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Highlights • The entire brain is susceptible to dose-dependent volume loss after RT. • Future studies should examine the impact of cerebral volume loss on cognition. • Current sparing strategies in RT for brain tumours may need to be reconsidered., Purpose Numerous brain MR imaging studies have been performed to understand radiation-induced cognitive decline. However, many of them focus on a single region of interest, e.g. cerebral cortex or hippocampus. In this study, we use deformation-based morphometry (DBM) and voxel-based morphometry (VBM) to measure the morphological changes in patients receiving fractionated photon RT, and relate these to the dose. Additionally, we study tissue specific volume changes in white matter (WM), grey matter (GM), cerebrospinal fluid and total intracranial volume (TIV). Methods and materials From our database, we selected 28 patients with MRI of high quality available at baseline and 1 year after RT. Scans were rigidly registered to each other, and to the planning CT and dose file. We used DBM to study non-tissue-specific volumetric changes, and VBM to study volume loss in grey matter. Observed changes were then related to the applied radiation dose (in EQD2). Additionally, brain tissue was segmented into WM, GM and cerebrospinal fluid, and changes in these volumes and TIV were tested. Results Performing DBM resulted in clusters of dose-dependent volume loss 1 year after RT seen throughout the brain. Both WM and GM were affected; within the latter both cerebral cortex and subcortical nuclei show volume loss. Volume loss rates ranging from 5.3 to 15.3%/30 Gy were seen in the cerebral cortical regions in which more than 40% of voxels were affected. In VBM, similar loss rates were seen in the cortex and nuclei. The total volume of WM and GM significantly decreased with rates of 5.8% and 2.1%, while TIV remained unchanged as expected. Conclusions Radiotherapy is associated with dose-dependent intracranial morphological changes throughout the entire brain. Therefore, we will consider to revise sparing of organs at risk based on future cognitive and neurofunctional data.

Highlights • Subcortical grey matter is susceptible to dose-dependent volume loss after RT. • Hippocampal age increases 1 year after radiotherapy, by a median of 11 years. • We may need to reconsider current sparing strategies in RT for brain tumours. • Future studies should examine the impact of deep GM volume loss on cognition., Background and purpose The relation between radiotherapy (RT) dose to the brain and morphological changes in healthy tissue has seen recent increased interest. There already is evidence for changes in the cerebral cortex and white matter, as well as selected subcortical grey matter (GM) structures. We studied this relation in all deep GM structures, to help understand the aetiology of post-RT neurocognitive symptoms. Materials and methods We selected 31 patients treated with RT for grade II-IV glioma. Pre-RT and 1 year post-RT 3D T1-weighted MRIs were automatically segmented, and the changes in volume of the following structures were assessed: amygdala, nucleus accumbens, caudate nucleus, hippocampus, globus pallidus, putamen, and thalamus. The volumetric changes were related to the mean RT dose received by each structure. Hippocampal volumes were entered into a population-based nomogram to estimate hippocampal age. Results A significant relation between RT dose and volume loss was seen in all examined structures, except the caudate nucleus. The volume loss rates ranged from 0.16 to 1.37%/Gy, corresponding to 4.9–41.2% per 30 Gy. Hippocampal age, as derived from the nomogram, was seen to increase by a median of 11 years. Conclusion Almost all subcortical GM structures are susceptible to radiation-induced volume loss, with higher volume loss being observed with increasing dose. Volume loss of these structures is associated with neurological deterioration, including cognitive decline, in neurodegenerative diseases. To support a causal relationship between radiation-induced deep GM loss and neurocognitive functioning in glioma patients, future studies are needed that directly correlate volumetrics to clinical outcomes.

Compartmental diffusion MRI models that account for intravoxel incoherent motion (IVIM) of blood perfusion allow for estimation of the fractional volume of the microvascular compartment. Conventional IVIM models are known to be biased by not accounting for partial volume effects caused by free water and cerebrospinal fluid (CSF), or for tissue-dependent relaxation effects. In this work, a three-compartment model (tissue, free water and blood) that includes relaxation terms is introduced. To estimate the model parameters, in vivo human data were collected with multiple echo times (TE), inversion times (TI) and b-values, which allowed a direct relaxation estimate alongside estimation of perfusion, diffusion and fractional volume parameters. Compared to conventional two-compartment models (with and without relaxation compensation), the three-compartment model showed less effects of CSF contamination. The proposed model yielded significantly different volume fractions of blood and tissue compared to the non-relaxation-compensated model, as well as to the conventional two-compartment model, suggesting that previously reported parameter ranges, using models that do not account for relaxation, should be reconsidered. Keywords: Intravoxel incoherent motion, Perfusion fraction, Pseudo-diffusion, Relaxation, Diffusion

The insula is important for the processing of pleasant aspects of touch whereas its role in the processing of emotionally neutral touch has been less explored. Here, we used a network approach to investigate the insular processing of pleasant stroking touch and emotionally neutral vibratory touch, analysing functional magnetic resonance imaging data from 23 healthy adult participants. Vibration and skin stroking activated areas in the posterior, middle and anterior insula. Psychophysiological interaction analyses suggested that skin stroking increased functional connectivity between the posterior and ventral anterior insula. Vibration instead increased functional connectivity between the posterior and dorsal anterior insula, and induced a stronger decrease of the default mode network activity compared to stroking. These results confirmed findings from previous studies showing that the posterior insula processes affective touch information. We suggest that this is accomplished by relaying tactile information from the posterior insula to ventral anterior insula, an area tightly connected to the emotional parts of the brain. However, our results also suggested that the insula processes tactile information with less emotional valence. A central hub in this processing seemed to be the right dorsal anterior insula. Keywords: Touch, fMRI, Insula, Resting state networks

Highlights • Bulbar symptom onset shows more structural impairment than limb-onset in ALS. • Bulbar-onset ALS is characterized by an early and widespread cortical pathology. • Application of the D50 model enables comparability of heterogenous patient cohorts., Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease that is characterized by a high heterogeneity in patients’ disease course. Patients with bulbar onset of symptoms (b-ALS) have a poorer prognosis than patients with limb onset (l-ALS). However, neuroimaging correlates of the assumed biological difference between b-ALS and l-ALS may have been obfuscated by patients’ diversity in the disease course. We conducted Voxel-Based-Morphometry (VBM) and Tract-Based-Spatial-Statistics (TBSS) in a group of 76 ALS patients without clinically relevant cognitive deficits. The subgroups of 26 b-ALS and 52 l-ALS patients did not differ in terms of disease Phase or disease aggressiveness according to the D50 progression model. VBM analyses showed widespread ALS-related changes in grey and white matter, that were more pronounced for b-ALS. TBSS analyses revealed that b-ALS was predominantly characterized by frontal fractional anisotropy decreases. This demonstrates a higher degree of neurodegenerative burden for the group of b-ALS patients in comparison to l-ALS. Correspondingly, higher bulbar symptom burden was associated with right-temporal and inferior-frontal grey matter density decreases as well as fractional anisotropy decreases in inter-hemispheric and long association tracts. Contrasts between patients in Phase I and Phase II further revealed that b-ALS was characterized by an early cortical pathology and showed a spread only outside primary motor regions to frontal and temporal areas. In contrast, l-ALS showed ongoing structural integrity loss within primary motor-regions until Phase II. We therefore provide a strong rationale to treat both onset types of disease separately in ALS studies.

Highlights • Quantitative MRI metrics (MD, Volume) can be combined to stage sCJD radiologically. • Quantitative multiparametric approach improves sCJD clinical-imaging correlation. • MRI Disease-Staging might be useful to track sCJD progression., Diffusion imaging is very useful for the diagnosis of sporadic Creutzfeldt-Jakob disease, but it has limitations in tracking disease progression as mean diffusivity changes non-linearly across the disease course. We previously showed that mean diffusivity changes across the disease course follow a quasi J-shaped curve, characterized by decreased values in earlier phases and increasing values later in the disease course. Understanding how MRI metrics change over-time, as well as their correlations with clinical deficits are crucial steps in developing radiological biomarkers for trials. Specifically, as mean diffusivity does not change linearly and atrophy mainly occurs in later stages, neither alone is likely to be a sufficient biomarker throughout the disease course. We therefore developed a model combining mean diffusivity and Volume loss (MRI Disease-Staging) to take into account mean diffusivity’s non-linearity. We then assessed the associations between clinical outcomes and mean diffusivity alone, Volume alone and finally MRI Disease-Staging. In 37 sporadic Creutzfeldt-Jakob disease subjects and 30 age- and sex-matched healthy controls, high angular resolution diffusion and high-resolution T1 imaging was performed cross-sectionally to compute z-scores for mean diffusivity (MD) and Volume. Average MD and Volume were extracted from 41 GM volume of interest (VOI) per hemisphere, within the images registered to the Montreal Neurological Institute (MNI) space. Each subject’s volume of interest was classified as either “involved” or “not involved” using a statistical threshold of ± 2 standard deviation (SD) for mean diffusivity changes and/or −2 SD for Volume. Volumes of interest were MRI Disease-Staged as: 0 = no abnormalities; 1 = decreased mean diffusivity only; 2 = decreased mean diffusivity and Volume; 3 = normal (“pseudo-normalized”) mean diffusivity, reduced Volume; 4 = increased mean diffusivity, reduced Volume. We correlated Volume, MD and MRI Disease-Staging with several clinical outcomes (scales, score and symptoms) using 4 major regions of interest (Total, Cortical, Subcortical and Cerebellar gray matter) or smaller regions pre-specified based on known neuroanatomical correlates. Volume and MD z-scores correlated inversely with each other in all four major ROIs (cortical, subcortical, cerebellar and total) highlighting that ROIs with lower Volumes had higher MD and vice-versa. Regarding correlations with symptoms and scores, higher MD correlated with worse Mini-Mental State Examination and Barthel scores in cortical and cerebellar gray matter, but subjects with cortical sensory deficits showed lower MD in the primary sensory cortex. Volume loss correlated with lower Mini-Mental State Examination, Barthel scores and pyramidal signs. Interestingly, for both Volume and MD, changes within the cerebellar ROI showed strong correlations with both MMSE and Barthel. Supporting using a combination of MD and Volume to track sCJD progression, MRI Disease-Staging showed correlations with more clinical outcomes than Volume or MD alone, specifically with Mini-Mental State Examination, Barthel score, pyramidal signs, higher cortical sensory deficits, as well as executive and visual-spatial deficits. Additionally, when subjects in the cohort were subdivided into tertiles based on their Barthel scores and their percentile of disease duration/course (“Time-Ratio”), subjects in the lowest (most impaired) Barthel tertile showed a much greater proportion of more advanced MRI Disease-Stages than the those in the highest tertile. Similarly, subjects in the last Time-Ratio tertile (last tertile of disease) showed a much greater proportion of more advanced MRI Disease-Stages than the earliest tertile. Therefore, in later disease stages, as measured by time or Barthel, there is overall more Volume loss and increasing MD. A combined multiparametric quantitative MRI Disease-Staging is a useful tool to track sporadic Creutzfeldt-Jakob- disease progression radiologically.

Highlights • Thalamus atrophy is associated with cognitive impairment in multiple sclerosis. • This was confirmed by automated and manual segmentations, but effect sizes varied. • The algorithms work in a multi-center setting. • Automated techniques exhibit proportional bias with respect to thalamus size. • Differences between vendors can affect the robustness of these associations., Background and rationale Thalamus atrophy has been linked to cognitive decline in multiple sclerosis (MS) using various segmentation methods. We investigated the consistency of the association between thalamus volume and cognition in MS for two common automated segmentation approaches, as well as fully manual outlining. Methods Standardized neuropsychological assessment and 3-Tesla 3D-T1-weighted brain MRI were collected (multi-center) from 57 MS patients and 17 healthy controls. Thalamus segmentations were generated manually and using five automated methods. Agreement between the algorithms and manual outlines was assessed with Bland-Altman plots; linear regression assessed the presence of proportional bias. The effect of segmentation method on the separation of cognitively impaired (CI) and preserved (CP) patients was investigated through Generalized Estimating Equations; associations with cognitive measures were investigated using linear mixed models, for each method and vendor. Results In smaller thalami, automated methods systematically overestimated volumes compared to manual segmentations [ρ=(-0.42)-(-0.76); p-values

Highlights • 7T MRS separately measured glutamate, glutamine and GABA towards triggered attacks. • Visual cortex GABA levels increased towards a preictal migraine state. • Visual cortex glutamate and glutamine levels were stable across migraine states., Enhanced activity of the glutamatergic system has been linked to migraine pathophysiology. The present study aimed to assess the involvement of the glutamatergic system in the onset of attacks. We provoked attacks by infusion of glyceryl trinitrate (GTN; 0.5 µg/kg/min over 20 min) in 24 female episodic migraineurs without aura and 13 female age-matched healthy controls. Over the course of a single day participants were scanned three times at fixed time slots (baseline before GTN infusion, 90 min and 270 min after start of GTN infusion). Single-volume proton magnetic resonance spectra (1H–MRS) were acquired at 7 Tesla from a volume of interest (VOI, 2x2x3 cm) in the visual cortex. We assessed the concentrations of glutamate, its major precursor glutamine, and its product gamma-aminobutyric acid (GABA) over the course of a provoked attack. The preictal state was defined as the period after GTN infusion until the migraine-like headache started, independent of possible experienced premonitory symptoms, and the ictal state was defined as the period with provoked migraine-like headache. Data were analyzed using a linear mixed-effect model for repeated measures. Glutamate and glutamine levels did not change from interictal to the preictal and ictal state. GABA levels increased from interictal towards the preictal state for migraine patients compared with healthy controls. We conclude that high resolution 7T MRS is able to show changes in the glutamatergic system towards a triggered migraine attack, by revealing an increased GABA concentration associated with the onset of a migraine attack.

Highlights • Diffusion MRI method reveals heterogeneity within white matter hyperintensities. • Lesion classes can be differentiated by their multi-tissue diffusion profiles. • Variability within lesion classes was identified based on microstructural features. • Offers in vivo method to probe relevance of lesion types to Alzheimer’s disease., White matter hyperintensities (WMH) are regions of high signal intensity typically identified on fluid attenuated inversion recovery (FLAIR). Although commonly observed in elderly individuals, they are more prevalent in Alzheimer’s disease (AD) patients. Given that WMH appear relatively homogeneous on FLAIR, they are commonly partitioned into location- or distance-based classes when investigating their relevance to disease. Since pathology indicates that such lesions are often heterogeneous, probing their microstructure in vivo may provide greater insight than relying on such arbitrary classification schemes. In this study, we investigated WMH in vivo using an advanced diffusion MRI method known as single-shell 3-tissue constrained spherical deconvolution (SS3T-CSD), which models white matter microstructure while accounting for grey matter and CSF compartments. Diffusion MRI data and FLAIR images were obtained from AD (n = 48) and healthy elderly control (n = 94) subjects. WMH were automatically segmented, and classified: (1) as either periventricular or deep; or (2) into three distance-based contours from the ventricles. The 3-tissue profile of WMH enabled their characterisation in terms of white matter-, grey matter-, and fluid-like characteristics of the diffusion signal. Our SS3T-CSD findings revealed substantial heterogeneity in the 3-tissue profile of WMH, both within lesions and across the various classes. Moreover, this heterogeneity information indicated that the use of different commonly used WMH classification schemes can result in different disease-based conclusions. We conclude that future studies of WMH in AD would benefit from inclusion of microstructural information when characterising lesions, which we demonstrate can be performed in vivo using SS3T-CSD.

Highlights • Parieto-occipital sulcus visual rating scale can distinguish PCA from typical AD. • Visual rating scales have been validated using VBM and Brainvisa Morphologist. • Visual rating score reflects sulcal widening rather than grey matter reduction., Objectives Posterior Cortical Atrophy (PCA) is an atypical presentation of Alzheimer disease (AD) characterized by atrophy of posterior brain regions. This pattern of atrophy is usually evaluated with Koedam visual rating scale, a score developed to enable visual assessment of parietal atrophy on magnetic resonance imaging (MRI). However, Koedam scale is complex to assess and its utility in the differential diagnosis between PCA and typical AD has not been demonstrated yet. The aim of this study is therefore to spot a simple and reliable MRI element able to differentiate between PCA and typical AD using visual rating scales. Methods 15 patients who presented with progressive complex visual disorders and predominant occipitoparietal hypometabolism on PET-FDG were selected from our centre and compared with 30 typical AD patients and 15 healthy subjects. We used previously validated visual rating scales including Koedam scale, which we divided into three major components: posterior cingulate, precuneus and parieto-occipital. Subsequently we validated the results using the automated software Brainvisa Morphologist and Voxel Based Morphometry (VBM). Results Patients with PCA, compared to typical AD, showed higher widening of the parieto-occipital sulcus, assessed both with visual rating scales and Brainvisa. In the corresponding areas, the VBM analysis showed an inverse correlation between the results obtained from the visual evaluation scales with the volume of the grey matter and a direct correlation between the same results with the cerebrospinal fluid volume. Conclusions A visually based rating scale for parieto-occipital sulcus can distinguish Posterior Cortical Atrophy from typical Alzheimer disease.

Highlights • We found a visual restitution training effect modulated by attention in hemianopia. • When at rest, Precuneus and Occipital Pole Network are functionally connected. • The strength of this connection prior to training was positively related to training effect. • Precuneus may play a role in visual field improvements by modulating attention. • Our finding may help identifying patients most likely to benefit from training., Visual field defects in chronic hemianopia can improve through visual restitution training, yet not all patients benefit equally from this long and exhaustive procedure. Here, we asked if resting-state functional connectivity prior to visual restitution could predict training success. In two training sessions of eight weeks each, 20 patients with chronic hemianopia performed a visual discrimination task by directing spatial selective attention towards stimuli presented in either hemifield, while suppressing eye movements. We examined two effects: a sensitivity change in the attended (trained) minus the unattended (control) hemifield (i.e., a training-specific improvement), and an overall improvement (i.e., a total change in sensitivity after both sessions). We then identified five visual resting-state networks and evaluated their functional connectivity in relation to both training effects. We found that the functional connectivity strength between the anterior Precuneus and the Occipital Pole Network was positively related to the attention modulated (i.e., training-specific) improvement. No such relationship was found for the overall improvement or for the other visual networks of interest. Our finding suggests that the anterior Precuneus plays a role in attention-modulated visual field improvements. The resting-state functional connectivity between the anterior Precuneus and the Occipital Pole Network may thus serve as an imaging-based biomarker that quantifies a patient's potential capacity to direct spatial attention. This may help to identify hemianopia patients that are most likely to benefit from visual restitution training.

Amyotrophic lateral sclerosis (ALS) can be associated with a spectrum of cognitive and behavioural symptoms, but the related patterns of focal cortical atrophy in non-demented ALS patients remain largely unknown. We enrolled 48 non-demented ALS patients and 26 healthy controls for a comprehensive neuropsychological assessment and a magnetic resonance exam. Behavioural and cognitive impairment was defined on the basis of a data-driven multi-domain approach in 21 ALS patients. Averaged cortical thickness of 74 bilateral brain regions was used as a measure of cortical atrophy. Cortical thinning in a fronto-parietal network, suggesting a disease-specific pattern of neurodegeneration, was present in all patients, independent of cognitive and behavioural status. Between-group and correlational analyses revealed that inferior frontal, temporal, cingular and insular thinning are markers for cognitive and behavioural deficits, with language impairment mainly related to left temporal pole and insular involvement. These specific correlates support the concept of a spectrum of deficits, with an overlap between the ALS cognitive phenotypes and the syndromes of frontotemporal dementia., Highlights • Language, social cognition and executive dysfunctions are frequent symptoms in ALS. • Fronto-parietal cortical thinning is present in non-demented ALS patients. • Temporal, cingular and insular thinning are markers for cognitive impairment in ALS. • Left temporal pole and insular thinning is linked to language impairment in ALS.

Atrophy of the brain grey matter (GM) is an accepted and important feature of multiple sclerosis (MS). However, its accurate measurement is hampered by various technical, pathological and physiological factors. As a consequence, it is challenging to investigate the role of GM atrophy in the disease process as well as the effect of treatments that aim to reduce neurodegeneration. In this paper we discuss the most important challenges currently hampering the measurement and interpretation of GM atrophy in MS. The focus is on measurements that are obtained in individual patients rather than on group analysis methods, because of their importance in clinical trials and ultimately in clinical care. We discuss the sources and possible solutions of the current challenges, and provide recommendations to achieve reliable measurement and interpretation of brain GM atrophy in MS., Highlights • Accurate measurement of brain GM atrophy in MS is hampered by various physiological, pathological and technical factors. • Challenges to achieve accuracy in quantification and interpretation of atrophy in MS are discussed. • Recommendations on how to achieve reliable measurement and interpretation of GM atrophy in MS are suggested.

Aberrant brain structural change in cirrhotic patients with or without hepatic encephalopathy is one of the most typical cases in voxel-based morphometry (VBM) studies. However, there exist inconsistent results regarding to the volume change of the thalamus. Furthermore, the relationship between thalamus structural change and cirrhotic symptoms has not yet been fully elucidated. To address these two issues, we repeated two VBM analyses in SPM and FreeSurfer and compared the two measurements with manually measured thalamic volumes. We also correlated the VBM results with clinical indexes related to cirrhosis to further investigate the relationship between thalamic structural change and liver cirrhosis. The inconsistent result of thalamic structural change was successfully reproduced in regard to the volume measurements of SPM and FreeSurfer. The manually measured results demonstrate an increase in the volume of the thalamus in cirrhotic patients compared to healthy controls, which differs from the results of FreeSurfer. The structural change of thalamus closely correlated with the blood biochemical indexes, including albumin levels, blood coagulation time, and AST/ALT ratio. All of these biochemical indexes are closely related to the severity of liver cirrhosis. Beyond all the results, this study also provides a good demonstration of the difference between multiple VBM measurements for clinicians., Highlights • The inconsistent results of thalamus structural change are software dependent. • The cirrhotic patients with hepatic decompensation have a larger thalamus volume than healthy controls. • The grey matter volume of thalamus closely correlate with the blood biochemical tests related to liver cirrhosis. • Relative intensity change is more sensitive than volume change in thalamus for discriminating the degree of cirrhosis.

Sickle cell disease (SCD) is a life-threatening genetic condition. Patients suffer from chronic systemic and cerebral vascular disease that leads to early and cumulative neurological damage. Few studies have quantified the effects of this disease on brain morphometry and even fewer efforts have been devoted to older patients despite the progressive nature of the disease. This study quantifies global and regional brain volumes in adolescent and young adult patients with SCD and racially matched controls with the aim of distinguishing between age related changes associated with normal brain maturation and damage from sickle cell disease. T1 weighted images were acquired on 33 clinically asymptomatic SCD patients (age = 21.3 ± 7.8; F = 18, M = 15) and 32 racially matched control subjects (age = 24.4 ± 7.5; F = 22, M = 10). Exclusion criteria included pregnancy, previous overt stroke, acute chest, or pain crisis hospitalization within one month. All brain volume comparisons were corrected for age and sex. Globally, grey matter volume was not different but white matter volume was 8.1% lower (p = 0.0056) in the right hemisphere and 6.8% (p = 0.0068) in the left hemisphere in SCD patients compared with controls. Multivariate analysis retained hemoglobin (β = 0.33; p = 0.0036), sex (β = 0.35; p = 0.0017) and mean platelet volume (β = 0.27; p = 0.016) as significant factors in the final prediction model for white matter volume for a combined r2 of 0.37 (p, Graphical abstract Image 1, Highlights • Total white matter brain volume is decreased in sickle cell disease patients. • Global white matter decrease is found to be due to anemia. • Diffuse WM volume decrease is found especially in watershed areas. • Diffuse WM volume decrease spatially colocalize with silent stroke in SCD patients.

Preterm infants are at high risk of neurodevelopmental impairment, which may be due to altered development of brain connectivity. We aimed to (i) assess structural brain development from 25 to 45 weeks gestational age (GA) using graph theoretical approaches and (ii) test the hypothesis that preterm birth results in altered white matter network topology. Sixty-five infants underwent MRI between 25+3 and 45+6 weeks GA. Structural networks were constructed using constrained spherical deconvolution tractography and were weighted by measures of white matter microstructure (fractional anisotropy, neurite density and orientation dispersion index). We observed regional differences in brain maturation, with connections to and from deep grey matter showing most rapid developmental changes during this period. Intra-frontal, frontal to cingulate, frontal to caudate and inter-hemispheric connections matured more slowly. We demonstrated a core of key connections that was not affected by GA at birth. However, local connectivity involving thalamus, cerebellum, superior frontal lobe, cingulate gyrus and short range cortico-cortical connections was related to the degree of prematurity and contributed to altered global topology of the structural brain network. The relative preservation of core connections at the expense of local connections may support more effective use of impaired white matter reserve following preterm birth., Graphical abstract fx1, Highlights • First characterisation of preterm brain networks weighted by microstructural features. • Preterm brain is resistant to disruptions in development of core connections. • Peripheral connections associated with cognition and behaviour are more vulnerable.

Highlights • Abnormal diffusion metrics are observed in sensory(motor) projections in ED. • Left S1-putamen trajectory diffusion changes associate with putaminal FC reduction. • Sensory cortex-related changes support a key role of sensory dysfunction in ED., Background Embouchure dystonia (ED) is a task-specific focal dystonia in professional brass players leading to abnormal orofacial muscle posturing/spasms during performance. Previous studies have outlined abnormal cortical sensorimotor function during sensory/motor tasks and in the resting state as well as abnormal cortical sensorimotor structure. Yet, potentially underlying white-matter tract abnormalities in this network disease are unknown. Objective To delineate structure-function abnormalities within cerebral sensorimotor trajectories in ED. Method Probabilistic tractography and seed-based functional connectivity analysis were performed in 16/16 ED patients/healthy brass players within a simple literature-informed network model of cortical sensorimotor processing encompassing supplementary motor, superior parietal, primary somatosensory and motor cortex as well as the putamen. Post-hoc grey matter volumetry was performed within cortices of abnormal trajectories. Results ED patients showed average axial diffusivity reduction within projections between the primary somatosensory cortex and putamen, with converse increases within projections between supplementary motor and superior parietal cortex in both hemispheres. Increase in the mode of anisotropy in patients was accompanying the latter left-hemispheric projection, as well as in the supplementary motor area’s projection to the left primary motor cortex. Patient’s left primary somatosensory functional connectivity with the putamen was abnormally reduced and significantly associated with the axial diffusivity reduction. Left primary somatosensory grey matter volume was increased in patients. Conclusion Correlates of abnormal tract integrity within primary somatosensory cortico-subcortical projections and higher-order sensorimotor projections support the key role of dysfunctional sensory information propagation in ED pathophysiology. Differential directionality of cortico-cortical and cortico-subcortical abnormalities hints at non-uniform sensory system changes.

Highlights • Fractionating insight into objects aids its neuroanatomical exploration in dementia. • Distinctive neural correlates seem to underpin different insight objects in FTD. • Altered insight into disease/health condition mostly involves right frontal areas. • Altered insight into social cognition implicates frontal, temporal and limbic areas. • Frontal, medial temporal and parietal areas underpin insight into memory problems., Altered insight into disease or specific symptoms is a prominent clinical feature of frontotemporal dementia (FTD). Understanding the neural bases of insight is crucial to help improve FTD diagnosis, classification and management. A systematic review to explore the neural correlates of altered insight in FTD and associated syndromes was conducted. Insight was fractionated to examine whether altered insight into different neuropsychological/behavioural objects is underpinned by different or compatible neural correlates. 6 databases (Medline, Embase, PsycINFO, Web of Science, BIOSIS and ProQuest Dissertations & Theses Global) were interrogated between 1980 and August 2019. 15 relevant papers were found out of 660 titles screened. The studies included suggest that different objects of altered insight are associated with distinctive brain areas in FTD. For example, disease unawareness appears to predominantly correlate with right frontal involvement. In contrast, altered insight into social cognition potentially involves, in addition to frontal areas, the temporal gyrus, insula, parahippocampus and amygdala. Impaired insight into memory problems appears to be related to the frontal lobes, postcentral gyrus, parietal cortex and posterior cingulate. These results reflect to a certain extent those observed in other neurodegenerative conditions like Alzheimer's disease (AD) and also other brain disorders. Nevertheless, they should be cautiously interpreted due to variability in the methodological aspects used to reach those conclusions. Future work should triangulate different insight assessment approaches and brain imaging techniques to increase the understanding of this highly relevant clinical phenomenon in dementia.

Frontotemporal dementia (FTD) is a heterogeneous group of neurodegenerative disorders with both sporadic and genetic forms. Mutations in the progranulin gene (GRN) are a common cause of genetic FTD, causing either a behavioural presentation or, less commonly, language impairment. Presence on T2-weighted images of white matter hyperintensities (WMH) has been previously shown to be more commonly associated with GRN mutations rather than other forms of FTD. The aim of the current study was to investigate the longitudinal change in WMH and the associations of WMH burden with grey matter (GM) loss, markers of neurodegeneration and cognitive function in GRN mutation carriers. 336 participants in the Genetic FTD Initiative (GENFI) study were included in the analysis: 101 presymptomatic and 32 symptomatic GRN mutation carriers, as well as 203 mutation-negative controls. 39 presymptomatic and 12 symptomatic carriers, and 73 controls also had longitudinal data available. Participants underwent MR imaging acquisition including isotropic 1 mm T1-weighted and T2-weighted sequences. WMH were automatically segmented and locally subdivided to enable a more detailed representation of the pathology distribution. Log-transformed WMH volumes were investigated in terms of their global and regional associations with imaging measures (grey matter volumes), biomarker concentrations (plasma neurofilament light chain, NfL, and glial fibrillary acidic protein, GFAP), genetic status (TMEM106B risk genotype) and cognition (tests of executive function). Analyses revealed that WMH load was higher in both symptomatic and presymptomatic groups compared with controls and this load increased over time. In particular, lesions were seen periventricularly in frontal and occipital lobes, progressing to medial layers over time. However, there was variability in the WMH load across GRN mutation carriers - in the symptomatic group 25.0% had none/mild load, 37.5% had medium and 37.5% had a severe load - a difference not fully explained by disease duration. GM atrophy was strongly associated with WMH load both globally and in separate lobes, and increased WMH burden in the frontal, periventricular and medial regions was associated with worse executive function. Furthermore, plasma NfL and to a lesser extent GFAP concentrations were seen to be associated with increased lesion burden. Lastly, the presence of the homozygous TMEM106B rs1990622 TT risk genotypic status was associated with an increased accrual of WMH per year. In summary, WMH occur in GRN mutation carriers and accumulate over time, but are variable in their severity. They are associated with increased GM atrophy and executive dysfunction. Furthermore, their presence is associated with markers of WM damage (NfL) and astrocytosis (GFAP), whilst their accrual is modified by TMEM106B genetic status. WMH load may represent a target marker for trials of disease modifying therapies in individual patients but the variability across the GRN population would prevent use of such markers as a global outcome measure across all participants in a trial. ispartof: NEUROIMAGE-CLINICAL vol:24 ispartof: location:Netherlands status: published

Background Grey matter (GM) atrophy in Alzheimer's disease (AD) is most commonly modeled as a function of time. However, this approach does not take into account inter-individual differences in initial disease severity or changes due to aging. Here, we modeled GM atrophy within individuals across the AD clinical spectrum as a function of time, aging and MMSE, as a proxy for disease severity, and investigated how these models influence estimates of GM atrophy. Methods We selected 523 individuals from ADNI (100 preclinical AD, 288 prodromal AD, 135 AD dementia) with abnormal baseline amyloid PET/CSF and ≥1 year of MRI follow-up. We calculated total and 90 regional GM volumes for 2281 MRI scans (median [IQR]; 4 [3–5] scans per individual over 2 [1.6–4] years) and used linear mixed models to investigate atrophy as a function of time, aging and decline on MMSE. Analyses included clinical stage as interaction with the predictor and were corrected for baseline age, sex, education, field strength and total intracranial volume. We repeated analyses for a sample of participants with normal amyloid (n = 387) to assess whether associations were specific for amyloid pathology. Results Using time or aging as predictors, amyloid abnormal participants annually declined −1.29 ± 0.08 points and − 0.28 ± 0.03 points respectively on the MMSE and −12.23 ± 0.47 cm3 and −8.87 ± 0.34 respectively in total GM volume (p, Highlights • Modeling atrophy as a function of time or aging show similar anatomical patterns. • GM atrophy as a function of time or aging seems nonspecific for amyloid pathology. • GM atrophy as a function of MMSE shows involvement of different anatomical patterns. • Atrophy modeled based on time or age was steeper than modeled based on MMSE. • Atrophy patterns based on MMSE were specific for amyloid pathology.

Background Classification models based on magnetic resonance imaging (MRI) may aid early diagnosis of frontotemporal dementia (FTD) but have only been applied in established FTD cases. Detection of FTD patients in earlier disease stages, such as presymptomatic mutation carriers, may further advance early diagnosis and treatment. In this study, we aim to distinguish presymptomatic FTD mutation carriers from controls on an individual level using multimodal MRI-based classification. Methods Anatomical MRI, diffusion tensor imaging (DTI) and resting-state functional MRI data were collected in 55 presymptomatic FTD mutation carriers (8 microtubule-associated protein Tau, 35 progranulin, and 12 chromosome 9 open reading frame 72) and 48 familial controls. We calculated grey and white matter density features from anatomical MRI scans, diffusivity features from DTI, and functional connectivity features from resting-state functional MRI. These features were applied in a recently introduced multimodal behavioural variant FTD (bvFTD) classification model, and were subsequently used to train and test unimodal and multimodal carrier-control models. Classification performance was quantified using area under the receiver operator characteristic curves (AUC). Results The bvFTD model was not able to separate presymptomatic carriers from controls beyond chance level (AUC = 0.570, p = 0.11). In contrast, one unimodal and several multimodal carrier-control models performed significantly better than chance level. The unimodal model included the radial diffusivity feature and had an AUC of 0.646 (p = 0.021). The best multimodal model combined radial diffusivity and white matter density features (AUC = 0.680, p = 0.005). Conclusions FTD mutation carriers can be separated from controls with a modest AUC even before symptom-onset, using a newly created carrier-control classification model, while this was not possible using a recent bvFTD classification model. A multimodal MRI-based classification score may therefore be a useful biomarker to aid earlier FTD diagnosis. The exclusive selection of white matter features in the best performing model suggests that the earliest FTD-related pathological processes occur in white matter., Highlights • MRI-based classification was performed on presymptomatic FTD gene carriers and controls. • Presymptomatic carriers were separated from controls significantly better than chance-level. • The best performing model was based on white matter features from structural and diffusion scans. • Multimodal MRI-based classification scores may be useful to aid earlier FTD diagnosis.

Purpose To develop a statistical method of combining multimodal MRI (mMRI) of adult glial brain tumours to generate tissue heterogeneity maps that indicate tumour grade and infiltration margins. Materials and methods We performed a retrospective analysis of mMRI from patients with histological diagnosis of glioma (n = 25). 1H Magnetic Resonance Spectroscopic Imaging (MRSI) was used to label regions of “pure” low- or high-grade tumour across image types. Normal brain and oedema characteristics were defined from healthy controls (n = 10) and brain metastasis patients (n = 10) respectively. Probability density distributions (PDD) for each tissue type were extracted from intensity normalised proton density and T2-weighted images, and p and q diffusion maps. Superpixel segmentation and Bayesian inference was used to produce whole-brain tissue-type maps. Results Total lesion volumes derived automatically from tissue-type maps correlated with those from manual delineation (p 2 years (Mann Witney p = 0.0001). Regions classified from mMRI as oedema had non-tumour-like 1H MRS characteristics. Conclusions 1H MRSI can label tumour tissue types to enable development of a mMRI tissue type mapping algorithm, with potential to aid management of patients with glial tumours., Highlights • Non-Gaussian multimodal MRI characteristics of high and low grade glioma tissue. • Bayesian inference of multimodal MRI derives whole brain tumour tissue-type maps. • Automated segmentation of normal and tumour tissue volumes. • Visualisation of glioma heterogeneity, infiltration, necrosis and vasogenic oedema.

Spinal muscular atrophy (SMA) type III and IV are autosomal recessive, slowly progressive lower motor neuron syndromes. Nevertheless, wider cerebral involvement has been consistently reported in mouse models. The objective of this study is the characterisation of spinal and cerebral pathology in adult forms of SMA using multimodal quantitative imaging. Methods Twenty-five type III and IV adult SMA patients and 25 age-matched healthy controls were enrolled in a spinal cord and brain imaging study. Structural measures of grey and white matter involvement and diffusion parameters of white matter integrity were evaluated at each cervical spinal level. Whole-brain and region-of-interest analyses were also conducted in the brain to explore cortical thickness, grey matter density and tract-based white matter alterations. Results In the spinal cord, considerable grey matter atrophy was detected between C2-C6 vertebral levels. In the brain, increased grey matter density was detected in motor and extra-motor regions of SMA patients. No white matter pathology was identified neither at brain and spinal level. Conclusions Adult forms of SMA are associated with selective grey matter degeneration in the spinal cord with preserved white matter integrity. The observed increased grey matter density in the motor cortex may represent adaptive reorganisation., Highlights • (SMA) type 3 and 4 is a lower motor neuron syndrome. Nevertheless, wider involvement of the nervous system might be possible. • 25 adults type 3 and 4 SMA patients were studied using brain and cervical spinal cord neuroimaging techniques. • Grey matter atrophy was observed in the spinal cord. No white matter degeneration was present at brain and spinal level. • Increased grey matter density was detected in cerebral motor regions and explained as compensatory mechanism.

Hepatic encephalopathy (HE) is a common complication in liver cirrhosis and associated with an invasion of ammonia into the brain through the blood-brain barrier. Resulting higher ammonia concentrations in the brain are suggested to lead to a dose-dependent gradual increase of HE severity and an associated impairment of brain function. Amide proton transfer-weighted (APTw) chemical exchange saturation transfer (CEST) imaging has been found to be sensitive to ammonia concentration. The aim of this work was to study APTw CEST imaging in patients with HE and to investigate the relationship between disease severity, critical flicker frequency (CFF), psychometric test scores, blood ammonia, and APTw signals in different brain regions. Whole-brain APTw CEST images were acquired in 34 participants (14 controls, 20 patients (10 minimal HE, 10 manifest HE)) on a 3 T clinical MRI system accompanied by T1 mapping and structural images. T1 normalized magnetization transfer ratio asymmetry analysis was performed around 3 ppm after B0 and B1 correction to create APTw images. All APTw images were spatially normalized into a cohort space to allow direct comparison. APTw images in 6 brain regions (cerebellum, occipital cortex, putamen, thalamus, caudate, white matter) were tested for group differences as well as the link to CFF, psychometric test scores, and blood ammonia. A decrease in APTw intensities was found in the cerebellum and the occipital cortex of manifest HE patients. In addition, APTw intensities in the cerebellum correlated positively with several psychometric scores, such as the fine motor performance scores MLS1 for hand steadiness / tremor (r = 0.466; p = .044) and WRT2 for motor reaction time (r = 0.523; p = .022). Moreover, a negative correlation between APTw intensities and blood ammonia was found for the cerebellum (r = −0.615; p = .007) and the occipital cortex (r = −0.478; p = .045). An increase of APTw intensities was observed in the putamen of patients with minimal HE and correlated negatively with the CFF (r = −0.423; p = .013). Our findings demonstrate that HE is associated with regional differential alterations in APTw signals. These variations are most likely a consequence of hyperammonemia or hepatocerebral degeneration processes, and develop in parallel with disease severity., Graphical abstract Unlabelled Image, Highlights • Ammonia is suggested to play a key role in the emergence of HE. • Increase of ammonia in HE patients might be studied with APTw CEST. • HE leads to regionally decreasing APTw CEST signal. • APTw CEST correlates with blood ammonia levels and psychometric test scores. • APTw CEST is possibly linked to hyperammonemia or hepatocerebral degeneration.

Kabuki syndrome (KS) is a rare congenital disorder (1/32000 births) characterized by distinctive facial features, intellectual disability, short stature, and dermatoglyphic and skeletal abnormalities. In the last decade, mutations in KMT2D and KDM6A were identified as a major cause of kabuki syndrome. Although genetic abnormalities have been highlighted in KS, brain abnormalities have been little explored. Here, we have investigated brain abnormalities in 6 patients with KS (4 males; Mage = 10.96 years, SD = 2.97 years) with KMT2D mutation in comparison with 26 healthy controls (17 males; Mage = 10.31 years, SD = 2.96 years). We have used MRI to explore anatomical and functional brain abnormalities in patients with KS. Anatomical abnormalities in grey matter volume were assessed by cortical and subcortical analyses. Functional abnormalities were assessed by comparing rest cerebral blood flow measured with arterial spin labeling-MRI. When compared to healthy controls, KS patients had anatomical alterations characterized by grey matter decrease localized in the bilateral precentral gyrus and middle frontal gyrus. In addition, KS patients also presented functional alterations characterized by cerebral blood flow decrease in the left precentral gyrus and middle frontal gyrus. Moreover, subcortical analyses revealed significantly decreased grey matter volume in the bilateral hippocampus and dentate gyrus in patients with KS. Our results strongly indicate anatomical and functional brain abnormalities in KS. They suggest a possible neural basis of the cognitive symptoms observed in KS, such as fine motor impairment, and indicate the need to further explore the consequences of such brain abnormalities in this disorder. Finally, our results encourage further imaging-genetics studies investigating the link between genetics, anatomical and functional brain alterations in KS., Highlights • Kabuki syndrome children show decreased grey matter in precentral and frontal areas • Decreased rest cerebral blood flow is also observed in the same regions • Hippocampus and dentate gyrus volumes are reduced • Brain abnormalities, so far understudied, could underpin clinical deficits

Prader-Willi syndrome (PWS) is the most common genetic obesity syndrome, with associated learning difficulties, neuroendocrine deficits, and behavioural and psychiatric problems. As the life expectancy of individuals with PWS increases, there is concern that alterations in brain structure associated with the syndrome, as a direct result of absent expression of PWS genes, and its metabolic complications and hormonal deficits, might cause early onset of physiological and brain aging. In this study, a machine learning approach was used to predict brain age based on grey matter (GM) and white matter (WM) maps derived from structural neuroimaging data using T1-weighted magnetic resonance imaging (MRI) scans. Brain-predicted age difference (brain-PAD) scores, calculated as the difference between chronological age and brain-predicted age, are designed to reflect deviations from healthy brain aging, with higher brain-PAD scores indicating premature aging. Two separate adult cohorts underwent brain-predicted age calculation. The main cohort consisted of adults with PWS (n = 20; age mean 23.1 years, range 19.8–27.7; 70.0% male; body mass index (BMI) mean 30.1 kg/m2, 21.5–47.7; n = 19 paternal chromosome 15q11–13 deletion) and age- and sex-matched controls (n = 40; age 22.9 years, 19.6–29.0; 65.0% male; BMI 24.1 kg/m2, 19.2–34.2) adults (BMI PWS vs. control P = .002). Brain-PAD was significantly greater in PWS than controls (effect size mean ± SEM +7.24 ± 2.20 years [95% CI 2.83, 11.63], P = .002). Brain-PAD remained significantly greater in PWS than controls when restricting analysis to a sub-cohort matched for BMI consisting of n = 15 with PWS with BMI range 21.5–33.7 kg/m2, and n = 29 controls with BMI 21.7–34.2 kg/m2 (effect size +5.51 ± 2.56 years [95% CI 3.44, 10.38], P = .037). In the PWS group, brain-PAD scores were not associated with intelligence quotient (IQ), use of hormonal and psychotropic medications, nor severity of repetitive or disruptive behaviours. A 24.5 year old man (BMI 36.9 kg/m2) with PWS from a SNORD116 microdeletion also had increased brain PAD of 12.87 years, compared to 0.84 ± 6.52 years in a second control adult cohort (n = 95; age mean 34.0 years, range 19.9–55.5; 38.9% male; BMI 28.7 kg/m2, 19.1–43.1). This increase in brain-PAD in adults with PWS indicates abnormal brain structure that may reflect premature brain aging or abnormal brain development. The similar finding in a rare patient with a SNORD116 microdeletion implicates a potential causative role for this PWS region gene cluster in the structural brain abnormalities associated primarily with the syndrome and/or its complications. Further longitudinal neuroimaging studies are needed to clarify the natural history of this increase in brain age in PWS, its relationship with obesity, and whether similar findings are seen in those with PWS from maternal uniparental disomy., Highlights • Prader-Willi syndrome is the commonest genetic obesity syndrome. • 19 of the 20 adults with PWS had a paternal deletion in chromosome 15q11–13. • Adults with PWS had increased brain age using structural MRI with machine learning. • This was independent of their higher BMI, and use of growth and sex hormones. • Another man with a SNORD116 microdeletion also had an increased brain age.

Highlights • Women lost more total brain volume than men during 8.5 years follow-up in midlife. • Women showed greater brain reduction in bilateral brain regions with and without co-varying for total brain volume loss. • Men exhibited greater brain reduction in mid-line brain regions after correcting for the total brain volume loss., Brain development during childhood and adolescence differs between boys and girls. Structural changes continue during adulthood and old age, particularly in terms of brain volume reductions that accelerate beyond age 35 years. We investigated whether brain structural change in mid-life differs between men and women. 43 men and 28 women from the Northern Finland 1966 Birth Cohort underwent MRI brain scans at age 33–35 (SD = 0.67) and then again at age 42–44 (SD = 0.41). We examined sex differences in total percentage brain volume change (PBVC) and regional brain change with FSL SIENA software. Women showed significant PBVC reduction compared with men between the ages of 33–35 and 42–44 years (Mean = −3.21% in men, Mean = −4.03% in women, F (1, 68) = 6.37, p

T2-FLAIR is the single most sensitive MRI contrast to detect lesions underlying focal epilepsies but 3D sequences used to obtain isotropic high-resolution images are susceptible to motion artefacts. Prospective motion correction (PMC) – demonstrated to improve 3D-T1 image quality in a pediatric population – was applied to high-resolution 3D-T2-FLAIR scans in adult epilepsy patients to evaluate its clinical benefit. Coronal 3D-T2-FLAIR scans were acquired with a 1 mm isotropic resolution on a 3 T MRI scanner. Two expert neuroradiologists reviewed 40 scans without PMC and 40 with navigator-based PMC. Visual assessment addressed six criteria of image quality (resolution, SNR, WM-GM contrast, intensity homogeneity, lesion conspicuity, diagnostic confidence) on a seven-point Likert scale (from non-diagnostic to outstanding). SNR was also objectively quantified within the white matter. PMC scans had near-identical scores on the criteria of image quality to non-PMC scans, with the notable exception that intensity homogeneity was generally worse. Using PMC, the percentage of scans with bad image quality was substantially lower than without PMC (3.25% vs. 12.5%) on the other five criteria. Quantitative SNR estimates revealed that PMC and non-PMC had no significant difference in SNR (P = 0.07). Application of prospective motion correction to 3D-T2-FLAIR sequences decreased the percentage of low-quality scans, reducing the number of scans that need to be repeated to obtain clinically useful data.

Purpose of the research Although single nucleotide polymorphisms of membrane-spanning 4A (MS4A) (rs670139) and several other susceptibility genes have shown interaction effects on the risk of Alzheimer's disease (AD), little is known about the interaction effects of apolipoprotein E (APOE) with MS4A (rs670139) on cognitive performances, and the underlying pathogenesis is unclear. The study aimed to investigate the APOE-MS4A (rs670139) interaction effects on cognitive performances, cortical volumes, and functional connectivity (FC) in brain networks. Principal results Cognitive performances were characterized in each genotypic group, and were compared between normal controls and patients in each genotypic group. APOE-MS4A interaction effects on memory and executive function scores, cortical volumes, and FC in brain networks were demonstrated. Significant effects of APOE-MS4A interactions on FC were observed in executive control network (ECN) (T maxima = 4.99, false discovery rate-corrected p, Highlights • APOE-MS4A interactions affect executive control network (ECN) and calculation score. • Calculation score is correlated with functional connectivity in ECN. • Variation in ECN is associated with genetic effects on calculation performances. • The calculation score is correlated with each frontal volume. • Genotypic variation affects the relationship between calculation and frontal volume.

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder of genomic imprinting, presenting with a characteristic overeating disorder, mild to moderate intellectual disability, and a variable range of social and behavioral difficulties. Consequently, widespread alterations in neural structure and developmental and maturational trajectory would be expected. To date, there have been few quantitative and systematic studies of brain morphology in PWS, although alterations of volume and of cortical organisation have been reported. This study aimed to investigate, in detail, the structure of grey matter and cortex in the brain in a sample of young adults with PWS in a well-matched case-controlled analysis. 20 young adults with PWS, aged 19–27 years, underwent multiparameter mapping magnetic resonance imaging sequences, from which measures of grey matter volume, cortical thickness and magnetisation transfer saturation, as a proxy measure of myelination, were examined. These variables were investigated in comparison to a control group of 40 typically developing young adults, matched for age and sex. A voxel-based morphometry analysis identified large and widespread bilateral clusters of both increased and decreased grey matter volume in the brain in PWS. In particular, widespread areas of increased volume encompassed parts of the prefrontal cortex, especially medially, the majority of the cingulate cortices, from anterior to posterior aspects, insula cortices, and areas of the parietal and temporal cortices. Increased volume was also reported in the caudate, putamen and thalamus. The most ventromedial prefrontal areas, in contrast, showed reduced volume, as did the parts of the medial temporal lobe, bilateral temporal poles, and a small cluster in the right lateral prefrontal cortex. Analysis of cortical structure revealed that areas of increased volume in the PWS group were largely driven by greater cortical thickness. Conversely, analysis of myelin content using magnetisation transfer saturation indicated that myelination of the cortex was broadly similar in the PWS and control groups, with the exception of highly localised areas, including the insula. The bilateral nature of these abnormalities suggests a systemic biological cause, with possible developmental and maturational mechanisms discussed, and may offer insight into the contribution of imprinted genes to neural development., Highlights • Twenty young adults with PWS and forty age and sex-matched control participants underwent multiparameter mapping MRI. • Large and widespread bilateral clusters of both increased and decreased grey matter volume were identified in PWS. • Volumetric increases in PWS were largely driven by greater cortical thickness. • Myelination of the cortex in PWS was broadly similar to the typically-developing control group. • Potential developmental and maturational explanations are considered, including insights into the of the role of imprinted genes.

In Alzheimer's disease (AD), defects in essential metabolic processes for energy supply and phospholipid membrane function have been implicated in the pathological process. However, post-mortem investigations are generally limited to late stage disease and prone to tissue decay artifacts. In vivo assessments of high energy phosphates, tissue pH and phospholipid metabolites are possible by phosphorus MR spectroscopy (31P–MRS), but so far only small studies, mostly focusing on single brain regions, have been performed. Therefore, we assessed phospholipid and energy metabolism in multiple brain regions of 31 early stage AD patients and 31 age- and gender-matched controls using 31P–MRS imaging. An increase of phosphocreatine (PCr) was found in AD patients compared with controls in the retrosplenial cortex, and both hippocampi, but not in the anterior cingulate cortex. While PCr/inorganic phosphate and pH were also increased in AD, no changes were found for phospholipid metabolites. This study showed that PCr levels are specifically increased in regions that show early degeneration in AD. Together with an increased pH, this indicates an altered energy metabolism in mild AD., Highlights • Phosphocreatine and pH are increased in mild Alzheimer's disease. • Phosphocreatine increase occurs in early affected brain regions. • Brain energy metabolism may be altered in mild Alzheimer's disease. • Phospholipid and energy metabolites as well as pH, differ across brain regions.

SPG11 mutations are the major cause of autosomal recessive Hereditary Spastic Paraplegia. The disease has a wide phenotypic variability indicating many regions of the nervous system besides the corticospinal tract are affected. Despite this, anatomical and phenotypic characterization is restricted. In the present study, we investigate the anatomical abnormalities related to SPG11 mutations and how they relate to clinical and cognitive measures. Moreover, we aim to depict how the disease course influences the regions affected, unraveling different susceptibility of specific neuronal populations. We performed clinical and paraclinical studies encompassing neuropsychological, neuroimaging, and neurophysiological tools in a cohort of twenty-five patients and age matched controls. We assessed cortical thickness (FreeSurfer software), deep grey matter volumes (T1-MultiAtlas tool), white matter microstructural damage (DTI-MultiAtlas) and spinal cord morphometry (Spineseg software) on a 3 T MRI scan. Mean age and disease duration were 29 and 13.2 years respectively. Sixty-four percent of the patients were wheelchair bound while 84% were demented. We were able to unfold a diffuse pattern of white matter integrity loss as well as basal ganglia and spinal cord atrophy. Such findings contrasted with a restricted pattern of cortical thinning (motor, limbic and parietal cortices). Electromyography revealed motor neuronopathy affecting 96% of the probands. Correlations with disease duration pointed towards a progressive degeneration of multiple grey matter structures and spinal cord, but not of the white matter. SPG11-related hereditary spastic paraplegia is characterized by selective neuronal vulnerability, in which a precocious and widespread white matter involvement is later followed by a restricted but clearly progressive grey matter degeneration., Highlights • SPG11 leads to widespread White matter (WM) and deep grey matter (GM) damage. • Cortical thinning is restricted to motor, limbic and parietal regions. • Motor Cortex thinning as well as Spinal Cord and basal ganglia atrophy correlate with motor handicap and disease duration. • WM and thalamic damage correlate with cognitive impairment. • Progressive damage of GM contrasts with an apparently static WM involvement.

Background Writer's cramp is a task-specific dystonia impairing writing and sometimes other fine motor tasks. Neuroimaging studies using manifold designs have shown varying results regarding the nature of changes in the disease. Objective To clarify and extend the knowledge of underlying changes by investigating functional connectivity (FC) in intrinsic connectivity networks with putative sensorimotor function at rest in an increased number of study subjects. Methods Resting-state functional magnetic resonance imaging with independent component analysis was performed in 26/27 writer's cramp patients/healthy controls, and FC within and between resting state networks with putative sensorimotor function was compared. Additionally, voxel-based morphometry was carried out on the subjects' structural images. Results Patients displayed increased left- and reduced right-hemispheric primary sensorimotor FC in the premotor-parietal network. Mostly bilaterally altered dorsal/ventral premotor FC, as well as altered parietal FC were observed within multiple sensorimotor networks and showed differing network-dependent directionality. Beyond within-network FC changes and reduced right cerebellar grey matter volume in the structural analysis, the positive between-network FC of the cerebellar network and the basal ganglia network was reduced. Conclusions Abnormal resting-state FC in multiple networks with putative sensorimotor function may act as basis of preexisting observations made during task-related neuroimaging. Further, altered connectivity between the cerebellar and basal ganglia network underlines the important role of these structures in the disease., Highlights • Investigation of FC changes in various sensorimotor ICNs at rest in writer's cramp. • We saw multiple, network-specific FC changes in primary/higher sensorimotor cortices. • This may act as basis of the varying nature of sensorimotor changes during task-fMRI. • Further, findings supporting disrupted cerebellar-basal ganglia interaction were made. • An additional morphometric analysis demonstrated structural cerebellar abnormality.

Late-onset epilepsy (LOE), with onset after 50 years of age, is often attributed to underlying occult cerebrovascular disease. LOE is associated with a three-fold increase in subsequent stroke risk, therefore it is important to improve our understanding of pathophysiology. In this exploratory study, we aimed to determine whether established structural magnetic resonance imaging markers and novel physiological imaging markers of occult cerebrovascular disease were more common in patients with LOE than age-matched controls. Sixteen patients with LOE (mean age ± SD: 67.6 ± 6.5 years) and 15 age-matched control subjects (mean age: 65.1 ± 3.9 years) underwent a 3 T MRI scan protocol. T1-weighted images and T2-weighted fluid attenuated inversion recovery (FLAIR) images were used to determine cortical grey matter volume and white matter hyperintensity (WMH) volume respectively, whilst multiple delay time arterial spin labelling (ASL) images were collected at rest and during a hypercapnic challenge. Cerebral blood flow (CBF) and arterial arrival time (AAT) were calculated from ASL data under both normocapnic and hypercapnic conditions. Cerebrovascular reactivity was also calculated for both CBF and AAT relative to the change in end-tidal CO2. Patients with LOE were found to have significantly lower cortical volume than control subjects (33.8 ± 3.8% of intracranial volume vs. 38.0 ± 5.5%, p = 0.02) and significantly higher WMH volume (1339 ± 1408 mm3 vs. 514 ± 481 mm3, p = 0.047). Baseline whole brain AAT was found to be significantly prolonged in patients with LOE in comparison to control subjects (1539 ± 129 ms vs. 1363 ± 167 ms, p = 0.005). Voxel-based analysis showed the significant prolongation of AAT to be predominantly distributed in the frontal and temporal lobes. Voxel-based morphometry showed the lower cortical volume to be localised primarily to temporal lobes. No significant differences in CBF or cerebrovascular reactivity were found between the two groups. Baseline whole brain AAT and cortical volume differences persisted upon further analysis to take account of differences in smoking history between patients and control subjects. These findings suggest that occult cerebrovascular disease is relevant to the pathophysiology of LOE., Highlights • LOE patients were found to have increased WMHs and reduced GM volume on MRI imaging in comparison to HC. • Baseline arterial arrival time was significantly longer in LOE patients than HC. • Baseline cerebral blood flow did not differ between LOE patients and HC. • Cerebrovascular reactivity did not differ between LOE patients and HC.

This prospective study explored whether an approach combining structural [cortical thickness and white matter (WM) microstructure] and resting state functional MRI can aid differentiation between 62 early onset Alzheimer's disease (EOAD) and 27 behavioural variant of frontotemporal dementia (bvFTD) patients. Random forest and receiver operator characteristic curve analyses assessed the ability of MRI in classifying the two clinical syndromes. All patients showed a distributed pattern of brain alterations relative to controls. Compared to bvFTD, EOAD patients showed bilateral inferior parietal cortical thinning and decreased default mode network functional connectivity. Compared to EOAD, bvFTD patients showed bilateral orbitofrontal and temporal cortical thinning, and WM damage of the corpus callosum, bilateral uncinate fasciculus, and left superior longitudinal fasciculus. Random forest analysis revealed that left inferior parietal cortical thickness (accuracy 0.78, specificity 0.76, sensitivity 0.83) and WM integrity of the right uncinate fasciculus (accuracy 0.81, specificity 0.96, sensitivity 0.43) were the best predictors of clinical diagnosis. The combination of cortical thickness and DT MRI measures was able to distinguish patients with EOAD and bvFTD with accuracy 0.82, specificity 0.76, and sensitivity 0.96. The diagnostic ability of MRI models was confirmed in a subsample of patients with biomarker-based clinical diagnosis. Multiparametric MRI is useful to identify brain alterations which are specific to EOAD and bvFTD. A severe cortical involvement is suggestive of EOAD, while a prominent WM damage is indicative of bvFTD., Highlights • Multimodal MRI distinguishes in vivo EOAD and bvFTD patients • EOAD and bvFTD show a distributed pattern of structural brain alterations • A severe cortical involvement is suggestive of EOAD relative to bvFTD • A prominent WM damage is indicative of bvFTD relative to EOAD

This paper describes the data repository for the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) initial study cohort. The Cam-CAN Stage 2 repository contains multi-modal (MRI, MEG, and cognitive-behavioural) data from a large (approximately N = 700), cross-sectional adult lifespan (18–87 years old) population-based sample. The study is designed to characterise age-related changes in cognition and brain structure and function, and to uncover the neurocognitive mechanisms that support healthy cognitive ageing. The database contains raw and preprocessed structural MRI, functional MRI (active tasks and resting state), and MEG data (active tasks and resting state), as well as derived scores from cognitive behavioural experiments spanning five broad domains (attention, emotion, action, language, and memory), and demographic and neuropsychological data. The dataset thus provides a depth of neurocognitive phenotyping that is currently unparalleled, enabling integrative analyses of age-related changes in brain structure, brain function, and cognition, and providing a testbed for novel analyses of multi-modal neuroimaging data., Highlights • Cross-sectional uniform adult-lifespan population-based data • Multimodal MRI, fMRI and MEG neuroimaging data • Unprecedented depth of cognitive phenotyping • Age-related differences in brain structure, function, and cognition

Highlights • Computational neuroimaging captures focal brainstem pathology in motor neuron diseases in contrast to both healthy- and disease controls. • ALS patients exhibit progressive medulla oblongata, pontine and mesencephalic volume loss over time. • Brainstem atrophy in ALS and PLS is dominated by medulla oblongata volume reductions. • Vertex analyses of ALS patients reveal flattening of the medullary pyramids bilaterally. • Morphometric analyses in ALS detect density reductions in the mesencephalic crura consistent with corticospinal tract degeneration., Background Brainstem pathology is a hallmark feature of ALS, yet most imaging studies focus on cortical grey matter alterations and internal capsule white matter pathology. Brainstem imaging in ALS provides a unique opportunity to appraise descending motor tract degeneration and bulbar lower motor neuron involvement. Methods A prospective longitudinal imaging study has been undertaken with 100 patients with ALS, 33 patients with PLS, 30 patients with FTD and 100 healthy controls. Volumetric, vertex and morphometric analyses were conducted correcting for demographic factors to characterise disease-specific patterns of brainstem pathology. Using a Bayesian segmentation algorithm, the brainstem was segmented into the medulla, pons and mesencephalon to measure regional volume reductions, shape analyses were performed to ascertain the atrophy profile of each study group and region-of-interest morphometry was used to evaluate focal density alterations. Results ALS and PLS patients exhibit considerable brainstem atrophy compared to both disease- and healthy controls. Volume reductions in ALS and PLS are dominated by medulla oblongata pathology, but pontine atrophy can also be detected. In ALS, vertex analyses confirm the flattening of the medullary pyramids bilaterally in comparison to healthy controls and widespread pontine shape deformations in contrast to PLS. The ALS cohort exhibit bilateral density reductions in the mesencephalic crura in contrast to healthy controls, central pontine atrophy compared to disease controls, peri-aqueduct mesencephalic and posterior pontine changes in comparison to PLS patients. Conclus ions: Computational brainstem imaging captures the degeneration of both white and grey matter components in ALS. Our longitudinal data indicate progressive brainstem atrophy over time, underlining the biomarker potential of quantitative brainstem measures in ALS. At a time when a multitude of clinical trials are underway worldwide, there is an unprecedented need for accurate biomarkers to monitor disease progression and detect response to therapy. Brainstem imaging is a promising addition to candidate biomarkers of ALS and PLS.

Statistical parametric mapping (SPM) locates significant clusters based on a ratio of signal to noise (a ‘contrast’ of the parameters divided by its standard error) meaning that very low noise regions, for example outside the brain, can attain artefactually high statistical values. Similarly, the commonly applied preprocessing step of Gaussian spatial smoothing can shift the peak statistical significance away from the peak of the contrast and towards regions of lower variance. These problems have previously been identified in positron emission tomography (PET) (Reimold et al., 2006) and voxel-based morphometry (VBM) (Acosta-Cabronero et al., 2008), but can also appear in functional magnetic resonance imaging (fMRI) studies. Additionally, for source-reconstructed magneto- and electro-encephalography (M/EEG), the problems are particularly severe because sparsity-favouring priors constrain meaningfully large signal and variance to a small set of compactly supported regions within the brain. (Acosta-Cabronero et al., 2008) suggested adding noise to background voxels (the ‘haircut’), effectively increasing their noise variance, but at the cost of contaminating neighbouring regions with the added noise once smoothed. Following theory and simulations, we propose to modify – directly and solely – the noise variance estimate, and investigate this solution on real imaging data from a range of modalities., Highlights ► Statistical parametric mapping judges significance with a signal-to-noise ratio. ► Low noise, e.g. outside the brain, can yield artefactually high statistical values. ► Spatial smoothing can shift peaks substantially towards regions of low variance. ► Source-reconstructed M/EEG data exhibits the problem particularly severely. ► The problem can be addressed by modifying the noise variance estimate.

Aims Multiple sclerosis (MS) leaves a signature on the phosphorylation and thus proton binding capacity of axonal neurofilament (Nf) proteins. The proton binding capacity in a tissue is the major determinant for exchange between bound and free protons and thus the magnetisation transfer ratio (MTR). This study investigated whether the MTR of non-lesional white matter (NLWM) was related to the brain tissue concentration of neurofilament phosphoforms. Methods Unfixed post-mortem brain slices of 12 MS patients were analysed using MTR, T1 at 1.5 T. Blocks containing NLWM were processed for embedding in paraffin and inspected microscopically. Adjacent tissue was microdissected, homogenised and specific protein levels were quantified by ELISA for the Nf heavy chain (NfH) phosphoforms, glial fibrillary acidic protein (GFAP), S100B and ferritin. Results Averaged hyperphosphorylated NfH (SMI34) but not phosphorylated NfH (SMI35) levels were different between individual patients NLWM. The concentration of hyperphosphorylated NfH-SMI34 correlated with T1 (R = 0.70, p = 0.0114) and — inversely — with MTR (R =−0.73, p = 0.0065). NfH-SMI35 was not correlated to any of the MR indices. Conclusions Post-translational modifications of axonal proteins such as phosphorylation of neurofilaments occur in NLWM and may precede demyelination. The resulting change of proton mobility influences MTR and T1. This permits the in vivo detection of these subtle tissue changes on a proteomic level in patients with MS., Highlights ► Neurofilaments are phosphorylated ► Protein phosphorylation competes with the free proton binding capacity ► Magnetisation transfer depends on magnetisation exchange between macromolecular bound and free protons ► In multiple sclerosis the phosphorylation status of neurofilaments is changed in otherwise normal appearing axons ► In vivo assessment of early axonal pathology is possible using magnetisation transfer

Autonomic changes are often associated with the chronic fatigue syndrome (CFS), but their pathogenetic role is unclear and brain imaging investigations are lacking. The vasomotor centre and, through it, nuclei in the midbrain and hypothalamus play a key role in autonomic nervous system regulation of steady state blood pressure (BP) and heart rate (HR). In this exploratory cross-sectional study, BP and HR, as indicators of autonomic function, were correlated with volumetric and T1- and T2-weighted spin-echo (T1w and T2w) brain MRI in 25 CFS subjects and 25 normal controls (NC). Steady state BP (systolic, diastolic and pulse pressure) and HR in two postures were extracted from 24 h blood pressure monitoring. We performed (1) MRI versus autonomic score interaction-with-group regressions to detect locations where regression slopes differed in the CFS and NC groups (collectively indicating abnormality in CFS), and (2) MRI regressions in the CFS and NC groups alone to detect additional locations with abnormal correlations in CFS. Significant CFS regressions were repeated controlling for anxiety and depression (A&D). Abnormal regressions were detected in nuclei of the brainstem vasomotor centre, midbrain reticular formation and hypothalamus, but also in limbic nuclei involved in stress responses and in prefrontal white matter. Group comparisons of CFS and NC did not find MRI differences in these locations. We propose therefore that these regulatory nuclei are functioning correctly, but that two-way communication between them is impaired in CFS and this affects signalling to/from peripheral effectors/sensors, culminating in inverted or magnified correlations. This single explanation for the diverse abnormal correlations detected here consolidates the conclusion for a brainstem/midbrain nerve conduction deficit inferred earlier (Barnden et al., 2015). Strong correlations were also detected in isolated NC regressions., Graphical abstract Image 1, Highlights • For the first time in CFS, we performed MRI regressions with steady state BP and HR. • Vasomotor centre, midbrain and hypothalamus correlations were abnormal in CFS. • MRI group comparisons between CFS and controls detected no differences. • Regulatory nuclei and peripheral effectors/sensors appear to function correctly. • Signalling between brainstem/midbrain regulatory nuclei appears to be impaired.

Why only certain patients develop debilitating pain after spinal chord injury and whether structural brain changes are implicated remain unknown. The aim of this study was to determine if patients with chronic, neuropathic below-level pain have specific cerebral changes compared to those who remain pain-free. Voxel-based morphometry of high resolution, T1-weighted images was performed on three subject groups comprising patients with pain (SCI-P, n = 18), patients without pain (SCI-N, n = 12) and age- and sex-matched controls (n = 18). The SCI-P group was first compared directly with the SCI-N group and then subsequently with controls. Overall, grey and white matter changes dependent on the presence of pain were revealed. Significant changes were found within the somatosensory cortex and also in corticospinal tracts and visual-processing areas. When the SCI-P group was directly compared with the SCI-N group, reduced grey matter volume was found in the deafferented leg area of the somatosensory cortex bilaterally. This region negatively correlated with pain intensity. Relative to controls, grey matter in this paracentral primary sensory cortex was decreased in SCI-P but conversely increased in SCI-N. When compared with controls, discrepant corticospinal tract white matter reductions were found in SCI-P and in SCI-N. In the visual cortex, SCI-N showed increased grey matter, whilst the SCI-N showed reduced white matter. In conclusion, structural changes in SCI are related to the presence and degree of below-level pain and involve but are not limited to the sensorimotor cortices. Pain-related structural plasticity may hold clinical implications for the prevention and management of refractory neuropathic pain., Highlights • Voxel-based morphometry was performed on spinal cord injury patients and controls. • Patients with below-level neuropathic pain had reduced somatosensory cortex volume. • Patients without pain had increased somatosensory cortex volume. • Other structural changes were also found outside the sensorimotor cortices. • Structural brain changes showed associations with the degree of neuropathic pain.

The known genetic mutation causing Huntington's disease (HD) makes this disease an important model to study links between gene and brain function. An autosomal dominant family history and the availability of a sensitive and specific genetic test allow pre-clinical diagnosis many years before the onset of any typical clinical signs. This review summarizes recent magnetic resonance imaging (MRI)–based findings in HD with a focus on the requirements if imaging is to be used in treatment trials. Despite its monogenetic cause, HD presents with a range of clinical manifestations, not explained by variation in the number of CAG repeats in the affected population. Neuroimaging studies have revealed a complex pattern of structural and functional changes affecting widespread cortical and subcortical regions far beyond the confines of the striatal degeneration that characterizes this disorder. Besides striatal dysfunction, functional imaging studies have reported a variable pattern of increased and decreased activation in cortical regions in both pre-clinical and clinically manifest HD-gene mutation carriers. Beyond regional brain activation changes, evidence from functional and diffusion-weighted MRI further suggests disrupted connectivity between corticocortical and corticostriatal areas. However, substantial inconsistencies with respect to structural and functional changes have been reported in a number of studies. Possible explanations include methodological factors and differences in study samples. There may also be biological explanations but these are poorly characterized and understood at present. Additional insights into this phenotypic variability derived from study of mouse models are presented to explore this phenomenon.