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INTRODUCTION\ud Non-linguistic properties of speech are widely heterogeneous and require complex neurological integration. The association between white matter integrity and the severity of dysarthria was investigated in a group of patients diagnosed with amyotrophic lateral sclerosis (ALS).\ud \ud METHODS\ud Thirty-six patients diagnosed with amyotrophic lateral sclerosis completed a magnetic resonance imaging protocol inclusive of diffusion-weighted images. A clinical assessment of pneumo-phono-articulatory abilities was conducted for each patient, and a composite score of residual speech capacity was calculated. Tract-Based Spatial Statistics was carried out to model the potential association between residual speech capacity and microstructural properties of white matter (fractional anisotropy, mean and radial diffusivity).\ud \ud \ud RESULTS\ud A significant negative association was found between residual speech capacity and mean diffusivity in a large white matter cluster located in frontal, parietal and right temporal regions. These subcortical areas were characterised by pathological microstructural disruption, as revealed bypost hoc analyses.\ud \ud \ud CONCLUSIONS\ud Non-linguistic aspects of speech are associated with microstructural integrity of frontal, parietal and right temporal white matter in amyotrophic lateral sclerosis. Such mapping is consistent with the centres responsible of volitional control of speech and sensory feedback during non-linguistic speech production.

Whilst countless studies have shown that aging is associated with cognitive decline in the general population, near to nothing is known about this association in elderly individuals naturally exhibiting enhanced memory capabilities. The identification of a 75 years old individual (GC) with highly superiorautobiographical memory(HSAM), and his willingness to volunteer to our study over a period of five years, allowed us to investigate this issue in a single case study. At the age of 75 years, GC was screened for HSAM with the Public Events Quiz and the Random Dates Quiz, with a positive outcome. GC's memory performance was extraordinarily higher than normal-memory control subjects (>3 standard deviations), and comparable to a group of younger HSAM individuals (mean age of 32.5 years; Santangelo etal., 2018). GC underwent general neuropsychological (Mini-Mental State Examination), personality (Personality Assessment Inventory), and brain morphological (brain volumes and lesions) assessments, showing no deviation from normal ranges. To gain insight into the brain mechanisms underlying his memory performance, GC underwent functionalbrain imagingduring the retrieval of memories associated with random dates. The latter were also rated in terms of reliving quality and emotional valence. Similar to younger HSAM individuals, GC's access to past memories recruited a wide network of prefrontal and temporo-parietal regions, especially during the recollection of memories associated with a lower reliving rating, suggesting a compensatory mechanism in HSAM. Increased activity in theinsulawas instead associated with emotionally-positive memories. Five years later, GC was tested again for HSAM and showed no sign of memory decline, whereby his memory performance was indistinguishable from the tests he performed five years earlier. GC's case suggests that highly superior memory performance can manifest without apparent decline in physiological aging. Implications of the current findings for the extant models of autobiographical memory are discussed.

© 2021 Elsevier Ltd. All rights reserved., Background: subthalamic nucleus deep brain stimulation (STN-DBS) may have a detrimental effect on speech in Parkinson's disease (PD) patients and new stimulation technologies may help in addressing this issue. Objective: to evaluate the STN-DBS acute effect of 30 μs pulse width (30PW) versus conventional 60 μs PW (60PW) on speech and identify the core features of voice modified by 30PW. Methods: seven STN-DBS treated PD patients participated into a pilot cross-sectional study. Motor and speech performances were tested by means of both automatic analysis and blinded clinical evaluations in four stimulation conditions: 30PW and 60PW both at the usual amplitude and at an amplitude just below the threshold for stimulation-related side effects. Results: at the threshold amplitude, 30PW stimulation improved speech intelligibility for both words (p = 0.02) and sentences (p = 0.04), without worsening motor performance. A lower but not statistically significant voice variability and instability and percentage of stuttering disfluencies was also observed. The beneficial effect of 30PW detected by automatic analysis, was confirmed by patients' perception. Conclusions: STN-DBS treated patients experiencing low speech intelligibility may benefit from a 30PW stimulation trial at a higher amplitude. Deep characterization of PD speech profiles may help in a better application of recent DBS hardware advances.

Interhemispheric interactions in stroke patients are frequently characterized by abnormalities, in terms of balance and inhibition. Previous results showed an impressive variability, mostly given to the instability of motor‐evoked potentials when evoked from the affected hemisphere. We aim to find reliable interhemispheric measures in stroke patients with a not‐evocable motor‐evoked potential from the affected hemisphere, by combining transcranial magnetic stimulation (TMS) and electroencephalography. Ninteen stroke patients (seven females; 61.26 ± 9.8 years) were studied for 6 months after a first‐ever stroke in the middle cerebral artery territory. Patients underwent four evaluations: clinical, cortical, corticospinal, and structural. To test the reliability of our measures, the evaluations were repeated after 3 weeks. To test the sensitivity, 14 age‐matched healthy controls were compared to stroke patients. In stroke patients, stimulation of the affected hemisphere did not result in any inhibition onto the unaffected. The stimulation of the unaffected hemisphere revealed a preservation of the inhibition mechanism onto the affected. This resulted in a remarkable interhemispheric imbalance, whereas this mechanism was steadily symmetric in healthy controls. This result was stable when cortical evaluation was repeated after 3 weeks. Importantly, patients with a better recovery of the affected hand strength were the ones with a more stable interhemispheric balance. Finally, we found an association between microstructural integrity of callosal fibers, suppression of interhemispheric TMS‐evoked activity and interhemispheric connectivity. We provide direct and sensitive cortical measures of interhemispheric imbalance in stroke patients. These measures offer a reliable means of distinguishing healthy and pathological interhemispheric dynamics., We used transcranial magnetic stimulation–electroencephalography (TMS–EEG) to characterize interhemispheric dynamics in stroke patients. We provide a direct evidence of interhemispheric imbalance in stroke patients. TMS–EEG offers a reliable assessment of cerebral state during evolution of stroke.

Accurate and reproducible automated segmentation of human hippocampal subfields is of interest to study their roles in cognitive functions and disease processes. Multispectral structural MRI methods have been proposed to improve automated hippocampal subfield segmentation accuracy, but the reproducibility in a multicentric setting is, to date, not well characterized. Here, we assessed test–retest reproducibility of FreeSurfer 6.0 hippocampal subfield segmentations using multispectral MRI analysis pipelines (22 healthy subjects scanned twice, a week apart, at four 3T MRI sites). The harmonized MRI protocol included two 3D-T1, a 3D-FLAIR, and a high-resolution 2D-T2. After within-session T1 averaging, subfield volumes were segmented using three pipelines with different multispectral data: two longitudinal (“long_T1s” and “long_T1s_FLAIR”) and one cross-sectional (“long_T1s_FLAIR_crossT2”). Volume reproducibility was quantified in magnitude (reproducibility error—RE) and space (DICE coefficient). RE was lower in all hippocampal subfields, except for hippocampal fissure, using the longitudinal pipelines compared to long_T1s_FLAIR_crossT2 (average RE reduction of 0.4–3.6%). Similarly, the longitudinal pipelines showed a higher spatial reproducibility (1.1–7.8% of DICE improvement) in all hippocampal structures compared to long_T1s_FLAIR_crossT2. Moreover, long_T1s_FLAIR provided a small but significant RE improvement in comparison to long_T1s (p = 0.015), whereas no significant DICE differences were found. In addition, structures with volumes larger than 200 mm3 had better RE (1–2%) and DICE (0.7–0.95) than smaller structures. In summary, our study suggests that the most reproducible hippocampal subfield FreeSurfer segmentations are derived from a longitudinal pipeline using 3D-T1s and 3D-FLAIR. Adapting a longitudinal pipeline to include high-resolution 2D-T2 may lead to further improvements. Electronic supplementary material The online version of this article (10.1007/s00429-020-02172-w) contains supplementary material, which is available to authorized users.

Cognitive reserve (CR) is known to modulate the clinical features of Alzheimer's disease (AD). This concept may be critical for the development of non-pharmacological interventions able to slow down patients' cognitive decline in the absence of disease-modifying treatments. We aimed at identifying the neurobiological substrates of CR (i.e., neural reserve) over the transition between normal aging and AD, by assessing the underlying brain networks and their topological properties. A cohort of 154 participants (n = 68 with AD, n = 61 with amnestic mild cognitive impairment (aMCI), and 25 healthy subjects) underwent resting-state functional MRI and neuropsychological testing. Within each group, participants were classified as having high or low CR, and functional connectivity measures were compared, within group, between high and low CR individuals. Network-based statistics and topological network properties derived from graph theory were explored. Connectivity differences between high and low CR were evident only for aMCI patients, with participants with high CR showing a significant increase of connectivity in a network involving mainly fronto-parietal nodes. Conversely, they showed significantly decreased connectivity in a network involving fronto-temporo-cerebellar nodes. Consistently, changes to topological measures were observed in either direction, and were associated with measures of global cognitive function. These findings support the hypothesis that CR impacts on neurodegenerative process in the early phase of AD only. In addition, they fit with the existence of a "neural reserve", characterized by specific neural networks and their efficiency. It remains to be demonstrated whether interventions later in life can modulate this "neural reserve".

PURPOSE\ud The disease course of multiple sclerosis (MS) is unpredictable, and reliable prognostic biomarkers are needed. Positron emission tomography (PET) with β-amyloid tracers is a promising tool for evaluating white matter (WM) damage and repair. Our aim was to investigate amyloid uptake in damaged (DWM) and normal-appearing WM (NAWM) of MS patients, and to evaluate possible correlations between cerebrospinal fluid (CSF) β-amyloid (Aβ) levels, amyloid tracer uptake, and brain volumes.\ud \ud METHODS\ud Twelve MS patients were recruited and divided according to their disease activity into active and non-active groups. All participants underwent neurological examination, neuropsychological testing, lumbar puncture, brain magnetic resonance (MRI) imaging, and F-florbetapir PET. Aβ levels were determined in CSF samples from all patients. MRI and PET images were co-registered, and mean standardized uptake values (SUV) were calculated for each patient in the NAWM and in the DWM. To calculate brain volumes, brain segmentation was performed using statistical parametric mapping software. Nonparametric statistical analyses for between-group comparisons and regression analyses were conducted.\ud \ud RESULTS\ud We found a lower SUV in DWM compared to NAWM (p

Background: The importance of predicting disease progression in multiple sclerosis (MS) has increasingly been recognized, and hence reliable biomarkers are needed. Objectives: To investigate the prognostic role of cerebrospinal fluid (CSF) amyloid beta1–42 (Aβ) levels by the determination of a cut-off value to classify patients in slow and fast progressors. To evaluate possible association with white matter (WM) and grey matter (GM) damage at early disease stages. Methods: Sixty patients were recruited and followed up for 3–5 years. Patients underwent clinical assessment, brain magnetic resonance imaging (MRI; at baseline and after 1 year), and CSF analysis to determine Aβ levels. T1-weighted volumes were calculated. T2-weighted scans were used to quantify WM lesion loads. Results: Lower CSF Aβ levels were observed in patients with a worse follow-up Expanded Disability Status Scale (EDSS; r = −0.65, p 0.05). Conclusion: Low CSF Aβ levels may represent a predictive biomarker of disease progression in MS.

Microstructural imaging and connectomics are two research areas that hold great potential for investigating brain structure and function. Combining these two approaches can lead to a better and more complete characterization of the brain as a network. The aim of this work is\ud characterizing the connectome from a novel perspective using the myelination measure given by the g-ratio. The g-ratio is the ratio of the inner to the outer diameters of a myelinated axon, whose aggregated value can now be estimated in vivo using MRI. In two different datasets of\ud healthy subjects, we reconstructed the structural connectome and then used the g-ratio estimated from diffusion and magnetization transfer data to characterise the network structure. Significant characteristics of g-ratio weighted graphs emerged. First, the g-ratio\ud distribution across the edges of the graph did not show the power-law distribution observed using the number of streamlines as a weight. Second, connections involving regions related to motor and sensory functions were the highest in myelin content. We also observed significant\ud differences in terms of the hub structure and the rich-club organization suggesting that connections involving hub regions present higher myelination than peripheral connections. Taken together, these findings offer a characterization of g-ratio distribution across the\ud connectome in healthy subjects and lay the foundations for further investigating plasticity and pathology using a similar approach.

The frontal aslant tract (FAT) has been described as a bundle connecting the Broca’s area to the supplementary motor area (SMA) and the pre-SMA in both hemispheres. The functional properties of this tract and its role in degenerative dementia, such as Alzheimer’s disease (AD), still need to be fully clarified. The aim of this study was to explore the microstructural integrity of the FAT in patients with AD and its potential relationship with cognitive functioning. Twenty-three patients with AD and 25 healthy subjects (HS) were enrolled. All subjects underwent cognitive and MRI examination. MRI, including diffusion sequences, was used for probabilistic tractography analysis. We reconstructed individual FATs bilaterally and assessed their microstructural integrity using fractional anisotropy (FA), computed as both mean tract value and voxel-wise using SPM-8. Mean FA values were then used to test for correlations with cognitive measures. Mean tract FA and voxel-wise analyses revealed that patients with AD, compared to HS, had decreased FA in the FAT bilaterally. In addition, positive associations were found between FA in the FATs and patients’ performance at tests for constructional praxis and visuospatial logical reasoning. The present results reveal a bilateral damage of FAT in AD patients. The association between FATs’ microscopic abnormalities and constructive abilities fits well with the knowledge of a functional involvement of SMA and pre-SMA in movement sequences when executing constructive praxis tasks. The FAT is an associative bundle critically involved in the network sub-serving constructional praxis in patients with AD.

ObjectiveTo assess the connection between amyloid pathology and white matter (WM) macrostructural and microstructural damage in demented patients compared with controls.MethodsEighty-five participants were recruited: 65 with newly diagnosed Alzheimer’s disease (AD), non-AD dementia or mild cognitive impairment and 20 age-matched and sex-matched healthy controls. β-amyloid1-42 (Aβ) levels were determined in cerebrospinal fluid (CSF) samples from all patients and five controls. Among patients, 42 had pathological CSF Aβ levels (Aβ(+)), while 23 had normal CSF Aβ levels (Aβ(−)). All participants underwent neurological examination, neuropsychological testing and brain MRI. We used T2-weighted scans to quantify WM lesion loads (LLs) and diffusion-weighted images to assess their microstructural substrate. Non-parametric statistical tests were used for between-group comparisons and multiple regression analyses.ResultsWe found an increased WM-LL in Aβ(+) compared with both, healthy controls (p=0.003) and Aβ(−) patients (p=0.02). Interestingly, CSF Aβ concentration was the best predictor of patients’ WM-LL (r=−0.30, pConclusionsWM damage is crucial in AD pathogenesis. The correlation between CSF Aβ levels and WM-LL suggests a direct link between amyloid pathology and WM macrostructural and microstructural damage.

Graph-theoretical approaches have become a popular way to model brain data collected using magnetic resonance imaging (MRI), both from the structural and the functional perspectives. In structural networks, tract-based mapping allows to model different aspects of brain structures by means of the specific characteristics of the different MRI modalities. However, there has been little effort to join the information carried by each modality and to understand what level of common variance is shown in these data. In this paper, we proposed a combined approach based on graph theory and factor analysis to model magnetization transfer and microstructural properties in 18 relapsing remitting multiple sclerosis (RRMS) patients and 17 healthy controls. After defining the common factors and outlining their relationships with MRI data, we evaluated between-group differences using global and local graph measures. The results showed that one common factor describes brain structures in terms of myelin and global integrity, and such factor is able to highlight specific between-group differences.

Obstructive sleep apnea (OSA) is accompanied by neurocognitive impairment, likely mediated by injury to various brain regions. We evaluated brain morphological changes in patients with OSA and their relationship to neuropsychological and oximetric data. Sixteen patients affected by moderate-severe OSA (age: 55.8±6.7 years, 13 males) and fourteen control subjects (age: 57.6±5.1 years, 9 males) underwent 3.0 Tesla brain magnetic resonance imaging (MRI) and neuropsychological testing evaluating short and long-term memory, executive functions, language, attention, praxia and non-verbal learning. Volumetric segmentation of cortical and subcortical structures and voxel-based morphometry (VBM) were performed. Patients and controls differed significantly in Rey Auditory- Verbal Learning test (immediate and delayed recall), Stroop test and Digit span backward scores. Volumes of cortical gray matter (GM), right hippocampus, right and left caudate were smaller in patients compared to controls, with also brain parenchymal fraction (a normalized measure of cerebral atrophy) approaching statistical significance. Differences remained significant after controlling for comorbidities (hypertension, diabetes, smoking, hypercholesterolemia). VBM analysis showed regions of decreased GM volume in right and left hippocampus and within more lateral temporal areas in patients with OSA. Our findings indicate that the significant cognitive impairment seen in patients with moderate-severe OSA is associated with brain tissue damage in regions involved in several cognitive tasks. We conclude that OSA can increase brain susceptibility to the effects of aging and other clinical and pathological occurrences.

This longitudinal study investigates the modifications in structure and function occurring to typical Alzheimer's disease (AD) brains over a 2-year follow-up, from pre-dementia stages of disease, with the aim of identifying biomarkers of prognostic value. Thirty-one patients with amnestic mild cognitive impairment were recruited and followed-up with clinical, neuropsychological, and MRI assessments. Patients were retrospectively classified as AD Converters or Non-Converters, and the data compared between groups. Cross-sectional MRI data at baseline, assessing volume and functional connectivity abnormalities, confirmed previous findings, showing a more severe pattern of regional grey matter atrophy and default-mode network disconnection in Converters than in Non-Converters. Longitudinally, Converters showed more grey matter atrophy in the frontotemporal areas, accompanied by increased connectivity in the precuneus. Discriminant analysis revealed that functional connectivity of the precuneus within the default mode network at baseline is the parameter able to correctly classify patients in Converters and Non-Converters with high sensitivity, specificity, and accuracy.

Behavioral disorders and psychological symptoms (BPSD) in Alzheimer’s disease (AD) are known to correlate with grey matter (GM) atrophy and, as shown recently, also with white matter (WM) damage. WM damage and its relationship with GM atrophy are reported in AD, reinforcing the interpretation of the AD pathology in light of a disconnection syndrome. It remains uncertain whether this disconnection might account also for different BPSD observable in AD. Here, we tested the hypothesis of different patterns of association between WM damage of the corpus callosum (CC) and GM atrophy in AD patients exhibiting one of the following BPSD clusters: Mood (i.e., anxiety and depression; ADmood), Frontal (i.e., dishinibition and elation; ADfrontal), and Psychotic (delusions and hallucinations; ADpsychotic) related symptoms, as well as AD patients without BPSD. Overall, this study brings to light the strict relationship between WM alterations in different parts of the CC and GM atrophy in AD patients exhibiting BPSD, supporting the hypothesis that such symptoms are likely to be caused by characteristic patterns of neurodegeneration of WM and GM, rather than being a reactive response to accumulation of cognitive disabilities, and should therefore be regarded as potential markers of diagnostic and prognostic value in AD.

BACKGROUND\ud \ud Behavioural disorders and psychological symptoms of Dementia (BPSD) are commonly observed in Alzheimer's disease (AD), and strongly contribute to increasing patients' disability. Using voxel-lesion-symptom mapping (VLSM), we investigated the impact of white matter lesions (WMLs) on the severity of BPSD in patients with amnestic mild cognitive impairment (a-MCI).\ud \ud METHODS\ud \ud Thirty-one a-MCI patients (with a conversion rate to AD of 32% at 2 year follow-up) and 26 healthy controls underwent magnetic resonance imaging (MRI) examination at 3T, including T2-weighted and fluid-attenuated-inversion-recovery images, and T1-weighted volumes. In the patient group, BPSD was assessed using the Neuropsychiatric Inventory-12. After quantitative definition of WMLs, their distribution was investigated, without an a priori anatomical hypothesis, against patients' behavioural symptoms. Unbiased regional grey matter volumetrics was also used to assess the contribution of grey matter atrophy to BPSD.\ud \ud RESULTS\ud \ud Apathy, irritability, depression/dysphoria, anxiety and agitation were shown to be the most common symptoms in the patient sample. Despite a more widespread anatomical distribution, a-MCI patients did not differ from controls in WML volumes. VLSM revealed a strict association between the presence of lesions in the anterior thalamic radiations (ATRs) and the severity of apathy. Regional grey matter atrophy did not account for any BPSD.\ud \ud CONCLUSIONS\ud \ud This study indicates that damage to the ATRs is strategic for the occurrence of apathy in patients with a-MCI. Disconnection between the prefrontal cortex and the mediodorsal and anterior thalamic nuclei might represent the pathophysiological substrate for apathy, which is one of the most common psychopathological symptoms observed in dementia.

Myotonic dystrophy type 1 (DM1) is a multisystemic disorder dominated by muscular impairment and brain dysfunctions. Although brain damage has previously been demonstrated in DM1, its associations with the genetics and clinical/neuropsychological features of the disease are controversial. This study assessed the differential role of gray matter (GM) and white matter (WM) damage in determining higher-level dysfunctions in DM1. Ten patients with genetically confirmed DM1 and 16 healthy How genetics affects the brain to produce higher-level dysfunctions in myotonic dystrophy type 1 matched controls entered the study. The patients underwent a neuropsychological assessment and quantification of CTG triplet expansion. All the subjects underwent MR scanning at 3T, with studies including T1-weighted volumes and diffusion-weighted images. Voxel-based morphometry and tractbased spatial statistics were used for unbiased quantification of regional GM atrophy and WM integrity. The DM1 patients showed widespread involvement of both tissues. The extent of the damage correlated with CTG triplet expansion and cognition. This study supports the idea that genetic abnormalities in DM1mainly target the WM, but GM involvement is also crucial in determining the clinical characteristics of DM1.

This study investigates how cognitive reserve (CR) interacts with neurodegeneration (quantified by medial temporal atrophy, MTA) and macroscopic white matter lesions (WMLs) in delaying the conversion from amnestic mild cognitive impairment to Alzheimer's disease (AD). Forty-two amnestic mild cognitive impairment patients were consecutively recruited. They underwent magnetic resonance imaging and a comprehensive questionnaire to classify them as individuals with low or high CR. Patients were then clinically followed-up for 2 years. The patients' risk for conversion to AD because of CR was estimated by controlling for cognitive efficiency, MTA, and WMLs at baseline. Global cognition was the best predictor of conversion to AD in low CR patients. Conversely, in high CR patients only, WMLs (but not MTA) highly contributed in increasing the risk for conversion to AD. In conclusion, CR interacts with both patients' cognitive features and WMLs in modulating the impact of AD pathology. This seems relevant for clinical prognosis and therapeutic strategies.

A novel approach based on diffusion tractography was used here to characterise the cortico-thalamic connectivity in two patients, both presenting with an isolated bilateral infarct in the thalamus, but exhibiting partially different cognitive and behavioural profiles. Both patients (G.P. and R.F.) had a pervasive deficit in episodic memory, but only one of them (R.F.) suffered also from a dysexecutive syndrome. Both patients had an MRI scan at 3T, including a T1-weighted volume. Their lesions were manually segmented. T1-volumes were normalised to standard space, and the same transformations were applied to the lesion masks. Nineteen healthy controls underwent a diffusion-tensor imaging (DTI) scan. Their DTI data were normalised to standard space and averaged. An atlas of Brodmann areas was used to parcellate the prefrontal cortex. Probabilistic tractography was used to assess the probability of connection between each voxel of the thalamus and a set of prefrontal areas. The resulting map of corticothalamic connections was superimposed onto the patients' lesion masks, to assess whether the location of the thalamic lesions in R.F. (but not in G. P.) implied connections with prefrontal areas involved in dysexecutive syndromes. In G.P., the lesion fell within areas of the thalamus poorly connected with prefrontal areas, showing only a modest probability of connection with the anterior cingulate cortex (ACC). Conversely, R.F.'s lesion fell within thalamic areas extensively connected with the ACC bilaterally, with the right dorsolateral prefrontal cortex, and with the left supplementary motor area. Despite a similar, bilateral involvement of the thalamus, the use of connectivity-based segmentation clarified that R.F.'s lesions only were located within nuclei highly connected with the prefrontal cortical areas, thus explaining the patient's frontal syndrome. This study confirms that DTI tractography is a useful tool to examine in vivo the effect of focal lesions on interconnectivity brain patterns.

Background: Brain disconnection plays a major role in determining cognitive disabilities in multiple sclerosis (MS). We recently developed a novel diffusion-weighted magnetic resonance imaging (DW-MRI) tractography approach, namely anatomical connectivitity mapping (ACM), that quantifies structural brain connectivity. Objective: Use of ACM to assess structural connectivity modifications in MS brains and ascertain their relationship with the patients’ Paced-Auditory-Serial-Addition-Test (PASAT) scores. Methods: Relapsing–remitting MS (RRMS) patients ( n = 25) and controls ( n = 25) underwent MRI at 3T, including conventional images, T1-weighted volumes and DW-MRI. Volumetric scans were coregistered to fractional anisotropy (FA) images, to obtain parenchymal FA maps for both white and grey matter. We initiated probabilistic tractography from all parenchymal voxels, obtaining ACM maps by counting the number of streamlines passing through each voxel, then normalizing by the total number of streamlines initiated. The ACM maps were transformed into standard space, for statistical use. Results: RRMS patients had reduced grey matter volume and FA, consistent with previous literature. Also, we showed reduced ACM in the thalamus and in the head of the caudate nucleus, bilaterally. In our RRMS patients, ACM was associated with PASAT scores in the corpus callosum, right hippocampus and cerebellum. Conclusions: ACM opens a new perspective, clarifying the contribution of anatomical brain disconnection to clinical disabilities in MS.

Several causative gene mutations have been identified in frontotemporal lobar degeneration (FTLD), including mutations within Granulin (GRN) genes. It was recently shown that FTLD patients carriers of GRN Thr272fs mutation [FTLD-GRN(m+)] exhibit more severe abnormalities, as assessed by magnetic resonance imaging (MRI), than those with sporadic FTLD [FTLD-GRN(m-)]. The aim of this study was to investigate the relationship between grey (GM) and white matter (WM) microstructural damage in FTLD patients, carriers, and non-carriers of the mutation. Twenty-three FTLD patients [6 GRN(m+) and 17 GRN(m-)] and 12 healthy subjects received an MRI scan including volumetric and diffusion imaging. GM was assessed using voxel-based morphometry, while the corpus callosum was reconstructed using diffusion tractography. Mean diffusivity and fractional anisotropy of the corpus callosum were compared between groups. FTLD patients showed widespread GM atrophy and altered diffusion indices in the corpus callosum when compared to healthy subjects. When contrasting GRN(m+) against GRN(m-) patients, the former group had more atrophy in the left frontal GM, and reduced fractional anisotropy and increased mean diffusivity in the left anterior part of the corpus callosum. Significant correlations between the GM and WM damage were found in GRN(m+) patients. This pattern of damage was able to predict some of the additional neuropsychological deficits observed in GRN(m+) as compared to GRN(m-) patients. A more prominent involvement of WM in GRN(m+) patients is consistent with the knowledge that GRN genes are expressed in the microglia. This involvement might be responsible for the accrual of additional GM atrophy via disconnection mechanisms.

This study investigates the differential contribution of gray matter (GM) atrophy and deafferentation through white matter (WM) damage in the clinical progression of Alzheimer's disease (AD). Thirty‐one patients with probable AD, 23 with amnestic mild cognitive impairment (a‐MCI), and 14 healthy subjects underwent MRI scanning at 3T. Voxel‐based morphometry was used to assess regional GM atrophy in AD and a‐MCI patients. Diffusion tensor‐MRI tractography was used to reconstruct the cingulum bilaterally, and to quantify, voxel‐by‐voxel, its fractional anisotropy (FA) and mean diffusivity (MD) (measures of microscopic WM integrity). Atrophy of the cinguli was also assessed by means of jacobian determinants (JD) of local transformations. In AD patients, four clusters of reduced GM were found nearby the cinguli, in the posterior (PCC) and anterior cingulate cortex, and in the hippocampal/parahippocampal areas. Widespread areas of reduced FA and increased MD were found in the cinguli of both, AD and a‐MCI patients. A region of macroscopic atrophy was detectable in AD patients only. Strong associations were found between local GM densities in the four identified clusters, and measures of micro‐ and (to a lesser extent) macroscopic damage of patients' cinguli. Linear regression analyses revealed that MD in the cinguli predicts patients' measures of episodic memory in combination with GM density of hippocampal/parahippocampal areas, and measures of global cognition in combination with GM density of the PCC. This study indicates that brain deafferentation though the cingulum is likely to play a remarkable role in progressive development of cognitive impairment in AD. Hum Brain Mapp, 2011. © 2011 Wiley‐Liss, Inc.

Preliminary studies, based on a region-of-interest approach, suggest that quantitative magnetization transfer (qMT), an extension of magnetization transfer imaging, provides complementary information to conventional magnetic resonance imaging (MRI) in the characterisation of Alzheimer's disease (AD). The aim of this study was to extend these findings to the whole brain, using a voxel-wise approach. We recruited 19AD patients and 11 healthy subjects (HS). All subjects had an MRI acquisition at 3.0T including a T(1)-weighted volume, 12 MT-weighted volumes for qMT, and data for computing T(1) and B(1) maps. The T(1)-weighted volumes were processed to yield grey matter (GM) volumetric maps, while the other sequences were used to compute qMT parametric maps of the whole brain. qMT maps were warped to standard space and smoothed, and subsequently compared between groups. Of all the qMT parameters considered, only the forward exchange rate, RM(0)(B), showed significant group differences. These images were therefore retained for the multimodal statistical analysis, designed to locate brain regions of RM(0)(B) differences between AD and HS groups, adjusting for local GM atrophy. Widespread areas of reduced RM(0)(B) were found in AD patients, mainly located in the hippocampus, in the temporal lobe, in the posterior cingulate and in the parietal cortex. These results indicate that, among qMT parameters, RM(0)(B) is the most sensitive to AD pathology. This quantity is altered in the hippocampus of patients with AD (as found by previous works) but also in other brain areas, that PET studies have highlighted as involved with both, reduced glucose metabolism and amyloid β deposition. RM(0)(B) might reflect, through the measurement of the efficiency of MT exchange, some information with a specific pathological counterpart. Given previous evidence of a strict relationship between RM(0)(B) and intracellular pH, an intriguing speculation is that our findings might reflect metabolic changes related to mitochondrial dysfunction, which has been proposed as a contributor to neurodegeneration in AD.

One theory to account for neglect symptoms in patients with right focal damage invokes a release of inhibition of the right parietal cortex over the left parieto-frontal circuits, by disconnection mechanism. This theory is supported by transcranial magnetic stimulation studies showing the existence of asymmetric inhibitory interactions between the left and right posterior parietal cortex, with a right hemispheric advantage. These inhibitory mechanisms are mediated by direct transcallosal projections located in the posterior portions of the corpus callosum. The current study, using diffusion imaging and tract-based spatial statistics (TBSS), aims at assessing, in a data-driven fashion, the contribution of structural disconnection between hemispheres in determining the presence and severity of neglect. Eleven patients with right acute stroke and 11 healthy matched controls underwent MRI at 3T, including diffusion imaging, and T1-weighted volumes. TBSS was modified to account for the presence of the lesion and used to assess the presence and extension of changes in diffusion indices of microscopic white matter integrity in the left hemisphere of patients compared to controls, and to investigate, by correlation analysis, whether this damage might account for the presence and severity of patients' neglect, as assessed by the Behavioural Inattention Test (BIT). None of the patients had any macroscopic abnormality in the left hemisphere; however, 3 cases were discarded due to image artefacts in the MRI data. Conversely, TBSS analysis revealed widespread changes in diffusion indices in most of their left hemisphere tracts, with a predominant involvement of the corpus callosum and its projections on the parietal white matter. A region of association between patients' scores at BIT and brain FA values was found in the posterior part of the corpus callosum. This study strongly supports the hypothesis of a major role of structural disconnection between the right and left parietal cortex in determining 'neglect'.

This study investigates whether different patterns of grey matter (GM) loss may account for the different neuropsychological profiles observed in patients with amnestic (a-) and non-amnestic (na-) mild cognitive impairment (MCI), and may predict patients' clinical evolution. Fifty-five consecutive individuals complaining of cognitive dysfunction (referred to specialist dementia clinics) were screened and included in the study if they met the diagnostic criteria for MCI on a neurodegenerative basis. After an extensive neuropsychological assessment, patients were classified as suffering from a-MCI or na-MCI. Twenty-eight healthy individuals were also recruited and served as controls. All participants underwent magnetic resonance imaging at 3T, including conventional images and volumetric scans. Volumetric data were processed using voxel-based morphometry to assess between-group differences in regional GM volumes and correlations with neuropsychological performances. When compared to controls, a-MCI patients showed prominent GM volume reductions in the medial temporal lobes, while those with na-MCI showed reduced GM volumes in the orbito-frontal cortex and basal ganglia. In a-MCI patients, significant associations were found between verbal long-term memory performance and GM volumes in the hippocampus. Conversely, in na-MCI patients, associations were found between scores at tests exploring executive functions and GM volumes in the orbito-frontal cortex. At one-year follow-up, conversions were recorded exclusively toward Alzheimer's disease (AD) in the a-MCI group, and toward non-AD dementia in the na-MCI group. This study confirms that MCI is a heterogeneous clinical identity including different neurodegenerative entities; specific patterns of regional GM loss appear to account for specific neuropsychological features and are likely to predict patients' clinical evolution.

The number of functional magnetic resonance imaging (fMRI) studies performed on the human spinal cord (SC) has considerably increased in recent years. The lack of a validated processing pipeline is, however, a significant obstacle to the spread of SC fMRI. One component likely to be involved in any such pipeline is the process of SC masking, analogous to brain extraction in cerebral fMRI. In general, SC masking has been performed manually, with the incumbent costs of being very time consuming and operator dependent. To overcome these drawbacks, we have developed a tailored semiautomatic method for segmenting echoplanar images (EPI) of human spine that is able to identify the spinal canal and the SC. The method exploits both temporal and spatial features of the EPI series and was tested and optimized on EPI images of cervical spine acquired at 3 T. The dependence of algorithm performance on the degree of EPI image distortion was assessed by computing the displacement warping field that best matched the EPI to the corresponding high-resolution T 2 images. Segmentation accuracy was above 80%, a significant improvement over values obtained with similar approaches, but not exploiting temporal information. Geometric distortion was found to explain about 50% of the variance of algorithm classification efficiency.

Functional magnetic resonance imaging (fMRI) has emerged during the last decade as the main non-invasive technique for the investigation of human brain function. More recently, fMRI was also proposed for functional studies of the human spinal cord, but with controversial results. In fact, the functional contrast is not well-characterized, and even its origin has been challenged. In the present work, we characterized the temporal features of the functional signal evoked in the human spinal cord by a motor task, studied with an approach based on time-locked averaging of functional time series of different durations. Based on the results here reported, we defined an impulse-response function (irf) able to explain the functional response for motor tasks in the interval of 15-42 s of duration, thus suggesting the linearity of the phenomenon in this interval. Conversely, with stimulation durations ranging between 3 and 9 s, the functional signal was not detectable, and was under the level predicted by a linear behavior, suggesting deviation from linearity during short stimulations. The impulse-response function appeared slower than in the brain, peaking at about 9 s after its beginning. The observed contrast was generally larger than in the brain, on the order of about 5.4% of baseline signal at 1.5 T. The findings further suggested that the physiological origin of T(2) weighted functional imaging is similar in the spinal cord and in the brain.

Patients with drug-resistant focal epilepsy may require intracranial investigations with subdural electrodes. These must be correctly localized with respect to the brain cortical surface and require appropriate monitoring. For this purpose, coregistration techniques, which fuse preimplantation 3D magnetic resonance imaging scans with postimplantation computed tomography scans, have been implemented. In order to reduce localization errors due to the fusion process, we used a coregistration method based on the maximization of mutual information (MI) in 11 patients with extratemporal epilepsy who were invasively investigated. Our registration method is based on three processing steps: rigid-body transformation for coregistration, computation of MI as a similarity measure and the use of the Downhill Simplex optimization method. After consistency analysis, the shift of the registration method reached 0.14+/-0.27 mm in translation and 0.03+/-0.14 degrees in rotation, and the accuracies assessed on voxels of skull surface and voxels of the center of the brain volume were 1.42+/-0.61 and 1.15+/-0.53 mm, respectively. The accuracy of the fusion process reached submillimeter range, and results were considered reliable for surgical planning in all studied patients.