of concept study in ABI patients.

Patients with acquired brain injury (ABI) suffer from cognitive deficits that interfere significantly with their daily lives. These deficits are long-lasting and no treatment options are available. A better understanding of the mechanistic basis for these cognitive deficits is needed to develop novel treatments. Intracellular cyclic adenosine monophosphate (cAMP) levels are decreased in ABI. Herein, we focus on augmentation of cAMP by PDE4 inhibitors and the potentially synergistic mechanisms in traumatic brain injury. A major acute pathophysiological event in ABI is the breakdown of the blood- brain-barrier (BBB). Intracellular cAMP pathways are involved in the subsequent emergence of edema, inflammation and hyperexcitability. We propose that PDE4 inhibitors such as roflumilast can improve cognition by modulation of the activity in the cAMP-Phosphokinase A-Ras-related C3 botulinum toxin substrate (RAC1) inflammation pathway. In addition, PDE4 inhibitors can also directly enhance network plasticity and attenuate degenerative processes and cognitive dysfunction by increasing activity of the canonical cAMP/phosphokinase-A/cAMP Responsive Element Binding protein (cAMP/PKA/CREB) plasticity pathway. Doublecourtin and microtubule-associated protein 2 are generated following activation of the cAMP/PKA/CREB pathway and are decreased or even absent after injury. Both proteins are involved in neuronal plasticity and may consist of viable markers to track these processes. It is concluded that PDE4 inhibitors may consist of a novel class of drugs for the treatment of residual symptoms in ABI attenuating the pathophysiological consequences of a BBB breakdown by their anti- inflammatory actions via the cAMP/PKA/RAC1 pathway and by increasing synaptic plasticity via the cAMP/PKA/CREB pathway. Roflumilast improves cognition in young and elderly humans and would be an excellent candidate for a proof of concept study in ABI patients.

Image calibration; Integrity; Multiple sclerosis Calibración de imagen; Integridad; Esclerosis múltiple Calibració d'imatge; Integritat; Esclerosi múltiple Introduction Calculation of a T1w/T2w ratio was introduced as a proxy for myelin integrity in the brain of multiple sclerosis (MS) patients. Since nowadays 3D FLAIR is commonly used for lesion detection instead of T2w images, we introduce a T1w/FLAIR ratio as an alternative for the T1w/T2w ratio. Objectives Bias and intensity variation are widely present between different scanners, between subjects and within subjects over time in T1w, T2w and FLAIR images. We present a standardized method for calculating a histogram calibrated T1w/FLAIR ratio to reduce bias and intensity variation in MR sequences from different scanners and at different time-points. Material and methods 207 Relapsing Remitting MS patients were scanned on 4 different 3 T scanners with a protocol including 3D T1w, 2D T2w and 3D FLAIR images. After bias correction, T1w/FLAIR ratio maps and T1w/T2w ratio maps were calculated in 4 different ways: without calibration, with linear histogram calibration as described by Ganzetti et al. (2014), and by using 2 methods of non-linear histogram calibration. The first nonlinear calibration uses a template of extra-cerebral tissue and cerebrospinal fluid (CSF) brought from Montreal Neurological Institute (MNI) space to subject space; for the second nonlinear method we used an extra-cerebral tissue and CSF template of our own subjects. Additionally, we segmented several brain structures such as Normal Appearing White Matter (NAWM), Normal Appearing Grey Matter (NAGM), corpus callosum, thalami and MS lesions using Freesurfer and Samseg. Results The coefficient of variation of T1w/FLAIR ratio in NAWM for the no calibrated, linear, and 2 nonlinear calibration methods were respectively 24, 19.1, 9.5, 13.8. The nonlinear methods of calibration showed the best results for calculating the T1w/FLAIR ratio with a smaller dispersion of the data and a smaller overlap of T1w/FLAIR ratio in the different segmented brain structures. T1w/T2w and T1w/FLAIR ratios showed a wider range of values compared to MTR values. Conclusions Calibration of T1w/T2w and T1w/FLAIR ratio maps is imperative to account for the sources of variation described above. The nonlinear calibration methods showed the best reduction of between-subject and within-subject variability. The T1w/T2w and T1w/FLAIR ratio seem to be more sensitive to smaller changes in tissue integrity than MTR. Future work is needed to determine the exact substrate of T1w/FLAIR ratio and to obtain correlations with clinical outcome.

Breast cancer treatment can induce alterations in blood-and neuroimaging-based markers. However, an overview of the predictive value of these markers for cognition is lacking for breast cancer survivors.This systematic review summarized studies of the last decade, using the PubMed database, evaluating blood markers, and the association between blood-or structural neuroimaging markers and cognition across the chemotherapy trajectory for primary breast cancer, following PRISMA guidelines.Forty-four studies were included. Differences were observed in all blood marker categories, from on-therapy until years post-chemotherapy. Associations were found between cognitive functioning and (1) blood markers (mainly inflammation-related) during, shortly-, or years post-chemotherapy and (2) white and gray matter metrics in frontal, temporal and parietal brain regions months up until years post-chemotherapy. Preliminary evidence exists for epigenetic and metabolic changes being associated with cognition, only after chemotherapy.This review demonstrated time-dependent associations between specific blood-based and structural neuroimaging markers with cognitive impairment in patients with breast cancer. Future studies are encouraged to include both neuroimaging-and blood markers (e.g. of neuronal integrity, epigenetics and metabolism) to predict long-term cognitive effects of chemotherapy.