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Besides being responsible for olfaction and air intake, the nose contains abundant vasculature and autonomic nervous system innervations, and it is a cerebrospinal fluid clearance site. Therefore, the nose is an attractive target for functional MRI (fMRI). Yet, nose fMRI has not been possible so far due to signal losses originating from nasal air-tissue interfaces. Here, we demonstrated feasibility of nose fMRI by using novel ultrashort/zero echo time (TE) MRI. Results obtained in the resting-state from 13 healthy participants at 7T and in 5 awake mice at 9.4T revealed a highly reproducible resting-state nose functional network that likely reflects autonomic nervous system activity. Another network observed in humans involves the nose, major brain vessels and CSF spaces, presenting a temporal dynamic that correlates with heart rate and breathing rate. These resting-state nose functional signals should help elucidate peripheral and central nervous system integrations., (© 2024. The Author(s).)

Quantitative maps of rotating frame relaxation (RFR) time constants are sensitive and useful magnetic resonance imaging tools with which to evaluate tissue integrity in vivo. However, to date, only moderate image resolutions of 1.6 x 1.6 x 3.6 mm 3 have been used for whole-brain coverage RFR mapping in humans at 3 T. For more precise morphometrical examinations, higher spatial resolutions are desirable. Towards achieving the long-term goal of increasing the spatial resolution of RFR mapping without increasing scan times, we explore the use of the recently introduced Transform domain NOise Reduction with DIstribution Corrected principal component analysis (T-NORDIC) algorithm for thermal noise reduction. RFR acquisitions at 3 T were obtained from eight healthy participants (seven males and one female) aged 52 ± 20 years, including adiabatic T1ρ, T2ρ, and nonadiabatic Relaxation Along a Fictitious Field (RAFF) in the rotating frame of rank n = 4 (RAFF4) with both 1.6 x 1.6 x 3.6 mm 3 and 1.25 x 1.25 x 2 mm 3 image resolutions. We compared RFR values and their confidence intervals (CIs) obtained from fitting the denoised versus nondenoised images, at both voxel and regional levels separately for each resolution and RFR metric. The comparison of metrics obtained from denoised versus nondenoised images was performed with a two-sample paired t-test and statistical significance was set at p less than 0.05 after Bonferroni correction for multiple comparisons. The use of T-NORDIC on the RFR images prior to the fitting procedure decreases the uncertainty of parameter estimation (lower CIs) at both spatial resolutions. The effect was particularly prominent at high-spatial resolution for RAFF4. Moreover, T-NORDIC did not degrade map quality, and it had minimal impact on the RFR values. Denoising RFR images with T-NORDIC improves parameter estimation while preserving the image quality and accuracy of all RFR maps, ultimately enabling high-resolution RFR mapping in scan times that are suitable for clinical settings., (© 2024 The Author(s). NMR in Biomedicine published by John Wiley & Sons Ltd.)

Background: Brain injury in hereditary hemoglobinopathies is commonly attributed to anemia-related relative hypoperfusion in terms of impaired oxygen blood supply. Supratentorial and infratentorial vascular watershed regions seem to be especially vulnerable, but data are very scarce., Aims: We investigated a large beta-thalassemia sample with arterial spin labeling in order to characterize regional perfusion changes and their correlation with phenotype and anemia severity., Methods: We performed a multicenter single-scanner cross-sectional 3T-MRI study analyzing non-invasively the brain perfusion in 54 transfusion-dependent thalassemia (TDT), 23 non-transfusion-dependent thalassemia (NTDT) patients and 56 Healthy Controls (HC). Age, hemoglobin levels, and cognitive functioning were recorded., Results: Both TDT and NTDT patients showed globally increased brain perfusion values compared to healthy controls, while no difference was found between patient subgroups. Using age and sex as covariates and scaling the perfusion maps for the global cerebral blood flow, beta-thalassemia patients showed relative hyperperfusion in supratentorial/infratentorial watershed regions. Perfusion changes correlated with hemoglobin levels (p = 0.013) and were not observed in the less severely anemic patients (hemoglobin level > 9.5 g/dL). In the hyperperfused regions, white matter density was significantly decreased (p = 0.0003) in both patient subgroups vs. HC. In NTDT, white matter density changes correlated inversely with full-scale Intelligence Quotient (p = 0.007) while in TDT no correlation was found., Conclusion: Relative hyperperfusion of watershed territories represents a hemodynamic hallmark of beta-thalassemia anemia challenging previous hypotheses of brain injury in hereditary anemias. A careful management of anemia severity might be crucial for preventing structural white matter changes and subsequent long-term cognitive impairment., (© 2024. The Author(s).)

The exact pathophysiology of cognitive impairment in multiple system atrophy (MSA) is unclear. In our longitudinal study, we aimed to analyze (I) the relationships between cognitive functions and some subcortical structures, such as putamen and cerebellum assessed by voxel-based morphometry (VBM) and T1-weighted/T2-weighted (T1w/T2w) ratio, and (II) the neuroimaging predictors of the progression of cognitive deficits. Twenty-six patients with MSA underwent a comprehensive neuropsychological battery, motor examination, and brain MRI at baseline (T 0 ) and 1-year follow-up (T 1 ). Patients were then divided according to cognitive status into MSA with normal cognition (MSA-NC) and MSA with mild cognitive impairment (MCI). At T 1 , we divided the sample according to worsening/non worsening of cognitive status compared to baseline evaluation. Logistic regression analysis showed that age (β =  - 9.45, p = .02) and T1w/T2w value in the left putamen (β = 230.64, p = .01) were significant predictors of global cognitive status at T 0 , explaining 65% of the variance. Logistic regression analysis showed that ∆-values of WM density in the cerebellum/brainstem (β = 2188.70, p = .02) significantly predicted cognitive worsening at T 1 , explaining 64% of the variance. Our results suggest a role for the putamen and cerebellum in the cognitive changes of MSA, probably due to their connections with the cortex. The putaminal T1w/T2w ratio may deserve further studies as a marker of cognitive impairment in MSA., (© 2022. The Author(s).)

Neuropsychiatric symptoms are intrinsic to Progressive Supranuclear Palsy (PSP) and a spoonful of studies investigated their imaging correlates. Describe (I) the frequency and severity of neuropsychiatric symptoms in PSP and (II) their structural imaging correlates. Twenty-six PSP patients underwent Neuropsychiatric Inventory (NPI) and brain 3D T1-weighted MRI. Spearman's rho with Bonferroni correction was used to investigate correlations between NPI scores and volumes of gray matter regions. More than 80% of patients presented at least one behavioral symptom of any severity. The most frequent and severe were depression/dysphoria, apathy, and irritability/lability. Significant relationships were found between the severity of irritability and right pars opercularis volume (p < 0.001) as well as between the frequency of agitation/aggression and left lateral occipital volume (p < 0.001). Depression, apathy, and irritability are the most common neuropsychiatric symptoms in PSP. Moreover, we found a relationship between specific positive symptoms as irritability and agitation/aggression and greater volume of the right pars opercularis cortex and lower volume of the left occipital cortex, respectively, which deserve further investigations., (© 2023. The Author(s).)

Craving is a core symptom of cocaine use disorder and a major factor for relapse risk. To date, there is no pharmacological therapy to treat this disease or at least to alleviate cocaine craving as a core symptom. In animal models, impaired prefrontal-striatal signalling leading to altered glutamate release in the nucleus accumbens appear to be the prerequisite for cocaine-seeking. Thus, those network and metabolic changes may constitute the underlying mechanisms for cocaine craving and provide a potential treatment target. In humans, there is recent evidence for corresponding glutamatergic alterations in the nucleus accumbens, however, the underlying network disturbances that lead to this glutamate imbalance remain unknown. In this state-dependent randomized, placebo-controlled, double-blinded, cross-over multimodal study, resting state functional magnetic resonance imaging in combination with small-voxel proton magnetic resonance spectroscopy (voxel size: 9.4 × 18.8 × 8.4 mm 3 ) was applied to assess network-level and associated neurometabolic changes during a non-craving and a craving state, induced by a custom-made cocaine-cue film, in 18 individuals with cocaine use disorder and 23 healthy individuals. Additionally, we assessed the potential impact of a short-term challenge of N-acetylcysteine, known to normalize disturbed glutamate homeostasis and to thereby reduce cocaine-seeking in animal models of addiction, compared to a placebo. We found increased functional connectivity between the nucleus accumbens and the dorsolateral prefrontal cortex during the cue-induced craving state. However, those changes were not linked to alterations in accumbal glutamate levels. Whereas we additionally found increased functional connectivity between the nucleus accumbens and a midline part of the thalamus during the cue-induced craving state. Furthermore, obsessive thinking about cocaine and the actual intensity of cocaine use were predictive of cue-induced functional connectivity changes between the nucleus accumbens and the thalamus. Finally, the increase in accumbal-thalamic connectivity was also coupled with craving-related glutamate rise in the nucleus accumbens. Yet, N-acetylcysteine had no impact on craving-related changes in functional connectivity. Together, these results suggest that connectivity changes within the fronto-accumbal-thalamic loop, in conjunction with impaired glutamatergic transmission, underlie cocaine craving and related clinical symptoms, pinpointing the thalamus as a crucial hub for cocaine craving in humans., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Deep learning (DL) approaches may also inform the analysis of human brain activity. Here, a state-of-art DL tool for natural language processing, the Generative Pre-trained Transformer version 2 (GPT-2), is shown to generate meaningful neural encodings in functional MRI during narrative listening. Linguistic features of word unpredictability (surprisal) and contextual importance (saliency) were derived from the GPT-2 applied to the text of a 12-min narrative. Segments of variable duration (from 15 to 90 s) defined the context for the next word, resulting in different sets of neural predictors for functional MRI signals recorded in 27 healthy listeners of the narrative. GPT-2 surprisal, estimating word prediction errors from the artificial network, significantly explained the neural data in superior and middle temporal gyri (bilaterally), in anterior and posterior cingulate cortices, and in the left prefrontal cortex. GPT-2 saliency, weighing the importance of context words, significantly explained the neural data for longer segments in left superior and middle temporal gyri. These results add novel support to the use of DL tools in the search for neural encodings in functional MRI. A DL language model like the GPT-2 may feature useful data about neural processes subserving language comprehension in humans, including next-word context-related prediction., (© 2022. The Author(s).)

Several MRI techniques have become available to support the early diagnosis of multiple system atrophy (MSA), but few longitudinal studies on both MSA variants have been performed, and there are no established MRI markers of disease progression. We aimed to characterize longitudinal brain changes in 26 patients with MSA (14 MSA-P and 12 MSA-C) over a 1-year follow-up period in terms of local tissue density and T1w/T2w ratio in a-priori regions, namely, bilateral putamen, cerebellar gray matter (GM), white matter (WM), and substantia nigra (SN). A significant GM density decrease was found in cerebellum and left putamen in the entire group (10.7 and 33.1% variation, respectively) and both MSA subtypes (MSA-C: 15.4 and 33.0% variation; MSA-P: 7.7 and 33.2%) and in right putamen in the entire group (19.8% variation) and patients with MSA-C (20.9% variation). A WM density decrease was found in the entire group (9.3% variation) and both subtypes in cerebellum-brainstem (MSA-C: 18.0% variation; MSA-P: 5% variation). The T1w/T2w ratio increase was found in the cerebellar and left putamen GM (6.6 and 24.9% variation), while a significant T1w/T2w ratio decrease was detected in SN in the entire MSA group (31% variation). We found a more progressive atrophy of the cerebellum in MSA-C with a similar progression of putaminal atrophy in the two variants. T1w/T2w ratio can be further studied as a potential marker of disease progression, possibly reflecting decreased neuronal density or iron accumulation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ponticorvo, Manara, Russillo, Andreozzi, Forino, Erro, Picillo, Amboni, Cuoco, Di Salle, Di Salle, Barone, Esposito and Pellecchia.)

Background: Richardson's syndrome (RS) is considered the most symmetric phenotype of progressive supranuclear palsy (PSP) as opposed to PSP with predominant corticobasal syndrome (PSP-CBS) or parkinsonism (PSP-P)., Objectives: Evaluate asymmetrical motor and higher cortical features in probable PSP-RS and compare the degree of asymmetry of cortical lobes and hemispheres between PSP-RS, PSP-CBS, PSP-P, and age-matched healthy controls (HC)., Methods: Asymmetry of motor and higher cortical features evaluated with an extensive videotaped neurologic examination was investigated in 28 PSP-RS, 8 PSP-CBS, and 14 PSP-P. Brain MRI to compute the laterality index (LI) was performed in 36 patients as well as in 56 HC., Results: In PSP-RS, parkinsonism was the most common asymmetric motor feature (53.6%), followed by dystonia and myoclonus (21.4% and 17.9%, respectively). Among higher cortical features, limb apraxia was found asymmetric in about one-third of patients. PSP-RS disclosed higher LI for hemispheres compared to HC, indicating a greater degree of asymmetry (p = 0.003). The degree of asymmetry of clinical features was not different between PSP-RS and those qualifying for PSP-CBS or PSP-P. As for imaging, LI was not different between PSP-RS, PSP-CBS, and PSP-P in any cortical region., Conclusions: Motor and higher cortical features are asymmetric in up to 50% of PSP-RS who also present a greater degree of asymmetry in hemispheres compared to age-matched HC. Lateralization of clinical features should be annotated in PSP., (© 2022. The Author(s).)

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., (© 2022 IOP Publishing Ltd.)

Age-related sensorineural hearing loss (HL) leads to localized brain changes in the primary auditory cortex, long-range functional alterations, and is considered a risk factor for dementia. Nonhuman studies have repeatedly highlighted cross-modal brain plasticity in sensorial brain networks other than those primarily involved in the peripheral damage, thus in this study, the possible cortical alterations associated with HL have been analyzed using a whole-brain multimodal connectomic approach. Fifty-two HL and 30 normal hearing participants were examined in a 3T MRI study along with audiological and neurological assessments. Between-regions functional connectivity and whole-brain probabilistic tractography were calculated in a connectome-based manner and graph theory was used to obtain low-dimensional features for the analysis of brain connectivity at global and local levels. The HL condition was associated with a different functional organization of the visual subnetwork as revealed by a significant increase in global efficiency, density, and clustering coefficient. These functional effects were mirrored by similar (but more subtle) structural effects suggesting that a functional repurposing of visual cortical centers occurs to compensate for age-related loss of hearing abilities., Competing Interests: Disclosure statement The authors have no actual or potential conflicts of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The central gustatory pathway encompasses multiple subcortical and cortical regions whose neural functional connectivity can be modulated by taste stimulation. While gustatory perception has been previously linked to sex, whether and how the gustatory network differently responds to basic tastes between men and women is unclear. Here, we defined the regions of the central gustatory network by a meta-analysis of 35 fMRI taste activation studies and then analyzed the taste-evoked functional connectivity between these regions in 44 subjects (19 women) in a separate 3 Tesla activation study where sweet and bitter solutions, at five concentrations each, were administered during scanning. From the meta-analysis, a network model was set up, including bilateral anterior, middle and inferior insula, thalamus, precentral gyrus, left amygdala, caudate and dorsolateral prefrontal cortex. Higher functional connectivity than in women was observed in men between the right middle insula and bilateral thalami for bitter taste. Men exhibited higher connectivity than women at low bitter concentrations and middle-high sweet concentrations between bilateral thalamus and insula. A graph-based analysis expressed similar results in terms of nodal characteristics of strength and centrality. Our findings add new insights into the mechanisms of taste processing by highlighting sex differences in the functional connectivity of the gustatory network as modulated by the perception of sweet and bitter tastes. These results shed more light on the neural origin of sex-related differences in gustatory perception and may guide future research on the pathophysiology of taste perception in humans., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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 < 0.04). Relative auditory cortex perfusion values showed a significant U-shaped correlation with PTA values among hearing loss patients, and a linear correlation with the full scale intelligence quotient (right side 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., (© 2021. The Author(s).)

Background: Patients with age-related sensorineural hearing loss (HL) may benefit from auditory input amplification by using hearing aids (HAs). However, the impact of both HL- and HA-based rehabilitation on central auditory functional connectivity (FC) is not clear. Methodology: Sixty-two HL (22 females, aged 64.4 ± 7.6 years, pure-tone average 50.9 ± 14.7 dB right ear, 50.7 ± 12.9 dB left ear) and 32 normal hearing (NH) subjects (22 females, aged 59.3 ± 7.3 years) were examined in a 3T magnetic resonance imaging (MRI) study. HL patients were analyzed cross-sectionally at baseline (vs. NH subjects) and longitudinally at 6-month follow-up. Between the 2 scans, 31/62 patients used the HA 9.5 ± 3.8 h a day. Arterial spin labeling and blood oxygen level-dependent resting-state functional MRI were performed to measure regional perfusion in the primary auditory cortex and, from here to the whole brain, seed-based FC was performed. Before each scan, HL patients underwent audiological and neurological assessments. Results: At baseline, the HL condition was associated with regional hypoperfusion in right Heschl's gyrus (seed) and negative seed-based FC (anticorrelation) in posterior brain regions. Long-range FC in the precuneus correlated negatively with pure-tone and speech reception average thresholds. At 6-month follow-up, HA usage was associated with seed-based FC increase in the right superior frontal gyrus (SFG) and seed-based FC reduction in the right middle temporal gyrus. Long-range FC changes in the SFG correlated positively with executive function improvements. Conclusions: These findings suggest that HA-based rehabilitation may not reverse HL-related neural effects and yet carry neurological benefits by retuning long-range FC of the auditory system. Impact statement Age-related sensorineural hearing loss (HL) affects 40% to 60% of the worldwide population and a common, viable rehabilitation strategy is to provide auditory input amplification through hearing aids (HAs). By targeting metabolically depressed, auditory cortical centers, our work reveals a possible neural link between peripheral and central vulnerability in HL patients in the form of aberrant, long-range, functional connectivity effects. Similarly, we unveil how wearing HAs for 6 months may induce neuroplastic changes that positively correlate with improved neuropsychological performances.

Few studies have investigated the neuropsychological profile of Hearing Loss (HL) subjects and the effects of hearing-aid on cognitive decline. We investigated the neuropsychological profile of HL patients at baseline and compared the neuropsychological profiles of patients with and without hearing-aid at 6 month. Fifty-six HL patients and 40 healthy subjects (HC) underwent neuropsychological and behavioral examination and were compared at baseline. Changes at follow-up were compared between HL patients with (N = 25) and without (N = 31) hearing-aids. At baseline, significant differences between HL and HC were found in MOCA test, Raven's Coloured Progressive Matrices (CPM) and SF-36. Among mild-HL patients, patients with hearing-aid significantly improved on the Clock Drawing Test (CDT) as compared to patients without hearing-aid. Our findings indicate that hearing loss is associated with both a reduced efficiency of the global cognitive state and a worse quality of life as compared to HC, supporting the association between HL and cognitive impairment. Moreover, only patients with mild-HL shows some cognitive improvement after using hearing-aid, suggesting that rehabilitative strategies may be more effective to delay cognitive decline in such patients. However, we cannot exclude that hearing-aids may affect cognitive decline in more severe-HL, but a longer follow-up is needed.

Prolonged mastication may induce an asymmetric modification of the local perfusion of the trigeminal principal nucleus. The aim of the present study was to evaluate the possible influence of vitamin C (vit. C) on such effect. Four groups of healthy volunteers underwent arterial spin labeling magnetic resonance imaging (ASL-MRI) to evaluate the local perfusion of the trigeminal nuclei after a vit. C-enriched lunch or a control lunch. Two ASL-MRI scans were acquired, respectively, before and after a 1 h-long masticating exercise or a 1 h long resting period. The results showed (i) an increased global perfusion of the brain in the vit. C-enriched lunch groups, (ii) an increased local perfusion of the right principal trigeminal nucleus (Vp) due to mastication, and (iii) a reduction of the rightward asymmetry of the Vp perfusion, due to mastication, after the vit C-enriched meal compared to the control meal. These results confirmed a long-lasting effect of prolonged mastication on Vp perfusion and also suggest a possible effect of vit. C on cerebral vascular tone regulation. Moreover, the data strongly draw attention on the side-to-side relation in Vp perfusion as a possible physiological parameter to be considered to understand the origin of pathological conditions like migraine., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Viggiano, Ponticorvo, Canna, Secondulfo, Sbordone, Russo, Monda, Di Salle and Esposito.)

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., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

Objective: To verify the association of midbrain-based MRI measures as well as cortical volumes with disease core features and progression in patients with Progressive Supranuclear Palsy (PSP). Methods: Sixty-seven patients (52.2% with Richardson's syndrome) were included in the present analysis. Available midbrain-based MRI morphometric assessments as well as cortical lobar volumes were computed. Ocular, gait and postural involvement at the time of MRI was evaluated with the PSP rating scale. Specific milestones or death were used to estimate disease progression up to 72 months follow up. Hierarchical regression models and survival analysis were used for analyzing cross-sectional and longitudinal data, respectively. Results: Multivariate models showed vertical supranuclear gaze palsy was associated with smaller midbrain area (OR: 0.02, 95% CI 0.00-0.175, p = 0.006). Cox regression adjusted for age, disease duration, and phenotype demonstrated that lower midbrain area (HR: 0.122, 95% CI 0.030-0.493, p = 0.003) and diameter (HR: 0.313, 95% CI 0.112-0.878, p = 0.027), higher MR Parkinsonism Index (HR: 6.162, 95% CI 1.790-21.209, p = 0.004) and larger third ventricle width (HR: 2.755, 95% CI 1.068-7.108, p = 0.036) were associated with higher risk of dependency on wheelchair. Conclusions: Irrespective of disease features and other MRI parameters, reduced midbrain size is significantly associated with greater ocular motor dysfunction at the time of MRI and more rapid disease progression over follow up. This is the first comprehensive study to systematically assess the association of available midbrain-based MRI measures and cortical volumes with disease severity and progression in a large cohort of patients with PSP in a real-world setting., (Copyright © 2020 Picillo, Abate, Ponticorvo, Tepedino, Erro, Frosini, Del Prete, Cecchi, Cosottini, Ceravolo, Salle, Salle, Esposito, Pellecchia, Manara and Barone.)

Background: The clinical differentiation between Parkinson disease (PD) and multiple system atrophy (MSA) is difficult., Objectives: Arterial spin labeling (ASL) is an advanced MRI technique that obviates the use of an exogenous contrast agent for the estimation of cerebral perfusion. We explored the value of ASL in combination with structural MRI for the differentiation between PD and MSA., Methods: Ninety-four subjects (30 PD, 30 MSA and 34 healthy controls) performed a morphometric and ASL-MRI to measure volume and perfusion values within basal ganglia and cerebellum. A region-of-interest analysis was performed to test for structural atrophy and regional blood flow differences between groups., Results: MSA patients showed higher subcortical atrophy than both PD patients and HC, while no differences were observed between the latter. MSA and PD showed lower volume-corrected perfusion values than HC in several cerebellar areas (Crus I, Crus II, right VIIb, right VIIIa, right VIIIb), right caudate and both thalami. MSA and PD patients displayed similar perfusion values in all aforementioned areas, but the right cerebellar area VIIIb (lower in MSA) and right caudate and both thalami (lower in PD). Similar results were obtained when comparing PD and MSA patients with the parkinsonian variant., Conclusions: A perfusion reduction was equally observed in both MSA and PD patients in cerebellar areas that are putatively linked to cognitive (i.e., executive) rather than motor functions. The observed hypo-perfusion could not be explained by atrophy, suggesting the involvement of the cerebellum in the pathophysiology of both MSA and PD., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

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., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

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.

Objectives: To explore the role of the available midbrain-based MRI morphometric assessments in (1) differentiating among progressive supranuclear palsy (PSP) subtypes (PSP Richardson's syndrome (PSP-RS), PSP with predominant parkinsonism (PSP-P) and the other variant syndromes of PSP (vPSP)), and (2) supporting the diagnosis of PSP subtypes compared with Parkinson's disease (PD) and healthy controls (HC)., Methods: Seventy-eight patients with PSP (38 PSP-RS, 21 PSP-P and 19 vPSP), 35 PD and 38 HC were included in the present analysis. Available midbrain-based MRI morphometric assessments were calculated for all participants., Results: Current MRI midbrain-based assessments do not display an adequate sensitivity and specificity profile in differentiating PSP subtypes. On the other hand, we confirmed MR Parkinsonism Index (MRPI) and pons area to midbrain area ratio (P/M) have adequate diagnostic value to support PSP-RS clinical diagnosis compared with both PD and HC, but low sensitivity and specificity profile in differentiating PSP-P from PD as well as from HC. The same measures show acceptable sensitivity and specificity profile in supporting clinical diagnosis of vPSP versus HC but not versus PD. Similar findings were detected for the newer MRPI and P/M versions., Conclusions: Further studies are warranted to identify neuroimaging biomarkers supporting the clinical phenotypic categorisation of patients with PSP. MRPI and P/M have diagnostic value in supporting the clinical diagnosis of PSP-RS., Classification of Evidence: This study provides class III evidence that available MRI midbrain-based assessments do not have diagnostic value in differentiating the Movement Disorder Society PSP subtypes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (Copyright © 2019 Elsevier Inc. All rights reserved.)

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., (© 2019 Wiley Periodicals, Inc.)

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 34·5 ± 10·3 years; 53 transfusion-dependent [TDT], 21 non-transfusion dependent [NTDT]) and 45 healthy volunteers (mean-age 33·9 ± 10·7 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 (75·5 ± 17·9 vs. 97·4 ± 18·1, P < 0·0001) even after correction for education level. Compared to TDT, NTDT showed a trend of higher FSIQ (P = 0·08) but a similar cognitive profile at WAIS-subtests. FSIQ correlated with total and indirect bilirubin (P < 0·0001 and P = 0·002, 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 (28·74 ± 3·1 vs. 27·29 ± 4·8, P = 0·01) mainly because of increased depression and anxiety levels. Occupation rate was higher among controls (84·4% vs. 64·9%, P = 0·004) and correlated with higher FSIQ (P = 0·001) and education level (P = 0·001). 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., (© 2019 British Society for Haematology and John Wiley & Sons Ltd.)

Age-related hearing loss (HL) can be related to brain dysfunction or structural damage and may result in cerebral metabolic/perfusion abnormalities. Arterial spin labeling (ASL) magnetic resonance imaging (MRI) allows investigating noninvasively brain perfusion changes. Pseudocontinuous ASL and T1-weighted MRI (at 3 T) and neuropsychological testing (Montreal Cognitive Assessment) were performed in 31 HL (age range = 47-77 years, mean age ± SD = 63.4 ± 8.4 years, pure-tone average [PTA] HL > 50 dB) and 28 normal hearing (NH; age range = 48-78 years, mean age ± SD = 59.7 ± 7.4 years) subjects. Cerebral blood flow (CBF) and gray matter volume (GMV) were analyzed in the cortical volume to assess perfusion and structural group differences. Two HL subjects showing cognitive impairment were excluded from group comparisons. No significant differences in either global or local atrophy were detected between groups but the HL group exhibited significant regional effects of reduced perfusion within the bilateral primary auditory cortex, with maximal CBF difference (-17.2%) in the right lateral Heschl's gyrus. For the whole sample of HL and NH subjects (n = 59 = 31 HL + 28 NH), the regional CBF was correlated positively to the regional GMV (p = 0.020). In HL subjects (n = 31), the regional CBF was correlated negatively to the audiogram steepness (frequency range: 2-4 kHz, right ear: p = 0.022, left ear: p = 0.015). The observed cortical pattern of perfusion reduction suggests that neuronal metabolism can be related to HL before the recognition of brain structural damage. This also illustrates the potential of ASL-MRI to contribute early functional markers of reduced central processing associated with HL., (© 2019 Wiley Periodicals, Inc.)

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 ± 10·7 years; 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 ± 10·8 years). 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., (© 2019 British Society for Haematology and John Wiley & Sons Ltd.)

Objective: Multisystem iron poisoning is a major concern for long-term beta-thalassemia management. Quantitative MRI-based techniques routinely show iron overload in heart, liver, endocrine glands and kidneys. However, data on the brain are conflicting and monitoring of brain iron content is still matter of debate., Methods: This 3T-MRI study applied a well validated high-resolution whole-brain quantitative MRI assessment of iron content on 47 transfusion-dependent (mean-age: 36.9 ± 10.3 years, 63% females), 23 non-transfusion dependent (mean-age: 29.2 ± 11.7 years, 56% females) and 57 healthy controls (mean-age: 33.9 ± 10.8 years, 65% females). Clinical data, Wechsler Adult Intelligence Scale scores and treatment regimens were recorded. Beside whole-brain R2* analyses, regional R2*-values were extracted in putamen, globus pallidum, caudate nucleus, thalamus and red nucleus; hippocampal volumes were also determined., Results: Regional analyses yielded no significant differences between patients and controls, except in those treated with deferiprone that showed lower R2*-values (p<0.05). Whole-brain analyses of R2*-maps revealed strong age-R2* correlations (r 2 =0.51) in both groups and clusters of significantly increased R2*-values in beta-thalassemia patients in the hippocampal formations and around the Luschka foramina; transfusion treatment was associated with additional R2* increase in dorsal thalami. Hippocampal formation R2*-values did not correlate with hippocampal volume; hippocampal volume did not differ between patients and controls. All regions with increased R2*-values shared a strict anatomical contiguity with choroid plexuses suggesting a blooming effect as the likely cause of R2* increase, in agreement with the available histopathologic literature evidence., Conclusion: According to our MRI findings and the available histopathologic literature evidence, concerns about neural tissue iron overload in beta-thalassemia appear to be unjustified., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2018 Elsevier Inc. All rights reserved.)