Identifying the joint signature of brain atrophy and gene variant scores in Alzheimer's Disease.

The joint modeling of genetic data and brain imaging information allows for determining the pathophysiological pathways of neurodegenerative diseases such as Alzheimer's disease (AD). This task has typically been approached using mass-univariate methods that rely on a complete set of Single Nucleotide Polymorphisms (SNPs) to assess their association with selected image-derived phenotypes (IDPs). However, such methods are prone to multiple comparisons bias and, most importantly, fail to account for potential cross-feature interactions, resulting in insufficient detection of significant associations. Ways to overcome these limitations while reducing the number of traits aim at conveying genetic information at the gene level and capturing the integrated genetic effects of a set of genetic variants, rather than looking at each SNP individually. Their associations with brain IDPs are still largely unexplored in the current literature, though they can uncover new potential genetic determinants for brain modulations in the AD continuum. In this work, we explored an explainable multivariate model to analyze the genetic basis of the grey matter modulations, relying on the AD Neuroimaging Initiative (ADNI) phase 3 dataset. Cortical thicknesses and subcortical volumes derived from T1-weighted Magnetic Resonance were considered to describe the imaging phenotypes. At the same time the genetic counterpart was represented by gene variant scores extracted by the Sequence Kernel Association Test (SKAT) filtering model. Moreover, transcriptomic analysis was carried on to assess the expression of the resulting genes in the main brain structures as a form of validation. Results highlighted meaningful genotype-phenotype interactionsas defined by three latent components showing a significant difference in the projection scores between patients and controls. Among the significant associations, the model highlighted EPHX1 and BCAS1 gene variant scores involved in neurodegenerative and myelination processes, hence relevant for AD. In particular, the first was associated with decreased subcortical volumes and the second with decreasedtemporal lobe thickness. Noteworthy, BCAS1 is particularly expressed in the dentate gyrus. Overall, the proposed approach allowed capturing genotype-phenotype interactions in a restricted study cohort that was confirmed by transcriptomic analysis, offering insights into the underlying mechanisms of neurodegeneration in AD in line with previous findings and suggesting new potential disease biomarkers.

Insights into single-timepoint ASL hemodynamics: what visual assessment and spatial coefficient of variation can tell.

PURPOSE: Arterial spin labeling (ASL) represents a noninvasive perfusion biomarker, and, in the study of nonvascular disease, the use of the single-timepoint ASL technique is recommended. However, the obtained cerebral blood flow (CBF) maps may be highly influenced by delayed arterial transit time (ATT). Our aim was to assess the complexity of hemodynamic information of single-timepoint CBF maps using a new visual scale and comparing it with an ATT proxy, the "coefficient of spatial variation" (sCoV). MATERIAL AND METHODS: Individual CBF maps were estimated in a memory clinic population (mild cognitive impairment, dementia and cognitively unimpaired controls) and classified into four levels of delayed perfusion based on a visual rating scale. Calculated measures included global/regional sCoVs and common CBF statistics, as mean, median and standard deviation. One-way ANOVA was performed to compare these measures across the four groups of delayed perfusion. Spearman correlation was used to study the association of global sCoV with clinical data and CBF statistics. RESULTS: One hundred and forty-four participants (72 ± 7 years, 53% women) were included in the study. The proportion of maps with none, mild, moderate, and severe delayed perfusion was 15, 20, 37, and 28%, respectively. SCoV demonstrated a significant increase (p < 0.05) across the four groups, except when comparing none vs mild delayed perfusion groups (pBonf > 0.05). Global sCoV values, as an ATT proxy, ranged from 67 ± 4% (none) to 121 ± 24% (severe delayed) and were significantly associated with age and CBF statistics (p < 0.05). CONCLUSION: The impact of ATT delay in single-time CBF maps requires the use of a visual scale or sCoV in clinical or research settings.

Unraveling the MRI-Based Microstructural Signatures Behind Primary Progressive and Relapsing-Remitting Multiple Sclerosis Phenotypes.

BACKGROUND: The mechanisms driving primary progressive and relapsing-remitting multiple sclerosis (PPMS/RRMS) phenotypes are unknown. Magnetic resonance imaging (MRI) studies support the involvement of gray matter (GM) in the degeneration, highlighting its damage as an early feature of both phenotypes. However, the role of GM microstructure is unclear, calling for new methods for its decryption. PURPOSE: To investigate the morphometric and microstructural GM differences between PPMS and RRMS to characterize GM tissue degeneration using MRI. STUDY TYPE: Prospective cross-sectional study. SUBJECTS: Forty-five PPMS (26 females) and 45 RRMS (32 females) patients. FIELD STRENGTH/SEQUENCE: 3T scanner. Three-dimensional (3D) fast field echo T1-weighted (T1-w), 3D turbo spin echo (TSE) T2-w, 3D TSE fluid-attenuated inversion recovery, and spin echo-echo planar imaging diffusion MRI (dMRI). ASSESSMENT: T1-w and dMRI data were employed for providing information about morphometric and microstructural features, respectively. For dMRI, both diffusion tensor imaging and 3D simple harmonics oscillator based reconstruction and estimation models were used for feature extraction from a predefined set of regions. A support vector machine (SVM) was used to perform patients' classification relying on all these measures. STATISTICAL TESTS: Differences between MS phenotypes were investigated using the analysis of covariance and statistical tests (P < 0.05 was considered statistically significant). RESULTS: All the dMRI indices showed significant microstructural alterations between the considered MS phenotypes, for example, the mode and the median of the return to the plane probability in the hippocampus. Conversely, thalamic volume was the only morphometric feature significantly different between the two MS groups. Ten of the 12 features retained by the selection process as discriminative across the two MS groups regarded the hippocampus. The SVM classifier using these selected features reached an accuracy of 70% and a precision of 69%. DATA CONCLUSION: We provided evidence in support of the ability of dMRI to discriminate between PPMS and RRMS, as well as highlight the central role of the hippocampus. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 3.

Quantification of Upper Limb Motor Recovery and EEG Power Changes after Robot-Assisted Bilateral Arm Training in Chronic Stroke Patients: A Prospective Pilot Study.

Background: Bilateral arm training (BAT) has shown promise in expediting progress toward upper limb recovery in chronic stroke patients, but its neural correlates are poorly understood. Objective: To evaluate changes in upper limb function and EEG power after a robot-assisted BAT in chronic stroke patients. Methods: In a within-subject design, seven right-handed chronic stroke patients with upper limb paresis received 21 sessions (3 days/week) of the robot-assisted BAT. The outcomes were changes in score on the upper limb section of the Fugl-Meyer assessment (FM), Motricity Index (MI), and Modified Ashworth Scale (MAS) evaluated at the baseline (T0), posttraining (T1), and 1-month follow-up (T2). Event-related desynchronization/synchronization were calculated in the upper alpha and the beta frequency ranges. Results: Significant improvement in all outcomes was measured over the course of the study. Changes in FM were significant at T2, and in MAS at T1 and T2. After training, desynchronization on the ipsilesional sensorimotor areas increased during passive and active movement, as compared with T0. Conclusions: A repetitive robotic-assisted BAT program may improve upper limb motor function and reduce spasticity in the chronically impaired paretic arm. Effects on spasticity were associated with EEG changes over the ipsilesional sensorimotor network.

Dual-echo ASL contributes to decrypting the link between functional connectivity and cerebral blow flow.

Arterial spin labeling (ASL) MRI with a dual-echo readout module (DE-ASL) enables noninvasive simultaneous acquisition of cerebral blood flow (CBF)-weighted images and blood oxygenation level dependent (BOLD) contrast. Up to date, resting-state functional connectivity (FC) studies based on CBF fluctuations have been very limited, while the BOLD is still the method most frequently used. The purposes of this technical report were (i) to assess the potentiality of the DE-ASL sequence for the quantification of resting-state FC and brain organization, with respect to the conventional BOLD (cvBOLD) and (ii) to investigate the relationship between a series of complex network measures and the CBF information. Thirteen volunteers were scanned on a 3 T scanner acquiring a pseudocontinuous multislice DE-ASL sequence, from which the concomitant BOLD (ccBOLD) simultaneously to the ASL can be extracted. In the proposed comparison, the brain FC and graph-theoretical analysis were used for quantifying the connectivity strength between pairs of regions and for assessing the network model properties in all the sequences. The main finding was that the ccBOLD part of the DE-ASL sequence provided highly comparable connectivity results compared to cvBOLD. As expected, because of its different nature, ASL sequence showed different patterns of brain connectivity and graph indices compared to BOLD sequences. To conclude, the resting-state FC can be reliably detected using DE-ASL, simultaneously to CBF quantifications, whereas a single fMRI experiment precludes the quantitative measurement of BOLD signal changes. Hum Brain Mapp 38:5831-5844, 2017. © 2017 Wiley Periodicals, Inc.

Time-frequency modulation of ERD and EEG coherence in robot-assisted hand performance.

A better understanding of cortical modifications related to movement preparation and execution after robot-assisted training could aid in refining rehabilitation therapy protocols for stroke patients. Electroencephalography (EEG) modifications of cortical activity in healthy subjects were evaluated using time-frequency event-related EEG and task-related coherence (TRCoh). Twenty-one channel EEG was recorded in eight subjects during protocols of active, passive, and imagined movements. The subjects performed robot-assisted tasks using the Bi-Manu-Track robot-assisted arm trainer. We applied time-frequency event-related synchronization/desynchronization (ERS/ERD) and TRCoh approaches to investigate where movement-related decreases in power were localized and to study the functional relationships between areas. Our results showed ERD of sensorimotor (SM) area over the contralateral side before the movement and bilateral ERD during execution of the movement. ERD during passive movements was similar in topography to that observed during voluntary movements, but without pre-movement components. No significant difference in time course ERD was observed among the three types of movement over the two SM areas. The TRCoh topography was similar for active and imagined movement; before passive movement, the frontal regions were uncoupled from the SM regions and did not contribute to task performance. This study suggests new perspectives for the evaluation of brain oscillatory activity and the neurological assessment of motor performance by means of quantitative EEG to better understand the planning and execution of movement.

Combining ESI, ASL and PET for quantitative assessment of drug-resistant focal epilepsy.

When localization of the epileptic focus is uncertain, the epileptic activity generator may be more accurately identified with non-invasive imaging techniques which could also serve to guide stereo-electroencephalography (sEEG) electrode implantation. The aim of this study was to assess the diagnostic value of perfusion magnetic resonance imaging with arterial spin labeling (ASL) in the identification of the epileptogenic zone, as compared to the more invasive positron-emission tomography (PET) and other established investigation methods for source imaging of electroencephalography (EEG) data. In 6 patients with drug-resistant focal epilepsy, standard video-EEG was performed to identify clinical seizure semeiology, and high-density EEG, ASL and FDG-PET to non-invasively localize the epileptic focus. A standardized source imaging procedure, low-resolution brain electromagnetic tomography constrained to the individual matter, was applied to the averaged spikes of high-density EEG. Quantification of current density, cerebral blood flow, and standardized uptake value were compared over the same anatomical areas. In most of the patients, source in the interictal phase was associated with an area of hypoperfusion and hypometabolism. Conversely, in the patients presenting with early post-ictal discharges, the brain area identified by electrical source imaging (ESI) as the generating zone appeared to be hyperperfused. In 2 patients in whom the focus remained uncertain, the postoperative follow-up showed the disappearance of epileptic activity. As an innovative and more comprehensive approach to the study of epilepsy, the combined use of ESI, perfusion MRI, and PET may play an increasingly important role in the non-invasive evaluation of patients with refractory focal epilepsy.

Investigation of brain hemodynamic changes induced by active and passive movements: a combined arterial spin labeling-BOLD fMRI study.

PURPOSE: To assess the applicability of arterial spin labeling (ASL) in comparison to blood-oxygenation-level-dependent (BOLD) contrast fMRI in detecting brain activations elicited by active and passive hand movements. MATERIALS AND METHODS: A block design for ASL and BOLD fMRI was applied in 8 healthy subjects using active and passive hand tasks. Data analyses were performed at individual and group level, comparing both the different movements and the performance of the two techniques. RESULTS: Group analyses showed involvement of the same areas during both tasks, as the contralateral sensorimotor cortex, supplementary motor area, cerebellum, inferior parietal lobes, thalamus. ASL detected smaller activation volumes than BOLD, but the areas had a high degree of colocalization. Few significant differences (P < 0.05) were found when the two tasks were compared for the number of activated voxels, coordinates of center of mass, and CBF estimates. Considering together all the areas, the mean %BOLD change was 0.79 ± 0.27 and 0.73 ± 0.24 for the active and passive movements respectively, while the mean %CBF changes were 34.1 ± 8.9 and 27.1 ± 14.8. CONCLUSION: Our findings confirm passive and active tasks are strongly coupled, supporting the importance of passive tasks as a diagnostic tool in the clinical setting. ASL fMRI proved suitable for functional mapping and quantifying CBF changes, making it a promising technique for patient cohort applications.

Microstructural alterations in the locus coeruleus-entorhinal cortex pathway in Alzheimer's disease and frontotemporal dementia.

INTRODUCTION: We investigated in vivo the microstructural integrity of the pathway connecting the locus coeruleus to the transentorhinal cortex (LC-TEC) in patients with Alzheimer's disease (AD) and frontotemporal dementia (FTD). METHODS: Diffusion-weighted MRI scans were collected for 21 AD, 20 behavioral variants of FTD (bvFTD), and 20 controls. Fractional anisotropy (FA), mean, axial, and radial diffusivities (MD, AxD, RD) were computed in the LC-TEC pathway using a normative atlas. Atrophy was assessed using cortical thickness and correlated with microstructural measures. RESULTS: We found (i) higher RD in AD than controls; (ii) higher MD, RD, and AxD, and lower FA in bvFTD than controls and AD; and (iii) a negative association between LC-TEC MD, RD, and AxD, and entorhinal cortex (EC) thickness in bvFTD (all p < 0.050). DISCUSSION: LC-TEC microstructural alterations are more pronounced in bvFTD than AD, possibly reflecting neurodegeneration secondary to EC atrophy. Highlights: Microstructural integrity of LC-TEC pathway is understudied in AD and bvFTD.LC-TEC microstructural alterations are present in both AD and bvFTD.Greater LC-TEC microstructural alterations in bvFTD than AD.LC-TEC microstructural alterations in bvFTD are associated to EC neurodegeneration.

Modulation of event-related desynchronization in robot-assisted hand performance: brain oscillatory changes in active, passive and imagined movements.

BACKGROUND: Robot-assisted therapy in patients with neurological disease is an attempt to improve function in a moderate to severe hemiparetic arm. A better understanding of cortical modifications after robot-assisted training could aid in refining rehabilitation therapy protocols for stroke patients. Modifications of cortical activity in healthy subjects were evaluated during voluntary active movement, passive robot-assisted motor movement, and motor imagery tasks performed under unimanual and bimanual protocols. METHODS: Twenty-one channel electroencephalography (EEG) was recorded with a video EEG system in 8 subjects. The subjects performed robot-assisted tasks using the Bi-Manu Track robot-assisted arm trainer. The motor paradigm was executed during one-day experimental sessions under eleven unimanual and bimanual protocols of active, passive and imaged movements. The event-related-synchronization/desynchronization (ERS/ERD) approach to the EEG data was applied to investigate where movement-related decreases in alpha and beta power were localized. RESULTS: Voluntary active unilateral hand movement was observed to significantly activate the contralateral side; however, bilateral activation was noted in all subjects on both the unilateral and bilateral active tasks, as well as desynchronization of alpha and beta brain oscillations during the passive robot-assisted motor tasks. During active-passive movement when the right hand drove the left one, there was predominant activation in the contralateral side. Conversely, when the left hand drove the right one, activation was bilateral, especially in the alpha range. Finally, significant contralateral EEG desynchronization was observed during the unilateral task and bilateral ERD during the bimanual task. CONCLUSIONS: This study suggests new perspectives for the assessment of patients with neurological disease. The findings may be relevant for defining a baseline for future studies investigating the neural correlates of behavioral changes after robot-assisted training in stroke patients.

eXplainable AI Allows Predicting Upper Limb Rehabilitation Outcomes in Sub-Acute Stroke Patients.

While stroke is one of the leading causes of disability, the prediction of upper limb (UL) functional recovery following rehabilitation is still unsatisfactory, hampered by the clinical complexity of post-stroke impairment. Predictive models leading to accurate estimates while revealing which features contribute most to the predictions are the key to unveil the mechanisms subserving the post-intervention recovery, prompting a new focus on individualized treatments and precision medicine in stroke. Machine learning (ML) and explainable artificial intelligence (XAI) are emerging as the enabling technology in different fields, being promising tools also in clinics. In this study, we had the twofold goal of evaluating whether ML can allow deriving accurate predictions of UL recovery in sub-acute patients, and disentangling the contribution of the variables shaping the outcomes. To do so, Random Forest equipped with four XAI methods was applied to interpret the results and assess the feature relevance and their consensus. Our results revealed increased performance when using ML compared to conventional statistical approaches. Moreover, the features deemed as the most relevant were concordant across the XAI methods, suggesting good stability of the results. In particular, the baseline motor impairment as measured by simple clinical scales had the largest impact, as expected. Our findings highlight the core role of ML not only for accurately predicting the individual outcome scores after rehabilitation, but also for making ML results interpretable when associated to XAI methods. This provides clinicians with robust predictions and reliable explanations that are key factors in therapeutic planning/monitoring of stroke patients.

Explainable Artificial Intelligence and Cardiac Imaging: Toward More Interpretable Models.

Artificial intelligence applications have shown success in different medical and health care domains, and cardiac imaging is no exception. However, some machine learning models, especially deep learning, are considered black box as they do not provide an explanation or rationale for model outcomes. Complexity and vagueness in these models necessitate a transition to explainable artificial intelligence (XAI) methods to ensure that model results are both transparent and understandable to end users. In cardiac imaging studies, there are a limited number of papers that use XAI methodologies. This article provides a comprehensive literature review of state-of-the-art works using XAI methods for cardiac imaging. Moreover, it provides simple and comprehensive guidelines on XAI. Finally, open issues and directions for XAI in cardiac imaging are discussed.

Estimation of biological heart age using cardiovascular magnetic resonance radiomics.

We developed a novel interpretable biological heart age estimation model using cardiovascular magnetic resonance radiomics measures of ventricular shape and myocardial character. We included 29,996 UK Biobank participants without cardiovascular disease. Images were segmented using an automated analysis pipeline. We extracted 254 radiomics features from the left ventricle, right ventricle, and myocardium of each study. We then used Bayesian ridge regression with tenfold cross-validation to develop a heart age estimation model using the radiomics features as the model input and chronological age as the model output. We examined associations of radiomics features with heart age in men and women, observing sex-differential patterns. We subtracted actual age from model estimated heart age to calculate a "heart age delta", which we considered as a measure of heart aging. We performed a phenome-wide association study of 701 exposures with heart age delta. The strongest correlates of heart aging were measures of obesity, adverse serum lipid markers, hypertension, diabetes, heart rate, income, multimorbidity, musculoskeletal health, and respiratory health. This technique provides a new method for phenotypic assessment relating to cardiovascular aging; further studies are required to assess whether it provides incremental risk information over current approaches.

A low-dimensional cognitive-network space in Alzheimer's disease and frontotemporal dementia.

BACKGROUND: Alzheimer's disease (AD) and frontotemporal dementia (FTD) show network dysfunctions linked with cognitive deficits. Within this framework, network abnormalities between AD and FTD show both convergent and divergent patterns. However, these functional patterns are far from being established and their relevance to cognitive processes remains to be elucidated. METHODS: We investigated the relationship between cognition and functional connectivity of major cognitive networks in these diseases. Twenty-three bvFTD (age: 71±10), 22 AD (age: 72±6), and 20 controls (age: 72±6) underwent cognitive evaluation and resting-state functional MRI. Principal component analysis was used to describe cognitive variance across participants. Brain network connectivity was estimated with connectome analysis. Connectivity matrices were created assessing correlations between parcels within each functional network. The following cognitive networks were considered: default mode (DMN), dorsal attention (DAN), ventral attention (VAN), and frontoparietal (FPN) networks. The relationship between cognition and connectivity was assessed using a bootstrapping correlation and interaction analyses. RESULTS: Three principal cognitive components explained more than 80% of the cognitive variance: the first component (cogPC1) loaded on memory, the second component (cogPC2) loaded on emotion and language, and the third component (cogPC3) loaded on the visuo-spatial and attentional domains. Compared to HC, AD and bvFTD showed impairment in all cogPCs (p<0.002), and bvFTD scored worse than AD in cogPC2 (p=0.031). At the network level, the DMN showed a significant association in the whole group with cogPC1 and cogPC2 and the VAN with cogPC2. By contrast, DAN and FPN showed a divergent pattern between diagnosis and connectivity for cogPC2. We confirmed these results by means of a multivariate analysis (canonical correlation). CONCLUSIONS: A low-dimensional representation can account for a large variance in cognitive scores in the continuum from normal to pathological aging. Moreover, cognitive components showed both convergent and divergent patterns with connectivity across AD and bvFTD. The convergent pattern was observed across the networks primarily involved in these diseases (i.e., the DMN and VAN), while a divergent FC-cognitive pattern was mainly observed between attention/executive networks and the language/emotion cognitive component, suggesting the co-existence of compensatory and detrimental mechanisms underlying these components.

Brain network modulation in Alzheimer's and frontotemporal dementia with transcranial electrical stimulation.

The default mode (DMN) and the salience (SN) networks show functional hypo-connectivity in Alzheimer's disease (AD) and the behavioral variant of frontotemporal dementia (bvFTD), respectively, along with patterns of hyper-connectivity. We tested the clinical and neurobiological effects of noninvasive stimulation over these networks in 45 patients (AD and bvFTD) who received either anodal (target network: DMN in AD, SN in bvFTD) or cathodal stimulation (target network: SN in AD, DMN in bvFTD). We evaluated changes in clinical, cognitive, functional and structural connectivity, and perfusion measures. In both patient groups, cathodal stimulation was followed by behavioral improvement, whereas anodal stimulation led to cognitive improvement. Neither functional connectivity nor perfusion showed significant effects. A significant interaction between DMN and SN functional connectivity changes and stimulation protocol was reported in AD. These results suggest a protocol-dependent response, whereby the protocols studied show divergent effects on cognitive and clinical measures, along with a divergent modulatory pattern of connectivity in AD.

Brain age estimation at tract group level and its association with daily life measures, cardiac risk factors and genetic variants.

Brain age can be estimated using different Magnetic Resonance Imaging (MRI) modalities including diffusion MRI. Recent studies demonstrated that white matter (WM) tracts that share the same function might experience similar alterations. Therefore, in this work, we sought to investigate such issue focusing on five WM bundles holding that feature that is Association, Brainstem, Commissural, Limbic and Projection fibers, respectively. For each tract group, we estimated brain age for 15,335 healthy participants from United Kingdom Biobank relying on diffusion MRI data derived endophenotypes, Bayesian ridge regression modeling and 10 fold-cross validation. Furthermore, we estimated brain age for an Ensemble model that gathers all the considered WM bundles. Association analysis was subsequently performed between the estimated brain age delta as resulting from the six models, that is for each tract group as well as for the Ensemble model, and 38 daily life style measures, 14 cardiac risk factors and cardiovascular magnetic resonance imaging features and genetic variants. The Ensemble model that used all tracts from all fiber groups (FG) performed better than other models to estimate brain age. Limbic tracts based model reached the highest accuracy with a Mean Absolute Error (MAE) of 5.08, followed by the Commissural ([Formula: see text]), Association ([Formula: see text]), and Projection ([Formula: see text]) ones. The Brainstem tracts based model was the less accurate achieving a MAE of 5.86. Accordingly, our study suggests that the Limbic tracts experience less brain aging or allows for more accurate estimates compared to other tract groups. Moreover, the results suggest that Limbic tract leads to the largest number of significant associations with daily lifestyle factors than the other tract groups. Lastly, two SNPs were significantly (p value [Formula: see text]) associated with brain age delta in the Projection fibers. Those SNPs are mapped to HIST1H1A and SLC17A3 genes.

Voxel-based morphometry and task functional magnetic resonance imaging in essential tremor: evidence for a disrupted brain network.

The pathophysiology of essential tremor (ET) is controversial and might be further elucidated by advanced neuroimaging. Focusing on homogenous ET patients diagnosed according to the 2018 consensus criteria, this study aimed to: (1) investigate whether task functional MRI (fMRI) can identify networks of activated and deactivated brain areas, (2) characterize morphometric and functional modulations, relative to healthy controls (HC). Ten ET patients and ten HC underwent fMRI while performing two motor tasks with their upper limb: (1) maintaining a posture (both groups); (2) simulating tremor (HC only). Activations/deactivations were obtained from General Linear Model and compared across groups/tasks. Voxel-based morphometry and linear regressions between clinical and fMRI data were also performed. Few cerebellar clusters of gray matter loss were found in ET. Conversely, widespread fMRI alterations were shown. Tremor in ET (task 1) was associated with extensive deactivations mainly involving the cerebellum, sensory-motor cortex, and basal ganglia compared to both tasks in HC, and was negatively correlated with clinical tremor scales. Homogeneous ET patients demonstrated deactivation patterns during tasks triggering tremor, encompassing a network of cortical and subcortical regions. Our results point towards a marked cerebellar involvement in ET pathophysiology and the presence of an impaired cerebello-thalamo-cortical tremor network.

On the Viability of Diffusion MRI-Based Microstructural Biomarkers in Ischemic Stroke.

Recent tract-based analyses provided evidence for the exploitability of 3D-SHORE microstructural descriptors derived from diffusion MRI (dMRI) in revealing white matter (WM) plasticity. In this work, we focused on the main open issues left: (1) the comparative analysis with respect to classical tensor-derived indices, i.e., Fractional Anisotropy (FA) and Mean Diffusivity (MD); and (2) the ability to detect plasticity processes in gray matter (GM). Although signal modeling in GM is still largely unexplored, we investigated their sensibility to stroke-induced microstructural modifications occurring in the contralateral hemisphere. A more complete picture could provide hints for investigating the interplay of GM and WM modulations. Ten stroke patients and ten age/gender-matched healthy controls were enrolled in the study and underwent diffusion spectrum imaging (DSI). Acquisitions at three and two time points (tp) were performed on patients and controls, respectively. For all subjects and acquisitions, FA and MD were computed along with 3D-SHORE-based indices [Generalized Fractional Anisotropy (GFA), Propagator Anisotropy (PA), Return To the Axis Probability (RTAP), Return To the Plane Probability (RTPP), and Mean Square Displacement (MSD)]. Tract-based analysis involving the cortical, subcortical and transcallosal motor networks and region-based analysis in GM were successively performed, focusing on the contralateral hemisphere to the stroke. Reproducibility of all the indices on both WM and GM was quantitatively proved on controls. For tract-based, longitudinal group analyses revealed the highest significant differences across the subcortical and transcallosal networks for all the indices. The optimal regression model for predicting the clinical motor outcome at tp3 included GFA, PA, RTPP, and MSD in the subcortical network in combination with the main clinical information at baseline. Region-based analysis in the contralateral GM highlighted the ability of anisotropy indices in discriminating between groups mainly at tp1, while diffusivity indices appeared to be altered at tp2. 3D-SHORE indices proved to be suitable in probing plasticity in both WM and GM, further confirming their viability as a novel family of biomarkers in ischemic stroke in WM and revealing their potential exploitability in GM. Their combination with tensor-derived indices can provide more detailed insights of the different tissue modulations related to stroke pathology.

Arterial Spin Labeling Reveals Disrupted Brain Networks and Functional Connectivity in Drug-Resistant Temporal Epilepsy.

Resting-state networks (RSNs) and functional connectivity (FC) have been increasingly exploited for mapping brain activity and identifying abnormalities in pathologies, including epilepsy. The majority of studies currently available are based on blood-oxygenation-level-dependent (BOLD) contrast in combination with either independent component analysis (ICA) or pairwise region of interest (ROI) correlations. Despite its success, this approach has several shortcomings as BOLD is only an indirect and non-quantitative measure of brain activity. Conversely, promising results have recently been achieved by arterial spin labeling (ASL) MRI, primarily developed to quantify brain perfusion. However, the wide application of ASL-based FC has been hampered by its complexity and relatively low robustness to noise, leaving several aspects of this approach still largely unexplored. In this study, we firstly aimed at evaluating the effect of noise reduction on spatio-temporal ASL analyses and quantifying the impact of two ad-hoc processing pipelines (basic and advanced) on connectivity measures. Once the optimal strategy had been defined, we investigated the applicability of ASL for connectivity mapping in patients with drug-resistant temporal epilepsy vs. controls (10 per group), aiming at revealing between-group voxel-wise differences in each RSN and ROI-wise FC changes. We first found ASL was able to identify the main network (DMN) along with all the others generally detected with BOLD but never previously reported from ASL. For all RSNs, ICA-based denoising (advanced pipeline) allowed to increase their similarity with the corresponding BOLD template. ASL-based RSNs were visibly consistent with literature findings; however, group differences could be identified in the structure of some networks. Indeed, statistics revealed areas of significant FC decrease in patients within different RSNs, such as DMN and cerebellum (CER), while significant increases were found in some cases, such as the visual networks. Finally, the ROI-based analyses identified several inter-hemispheric dysfunctional links (controls > patients) mainly between areas belonging to the DMN, right-left thalamus and right-left temporal lobe. Conversely, fewer connections, predominantly intra-hemispheric, showed the opposite pattern (controls < patients). All these elements provide novel insights into the pathological modulations characterizing a "network disease" as epilepsy, shading light on the importance of perfusion-based approaches for identifying the disrupted areas and communications between brain regions.