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Objective. Real-time functional magnetic resonance imaging neurofeedback (rt-fMRI-NF) is a non-invasive procedure allowing the self-regulation of brain functions via enhanced self-control of fMRI based neural activation. In semantic rt-fMRI-NF, an estimated relation between multivariate fMRI activation patterns and abstract mental states is exploited for a multi-dimensional feedback stimulus via real-time representational similarity analysis (rt-RSA). Here, we assessed the performances of this framework in a multi-subject multi-session study on a 3 T MRI clinical scanner. Approach. Eighteen healthy volunteers underwent two semantic rt-fMRI-NF sessions on two different days. In each session, participants were first requested to engage in specific mental states while local fMRI patterns of brain activity were recorded during stimulated mental imagery of concrete objects (pattern generation). The obtained neural representations were to be replicated and modulated by the participants in subsequent runs of the same session under the guidance of a rt-RSA generated visual feedback (pattern modulation). Performance indicators were derived from the rt-RSA output to assess individual abilities in replicating (and maintaining over time) a target pattern. Simulations were carried out to assess the impact of the geometric distortions implied by the low-dimensional representation of patterns’ dissimilarities in the visual feedback. Main results. Sixteen subjects successfully completed both semantic rt-fMRI-NF sessions. Considering some performance indicators, a significant improvement between the first and the second runs, and within run increasing modulation performances were observed, whereas no improvements were found between sessions. Simulations confirmed that in a small percentage of cases visual feedback could be affected by metric distortions due to dimensionality reduction implicit to the rt-RSA approach. Significance. Our results proved the feasibility of the semantic rt-fMRI-NF at 3 T, showing that subjects can successfully modulate and maintain a target mental state when guided by rt-RSA derived feedback. Further development is needed to encourage future clinical applications.

Word-predictability measures, such as surprisal, have been used to show that linguistic prediction is an essential neural mechanism for successful comprehension. However, the neural dynamic of this mechanism may differ across individuals listening to the same narrative, revealing possible idiosyncrasies. Therefore, in this study, we investigated the ability of the surprisal measure to address the linguistic prediction in terms of the intersubject phase synchronization (ISPS) among healthy volunteers listening to a narrative during continuous functional Magnetic Resonance Imaging (fMRI) scanning. The data of twenty-seven participants, acquired in a previous study, were re-analyzed to estimate the ISPS associated with an audiobook listening, played forward and backward. Mean ISPS differences between playing conditions were first analyzed across the whole brain. ISPS time-series during the forward condition was explained with both a lexical-only and a semantics-weighted lexical surprisal model of the narrative word series to detect correlations between ISPS and word surprisal values. Compared to the backward condition, mean ISPS was significantly higher during forward condition in a broad network encompassing frontal, temporal, and parietal areas. The lexical-only model disclosed significant negative ISPS-surprisal correlations in the angular gyrus bilaterally, precuneus, left inferior parietal lobule, left middle frontal gyrus, left cerebellum, and left inferior frontal gyrus. The semantics-weighted surprisal model disclosed significant negative ISPS-surprisal correlations in the right angular gyrus, right precuneus, and left inferior frontal gyrus. Besides engaging language-related areas, narrative processing induces significant ISPS levels beyond the language network. The negative ISPS-surprisal correlations observed would signal divergent neural dynamics among individuals, leading to lower group synchronization, when the words to be integrated are characterized by higher surprisal levels. These results provide further support to the use of language models, such as the surprisal, to explain the neural processes of narrative comprehension and additional information into how the human brain exploits predictions during language comprehension.

Background Sensorineural hearing loss in beta-thalassemia is common and it is generally associated with iron chelation therapy. However, data are scarce, especially on adult populations, and a possible involvement of the central auditory areas has not been investigated yet. We performed a multicenter cross-sectional audiological and single-center 3Tesla brain perfusion MRI study enrolling 77 transfusion-dependent/non transfusion-dependent adult patients and 56 healthy controls. Pure tone audiometry, demographics, clinical/laboratory and cognitive functioning data were recorded. Results Half of patients (52%) presented with high-frequency hearing deficit, with overt hypoacusia (Pure Tone Average (PTA) > 25 dB) in 35%, irrespective of iron chelation or clinical phenotype. Bilateral voxel clusters of significant relative hypoperfusion were found in the auditory cortex of beta-thalassemia patients, regardless of clinical phenotype. In controls and transfusion-dependent (but not in non-transfusion-dependent) patients, the relative auditory cortex perfusion values increased linearly with age (p p = 0.01, left side p = 0.02) with its domain related to communication skills (right side p = 0.04, left side p = 0.07) in controls but not in beta-thalassemia patients. Audiometric test results did not correlate to cognitive test scores in any subgroup. Conclusions In conclusion, primary auditory cortex perfusion changes are a metabolic hallmark of adult beta-thalassemia, thus suggesting complex remodeling of the hearing function, that occurs regardless of chelation therapy and before clinically manifest hearing loss. The cognitive impact of perfusion changes is intriguing but requires further investigations.

Objective. Real-time functional magnetic resonance imaging neurofeedback (rt-fMRI-NF) is a non-invasive MRI procedure allowing examined participants to learn to self-regulate brain activity by performing mental tasks. A novel two-step rt-fMRI-NF procedure is proposed whereby the feedback display is updated in real-time based on high-level representations of experimental stimuli (e.g. objects to imagine) via real-time representational similarity analysis of multi-voxel patterns of brain activity. Approach. In a localizer session, the stimuli become associated with anchored points on a two-dimensional representational space where distances approximate between-pattern (dis)similarities. In the NF session, participants modulate their brain response, displayed as a movable point, to engage in a specific neural representation. The developed method pipeline is verified in a proof-of-concept rt-fMRI-NF study at 7 T involving a single healthy participant imagining concrete objects. Based on this data and artificial data sets with similar (simulated) spatio-temporal structure and variable (injected) signal and noise, the dependence on noise is systematically assessed. Main results. The participant in the proof-of-concept study exhibited robust activation patterns in the localizer session and managed to control the neural representation of a stimulus towards the selected target in the NF session. The offline analyses validated the rt-fMRI-NF results, showing that the rapid convergence to the target representation is noise-dependent. Significance. Our proof-of-concept study introduces a new NF method allowing the participant to navigate among different mental states. Compared to traditional NF designs (e.g. using a thermometer display to set the level of the neural signal), the proposed approach provides content-specific feedback to the participant and extra degrees of freedom to the experimenter enabling real-time control of the neural activity towards a target brain state without suggesting a specific mental strategy to the subject.

The visual system is primarily affected in sickle cell disease (SCD), and eye examination is recommended starting in late childhood. So far, to our knowledge, all studies have focused on the retina, neglecting the changes that might be present in the cortical portion of the visual system. We performed a multimodal magnetic resonance imaging (MRI) evaluation of the visual cortex in 25 children with SCD (mean age: 12·3 ± 1·9 years) and 31 controls (mean age: 12·7 ± 1·6 years). At ophthalmologic examination, 3/25 SCD children had mild visual acuity deficits and 2/25 had mild tortuosity of the retinal vessels. None showed optic pathway infarcts at MRI or Transcranial Doppler abnormal blood velocities, and 6/25 disclosed posterior cerebral artery stenosis (five mild and one severe) at MR-angiography. Compared to controls, SCD children had increased posterior pericalcarine cortical thickness, with a different trajectory of cortical maturation and decreased connectivity within medial and ventral visual neural networks. Our findings suggest that SCD affects the development and the tuning of the visual cortex, leading to anatomical and functional changes in childhood even in the absence of retinopathy, and set the basis for future studies to determine if these changes can represent useful predictors of visual impairment in adulthood, biomarkers of disease progression or treatment response.

The present research investigated the neural correlates of nominal inflection and aimed at disclosing their possible link with the frequency distribution of noun inflectional features: grammatical gender, inflectional suffixes and inflectional classes. The properties of the Italian nominal system were exploited since it allows to explore exhaustively fine-grained phenomena in the inflectional processing. An event-related functional magnetic resonance imaging (fMRI) experiment was carried out where Italian masculine and feminine nouns were visually presented to 50 healthy participants in an overt inflectional task: the generation of the plural from the singular and vice versa. The grammatical gender and the citation form suffix of nouns were manipulated in a factorial design. Functional data showed that inflectional operations for nouns activate an extensive cortical network involving the left inferior and right superior frontal gyri, the left and right middle temporal gyri, the posterior cingulate cortex and the cerebellum. Activations were variably modulated by the distributional features of gender-dependent properties of nouns. Particularly, cortical activity increased during inflectional operations for small and/or scarcely consistent inflectional classes. These findings demonstrate the relevance of specific morphological (inflectional suffixes) and distributional features (size and consistency) shared by groups of words (inflectional classes) in a language, particularly when implementing cognitive operations required for language processing.

ObjectiveReal-time functional magnetic resonance imaging neurofeedback (rt-fMRI-NF) is a non-invasive MRI procedure allowing examined participants to learn to self-regulate brain activity by performing mental tasks. A novel two-step rt-fMRI-NF procedure is proposed whereby the feedback display is updated in real-time based on high level (semantic) representations of experimental stimuli via real-time representational similarity analysis of multi-voxel patterns of brain activity.ApproachIn a localizer session, the stimuli become associated with anchored points on a two-dimensional representational space where distances approximate between-pattern (dis)similarities. In the NF session, participants modulate their brain response, displayed as a movable point, to engage in a specific neural representation. The developed method pipeline is verified in a proof-of-concept rt-fMRI-NF study at 7 Tesla using imagery of concrete objects. The dependence on noise is more systematically assessed on artificial fMRI data with similar (simulated) spatio-temporal structure and variable (injected) signal and noise. A series of brain activity patterns from the ventral visual cortex is evaluated via on-line and off-line analyses and the performances of the method are reported under different noise conditions.Main resultsThe participant in the proof-of-concept study exhibited robust activation patterns in the localizer session and managed to control the neural representation of a stimulus towards the selected target, in the NF session. The offline analyses validated the rt-fMRI-NF results, showing that the rapid convergence to the target representation is noise-dependent.SignificanceOur proof-of-concept study demonstrates the potential of semantic NF designs where the participant navigates among different mental states. Compared to traditional NF designs (e.g. using a thermometer display to set the level of the neural signal), the proposed approach provides content-specific feedback to the participant and extra degrees of freedom to the experimenter enabling real-time control of the neural activity towards a target brain state without suggesting a specific mental strategy to the subject.

Background No information is currently available regarding the natural history of asymptomatic intracranial aneurysms in beta-thalassemia, raising several concerns about their proper management. Methods We performed a prospective longitudinal three-year-long MR-angiography study on nine beta-thalassemia patients (mean-age 40.3 ± 7.5, six females, 8 transfusion dependent) harboring ten asymptomatic intracranial aneurysms. In addition, we analyzed the clinical files of all adult beta-thalassemia patients (160 patients including those followed with MR-angiography, 121 transfusion dependent) referring to our Centers between 2014 and 2019 searching for history of subarachnoid hemorrhage or history of symptomatic intracranial aneurysms. Results At the end of the three-year-long follow-up, no patient showed any change in the size and shape of the aneurysms, none presented new intracranial aneurysms or artery stenoses, none showed new brain vascular-like parenchymal lesions or enlargement of the preexisting ones. Besides, in our database of all adult beta-thalassemia patients, no one had history of subarachnoid hemorrhage or history of symptomatic intracranial aneurysms. Conclusions Incidental asymptomatic intracranial aneurysms do not seem to be associated, in beta-thalassemia, with an increased risk of complications (enlargement or rupture) at least in the short term period, helping to optimize human and economic resources and patient compliance during their complex long-lasting management.

Probabilistic language models are increasingly used to provide neural representations of linguistic features under naturalistic settings. Word surprisal models can be applied to continuous fMRI recordings during task-free listening of narratives, to detect regions linked to language prediction and comprehension. Here, to this purpose, a novel semantics-weighted lexical surprisal is applied to naturalistic fMRI data. FMRI was performed at 3 Tesla in 31 subjects during task-free listening to a 12-minute audiobook played in both original and word-reversed (control) version. Lexical-only and semantics-weighted lexical surprisal models were estimated for the original and control word series. The two series were alternatively chosen to build the predictor of interest in the first-level general linear model and were compared in the second-level (group) analysis. The addition of the surprisal predictor to the stimulus-related predictors significantly improved the fitting of the neural signal. In average, the semantics-weighted model yielded lower surprisal values and, in some areas, better fitting of the fMRI data compared to the lexical-only model. The two models produced both overlapping and distinct activations: while lexical-only surprisal activated secondary auditory areas in the superior temporal gyri and the cerebellum, semantics-weighted surprisal additionally activated the left inferior frontal gyrus. These results confirm the usefulness of surprisal models in the naturalistic fMRI analysis of linguistic processes and suggest that the use of semantic information may increase the sensitivity of a probabilistic language model in higher-order language-related areas, with possible implications for future naturalistic fMRI studies of language under normal and (clinically or pharmacologically) modified conditions.

Cortical surface-based morphometry is based on a semi-automated analysis of structural MRI images. In FreeSurfer, a widespread tool for surface-based analyses, a visual check of gray-white matter borders is followed by the manual placement of control points to drive the topological correction (editing) of segmented data. A novel algorithm combining radial sampling and machine learning is presented for the automated control point search (ACPS). Four data sets with 3 T MRI structural images were used for ACPS validation, including raw data acquired twice in 36 healthy subjects and both raw and FreeSurfer preprocessed data of 125 healthy subjects from public databases. The unedited data from a subgroup of subjects were submitted to manual control point search and editing. The ACPS algorithm was trained on manual control points and tested on new (unseen) unedited data. Cortical thickness (CT) and fractal dimensionality (FD) were estimated in three data sets by reconstructing surfaces from both unedited and edited data, and the effects of editing were compared between manual and automated editing and versus no editing. The ACPS-based editing improved the surface reconstructions similarly to manual editing. Compared to no editing, ACPS-based and manual editing significantly reduced CT and FD in consistent regions across different data sets. Despite the extra processing of control point driven reconstructions, CT and FD estimates were highly reproducible in almost all cortical regions, albeit some problematic regions (e.g. entorhinal cortex) may benefit from different editing. The use of control points improves the surface reconstruction and the ACPS algorithm can automate their search reducing the burden of manual editing.

Objectives A strikingly increased headache prevalence was recently noted in Sri Lankan beta-thalassemia patients, raising several concerns regarding long-term neurological involvement in this condition. Methods We interviewed on headache occurrence and characteristics 102 Italian beta-thalassemia patients and 129 healthy controls. 3T-MRI, MR-angiography, MR-venography, cognitive and psychiatric findings were considered. Results Headache was diagnosed in 39/102 (38.2%) beta-thalassemia patients without significant phenotype-related differences and in 51/129 (39.5%) controls. Patients and controls did not differ significantly regarding episode number (5.9 ± 6.2 vs 5.4 ± 4.4 days/month), subjective severity-score (6.8 ± 1.4 vs 7.1 ± 1.3), age-at-onset (24.3 ± 13.0 vs 19.5 ± 9.6 years) and headache-subtype rate. No main demographic, clinical or laboratory data was associated with headache but female gender. Headache was not associated with white matter lesions (number or maximal diameter), intracranial aneurysms, intracranial artery stenoses or venous sinus thrombosis. Cognitive and psychiatric evaluations were worse in beta-thalassemia, however, headache did not correlate with full-scale Intelligence Quotient (75.4 ± 18.0 vs 76.7 ± 15.3, with and without headache, respectively) or Brief Psychiatric Rating Scale scores (29.1 ± 2.7 vs 28.5 ± 3.4). Conclusions Among Italian beta-thalassemia patients, headache does not seem to be more common or severe than in the general population. In addition, patients with headache do not seem to present increased conventional MRI, MR-angiography and cognitive/psychiatric changes.

Eating disorders (EDs) have a possible neurodevelopmental pathogenesis. Our study aim was to assess regional cortical thickness (CT), local gyrification index (lGI) and fractal dimensionality (FD), as specific markers of cortical neurodevelopment in ED females. Twenty-two women with acute anorexia nervosa (acuAN), 10 with recovered anorexia nervosa (recAN), 24 with bulimia nervosa (BN) and 35 female healthy controls (HC) underwent a 3T MRI scan. All data were processed by FreeSurfer. Compared to recAN group women with acuAN showed a lower CT in multiple areas, while compared to HC they showed lower CT in temporal regions. BN group showed higher CT values in temporal and paracentral areas compared to HC. In multiple cortical areas, AcuAN group showed greater values of lGI compared to recAN group and lower values of lGI compared to HC. The BN group showed lower lGI in left medial orbitofrontal cortex compared to HC. No significant differences were found in FD among the groups. Present results provide evidence of CT and lGI alterations in patients with AN and, for the first time, in those with BN. Although these alterations could be state-dependent phenomena, they may underlie psychopathological aspects of EDs.

Beta-thalassemia-related anemia and chronic hypercoagulative state are supposed to cause cumulative cerebrovascular damage with consequent parenchymal/vascular changes and functional impairment. However, recent conventional MRI/MR-angiography investigations failed to show an increased cerebrovascular involvement in beta-thalassemia patients managed according to current treatment guidelines, in spite of significantly decreased full-scale IQ scores. We therefore investigated those patients and controls by means of advanced quantitative MRI analyses (based on magnetization transfer and diffusion tensor imaging) searching for signs of possible cerebrovascular injuries undetected by conventional MRI/MR-angiography. The 3 T-MRI study protocol included diffusion tensor imaging and 3D-multi-echo FLASH sequences for magnetization transfer analysis. Whole-brain voxel-based analyses showed that magnetization transfer, fractional anisotropy, and mean, radial and axial diffusivity do not differ between healthy controls and beta-thalassemia patients (considered as a whole group or as distinct transfusion dependent and non-transfusion dependent subgroups). No correlation emerged between all the considered MRI metrics and cognitive findings (full-scale IQ) or the main clinical and laboratory data. According to our findings, adult neurologically-asymptomatic beta-thalassemia patients (regardless of clinical severity) do not seem to present an increased disease-related cerebrovascular vulnerability compared to healthy controls downsizing the need of regular brain MRI monitoring, at least when the current treatment guidelines are followed.

The human gustatory cortex analyzes the chemosensory properties of tastants, particularly the quality, intensity, and affective valence, to determine whether a perceived substance should be ingested or rejected. Among previous studies, the spatial distribution of taste intensity-related activations within the human insula has been scarcely addressed. To spatially characterize a specialized or distributed nature of the cortical responses to taste intensities, a functional magnetic resonance imaging study was performed at 3 T in 44 healthy subjects where sweet and bitter tastants were administered at five increasing concentrations and cortex-based factorial and parametric analyses were performed. Two clusters in the right middle-posterior and left middle insula were found specialized for taste intensity processing, exhibiting a highly nonlinear profile across concentrations. Multiple clusters were found activated by sweet and bitter taste stimuli at most concentrations, in the anterior, middle-posterior, and inferior portion of the bilateral insula. Across these clusters, respectively, for the right and left insula, a superior-to-inferior and an anterior-to-posterior spatial gradient for high-to-low concentrations were observed for the most responsive intensity of both tastes. These findings may gather new insights regarding how the gustatory cortex is spatially organized during the perceptual processing of taste intensity for two basic tastants.

Multi-factorial causes jeopardize brain integrity in β-thalassaemia. Intracranial parenchymal and vascular changes have been reported among young β-thalassaemia patients but conventional magnetic resonance imaging (MRI) findings are contradictory making early MRI and magnetic resonance angiography (MRA)/venography monitoring a matter of debate. This study prospectively investigated 75 neurologically asymptomatic β-thalassaemia patients (mean-age 35·2±10·7years; 52/75 transfusion-dependent; 41/75 splenectomised) using a 3T magnetic resonance scanner; clinical, laboratory and treatment data were also collected. White matter ischaemic-like abnormalities, intracranial artery stenoses, aneurysms and sinus venous thrombosis were compared between patients and 56 healthy controls (mean-age 33·9±10·8years). No patient or control showed silent territorial or lacunar strokes, intracranial artery stenoses or signs of sinus thrombosis. White matter lesions were found both in patients (35/75, 46·7%) and controls (28/56, 50·0%), without differences in terms of number (4·0±10·6 vs. 4·6±9·1, P=0·63), size and Fazekas' Score. Intracranial aneurysms did not differ between patients and controls for incidence rate (7/75, 9·3% vs. 5/56, 8·9%), size and site. Vascular and parenchymal abnormality rate did not differ according to treatments or clinical phenotype. According to this study, asymptomatic β-thalassaemia patients treated according to current guidelines do not seem to carry an increased risk of brain and intracranial vascular changes, thus weakening recommendations for regular brain MRI monitoring.

Cognitive involvement in beta-thalassaemia is strikingly controversial and poorly studied in adulthood. This multicentre prospective study investigated 74 adult neurologically-asymptomatic beta-thalassaemia patients (mean-age 34 center dot 5 +/- 10 center dot 3 years; 53 transfusion-dependent [TDT], 21 non-transfusion dependent [NTDT]) and 45 healthy volunteers (mean-age 33 center dot 9 +/- 10 center dot 7 years). Participants underwent testing with Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV), Brief Psychiatric Rating Scale (BPRS) and multiparametric brain 3T-magnetic resonance imaging (MRI) for parenchymal, vascular and iron content evaluation. Patients had lower Full-Scale Intelligence Quotient (FSIQ) than controls (75 center dot 5 +/- 17 center dot 9 vs. 97 center dot 4 +/- 18 center dot 1, P < 0 center dot 0001) even after correction for education level. Compared to TDT, NTDT showed a trend of higher FSIQ (P = 0 center dot 08) but a similar cognitive profile at WAIS-subtests. FSIQ correlated with total and indirect bilirubin (P P = 0 center dot 002, respectively); no correlation was found with splenectomy, intracranial MRI/magnetic resonance-angiography findings, brain tissue iron content or other disease-related clinical/laboratory/treatment data. FSIQ did not correlate with BPRS scores, although the latter were higher among patients (28 center dot 74 +/- 3 center dot 1 vs. 27 center dot 29 +/- 4 center dot 8, P = 0 center dot 01) mainly because of increased depression and anxiety levels. Occupation rate was higher among controls (84 center dot 4% vs. 64 center dot 9%, P = 0 center dot 004) and correlated with higher FSIQ (P = 0 center dot 001) and education level (P = 0 center dot 001). In conclusion, Italian adult beta-thalassaemia patients seem to present a characteristic cognitive profile impairment and an increased rate of psychological disorders with possible profound long-term socio-economic consequences.

The generation of regular and irregular inflected verb-forms has been taken as a crucial test between models of inflection in the mental lexicon, namely approaches which invoke different mechanisms for regular and irregular forms (rule-based procedures vs. recovery of whole forms stored in an associative network) and accounts which postulate a single procedure for all forms. An alternative hypothesis suggests that inflectional processes are explained by membership of words to clusters, for instance, Italian inflectional classes (conjugations). In a behavioural and a rapid event-related fMRI experiment, participants overtly generated the past participle of verbs from the three Italian conjugations. Results showed that the cognitive operations and the neural substrate underlying inflectional processes rely on specific properties of inflectional classes. Different patterns of cortical activations elicited by verbs from different conjugations were detected for the first time in the left middle frontal gyrus, left pre-supplementary motor area and left anterior cingulate cortex.

Quantitative MRI (qMRI) provides surrogate brain maps of myelin and iron content. After spatial normalization to a common standard brain space, these may be used to detect altered myelination and iron accumulation in clinical populations. Here, volumetric and combined volumetric and surface-based (CVS) normalization were compared to identify which procedure would afford the greatest sensitivity to inter-regional differences (contrast), and the lowest inter-subject variability (under normal conditions), of myelin- and iron-related qMRI parameters, in whole-brain group-level studies. Ten healthy volunteers were scanned twice at 3 Tesla. Three-dimensional T1-weighted, T2-weighted and multi-parametric mapping sequences for brain qMRI were used to map myelin and iron content over the whole brain. Parameter maps were spatially normalized using volumetric (DARTEL) and CVS procedures. Tissue probability weighting and isotropic Gaussian smoothing were integrated in DARTEL for voxel-based quantification (VBQ). Contrasts, coefficients of variations and sensitivity to detecting differences in the parameters were estimated in standard space for each approach on region of interest (ROI) and voxel-by-voxel bases. The contrast between cortical and subcortical ROIs with respectively different myelin and iron content was higher following CVS, compared to DARTEL-VBQ, normalization. Across cortical voxels, the inter-individual variability of myelin and iron qMRI maps were comparable between CVS (with no smoothing) and DARTEL-VBQ (with smoothing). CVS normalization of qMRI maps preserves higher myelin and iron contrast than DARTEL-VBQ over the entire brain, while exhibiting comparable variability in the cerebral cortex without extra smoothing. Thus, CVS may prove useful for detecting small microstructural differences in whole-brain group-level qMRI studies.