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Beat-by-beat variability (BBV) rhythms are observed in both cardiovascular (CV) and intracranial (IC) compartments, yet interactions between the two are not fully understood. Real-Time Phase-Contrast (RT-PC) MRI sequence was acquired for 30 healthy volunteers at 1st cervical level on a 3T scanner. The arterial (AF), venous (VF), and cerebrospinal fluid (CSF) flow (CSFF) were computed as velocity integrals over the internal carotid artery, internal jugular vein, and CSF. AF, VF, and CSFF signals were segmented in inspiration and expiration beats, to assess the respiration influence. Systolic and diastolic BBV, and heart period series underwent autoregressive power spectral density analysis, to evaluate the low-frequency (LF, Mayer waves) and high frequency (HF, respiratory waves) components. The diastolic VF had the largest BBV. LF power was high in the diastolic AF series, poor in all CSFF series. The pulse wave analyses revealed higher mean amplitude during inspiration. Findings suggests a possible role of LF modulation of IC resistances and propagation of HF waves from VF to AF and CCSF. PC-RT-MRI could provide new insight into the interaction between CV and IC regulation and pave the way for a detailed analysis of the cerebrovascular effects of varied respiration patterns due to exercise and rehabilitation.

The strategically acquired gradient echo (STAGE) protocol, developed for 3T scanners, allows one to derive quantitative maps such as T1, T2*, proton density, and quantitative susceptibility mapping in about 5 min. Our aim was to adapt the STAGE sequences for 1.5T scanners which are still commonly used in clinical practice. Furthermore, the accuracy and repeatability of the STAGE-derived T1 estimate were tested. Flip angle (FA) optimization was performed using a theoretical simulation by maximizing signal-to-noise ratio, contrast-to-noise ratio, and T1 precision. The FA choice was further refined with the ISMRM/NIST phantom and in vivo acquisitions. The accuracy of the T1 estimate was assessed by comparing STAGE-derived T1 values with T1 maps obtained with an inversion recovery sequence. T1 accuracy was investigated for both the phantom and in vivo data. Finally, one subject was acquired 10 times once a week and a group of 27 subjects was scanned once. The T1 coefficient of variation (COV) was computed to assess scan-rescan and physiological variability, respectively. The FA1,2 = 7°,38° were identified as the optimal FA pair at 1.5T. The T1 estimate errors were below 3% and 5% for phantom and in vivo measurements, respectively. COV for different tissues ranged from 1.8 to 4.8% for physiological variability, and between 0.8 and 2% for scan-rescan repeatability. The optimized STAGE protocol can provide accurate and repeatable T1 mapping along with other qualitative images and quantitative maps in about 7 min on 1.5T scanners. This study provides the groundwork to assess the role of STAGE in clinical settings. • The STAGE imaging protocol was optimized for use on 1.5T field strength scanners. • A practical STAGE protocol makes it possible to derive quantitative maps (i.e., T1, T2*, PD, and QSM) in about 7 min at 1.5T. • The T1 estimate derived from the STAGE protocol showed good accuracy and repeatability.

The substantia nigra (SN) pars compacta (SNpc) and pars reticulata (SNpr) are differentially affected in Parkinson’s disease (PD). Separating the SNpc and SNpr is challenging with standard magnetic resonance imaging (MRI). Diffusion tensor imaging (DTI) allows for the characterization of SN microstructure in a non-invasive manner. In this study, 29 PD patients and 28 healthy controls (HCs) were imaged with 1.5T MRI for DTI. Images were nonlinearly registered to standard space and SNpc and SNpr DTI parameters were measured. ANCOVA and receiver operator characteristic (ROC) analyses were performed. Clinical associations were assessed with Spearman correlations. Multiple corrections were controlled for false discovery rate. PD patients presented with significantly increased SNpc axial diffusivity (AD) (1.207 ± 0.068 versus 1.156 ± 0.045, p = 0.024), with ROC analysis yielding an under the curve of 0.736. Trends with Unified Parkinson’s Disease Rating Scale (UPDRS) III scores were identified for SNpc MD (rs = 0.449), AD (rs = 0.388), and radial diffusivity (rs = 0.391) (all p < 0.1). A trend between baseline SNpr MD and H&Y change (rs = 0.563, p = 0.081) over 2.9 years of follow-up was identified (n = 14). In conclusion, SN microstructure shows robust, clinically meaningful associations in PD.

Perfusion alterations within several brain regions have been shown in multiple sclerosis patients using different magnetic resonance imaging (MRI) techniques. Furthermore, MRI-derived brain perfusion metrics have been investigated in association with multiple sclerosis phenotypes, physical disability, and cognitive impairment. However, a review focused on these aspects is still missing. Our aim was to review all the studies investigating the relationship between perfusion MRI and clinical severity during the last fifteen years to understand the clinical relevance of these findings. Perfusion differences among phenotypes were observed both with 1.5T and 3T scanners, with progressive multiple sclerosis presenting with lower perfusion values than relapsing-remitting multiple sclerosis patients. However, only 3T scanners showed a statistically significant distinction. Controversial results about the association between MRI-derived perfusion metrics and physical disability scores were found. However, the majority of the studies showed that lower brain perfusion and longer transit time are associated with more severe physical disability and worse cognitive performances.

The study of brain venous drainage has gained attention due to its hypothesized link with various neurological conditions. Intracranial and neck venous flow rate may be estimated using cardiac-gated cine phase-contrast (PC)-MRI. Although previous studies showed that breathing influences the neck’s venous flow, this aspect could not be studied using the conventional segmented PC-MRI since it reconstructs a single cardiac cycle. The advent of real-time PC-MRI has overcome these limitations. Using this technique, we measured the internal jugular veins and superior sagittal sinus flow rates in a group of 16 healthy subjects (12 females, median age of 23 years). Comparing forced-breathing and free-breathing, the average flow rate decreased and the respiratory modulation increased. The flow rate decrement may be due to a vasoreactive response to deep breathing. The respiratory modulation increment is due to the thoracic pump’s greater effect during forced breathing compared to free breathing. These results showed that the breathing mode influences the average blood flow and its pulsations. Since effective drainage is fundamental for brain health, rehabilitative studies might use the current setup to investigate if respiratory exercises positively affect clinical variables and venous drainage.

In a companion paper by Cohen-Adad et al. we introduce the spine generic quantitative MRI protocol that provides valuable metrics for assessing spinal cord macrostructural and microstructural integrity. This protocol was used to acquire a single subject dataset across 19 centers and a multi-subject dataset across 42 centers (for a total of 260 participants), spanning the three main MRI manufacturers: GE, Philips and Siemens. Both datasets are publicly available via git-annex. Data were analysed using the Spinal Cord Toolbox to produce normative values as well as inter/intra-site and inter/intra-manufacturer statistics. Reproducibility for the spine generic protocol was high across sites and manufacturers, with an average inter-site coefficient of variation of less than 5% for all the metrics. Full documentation and results can be found at https://spine-generic.rtfd.io/ . The datasets and analysis pipeline will help pave the way towards accessible and reproducible quantitative MRI in the spinal cord.

BACKGROUND Grey Matter (GM) atrophy has been extensively described in Multiple Sclerosis (MS) patients, while cerebral hypoperfusion has been less consistently reported. Since hypoperfusion might be related to atrophy, we evaluated the presence of both damages. OBJECTIVE We aimed to assess if the regions of altered perfusion and atrophy overlapped with one another and if the two parameters were locally related. METHOD 3D-T1 weighted and arterial spin labelling sequences were acquired using a 1.5T Magnetic Resonance Imaging scanner from 26 relapsing remitting MS patients and 26 Healthy Controls (HC). GM volume and Cerebral Blood Flow (CBF) differences and their correlation were tested with a voxel-wise approach. RESULTS MS patients (41.4±12.5 years; 14 females) had a median [25th-75th percentile range] Expanded Disability Status Scale of 1.0[1.0-2.4] and a median [25th-75th percentile range] disease duration of 8.0 [4.0-16.5] years. HC were age- and sex-matched (43.9±17.4 years; 11 females). GM atrophy was detected for MS group in the right parahippocampal gyrus, thalami and left caudate (pFWE≤0.05). Areas of significant (after family-wise error -FWE- correction for multiple comparisons) (pFWE≤0.05) hypoperfusion were found for MS in the anterior cingulate and paracingulate gyri, supplementary motor cortex, precentral and superior frontal gyrus. GM volume and CBF showed a significant correlation (pFWE≤0.05) in the right lateral occipital cortex and precuneus in the MS group. CONCLUSIONS GM atrophy and hypoperfusion in MS were located in different areas. Perfusion estimate might be used as a further marker of tissue damage, in addition to GM volume.

One major thrust in radiology today is image standardization with a focus on rapidly acquired quantitative multi-contrast information. This is critical for multi-center trials, for the collection of big data and for the use of artificial intelligence in evaluating the data. Strategically acquired gradient echo (STAGE) imaging is one such method that can provide 8 qualitative and 7 quantitative pieces of information in 5 min or less at 3 T. STAGE provides qualitative images in the form of proton density weighted images, T1 weighted images, T2* weighted images and simulated double inversion recovery (DIR) images. STAGE also provides quantitative data in the form of proton spin density, T1, T2* and susceptibility maps as well as segmentation of white matter, gray matter and cerebrospinal fluid. STAGE uses vendors' product gradient echo sequences. It can be applied from 0.35 T to 7 T across all manufacturers producing similar results in contrast and quantification of the data. In this paper, we discuss the strengths and weaknesses of STAGE, demonstrate its contrast-to-noise (CNR) behavior relative to a large clinical data set and introduce a few new image contrasts derived from STAGE, including DIR images and a new concept referred to as true susceptibility weighted imaging (tSWI) linked to fluid attenuated inversion recovery (FLAIR) or tSWI-FLAIR for the evaluation of multiple sclerosis lesions. The robustness of STAGE T1 mapping was tested using the NIST/NIH phantom, while the reproducibility was tested by scanning a given individual ten times in one session and the same subject scanned once a week over a 12-week period. Assessment of the CNR for the enhanced T1W image (T1WE) showed a significantly better contrast between gray matter and white matter than conventional T1W images in both patients with Parkinson's disease and healthy controls. We also present some clinical cases using STAGE imaging in patients with stroke, metastasis, multiple sclerosis and a fetus with ventriculomegaly. Overall, STAGE is a comprehensive protocol that provides the clinician with numerous qualitative and quantitative images.

Aqueduct of Sylvius (AoS) cerebrospinal fluid flow can be quantified using phase-contrast (PC) Magnetic Resonance Imaging. The software used for AoS segmentation might affect the PC-derived measures. We analyzed AoS PC data of 30 people with multiple sclerosis and 19 normal controls using three software packages, and estimated cross-sectional area (CSA), average and highest AoS velocity (Vmean and Vmax), flow rate and volume. Our aims were to assess the repeatability and reproducibility of each PC-derived measure obtained with the various software packages, including in terms of group differentiation. All the variables had good repeatability, except the average Vmean, flow rate and volume obtained with one software package. Substantial to perfect agreement was seen when evaluating the overlap between the AoS segmentations obtained with different software packages. No variable was significantly different between software packages, with the exception of Vmean diastolic peak and CSA. Vmax diastolic peak differentiated groups, regardless of the software package. In conclusion, a clinical study should preliminarily evaluate the repeatability in order to interpret its findings. Vmax seemed to be a repeatable and reproducible measure, since the pixel with its value is usually located in the center of the AoS, and is thus unlikely be affected by ROI size.

BACKGROUND AND PURPOSE With respect to healthy controls (HCs), increased iron concentrations in the deep gray matter (GM) and decreased white matter (WM) integrity are common findings in multiple sclerosis (MS) patients. The association between these features of the disease remains poorly understood. We investigated the relationship between deep iron deposition in the deep GM and WM injury in associated fiber tracts in MS patients. METHODS Sixty-six MS patients (mean age 50.0 years, median Expanded Disability Status Scale 5.25, mean disease duration 19.1 years) and 29 HCs, group matched for age and sex were imaged on a 1.5T scanner. Susceptibility-weighted imaging and diffusion tensor imaging (DTI) were used for assessing high-pass filtered phase values in the deep GM and normal appearing WM (NAWM) integrity in associated fiber tracts, respectively. Correlation analyses investigated the associations between filtered phase values (suggestive of iron content) and WM damage. RESULTS Areas indicative of increased iron levels were found in the left and right caudates as well as in the left thalamus. MS patients presented with decreased DTI-derived measures of tissue integrity in the associated WM tracts. Greater mean, axial and radial diffusivities were associated with increased iron levels in all three GM areas (r values .393 to .514 with corresponding P values .003 to

Objective The identification of regions of increased susceptibility (RoIS) in multiple sclerosis (MS) white matter lesions (WML) is currently performed by the radiologist’s visual inspection of magnetic resonance imaging (MRI) data acquired with high-field MRI scanners. The aims of this study were: 1) to define and validate a semi-automatic method for detecting RoIS in WML from quantitative susceptibility maps (QSM) and susceptibility-weighted imaging (SWI) acquired with a 1.5 T MRI scanner; 2) to assess the prevalence of WML with RoIS and the susceptibility in those areas; and 3) to test the association between RoIS in WML and clinical outcomes. Methods Thirty-eight MS patients were scanned on a 1.5 T MRI scanner. T2-hyperintense WML were segmented and superimposed on SWI and QSM images. Two intensity thresholds were defined and consecutively applied for identifying RoIS within WML (thrhyper_QSM to identify QSM hyperintensity within WML and thrhypoSWI to identify SWI hypointensity within WML). The sensitivity and specificity were assessed on a subgroup of subjects. The numbers of WML with RoIS and RoIS volume were determined. Differences between phenotypes and correlations with clinical outcome were tested. Results The method showed good sensitivity (95.6%) and specificity (92.1%). On average, 44.7% of the WML showed RoIS, occupying 11.0% of the total lesion volume, with an average susceptibility of 39.4 ± 12.2 ppb. The number of WML with RoIS was negatively correlated with disease duration (r = −0.342, p = 0.035). Conclusion The proposed semi-automatic method proved to be suitable for the detection of RoIS in WML at 1.5 T. This approach may be useful in longitudinal studies aiming to monitor susceptibility in WML.

We assessed cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) within gray matter (GM), normal appearing white matter (NAWM) and white matter (WM) lesions in a group of multiple sclerosis (MS) patients. Furthermore, correlations between CBF, CVR and age were investigated. 31 MS patients and 25 healthy controls (HC) were examined on a 1.5 T MRI scanner, using pseudo-continuous arterial spin labeling MRI. MS vs HC CBF and CVR differences were assessed in GM regions of interest (i.e. resting state networks and vascular territories), and within WM. Correlations between CBF/CVR and age were then computed for MS and HC groups. Whereas no significant CBF and CVR differences were observed between MS and HC in any of the considered brain areas, significantly lower CBF was found in WM lesions with respect to NAWM (p

Parkinson’s disease (PD) is a motor disorder that initially presents with unilateral symptoms. Widespread white matter (WM) alterations have been reported since the early stages of the disease. The aim of this study was to investigate WM alterations in right-dominant and left-dominant symptom PD patients (RPD and LPD, respectively) with respect to healthy controls (HC) by diffusion-weighted magnetic resonance imaging (MRI). Thirty-eight subjects participated in this study: 12 RPD (median H&Y [IQR] = 1.5 [1.1–2], median UPDRS III [IQR] = 23 [7.8–25]), 9 LPD (median H&Y [IQR] = 1.5 [1–2.5], median UPDRS III [IQR] = 17 [12–22]), and 17 HC. All the participants were scanned on a 1.5-T MRI scanner. Maps of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were computed for all the subjects. Tract-based spatial statistics (TBSS) was performed for each diffusion parameter, to test WM differences between RPD, LPD, and HC (ANCOVA design). Family-wise error (FWE) correction was performed and p values lower than 0.05 were considered significant. No significant FA and RD differences were observed between RPD, LPD, and HC. Significantly increased MD and AD were observed in RPD with respect to HC within widespread WM regions, bilaterally. Conversely, no significant WM alterations were detected in LPD. WM integrity was found to be significantly altered in RPD but not in LPD, suggesting that LPD profile may be associated to more favorable prognosis. Since clinical laterality onset may affect the extent of WM integrity changes, it should be taken into account in neuroimaging studies investigating PD.

Rehabilitation seems to promote brain plasticity, but objective measures of efficacy are lacking and there is a limited understanding of the mechanisms underlying functional recovery. To study functional and structural brain changes induced by gait rehabilitation. We enrolled MS inpatients (EDSS 4.5–6.5) undergoing a 4-week neurorehabilitation. Several clinical measures were obtained, including: 2-min walk test (2MWT), dynamic gait index (DGI), Berg balance scale (BBS). Furthermore, motor-task functional MRI (fMRI) of plantar dorsiflexion, resting state fMRI, and regional diffusion tensor imaging (DTI) metrics were obtained. All the assessments were performed at baseline (T0), after the end of the rehabilitation period (T1) and 3 months later (T2). Twenty-nine patients were enrolled at T0, 26 at T1, and 16 completed all timepoints. At T1, there was a significant improvement of 2MWT, DGI, and BBS scores, along with a reduced extent of the widespread activation related to the motor task at the fMRI and an increased functional connectivity in the precentral and post-central gyrus, bilaterally. None of these changes were maintained at T2. Our findings show a short-term beneficial effect of motor rehabilitation on gait performances in MS, accompanied by brain functional reorganization in the sensory-motor network.

Iron deposition has been noted widely in the subcortical deep gray matter (SDGM) of multiple sclerosis (MS) patients. Recent evidence suggests that serum iron may cross the blood-brain barrier and might be associated with SDGM iron deposition. The aim of the current study was to assess whether an iron-sensitive MRI measure is related to serum iron concentrations. This was a retrospective, cross-sectional study of 22 MS patients and 24 healthy controls (HCs), group matched for age and sex. Participants were imaged on a 1.5-T MRI scanner. High-resolution T1-weighted images and susceptibility-weighted images were acquired for assessing SDGM volumes and iron deposition within the SDGM, respectively. All participants also had blood drawn for the measurement of serum iron concentrations. MS and HC groups were compared with respect to SDGM tissue volumes and iron content. Partial correlations, controlling for age, sex, and structural volume, were used to assess the relationship between serum iron and SDGM iron content. MS patients presented with significantly smaller SDGM tissue volumes of the caudate, globus pallidus, putamen, and thalamus (all P≤0.0001). With respect to HCs, increased iron content was observed for MS patients in the globus pallidus (P=0.009) only. In MS patients only, there was a significant relationship between serum iron and putaminal iron volume (partial r=0.449, P=0.041), whereas trends were evidenced for the caudate (partial r=0.396, P=0.078) and the globus pallidus (partial r=0.410, P=0.065). Serum iron content in MS patients may be related to SDGM iron content. These results warrant confirmation in a larger study of MS patients.

We studied cerebrospinal fluid (CSF) flow dynamics at the cervical level in association with internal jugular veins (IJV) flow for 92 patients with multiple sclerosis (MS). Phase contrast magnetic resonance imaging was used to quantify flow of the CSF and major vessels (including the IJV and the carotid arteries) at the C2-C3 level in the neck. Contrast enhanced MR angiography and time-of-flight MR venography were used to subdivide MS patients into stenotic (ST) and non-stenotic (NST) populations. We evaluated: IJV flow normalized by arterial flow; CSF peaks; CSF outflow duration and its onset from systole. We tested if these variables were statistically different among different MS phenotypes and between ST and NST MS patients. The delay between the beginning of beginning of systole and the CSF outflow was higher in ST compared to NST MS. Less IJV flow was observed in ST vs NST MS. None of the measures was different between the different MS phenotypes. These results suggest that alterations of IJV morphology affect both IJV flow and CSF flow timing but not CSF flow amplitude.

The Virtual Navigator (VN) technology was used for the fusion of transcranial Ultrasound (US) and brain Magnetic Resonance Images (MRI), with a repeatability error under 0.1 cm. The superimposition of US to the previously acquired MRI volume consisted of external point-based registration, that was subsequently refined with image-based registration of internal brain structures. The common registration procedure with the usage of external fiducial markers acquired with the two modalities was improved using facial anatomical landmarks, with a reduction of the internal targeted structure residual shift (maximum 0.7 cm in the cranio-caudal direction). This allowed the investigation of Deep Cerebral Veins and dural sinuses insonated from the condyloid process of the mandible, a recently introduced US window. The fusion of these vessels to the MRI volume provided their anatomical position and helped excluding false Doppler signal sources.

With respect to healthy controls (HCs), increased iron concentrations in the deep gray matter (GM) and decreased white matter (WM) integrity are common findings in multiple sclerosis (MS) patients. The association between these features of the disease remains poorly understood. We investigated the relationship between deep iron deposition in the deep GM and WM injury in associated fiber tracts in MS patients.Sixty-six MS patients (mean age 50.0 years, median Expanded Disability Status Scale 5.25, mean disease duration 19.1 years) and 29 HCs, group matched for age and sex were imaged on a 1.5T scanner. Susceptibility-weighted imaging and diffusion tensor imaging (DTI) were used for assessing high-pass filtered phase values in the deep GM and normal appearing WM (NAWM) integrity in associated fiber tracts, respectively. Correlation analyses investigated the associations between filtered phase values (suggestive of iron content) and WM damage.Areas indicative of increased iron levels were found in the left and right caudates as well as in the left thalamus. MS patients presented with decreased DTI-derived measures of tissue integrity in the associated WM tracts. Greater mean, axial and radial diffusivities were associated with increased iron levels in all three GM areas (r values .393 to .514 with corresponding P values .003 to.0001). Global NAWM diffusivity measures were not related to mean filtered phase values within the deep GM.Increased iron concentration in the deep GM is associated with decreased tissue integrity of the connected WM in MS patients.

Background Diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI) abnormalities in patients with multiple sclerosis (MS) are currently measured by a complex combination of separate procedures. Therefore, the purpose of this study was to provide a reliable method for reducing analysis complexity and obtaining reproducible results. Methods We implemented a semi-automated measuring system in which different well-known software components for magnetic resonance imaging (MRI) analysis are integrated to obtain reliable measurements of DWI and PWI disturbances in MS. Results We generated the Diffusion/Perfusion Project (DPP) Suite, in which a series of external software programs are managed and harmonically and hierarchically incorporated by in-house developed Matlab software to perform the following processes: 1) image pre-processing, including imaging data anonymization and conversion from DICOM to Nifti format; 2) co-registration of 2D and 3D non-enhanced and Gd-enhanced T1-weighted images in fluid-attenuated inversion recovery (FLAIR) space; 3) lesion segmentation and classification, in which FLAIR lesions are at first segmented and then categorized according to their presumed evolution; 4) co-registration of segmented FLAIR lesion in T1 space to obtain the FLAIR lesion mask in the T1 space; 5) normal appearing tissue segmentation, in which T1 lesion mask is used to segment basal ganglia/thalami, normal appearing grey matter (NAGM) and normal appearing white matter (NAWM); 6) DWI and PWI map generation; 7) co-registration of basal ganglia/thalami, NAGM, NAWM, DWI and PWI maps in previously segmented FLAIR space; 8) data analysis. All these steps are automatic, except for lesion segmentation and classification. Conclusion We developed a promising method to limit misclassifications and user errors, providing clinical researchers with a practical and reproducible tool to measure DWI and PWI changes in MS.

SummaryIntroduction: This article is part of the Focus Theme of Methods of Information in Medicine on “Biosignal Interpretation: Advanced Methods for Neural Signals and Images”.Background: Voxel-based functional connectivity analysis is a common method for resting state fMRI data. However, correlations between the seed and other brain voxels are corrupted by random estimate errors yielding false connections within the functional connectivity map (FCmap). These errors must be taken into account for a correct interpretation of single-subject results.Objectives: We estimated the statistical range of random errors and propose two methods for an individual setting of correlation threshold for FCmaps.Methods: We assessed the amount of random errors by means of surrogate time series and described its distribution within the brain. On the basis of these results, the FCmaps of the posterior cingulate cortex (PCC) from 15 healthy subjects were thresholded with two innovative methods: the first one consisted in the computation of a unique (global) threshold value to be applied to all brain voxels, while the second method is to set a different (local) threshold of each voxel of the FCmap.Results: The distribution of random errors within the brain was observed to be homogeneous and, after thresholding with both methods, the default mode network areas were well identifiable. The two methods yielded similar results, however the application of a global threshold to all brain voxels requires a reduced computational load. The inter-subject variability of the global threshold was observed to be very low and not correlated with age. Global threshold values are also almost independent from the number of surrogates used for their computation, so the analyses can be optimized using a reduced number of surrogate time series.Conclusions: We demonstrated the efficacy of FCmaps thresholding based on random error estimation. This method can be used for a reliable single-subject analysis and could also be applied in clinical setting, to compute individual measures of disease progression or quantitative response to pharmacological or rehabilitation treatments.

Primary progressive multiple sclerosis (PPMS) and amyotrophic lateral sclerosis (ALS) seem to share some clinical and pathological features. MRI studies revealed the presence of grey matter (GM) atrophy in both diseases, but no comparative data are available. The objective was to compare the regional patterns of GM tissue loss in PPMS and ALS with voxel-based morphometry (VBM). Eighteen PPMS patients, 20 ALS patients, and 31 healthy controls (HC) were studied with a 1.5 Tesla scanner. VBM was performed to assess volumetric GM differences with age and sex as covariates. Threshold-free cluster enhancement analysis was used to obtain significant clusters. Group comparisons were tested with family-wise error correction for multiple comparisons (p < 0.05) except for HC versus MND which was tested at a level of p < 0.001 uncorrected and a cluster threshold of 20 contiguous voxels. Compared to HC, ALS patients showed GM tissue reduction in selected frontal and temporal areas, while PPMS patients showed a widespread bilateral GM volume decrease, involving both deep and cortical regions. Compared to ALS, PPMS patients showed tissue volume reductions in both deep and cortical GM areas. This preliminary study confirms that PPMS is characterized by a more diffuse cortical and subcortical GM atrophy than ALS and that, in the latter condition, brain damage is present outside the motor system. These results suggest that PPMS and ALS may share pathological features leading to GM tissue loss.

Artifact removal in resting state fMRI (rfMRI) data remains a serious challenge, with even subtle head motion undermining reliability and reproducibility. Here we compared some of the most popular single-echo de-noising methodsÐregression of Motion parameters, White matter and Cerebrospinal fluid signals (MWC method), FMRIB's ICA-based X-noiseifier (FIX) and ICA-based Automatic Removal Of motion Artifacts (ICA-AROMA)Ðwith a multiecho approach (ME-ICA) that exploits the linear dependency of BOLD on the echo time. Data were acquired using a clinical scanner and included 30 young, healthy participants (minimal head motion) and 30 Attention Deficit Hyperactivity Disorder patients (greater head motion). De-noising effectiveness was assessed in terms of data quality after each cleanup\ud procedure, ability to uncouple BOLD signal and motion and preservation of default mode network (DMN) functional connectivity. Most cleaning methods showed a positive impact on data quality. However, based on the investigated metrics, ME-ICA was the most robust. It minimized the impact of motion on FC even for high motion participants and preserved DMN functional connectivity structure. The high-quality results obtained using ME-ICA suggest that using a multi-echo EPI sequence, reliable rfMRI data can be obtained in a clinical setting.

Real-time Ultrasound (US) image fusion with a pre-acquired second imaging dataset - Computed Tomography (CT), Magnetic Resonance Imaging (MRI) and/or CT/PET - has become widely used in recent years for both diagnosis and image-guided interventional procedures. Liver and kidneys are the main focused anatomical districts, related to abdominal application. There are still nowadays some drawbacks, regarding the adoption of the fusion imaging technique in everyday practice especially regarding its ease of use and the time needed in order to obtain a precise real-time fusion between US and the second imaging modality. The present work is a preliminary study on the feasibility and practical use of an Automatic registration algorithm for CT-US real-time fusion imaging. Data obtained by tests performed on a Doppler phantom, for the assessment of the precision of the registration procedure and in-vivo Automatic registration tests, are presented.

Multiple sclerosis (MS) is characterized by a wide interpatient clinical variability and available biomarkers of disease severity still have suboptimal reliability. We aimed to assess immunological and MRI-derived measures of brain tissue damage in patients with different motor impairment degrees, forin vivoinvestigating the pathogenesis of MS-related disability. Twenty-two benign (B), 26 secondary progressive (SP), and 11 early, nondisabled relapsing-remitting (RR) MS patients and 37 healthy controls (HC) underwent conventional and diffusion tensor brain MRI and, as regards MS patients, immunophenotypic and functional analysis of stimulated peripheral blood mononuclear cells (PBMC). Corticospinal tract (CST) fractional anisotropy and grey matter volume were lower and CST diffusivity was higher in SPMS compared to RRMS and BMS patients. CD14+IL6+ and CD4+IL25+ cell percentages were higher in BMS than in SPMS patients. A multivariable model having EDSS as the dependent variable retained the following independent predictors: grey matter volume, CD14+IL6+ and CD4+IL25+ cell percentages. In patients without motor impairment after long-lasting MS, the grey matter and CST damage degree seem to remain as low as in the earlier disease stages and an immunological pattern suggestive of balanced pro- and anti-inflammatory activity is observed. MRI-derived and immunological measures might be used as complementary biomarkers of MS severity.

Guiding diffusion tract-based anatomy by functional magnetic resonance imaging (fMRI), we aim to investigate the relationship between structural connectivity and functional activity in the human brain. To this purpose, we introduced a novel groupwise fMRI-guided tractographic approach, that was applied on a population ranging between prodromic and moderate stages of Alzheimer's disease (AD). The study comprised of 15 subjects affected by amnestic mild cognitive impairment (aMCI), 14 diagnosed with AD and 14 elderly healthy adults who were used as controls. By creating representative (ensemble) functionally guided tracts within each group of participants, our methodology highlighted the white matter fiber connections involved in verbal fluency functions for a specific population, and hypothesized on brain compensation mechanisms that potentially counteract or reduce cognitive impairment symptoms in prodromic AD. Our hope is that this fMRI-guided tractographic approach could have potential impact in various clinical studies, while investigating white/gray matter connectivity, in both health and disease.

The study of the Internal Jugular Vein (IJV) hemodynamics has gained particular attention after the definition of Chronic Cerebrospinal Venous Insufficiency syndrome (CCSVI), and the discovery of highly debated possible links between the venous system and some neurological pathologies (Multiple Sclerosis, Cough Headache, Transient Global Amnesia). One of the most studied hemodynamic signs of the IJV blood flow is the presence and extent of the reflux during normal respiratory conditions or forced breathing maneuvers (Valsalva, Muller;s deep inspiration). The present work is related to the analysis of IJV reflux performed using Magnetic Resonance Imaging (MRI) Phase Contrast (PC) and Ultrasound (US) Doppler techniques. Regarding the US modality, the classic Color Doppler, Pulsed Wave Doppler and the innovative Multigate Quality Doppler Profiles technology will be considered. Comparisons between the results obtained with MRI and US will be discussed to highlight advantages of the proposed MRI and US technologies for IJV reflux presence detection and analysis.

Tractography based on Diffusion Tensor Imaging (DTI) represents a valuable tool for investigating brain white matter (WM) microstructure, allowing the computation of damage-related diffusion parameters such as Fractional Anisotropy (FA) in specific WM tracts. This technique appears relevant in the study of pathologies in which brain disconnection plays a major role, such as, for instance, Alzheimer's Disease (AD). Previous DTI studies have reported inconsistent results in defining WM abnormalities in AD and in its prodromal stage (i.e., amnestic Mild Cognitive Impairment; aMCI), especially when investigating the corpus callosum (CC). A reason for these inconsistencies is the use of different processing techniques, which may strongly influence the results. The aim of the current study was to compare a novel atlas-based tractography approach, that sub-divides the CC in eight portions, with Tract-Based Spatial Statistics (TBSS) when used to detect specific patterns of CC FA in AD at different clinical stages. FA data were obtained from 76 subjects (37 with mild AD, 19 with aMCI and 20 elderly healthy controls, HC) and analyzed using both methods. Consistent results were obtained for the two methods, concerning the comparisons AD vs. HC (significantly reduced FA in the whole CC of AD patients) and AD vs. aMCI (significantly reduced FA in the frontal portions of the CC in AD patients), thus identifying a relative preservation of the frontal CC regions in aMCI patients compared to AD. Conversely, the atlas-based method but not the TBSS showed the ability to detect a selective FA change in the CC parietal, left temporal and occipital regions of aMCI patients compared to HC. This finding indicates that an analysis including a higher number of voxels (with no restriction to tract skeletons) may detect characteristic pattern of FA in the CC of patients with preclinical AD, when brain atrophy is still modest.

BACKGROUND AND PURPOSE In multiple sclerosis (MS), the presence of lesions and normal-appearing white matter damage may affect the reliability of diffusion tensor (DT) magnetic resonance imaging (MRI)-based tractography. We compared the performance of an individual-based method for corpus callosum (CC) fiber tracking in MS with those of two atlas-based methods. METHODS Brain DT MRI scans were acquired from 35 patients with MS and 18 age-matched healthy volunteers (HV). DT-derived metrics from the CC—the mean diffusivity (MD) and fractional anisotropy (FA)—were calculated using an individual-based and two atlas-based methods with different types of subject registration (linear and nonlinear) to a CC atlas. Customized termination criteria were applied to stop the tracking algorithm when using the individual-based method. RESULTS All the methods were able to distinguish between MS patients and HV. Using the individual-based method, stronger relationships were found between CC DT-derived metrics and the subjects’ clinical condition. CONCLUSION CC DT tractography using an individual-based method is more sensitive than the atlas-based ones to tract-specific alterations related to MS disability. An atlas-based method with nonlinear registration can be a valid alternative when an automated postprocessing is warranted, such as in the case of high volumes of data.

The Chronic Cerebro-Spinal Venous Insufficiency, recently described as a possible role in Multiple Sclerosis pathogenesis, is diagnosed and classified with Echo Color Doppler (ECD) examination of the extra- and intra-cranial veins. As to the intracranial examination, the presence of reflux in the deep cerebral veins (DCVs) or in the dural sinuses is inspected, with a new insonation approach, i.e. the transcondylar window. This work describes a procedure for the co-registration of anatomical Proton Density-weighted Magnetic Resonance Images (MRI) with the intracranial ECD obtained through the transcondylar window. The procedure, preliminarily tested on 10 volunteers, allowed to assess what are the DCVs visible from this new insonation approach and their position relative to the surrounding brain tissues.

Background. Magnetic Resonance (MR) diffusion tensor imaging (DTI) is able to quantify in vivo tissue microstructure properties and to detect disease related pathology of the central nervous system. Nevertheless, DTI is limited by low spatial resolution associated with its low signal-to-noise-ratio (SNR).Aim. The aim is to select a DTI sequence for brain clinical studies, optimizing SNR and resolution.Methods and Results. We applied 6 methods for SNR computation in 26 DTI sequences with different parameters using 4 healthy volunteers (HV). We choosed two DTI sequences for their high SNR, they differed by voxel size and b-value. Subsequently, the two selected sequences were acquired from 30 multiple sclerosis (MS) patients with different disability and lesion load and 18 age matched HV. We observed high concordance between mean diffusivity (MD) and fractional anysotropy (FA), nonetheless the DTI sequence with smaller voxel size displayed a better correlation with disease progression, despite a slightly lower SNR. The reliability of corpus callosum (CC) fiber tracking with the chosen DTI sequences was also tested.Conclusion. The sensitivity of DTI-derived indices to MS-related tissue abnormalities indicates that the optimized sequence may be a powerful tool in studies aimed at monitoring the disease course and severity.

Diffusion tensor (DT) magnetic resonance imaging is able to quantify tissue microstructure properties and to detect pathological changes even in the normal appearing tissues. DT sequence parameters which provide optimal SNR and minimum acquisition time, and an individual-based tractography post-processing allowed corpus callosum tractography even in multiple sclerosis (MS) patients also with no need of a-priori atlas. In this preliminary study, we were able to obtain reliable individual-based tractography in 28/30 MS patients. DT-derived indices computed in tracks obtained with individual-based tractography were able to differentiate healthy volunteers from MS patients better than the same indices computed with the atlas method. This indicates that such an optimized sequence may be a reliable tool to be used in future MS studies.

Quantitative spinal cord (SC) magnetic resonance imaging (MRI) presents many challenges, including a lack of standardized imaging protocols. Here we present a prospectively harmonized quantitative MRI protocol, which we refer to as the spine generic protocol, for users of 3T MRI systems from the three main manufacturers: GE, Philips and Siemens. The protocol provides guidance for assessing SC macrostructural and microstructural integrity: T1-weighted and T2-weighted imaging for SC cross-sectional area computation, multi-echo gradient echo for gray matter cross-sectional area, and magnetization transfer and diffusion weighted imaging for assessing white matter microstructure. In a companion paper from the same authors, the spine generic protocol was used to acquire data across 42 centers in 260 healthy subjects. The key details of the spine generic protocol are also available in an open-access document that can be found at https://github.com/spine-generic/protocols . The protocol will serve as a starting point for researchers and clinicians implementing new SC imaging initiatives so that, in the future, inclusion of the SC in neuroimaging protocols will be more common. The protocol could be implemented by any trained MR technician or by a researcher/clinician familiar with MRI acquisition.

The tractographic reconstruction of anatomical and microstructural features provided by Magnetic Resonance (MR) Diffusion Tensor Imaging (DTI) gives essential information of brain damage in several pathological animal models. The optimization of a tractographic protocol is undertaken in normal rats for the future construction of a reference atlas, as prerequisite for preclinical pathological in-vivo studies. High field, preclinical in-vivo DTI faces important difficulties relevant to Signal-to-Noise Ratio (SNR), distortion, high required resolution, movement sensitivity. Given a pixel-size of 0.17 mm and TE/TR = 29/6500 ms, b value and slice thickness were fixed at 700 s/mm(2) and 0.58 mm, respectively, on preventive ex-vivo studies. In-vivo studies led to the choice of 30 diffusion directions, averaged on 16 runs. The final protocol required 51 min scanning and permitted a reliable reconstruction of main rat brain bundles. Tract reconstruction stopping rules required proper setting. In conclusion, the viability of DTI tractography on in-vivo rat studies was shown, towards the construction of a normal reference atlas.

Diffusion tensor imaging (DTI) tractography and functional magnetic resonance imaging (fMRI) are powerful techniques to elucidate the anatomical and functional aspects of brain connectivity. However, integrating these approaches to describe the precise link between structure and function within specific brain circuits remains challenging. In this study, a novel DTI-fMRI integration method is proposed, to provide the topographical characterization and the volumetric assessment of the functional and anatomical connections within the language circuit. In a group of 21 healthy elderly subjects (mean age 68.5 +/- 5.8 years), the volume of connection between the cortical activity elicited by a verbal fluency task and the cortico-cortical fiber tracts associated with this function are mapped and quantified. An application of the method to a case study in neuro-rehabilitation context is also presented. Integrating structural and functional data within the same framework, this approach provides an overall view of white and gray matter when studying specific brain circuits.