Brain perfusion changes in beta-thalassemia.

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.

Hearing loss in beta-thalassaemia: An Italian multicentre case-control study.

BACKGROUND: Despite numerous studies, the true scenario of hearing loss in beta-thalassaemia remains rather nebulous. MATERIALS AND METHODS: Pure tone audiometry, chelation therapy, demographics and laboratory data of 376 patients (mean age 38.5 ± 16.6 years, 204 females, 66 non-transfusion-dependent) and 139 healthy controls (mean age 37.6 ± 17.7 years, 81 females) were collected. RESULTS: Patient and control groups did not differ for age (p = 0.59) or sex (p = 0.44). Hypoacusis rate was higher in patients (26.6% vs. 7.2%; p < 0.00001), correlated with male sex (32.6% in males vs. 21.8% in females; p = 0.01) and it was sensorineural in 79/100. Hypoacusis rate correlated with increasing age (p = 0.0006) but not with phenotype (13/66 non-transfusion-dependent vs. 87/310 transfusion-dependent patients; p = 0.16). Sensorineural-notch prevalence rate did not differ between patients (11.4%) and controls (12.2%); it correlated with age (p = 0.01) but not with patients' sex or phenotype. Among adult patients without chelation therapy, the sensorineural hypoacusis rate was non-significantly lower compared to chelation-treated patients while it was significantly higher compared to controls (p = 0.003). CONCLUSIONS: Sensorineural hypoacusis rate is high in beta-thalassaemia (about 21%) and it increases with age and in males while disease severity or chelation treatment seems to be less relevant. The meaning of sensorineural-notch in beta-thalassaemia appears questionable.

Functional MRI activation of the nucleus tractus solitarius after taste stimuli at ultra-high field: a proof-of-concept single-subject study.

Using ultra-high field (7 Tesla) functional MRI (fMRI), we conducted the first in-vivo functional neuroimaging study of the normal human brainstem specifically designed to examine neural signals in the Nucleus Tractus Solitarius (NTS) in response to all basic taste stimuli. NTS represents the first relay station along the mammalian taste processing pathway which originates at the taste buds in the oral cavity and passes through the thalamus before reaching the primary taste cortex in the brain. In our proof-of-concept study, we acquired data from one adult volunteer using fMRI at 1.2 mm isotropic resolution and performed a univariate general linear model analysis. During fMRI acquisition, three shuffled injections of sweet, bitter, salty, sour, and umami solutions were administered following an event-related design. We observed a statistically significant blood oxygen level-dependent (BOLD) response in the anatomically predicted location of the NTS for all five basic tastes. The results of this study appear statistically robust, even though they were obtained from a single volunteer. The information derived from a similar experimental strategy may inspire novel research aimed at clarifying important details of central nervous system involvement in eating disorders, at designing and monitoring tailored therapeutic strategies.

Frequency and imaging correlates of neuropsychiatric symptoms in Progressive Supranuclear Palsy.

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.

Association between childhood maltreatment and cortical folding in women with eating disorders.

Childhood maltreatment (CM) is associated with distinct clinical and biological characteristics in people with eating disorders (EDs). The measurement of local gyrification index (lGI) may help to better characterize the impact of CM on cortical structure. Thus, the present study investigated the association of CM with lGI in women with EDs. Twenty-six women with anorexia nervosa (AN) and 24 with bulimia nervosa (BN) underwent a 3T MRI scan. All participants filled in the Childhood Trauma Questionnaire. All neuroimaging data were processed by FreeSurfer. LGI maps underwent a general linear model to evaluate differences between groups with or without CM. People with AN and BN were merged together. Based on the Childhood Trauma Questionnaire cutoff scores, 24 participants were identified as maltreated and 26 as non-maltreated. Maltreated people with EDs showed a significantly lower lGI in the left middle temporal gyrus compared with non-maltreated people, whereas no differences emerged in the right hemisphere between groups. The present study showed that in people with EDs, CM is associated with reduced cortical folding in the left middle temporal gyrus, an area that could be involved in ED psychopathology. This finding corroborates the hypothesis of a 'maltreated ecophenotype', which argues that CM may allow to biologically, other than clinically, distinguish individuals with the same psychiatric disorder.

Childhood maltreatment is associated with cortical thinning in people with eating disorders.

Childhood maltreatment (CM) is a non-specific risk factor for eating disorders (ED) and is associated with a greater severity in their clinical presentation and poorer treatment outcome. These data suggest that maltreated people with ED may be biologically other than clinically different from non-maltreated people. The aim of the present study was to investigate cortical thickness (CT), a possible biomarker of neurodevelopment, in people with ED with or without history of CM and in healthy women. Twenty-four healthy women, 26 with anorexia nervosa and 24 with bulimia nervosa underwent a 3T MRI scan. All participants filled in the childhood trauma questionnaire. All neuroimaging data were processed by FreeSurfer. Twenty-four participants with ED were identified as maltreated and 26 participants with ED as non-maltreated. All healthy women were non-maltreated. Compared to healthy women, maltreated people with ED showed lower CT in the left rostral anterior cingulate gyrus, while compared to people with ED without history of CM showed lower CT values in the left superior frontal and in right caudal middle frontal and superior parietal gyri. No significant differences emerged in CT measures between healthy women and people with ED without history of CM. The present findings show for the first time that in adult people with ED childhood maltreatment is associated with cortical thinning in areas implicated in the modulation of brain processes that are acknowledged to play a role in the psychopathology of ED.

Emergent carotid stenting versus no stenting for acute ischemic stroke due to tandem occlusion: a meta-analysis.

BACKGROUND: Emergent carotid artery stenting (eCAS) is performed during mechanical thrombectomy for acute ischemic stroke due to tandem occlusion. However, the optimal management strategy in this setting is still unclear. OBJECTIVE: To carry out a systematic review and meta-analysis to investigate the safety and efficacy of eCAS in patients with tandem occlusion. METHODS: Systematic review followed the PRISMA guidelines. Medline, EMBASE, and Scopus were searched from January 1, 2004 to March 7, 2022 for studies evaluating eCAS and no-stenting approach in patients with stroke with tandem occlusion. Primary endpoint was the 90-day modified Rankin Scale score 0-2; secondary outcomes were (1) symptomatic intracerebral hemorrhage (sICH), (2) recurrent stroke, (3) successful recanalization (Thrombolysis in Cerebral Infarction score 2b-3), (4) embolization in new territories, and (5) restenosis rate. Meta-analysis was performed using the Mantel-Haenszel method and random-effects modeling. RESULTS: Forty-six studies reached synthesis. eCAS was associated with higher good functional outcome compared with the no-stenting approach (OR=1.52, 95% CI 1.19 to 1.95), despite a significantly increased risk of sICH (OR=1.97, 95% CI 1.23 to 3.15), and higher successful recanalization rate (OR=1.91, 95% CI 1.29 to 2.85). Restenosis rate was lower in the eCAS group than in the no-stenting group (2% vs 9%, p=0.001). Recanalization rate was higher in retrograde than antegrade eCAS (OR=0.51, 95% CI 0.28 to 0.93). Intraprocedural antiplatelets during eCAS were associated with higher rate of good functional outcome (60% vs 46%, p=0.016) and lower rate of sICH (7% vs 11%; p=0.08) compared with glycoprotein IIb/IIIa inhibitors. CONCLUSIONS: In observational studies, eCAS seems to be associated with higher good functional outcome than no-stenting in patients with acute ischemic stroke due to tandem occlusion, despite the higher risk of sICH. Dedicated trials are needed to confirm these results.

Magnetic Resonance T1w/T2w Ratio in the Putamen and Cerebellum as a Marker of Cognitive Impairment in MSA: a Longitudinal Study.

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 (T0) and 1-year follow-up (T1). Patients were then divided according to cognitive status into MSA with normal cognition (MSA-NC) and MSA with mild cognitive impairment (MCI). At T1, we divided the sample according to worsening/non worsening of cognitive status compared to baseline evaluation. Logistic regression analysis showed that age (ß = - 9.45, p = .02) and T1w/T2w value in the left putamen (ß = 230.64, p = .01) were significant predictors of global cognitive status at T0, explaining 65% of the variance. Logistic regression analysis showed that ∆-values of WM density in the cerebellum/brainstem (ß = 2188.70, p = .02) significantly predicted cognitive worsening at T1, 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.

Combined regional T1w/T2w ratio and voxel-based morphometry in multiple system atrophy: A follow-up study.

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.

Explaining neural activity in human listeners with deep learning via natural language processing of narrative text.

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.

Negative correlation between word-level surprisal and intersubject neural synchronization during narrative listening.

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.

Sex differences in the taste-evoked functional connectivity network.

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.

Semantic fMRI neurofeedback: a multi-subject study at 3 tesla.

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.

Uncovering clinical and radiological asymmetry in progressive supranuclear palsy-Richardson's syndrome.

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.

Thea: empowering the therapeutic alliance of children with ASD by multimedia interaction.

The Therapeutic Alliance (TA) between patient and health provider (therapist or clinician) is one of the most relevant factors for the success of a therapy. In the case of people suffering from Autism Spectrum Disorder (ASD), the alliance is extended to all the people involved in their care (i.e., teachers, therapists, clinicians, relatives). In this paper, we propose a multimedia application named Thea for empowering the TA of children with ASD by improving the communication among the TA members, sharing guidelines, multimedia contents, and strategies to comply with challenging behaviors and progress with particular attention towards end-users who are occasional smart-users. A detailed process for empowering the TA members by enhancing the informed interaction among all of them is proposed and implemented. A vocal assistant also supports patients/caregivers and therapists in documenting their activity with the person with ASD by recording videos in a free-hand modality. After a contextual analysis based on Thematic Analysis Template, Thea has been implemented using a user-centered development approach. We performed three iterations involving the end-users. A user study is performed at the third iteration. Results of the user study revealed a positive attitude towards the application. In particular, the perception of empowerment of participants increased after the tool had been used. We also highlighted the guidelines and tools that may be adopted for empowering different kinds of patients. The first results seem to suggest that the use of Thea may increase the belief of the caregivers of a person with ASD to be able to better take care of her, in a more controlled and informed way.

Auditory cortex hypoperfusion: a metabolic hallmark in Beta Thalassemia.

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.

Hepatic Presentation of Late-Onset Multiple Acyl-CoA Dehydrogenase Deficiency (MADD): Case Report and Systematic Review.

Diagnosis of pediatric steatohepatitis is a challenging issue due to a vast number of established and novel causes. Here, we report a child with Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) presenting with an underrated muscle weakness, exercise intolerance and an atypically severe steatotic liver involvement. A systematic literature review of liver involvement in MADD was performed as well. Our patient is a 11-year-old otherwise healthy, non-obese, male child admitted for some weakness/asthenia, vomiting and recurrent severe hypertransaminasemia (aspartate and alanine aminotransferases up to ×20 times upper limit of normal). Hepatic ultrasound showed a bright liver. MRI detected mild lipid storage of thighs muscles. A liver biopsy showed a micro-macrovacuolar steatohepatitis with minimal fibrosis. Main causes of hypertransaminasemia were ruled out. Serum aminoacids (increased proline), acylcarnitines (increased C4-C18) and a large excretion of urinary glutaric acid, ethylmalonic, butyric, isobutyric, 2-methyl-butyric and isovaleric acids suggested a diagnosis of MADD. Serum acylcarnitines and urinary organic acids fluctuated overtime paralleling serum transaminases during periods of illness/catabolic stress, confirming their recurrent nature. Genetic testing confirmed the diagnosis [homozygous c.1658A > G (p.Tyr553Cys) in exon 12 of the ETFDH gene]. Lipid-restricted diet and riboflavin treatment rapidly ameliorated symptoms, hepatic ultrasonography/enzymes, and metabolic profiles. Literature review (37 retrieved eligible studies, 283 patients) showed that liver is an extramuscular organ rarely involved in late-onset MADD (70 patients), and that amongst 45 patients who had fatty liver only nine had severe presentation. Conclusion: MADD is a disorder with a clinically heterogeneous phenotype. Our study suggests that MADD warrants consideration in the work-up of obesity-unrelated severe steatohepatitis.

Vitamin C Acutely Affects Brain Perfusion and Mastication-Induced Perfusion Asymmetry in the Principal Trigeminal Nucleus.

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.

Towards semantic fMRI neurofeedback: navigating among mental states using real-time representational similarity analysis.

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.

Long-Range Auditory Functional Connectivity in Hearing Loss and Rehabilitation.

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.