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The glymphatic system (GS) is a whole-brain perivascular network, consisting of three compartments: the periarterial and perivenous spaces and the interposed brain parenchyma. GS dysfunction has been implicated in neurodegenerative diseases, particularly Alzheimer's disease (AD). So far, comprehensive research on GS in humans has been limited by the absence of easily accessible biomarkers. Recently, promising non-invasive methods based on magnetic resonance imaging (MRI) along with aquaporin-4 (AQP4) quantification in the cerebrospinal fluid (CSF) were introduced for an indirect assessment of each of the three GS compartments. We recruited 111 consecutive subjects presenting with symptoms suggestive of degenerative cognitive decline, who underwent 3 T MRI scanning including multi-shell diffusion-weighted images. Forty nine out of 111 also underwent CSF examination with quantification of CSF-AQP4. CSF-AQP4 levels and MRI measures-including perivascular spaces (PVS) counts and volume fraction (PVSVF), white matter free water fraction (FW-WM) and mean kurtosis (MK-WM), diffusion tensor imaging analysis along the perivascular spaces (DTI-ALPS) (mean, left and right)-were compared among patients with AD (n = 47) and other neurodegenerative diseases (nAD = 24), patients with stable mild cognitive impairment (MCI = 17) and cognitively unimpaired (CU = 23) elderly people. Two runs of analysis were conducted, the first including all patients; the second after dividing both nAD and AD patients into two subgroups based on gray matter atrophy as a proxy of disease stage. Age, sex, years of education, and scanning time were included as confounding factors in the analyses. Considering the whole cohort, patients with AD showed significantly higher levels of CSF-AQP4 (exp(b) = 2.05, p = .005) and FW-WM FW-WM (exp(b) = 1.06, p = .043) than CU. AQP4 levels were also significantly higher in nAD in respect to CU (exp(b) = 2.98, p < .001). CSF-AQP4 and FW-WM were significantly higher in both less atrophic AD (exp(b) = 2.20, p = .006; exp(b) = 1.08, p = .019, respectively) and nAD patients (exp(b) = 2.66, p = .002; exp(b) = 1.10, p = .019, respectively) compared to CU subjects. Higher total (exp(b) = 1.59, p = .013) and centrum semiovale PVS counts (exp(b) = 1.89, p = .016), total (exp(b) = 1.50, p = .036) and WM PVSVF (exp(b) = 1.89, p = .005) together with lower MK-WM (exp(b) = 0.94, p = .006), mean and left ALPS (exp(b) = 0.91, p = .043; exp(b) = 0.88, p = .010 respectively) were observed in more atrophic AD patients in respect to CU. In addition, more atrophic nAD patients exhibited higher levels of AQP4 (exp(b) = 3.39, p = .002) than CU. Our results indicate significant changes in putative MRI biomarkers of GS and CSF-AQP4 levels in AD and in other neurodegenerative dementias, suggesting a close interaction between glymphatic dysfunction and neurodegeneration, particularly in the case of AD. However, the usefulness of some of these biomarkers as indirect and standalone indices of glymphatic activity may be hindered by their dependence on disease stage and structural brain damage., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

Background and Purpose: Difficulties in emotion processing and social cognition identified in multiple sclerosis (MS) patients have a potential impact on their adaptation to the social environment. We aimed to explore the neural correlates of emotion recognition in MS and possible differences between relapsing-remitting MS (RRMS) and secondary progressive MS (SPMS) patients by the Reading the Mind in the Eyes test (RMEt)., Methods: A total of 43 MS patients (27 RRMS, 16 SPMS) and 25 matched healthy controls (HC) underwent clinical assessments, RMEt, and a high-resolution T1-weighted 3-T magnetic resonance imaging (MRI) scan. The number of correct answers on the RMEt was compared between groups. T1-weighted volumes were processed according to an optimized voxel-based morphometry (VBM) protocol to obtain gray matter (GM) maps. Voxelwise analyses were run to assess potential associations between RMEt performance and regional GM volumes., Results: Taken altogether, MS patients reported significantly lower performance on the RMEt compared to HC. When dividing the patients into those with RRMS and those with SPMS, only the latter group was found to perform significantly worse than HC on the RMEt. VBM analysis revealed significant association between RMEt scores and GM volumes in several cortical (temporoparieto-occipital cortex) and subcortical (hippocampus, parahippocampus, and basal ganglia) brain regions, and in the cerebellum in SPMS patients only., Conclusions: Results suggest that, in addition to other clinical differences between RRMS and SPMS, the ability to recognize others' emotional states may be affected in SPMS more significantly than RRMS patients. This is supported by both behavioral and MRI data., (© 2021 European Academy of Neurology.)

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., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

The aim of this research was to test a novel in-vivo brain MRI analysis method that could be used in clinical cohorts to investigate cortical architecture changes in patients with Alzheimer's Disease (AD). Three cohorts of patients with probable AD and healthy volunteers were used to assess the results of the method. The first group was used as the "Discovery" cohort, the second as the "Test" cohort and the last "ATN" (Amyloid, Tau, Neurodegeneration) cohort was used to test the method in an ADNI 3 cohort, comparing to amyloid and Tau PET. The method can detect altered quality of cortical grey matter in AD patients, providing an additional tool to assess AD, distinguishing between these and healthy controls with an accuracy range between good and excellent. These new measurements could be used within the "ATN" framework as an index of cortical microstructure quality and a marker of Neurodegeneration. Further development may aid diagnosis, patient selection, and quantification of the "Neurodegeneration" component in response to therapies in clinical trials., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Purpose: In this MRI study, diffusional kurtosis imaging (DKI) and T2 * multiecho relaxometry were measured from the white matter (WM) of human brains and correlated with each other, with the aim of investigating the influence of magnetic-susceptibility (Δχ (H2O-TISSUE) ) on the contrast., Methods: We focused our in vivo analysis on assessing the dependence of mean, axial, and radial kurtosis (MK, K‖ , K⊥ ), as well as DTI indices on Δχ (H2O-TISSUE) (quantified by T2 *) between extracellular water and WM tissue molecules. Moreover, Monte Carlo (MC) simulations were used to elucidate experimental data., Results: A significant positive correlation was observed between K⊥ , MK and R2 * = 1/T2 *, suggesting that Δχ (H2O-TISSUE) could be a source of DKI contrast. In this view, K⊥ and MK-map contrasts in human WM would not just be due to different restricted diffusion processes of compartmentalized water but also to local Δχ (H2O-TISSUE) . However, MC simulations show a strong dependence on microstructure rearrangement and a feeble dependence on Δχ (H2O-TISSUE) of DKI signal., Conclusion: Our results suggests a concomitant and complementary existence of multi-compartmentalized diffusion process and Δχ (H2O-TISSUE) in DKI contrast that might explain why kurtosis contrast is more sensitive than DTI in discriminating between different tissues. However, more realistic numerical simulations are needed to confirm this statement., (© 2014 Wiley Periodicals, Inc.)

A previous preliminary investigation based on a novel MRI approach to map anatomical connectivity revealed areas of increased connectivity in Alzheimer's disease (AD) but not in mild cognitive impairment patients. This prompted the hypothesis tested here, that these areas might reflect phenomena of brain plasticity driven by acetylcholinesterase inhibitors (AChEIs). Thirty-eight patients with probable AD (19 under medication with AChEIs and 19 drug-naïve) were recruited together with 11 healthy controls. All subjects had MRI scanning at 3T, including volumetric and diffusion-weighted scans. Probabilistic tractography was used to initiate streamlines from all parenchymal voxels, and anatomical connectivity maps (ACMs) were obtained by counting, among the total number of streamlines initiated, the fraction passing through each brain voxel. After normalization into standard space, ACMs were used to test for between-group comparisons, and for interactions between the exposure to AChEIs and global level of cognition. Patients with AD had reduced ACM values in the fornix, cingulum, and supramarginal gyri. The ACM value was strongly associated with the AChEI dosage-x-duration product in the anterior limb (non-motor pathway) of the internal capsule. Tractography from this region identified the anterior thalamic radiation as the main white matter (WM) tract passing through it. The reduced connectivity in WM bundles connecting the hippocampi with the rest of the brain (fornix/cingulum) suggests a possible mechanism for the spread of AD pathology. An intriguing explanation for the interaction between AChEIs and ACM is related to the mechanisms of brain plasticity, partially driven by neurotrophic properties of acetylcholine replacement., (Copyright © 2012 Wiley Periodicals, Inc.)

The effect of autonomic perturbation (AP) on the central nervous system functioning is still largely unknown. Using an automated neck suction device to stimulate the carotid mechanoreceptors in the carotid sinus (parasympathetic pathway), operated synchronously with functional magnetic resonance imaging (fMRI) acquisition, we investigated the effects of AP on the activity of the brain at rest and when engaged in a visuo-spatial attention task. ECG was always recorded to index changes in autonomic function. At rest, AP induced increased activation in the insula and in the amygdala, which have been previously associated with the autonomic control and emotion processing, as well as in the caudate nucleus and in the medial temporal cortex, both implicated in cognitive functions. Despite a preserved performance during visuo-spatial attention task, AP induced increased reaction times and a positive modulation on the activation of the right posterior parietal cortex, the occipital cortex, the periaquiductal gray, and nuclei of the brainstem. We speculate that this modulation of brain activity represents, at different anatomical levels, a compensation mechanism to maintain cognitive efficiency under parasympathetic stimulation, which is traditionally considered as the system for energy regain and storage. In conclusion, this study provides the first evidence of a dynamic interaction between AP and higher level functions in humans., (Copyright © 2012 Wiley Periodicals, Inc.)

Anatomical connectivity mapping (ACM) is a measure of anatomical connectivity obtained by initiating streamline diffusion tractography from all parenchymal voxels and then counting the number of streamlines passing through each voxel of the brain. ACM highlights WM structures that present multiple connections to the rest of the brain but not necessarily strong microstructural orientation coherence. In this study, ACM was used to develop an atlas of the human brain. The ACM template was constructed from 3 T diffusion-weighted data from 19 healthy adults. To account for multiple diffusion directions in a voxel, a high angular resolution diffusion imaging (HARDI) technique, namely Q-ball, was used to model diffusion. To bring data from different subjects into a common space, an algorithm for rotating and averaging the principal directions was implemented, which can be generalized to any application requiring algebraic operations on principal directions derived from any HARDI method. ACM from the average dataset was computed and several white matter connections of interest were identified and highlighted. Fractional anisotropy (FA) from standard diffusion tensor modelling was also derived and FA-modulated colour coded images obtained from the mean tensor were also shown for comparison, highlighting differences and similarities. The ACM template can serve for educational purposes and as future reference for studies based on the evaluation of ACM in subjects affected by neurological and psychiatric disorders., (Copyright © 2012 John Wiley & Sons, Ltd.)

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., (Copyright © 2011 Wiley-Liss, Inc.)

A new method to investigate anomalous diffusion in human brain, inspired by the stretched-exponential model proposed by Hall and Barrick, is proposed here, together with a discussion about its potential application to cerebral white matter characterization. Aim of the work was to show the ability of anomalous diffusion indices to characterize white matter structures, whose complexity is only partially accounted by diffusion tensor imaging indices. MR signal was expressed as a stretched-exponential only along the principal axes of diffusion; whereas, in a generic direction, it was modeled as a combination of three stretched-exponentials. Indices to quantify the tissue anomalous diffusion and its anisotropy, independently of the experiment reference frame, were derived. Experimental results, obtained on 10 healthy subjects at 3T, show that the new parameters are highly correlated to intrinsic local geometry when compared with Hall and Barrick indices. Moreover, they offer a different contrast in white matter regions when compared with diffusion tensor imaging. Specifically, the new indices show a higher capability to discriminate among areas of the corpus callosum associated to different distribution in axonal densities, thus offering a new potential tool to detect more specific patterns of brain abnormalities than diffusion tensor imaging in the presence of neurological and psychiatric disorders., (Copyright © 2010 Wiley-Liss, Inc.)

The feeling of guilt is a complex mental state underlying several human behaviors in both private and social life. From a psychological and evolutionary viewpoint, guilt is an emotional and cognitive function, characterized by prosocial sentiments, entailing specific moral believes, which can be predominantly driven by inner values (deontological guilt) or by more interpersonal situations (altruistic guilt). The aim of this study was to investigate whether there is a distinct neurobiological substrate for these two expressions of guilt in healthy individuals. We first run two behavioral studies, recruiting a sample of 72 healthy volunteers, to validate a set of stimuli selectively evoking deontological and altruistic guilt, or basic control emotions (i.e., anger and sadness). Similar stimuli were reproduced in a event-related functional magnetic resonance imaging (fMRI) paradigm, to investigate the neural correlates of the same emotions, in a new sample of 22 healthy volunteers. We show that guilty emotions, compared to anger and sadness, activate specific brain areas (i.e., cingulate gyrus and medial frontal cortex) and that different neuronal networks are involved in each specific kind of guilt, with the insula selectively responding to deontological guilt stimuli. This study provides evidence for the existence of distinct neural circuits involved in different guilty feelings. This complex emotion might account for normal individual attitudes and deviant social behaviors. Moreover, an abnormal processing of specific guilt feelings might account for some psychopathological manifestation, such as obsessive-compulsive disorder and depression., (Copyright © 2010 Wiley-Liss, Inc.)

Background and Purpose: At high altitudes barometric pressure is reduced and, thus, less oxygen is inhaled. Reduced oxygen concentration in brain tissue can lead to cerebral damage and neurological and cognitive deficits. The present study was designed to explore the effects of high-altitude exposure using a quantitative MRI technique, voxel-based morphometry., Methods: We studied nine world-class mountain climbers before (baseline) and after (follow-up) an extremely high-altitude ascent of Everest and K2. We investigated the effects of repeated extremely high-altitude exposures by comparing mountain climbers' scans at baseline with scans of 19 controls. In addition, we measured the effects of a single extremely high-altitude expedition by comparing mountain climbers' scans at baseline and follow-up., Results: A region of reduced white matter density/volume was found in the left pyramidal tract near the primary (BA 4) and supplementary (BA 6) motor cortex when mountain climbers at baseline were compared with controls. Further, when mountain climbers' scans before and after the expedition were compared, a region of reduced grey matter density/volume was found in the left angular gyrus (BA 39)., Conclusion: These findings suggest that extremely high-altitude exposures may cause subtle white and grey matter changes that mainly affect brain regions involved in motor activity.