Locus coeruleus features are linked to vagus nerve stimulation response in drug-resistant epilepsy.

The locus coeruleus-norepinephrine system is thought to be involved in the clinical effects of vagus nerve stimulation. This system is known to prevent seizure development and induce long-term plastic changes, particularly with the release of norepinephrine in the hippocampus. However, the requisites to become responder to the therapy and the mechanisms of action are still under investigation. Using MRI, we assessed the structural and functional characteristics of the locus coeruleus and microstructural properties of locus coeruleus-hippocampus white matter tracts in patients with drug-resistant epilepsy responding or not to the therapy. Twenty-three drug-resistant epileptic patients with cervical vagus nerve stimulation were recruited for this pilot study, including 13 responders or partial responders and 10 non-responders. A dedicated structural MRI acquisition allowed in vivo localization of the locus coeruleus and computation of its contrast (an accepted marker of LC integrity). Locus coeruleus activity was estimated using functional MRI during an auditory oddball task. Finally, multi-shell diffusion MRI was used to estimate the structural properties of locus coeruleus-hippocampus tracts. These characteristics were compared between responders/partial responders and non-responders and their association with therapy duration was also explored. In patients with a better response to the therapy, trends toward a lower activity and a higher contrast were found in the left medial and right caudal portions of the locus coeruleus, respectively. An increased locus coeruleus contrast, bilaterally over its medial portions, correlated with duration of the treatment. Finally, a higher integrity of locus coeruleus-hippocampus connections was found in patients with a better response to the treatment. These new insights into the neurobiology of vagus nerve stimulation may provide novel markers of the response to the treatment and may reflect neuroplasticity effects occurring in the brain following the implantation.

Dexterity in the Acute Phase of Stroke: Impairments and Neural Substrates.

BACKGROUND: Stroke can impair manual dexterity, leading to loss of independence following incomplete recovery. Enhancing our understanding of dexterity impairment may improve neurorehabilitation. OBJECTIVES: The study aimed to measure dexterity components in acute stroke patients with and without hand motor deficits, compare them to those of healthy controls (HC), and to explore the neural substrates involved in specific components of dexterity. METHODS: We used the Dextrain Manipulandum to quantify fine finger force control, finger selection accuracy, coactivation, and reaction time (RT). Dexterity was evaluated twice (2 days apart) in 74 patients and 14 HC. Voxel-Lesion-Symptom-Mapping (VLSM) was used to analyze the relationship between tissue damage and dexterity. Results. Due to severe paresis or fatigue, 24 patients could not perform these tasks. In 50 patients (included 4.6 ± 3.3 days post-stroke), finger force control improved (P < .001), as it did in HC (P = .03) who performed better than patients on both evaluations. Accuracy of finger selection did not improve significantly in any group, but the HC performed better on both evaluations. Unexpectedly, coactivation was better in patients than in HC at D3 (P = .03). There were no between-group differences in RT. VLSM showed that damage to the superior temporal gyrus (STG) impaired finger force control while damage to the posterior limb of the internal capsule (PLIC) impaired finger selectivity. CONCLUSIONS: Acute stroke affecting the STG or PLIC impaired selective components of dexterity. Patients with mild to moderate impairment showed better finger force control and accuracy selection within 48 hours, suggesting the feasibility of detecting early dexterity improvements.

Corrigendum: Brain morphological modifications in congenital and acquired auditory deprivation: a systematic review and coordinate-based meta-analysis.

[This corrects the article DOI: 10.3389/fnins.2022.850245.].

Baby HABIT-ILE intervention: study protocol of a randomised controlled trial in infants aged 6-18 months with unilateral cerebral palsy.

INTRODUCTION: Research using animal models suggests that intensive motor skill training in infants under 2 years old with cerebral palsy (CP) may significantly reduce, or even prevent, maladaptive neuroplastic changes following brain injury. However, the effects of such interventions to tentatively prevent secondary neurological damages have never been assessed in infants with CP. This study aims to determine the effect of the baby Hand and Arm Bimanual Intensive Therapy Including Lower Extremities (baby HABIT-ILE) in infants with unilateral CP, compared with a control intervention. METHODS AND ANALYSIS: This randomised controlled trial will include 48 infants with unilateral CP aged (corrected if preterm) 6-18 months at the first assessment. They will be paired by age and by aetiology of the CP, and randomised into two groups (immediate and delayed). Assessments will be performed at baseline and at 1 month, 3 months and 6 months after baseline. The immediate group will receive 50 hours of baby HABIT-ILE intervention over 2 weeks, between first and second assessment, while the delayed group will continue their usual activities. This last group will receive baby HABIT-ILE intervention after the 3-month assessment. Primary outcome will be the Mini-Assisting Hand Assessment. Secondary outcomes will include behavioural assessments for gross and fine motricity, visual-cognitive-language abilities as well as MRI and kinematics measures. Moreover, parents will determine and score child-relevant goals and fill out questionnaires of participation, daily activities and mobility. ETHICS AND DISSEMINATION: Full ethical approval has been obtained by the Comité d'éthique Hospitalo-Facultaire/Université catholique de Louvain, Brussels (2013/01MAR/069 B403201316810g). The recommendations of the ethical board and the Belgian law of 7 May 2004 concerning human experiments will be followed. Parents will sign a written informed consent ahead of participation. Findings will be published in peer-reviewed journals and conference presentations. TRIAL REGISTRATION NUMBER: NCT04698395. Registered on the International Clinical Trials Registry Platform (ICTRP) on 2 December 2020 and NIH Clinical Trials Registry on 6 January 2021. URL of trial registry record: https://clinicaltrials.gov/ct2/show/NCT04698395?term=bleyenheuft&draw=1&rank=7.

The spatial extent of tauopathy on [18F]MK-6240 tau PET shows stronger association with cognitive performances than the standard uptake value ratio in Alzheimer's disease.

PURPOSE: [18F]MK-6240, a second-generation tau PET tracer, is increasingly used for the detection and the quantification of in vivo cerebral tauopathy in Alzheimer's disease (AD). Given that neurological symptoms are better explained by the topography rather than by the nature of brain lesions, our study aimed to evaluate whether cognitive impairment would be more closely associated with the spatial extent than with the intensity of tau-PET signal, as measured by the standard uptake value ratio (SUVr). METHODS: [18F]MK6240 tau-PET data from 82 participants in the AD spectrum were quantified in three different brain regions (Braak ≤ 2, Braak ≤ 4, and Braak ≤ 6) using SUVr and the extent of tauopathy (EOT, percentage of voxels with SUVr ≥ 1.3). PET data were first compared between diagnostic categories, and ROC curves were computed to evaluate sensitivity and specificity. PET data were then correlated to cognitive performances and cerebrospinal fluid (CSF) tau values. RESULTS: The EOT in the Braak ≤ 2 region provided the highest diagnostic accuracies, distinguishing between amyloid-negative and positive clinically unimpaired individuals (threshold = 9%, sensitivity = 79%, specificity = 82%) as well as between prodromal AD and preclinical AD (threshold = 38%, sensitivity = 81%, specificity = 93%). The EOT better correlated with cognition than SUVr (∆R2 + 0.08-0.09) with the best correlation observed for EOT in the Braak ≤ 4 region (R2 = 0.64). Cognitive performances were more closely associated with PET metrics than with CSF values. CONCLUSIONS: Quantifying [18F]MK-6240 tau PET in terms of EOT rather than SUVr significantly increases the correlation with cognitive performances. Quantification in the mesiotemporal lobe is the most useful to diagnose preclinical AD or prodromal AD.

Suspecting Non-Alzheimer's Pathologies and Mixed Pathologies: A Comparative Study Between Brain Metabolism and Tau Images.

BACKGROUND: Alzheimer's disease (AD) pathology can be disclosed in vivo using amyloid and tau imaging, unlike non-AD neuropathologies for which no specific markers exist. OBJECTIVE: We aimed to compare brain hypometabolism and tauopathy to unveil non-AD pathologies. METHODS: Sixty-one patients presenting cognitive complaints (age 48-90), including 32 with positive AD biomarkers (52%), performed [18F]-Fluorodeoxyglucose (FDG)-PET (brain metabolism) and [18F]-MK-6240-PET (tau). We normalized these images using data from clinically normal individuals (n = 30), resulting in comparable FDG and tau z-scores. We computed between-patients correlations to evaluate regional associations. For each patient, a predominant biomarker (i.e., Hypometabolism > Tauopathy or Hypometabolism≤Tauopathy) was determined in the temporal and frontoparietal lobes. We computed within-patient correlations between tau and metabolism and investigated their associations with demographics, cognition, cardiovascular risk factors (CVRF), CSF biomarkers, and white matter hypointensities (WMH). RESULTS: We observed negative associations between tau and FDG in 37 of the 68 cortical regions-of-interest (average Pearson's r = -0.25), mainly in the temporal lobe. Thirteen patients (21%) had Hypometabolism > Tauopathy whereas twenty-five patients (41%) had Hypometabolism≤Tauopathy. Tau-predominant patients were more frequently females and had greater amyloid burden. Twenty-three patients (38%) had Hypometabolism≤Tauopathy in the temporal lobe, but Hypometabolism > Tauopathy in the frontoparietal lobe. This group was older and had higher CVRF than Tau-predominant patients. Patients with more negative associations between tau and metabolism were younger, had worse cognition, and greater amyloid and WMH burdens. CONCLUSIONS: Tau-FDG comparison can help suspect non-AD pathologies in patients presenting cognitive complaints. Stronger Tau-FDG correlations are associated with younger age, worse cognition, and greater amyloid and WMH burdens.

Connecting the dots: harnessing dual-site transcranial magnetic stimulation to quantify the causal influence of medial frontal areas on the motor cortex.

Dual-site transcranial magnetic stimulation has been widely employed to investigate the influence of cortical structures on the primary motor cortex. Here, we leveraged this technique to probe the causal influence of two key areas of the medial frontal cortex, namely the supplementary motor area and the medial orbitofrontal cortex, on primary motor cortex. We show that supplementary motor area stimulation facilitates primary motor cortex activity across short (6 and 8 ms) and long (12 ms) inter-stimulation intervals, putatively recruiting cortico-cortical and cortico-subcortico-cortical circuits, respectively. Crucially, magnetic resonance imaging revealed that this facilitatory effect depended on a key morphometric feature of supplementary motor area: individuals with larger supplementary motor area volumes exhibited more facilitation from supplementary motor area to primary motor cortex for both short and long inter-stimulation intervals. Notably, we also provide evidence that the facilitatory effect of supplementary motor area stimulation at short intervals is unlikely to arise from spinal interactions of volleys descending simultaneously from supplementary motor area and primary motor cortex. On the other hand, medial orbitofrontal cortex stimulation moderately suppressed primary motor cortex activity at both short and long intervals, irrespective of medial orbitofrontal cortex volume. These results suggest that dual-site transcranial magnetic stimulation is a fruitful approach to investigate the differential influence of supplementary motor area and medial orbitofrontal cortex on primary motor cortex activity, paving the way for the multimodal assessment of these fronto-motor circuits in health and disease.

Structural and functional characterization of the locus coeruleus in young and late middle-aged individuals.

Introduction: The brainstem locus coeruleus (LC) influences a broad range of brain processes, including cognition. The so-called LC contrast is an accepted marker of the integrity of the LC that consists of a local hyperintensity on specific Magnetic Resonance Imaging (MRI) structural images. The small size of the LC has, however, rendered its functional characterization difficult in humans, including in aging. A full characterization of the structural and functional characteristics of the LC in healthy young and late middle-aged individuals is needed to determine the potential roles of the LC in different medical conditions. Here, we wanted to determine whether the activation of the LC in a mismatch negativity task changes in aging and whether the LC functional response was associated to the LC contrast. Methods: We used Ultra-High Field (UHF) 7-Tesla functional MRI (fMRI) to record brain response during an auditory oddball task in 53 healthy volunteers, including 34 younger (age: 22.15y ± 3.27; 29 women) and 19 late middle-aged (age: 61.05y ± 5.3; 14 women) individuals. Results: Whole-brain analyses confirmed brain responses in the typical cortical and subcortical regions previously associated with mismatch negativity. When focusing on the brainstem, we found a significant response in the rostral part of the LC probability mask generated based on individual LC images. Although bilateral, the activation was more extensive in the left LC. Individual LC activity was not significantly different between young and late middle-aged individuals. Importantly, while the LC contrast was higher in older individuals, the functional response of the LC was not significantly associated with its contrast. Discussion: These findings may suggest that the age-related alterations of the LC structural integrity may not be related to changes in its functional response. The results further suggest that LC responses may remain stable in healthy individuals aged 20 to 70.

Unraveling multi-fixel microstructure with tractography and angular weighting.

Recent advances in MRI technology have enabled richer multi-shell sequences to be implemented in diffusion MRI, allowing the investigation of both the microscopic and macroscopic organization of the brain white matter and its complex network of neural fibers. The emergence of advanced diffusion models has enabled a more detailed analysis of brain microstructure by estimating the signal received from a voxel as the combination of responses from multiple fiber populations. However, disentangling the individual microstructural properties of different macroscopic white matter tracts where those pathways intersect remains a challenge. Several approaches have been developed to assign microstructural properties to macroscopic streamlines, but often present shortcomings. ROI-based heuristics rely on averages that are not tract-specific. Global methods solve a computationally-intensive global optimization but prevent the use of microstructural properties not included in the model and often require restrictive hypotheses. Other methods use atlases that might not be adequate in population studies where the shape of white matter tracts varies significantly between patients. We introduce UNRAVEL, a framework combining the microscopic and macroscopic scales to unravel multi-fixel microstructure by utilizing tractography. The framework includes commonly-used heuristics as well as a new algorithm, estimating the microstructure of a specific white matter tract with angular weighting. Our framework grants considerable freedom as the inputs required, a set of streamlines defining a tract and a multi-fixel diffusion model estimated in each voxel, can be defined by the user. We validate our approach on synthetic data and in vivo data, including a repeated scan of a subject and a population study of children with dyslexia. In each case, we compare the estimation of microstructural properties obtained with angular weighting to other commonly-used approaches. Our framework provides estimations of the microstructure at the streamline level, volumetric maps for visualization and mean microstructural values for the whole tract. The angular weighting algorithm shows increased accuracy, robustness to uncertainties in its inputs and maintains similar or better reproducibility compared to commonly-used analysis approaches. UNRAVEL will provide researchers with a flexible and open-source tool enabling them to study the microstructure of specific white matter pathways with their diffusion model of choice.

Links between psychopathological symptoms and cortical thickness in men with severe alcohol use disorder: A Magnetic Resonance Imaging study.

BACKGROUND: Anxiety and depression are psychopathological states frequently co-occurring with severe alcohol use disorder (SAUD). These symptoms generally disappear with abstinence but may persist in some patients, increasing the relapse risk. METHODS: The cerebral cortex thickness of 94 male patients with SAUD was correlated with symptoms of depression and anxiety, both measured at the end (2-3 weeks) of the detoxification treatment. Cortical measures were obtained using surface-based morphometry implemented with Freesurfer. RESULTS: Depressive symptoms were associated with reduced cortical thickness in the superior temporal gyrus of the right hemisphere. Anxiety level was correlated with lower cortical thickness in the rostral middle frontal region, inferior temporal region, and supramarginal, postcentral, superior temporal, and transverse temporal regions of the left hemisphere, as well as with a large cluster in the middle temporal region of the right hemisphere. CONCLUSIONS: At the end of the detoxification stage, the intensity of depressive and anxiety symptoms is inversely associated with the cortical thickness of regions involved in emotions-related processes, and the persistence of the symptoms could be explained by these brain deficits.

Brain structural changes in blindness: a systematic review and an anatomical likelihood estimation (ALE) meta-analysis.

In recent decades, numerous structural brain imaging studies investigated purported morphometric changes in early (EB) and late onset blindness (LB). The results of these studies have not yielded very consistent results, neither with respect to the type, nor to the anatomical locations of the brain morphometric alterations. To better characterize the effects of blindness on brain morphometry, we performed a systematic review and an Anatomical-Likelihood-Estimation (ALE) coordinate-based-meta-analysis of 65 eligible studies on brain structural changes in EB and LB, including 890 EB, 466 LB and 1257 sighted controls. Results revealed atrophic changes throughout the whole extent of the retino-geniculo-striate system in both EB and LB, whereas changes in areas beyond the occipital lobe occurred in EB only. We discuss the nature of some of the contradictory findings with respect to the used brain imaging methodologies and characteristics of the blind populations such as the onset, duration and cause of blindness. Future studies should aim for much larger sample sizes, eventually by merging data from different brain imaging centers using the same imaging sequences, opt for multimodal structural brain imaging, and go beyond a purely structural approach by combining functional with structural connectivity network analyses.

Hand-Arm Bimanual Intensive Therapy Including Lower Extremities (HABIT-ILE) in adults with chronic stroke: protocol of a randomised controlled trial.

INTRODUCTION: Stroke causes multiple deficits including motor, sensitive and cognitive impairments, affecting also individual's social participation and independence in activities of daily living (ADL) impacting their quality of life. It has been widely recommended to use goal-oriented interventions with a high amount of task-specific repetitions. These interventions are generally focused only on the upper or lower extremities separately, despite the impairments are observed at the whole-body level and ADL are both frequently bimanual and may require moving around. This highlights the need for interventions targeting both upper and lower extremities. This protocol presents the first adaptation of Hand-Arm Bimanual Intensive Therapy Including Lower Extremities (HABIT-ILE) for adults with acquired hemiparesis. METHODS AND ANALYSIS: This randomised controlled trial will include 48 adults with chronic stroke, aged ≥40 years. This study will compare the effect of 50 hours of HABIT-ILE against usual motor activity and regular rehabilitation. HABIT-ILE will be provided in a 2-week, adult's day-camp setting, promoting functional tasks and structured activities. These tasks will continuously progress by increasing their difficulty. Assessed at baseline, 3 weeks after and at 3 months, the primary outcome will be the adults-assisting-hand-assessment stroke; secondary outcomes include behavioural assessments for hand strength and dexterity, a motor learning robotic medical device for quality of bimanual motor control, walking endurance, questionnaires of ADL, stroke impact on participation and self-determined patient-relevant goals, besides neuroimaging measures. ETHICS AND DISSEMINATION: This study has full ethical approval from the Comité d'éthique Hospitalo-Facultaire/Université catholique de Louvain, Brussels (reference number: 2013/01MAR/069) and the local medical Ethical Committee of the CHU UCL Namur-site Godinne. Recommendations of the ethical board and the Belgian law of 7 May 2004, concerning human experiments will be followed. Participants will sign a written informed consent ahead of participation. Findings will be published in peer-reviewed journals and conference presentations. TRIAL REGISTRATION NUMBER: NCT04664673.

Default-Mode Network Connectivity Changes During the Progression Toward Alzheimer's Dementia: A Longitudinal Functional Magnetic Resonance Imaging Study.

Background/Purpose: Brain function changes with Alzheimer's disease (AD) progression. Evaluating those changes longitudinally is important to understand the complex relationships between brain pathologies and cognition. We aimed (1) to identify longitudinal changes in functional connectivity in patients with mild cognitive impairment (MCI) characterized for amyloid-ß (Aß) status and (2) to relate these functional changes to clinical progression. Methods: Forty-four patients with MCI were followed using serial functional magnetic resonance imaging (fMRI) over 1.2 years (three sessions) and cognitive testing over 3.1 years (five sessions). Intra and inter-network connectivities were computed to assess changes in brain connectivity using a network atlas adapted for late adulthood. Sixteen low-Aß clinically normal older adults underwent a single fMRI session for group comparisons at baseline. Linear mixed-effects models with random intercept and slope were used to predict changes in connectivity based on Aß status and progression to dementia. Results: At baseline, intra and inter-network resting-state fMRI connectivities did not differ by baseline clinical diagnosis, Aß status, or clinical progression to dementia. At the final imaging session, progressive MCI had significantly higher connectivity compared with stable MCI, specifically within the default-mode network (DMN). Longitudinally, progressive MCI had increasing intra-DMN connectivity over time compared with stable MCI, and the rate of changes in connectivity was significantly associated with the rate of cognitive decline. Conclusions: Intra-DMN connectivity increases in MCI patients progressing toward dementia, suggesting aberrant synchronization in the symptomatic stages of AD. Impact statement Changes in functional connectivity occur in the course of Alzheimer's disease. We observed a progressive increase over time in resting-state functional connectivity within the default-mode network in patients with mild cognitive impairment who progressed to dementia. The rate of connectivity increase was significantly associated with the rate of cognitive decline. The observation of increased functional connectivity during the progression to dementia, and not only in the pre-clinical stage, is interpreted as an aberrant synchronization rather than a compensation mechanism.

BMAT: An open-source BIDS managing and analysis tool.

Magnetic Resonance Imaging (MRI) is an established technique to study in vivo neurological disorders such as Multiple Sclerosis (MS). To avoid errors on MRI data organization and automated processing, a standard called Brain Imaging Data Structure (BIDS) has been recently proposed. The BIDS standard eases data sharing and processing within or between centers by providing guidelines for their description and organization. However, the transformation from the complex unstructured non-open file data formats coming directly from the MRI scanner to a correct BIDS structure can be cumbersome and time consuming. This hinders a wider adoption of the BIDS format across different study centers. To solve this problem and ease the day-to-day use of BIDS for the neuroimaging scientific community, we present the BIDS Managing and Analysis Tool (BMAT). The BMAT software is a complete and easy-to-use local open-source neuroimaging analysis tool with a graphical user interface (GUI) that uses the BIDS format to organize and process brain MRI data for MS imaging research studies. BMAT provides the possibility to translate data from MRI scanners to the BIDS structure, create and manage BIDS datasets as well as develop and run automated processing pipelines, and is faster than its competitor. BMAT software propose the possibility to download useful analysis apps, especially applied to MS research with lesion segmentation and processing of imaging contrasts for novel disease biomarkers such as the central vein sign and the paramagnetic rim lesions.

Brain adaptation following various unilateral vocal fold paralysis treatments: A magnetic resonance imaging based longitudinal case series.

Aim: Examination of central compensatory mechanisms following peripheral vocal nerve injury and recovery is essential to build knowledge about plasticity of the neural network underlying phonation. The objective of this prospective multiple-cases longitudinal study is to describe brain activity in response to unilateral vocal fold paralysis (UVFP) management and to follow central nervous system adaptation over time in three patients with different nervous and vocal recovery profiles. Materials and methods: Participants were enrolled within 3 months of the onset of UVFP. Within 1 year of the injury, the first patient did not recover voice or vocal fold mobility despite voice therapy, the second patient recovered voice and mobility in absence of treatment and the third patient recovered voice and vocal fold mobility following an injection augmentation with hyaluronic acid in the paralyzed vocal fold. These different evolutions allowed comparison of individual outcomes according to nervous and vocal recovery. All three patients underwent functional magnetic resonance imaging (fMRI task and resting-state) scans at three (patient 1) or four (patients 2 and 3) time points. The fMRI task included three conditions: a condition of phonation and audition of the sustained [a:] vowel for 3 s, an audition condition of this vowel and a resting condition. Acoustic and aerodynamic measures as well as laryngostroboscopic images and laryngeal electromyographic data were collected. Results and conclusion: This study highlighted for the first time two key findings. First, hyperactivation during the fMRI phonation task was observed at the first time point following the onset of UVFP and this hyperactivation was related to an increase in resting-state connectivity between previoulsy described phonatory regions of interest. Second, for the patient who received an augmentation injection in the paralyzed vocal fold, we subsequently observed a bilateral activation of the voice-related nuclei in the brainstem. This new observation, along with the fact that for this patient the resting-state connectivity between the voice motor/sensory brainstem nuclei and other brain regions of interest correlated with an aerodynamic measure of voice, support the idea that there is a need to investigate whether the neural recovery process can be enhanced by promoting the restoration of proprioceptive feedback.

Brain Morphological Modifications in Congenital and Acquired Auditory Deprivation: A Systematic Review and Coordinate-Based Meta-Analysis.

Neuroplasticity following deafness has been widely demonstrated in both humans and animals, but the anatomical substrate of these changes is not yet clear in human brain. However, it is of high importance since hearing loss is a growing problem due to aging population. Moreover, knowing these brain changes could help to understand some disappointing results with cochlear implant, and therefore could improve hearing rehabilitation. A systematic review and a coordinate-based meta-analysis were realized about the morphological brain changes highlighted by MRI in severe to profound hearing loss, congenital and acquired before or after language onset. 25 papers were included in our review, concerning more than 400 deaf subjects, most of them presenting prelingual deafness. The most consistent finding is a volumetric decrease in gray matter around bilateral auditory cortex. This change was confirmed by the coordinate-based meta-analysis which shows three converging clusters in this region. The visual areas of deaf children is also significantly impacted, with a decrease of the volume of both gray and white matters. Finally, deafness is responsible of a gray matter increase within the cerebellum, especially at the right side. These results are largely discussed and compared with those from deaf animal models and blind humans, which demonstrate for example a much more consistent gray matter decrease along their respective primary sensory pathway. In human deafness, a lot of other factors than deafness could interact on the brain plasticity. One of the most important is the use of sign language and its age of acquisition, which induce among others changes within the hand motor region and the visual cortex. But other confounding factors exist which have been too little considered in the current literature, such as the etiology of the hearing impairment, the speech-reading ability, the hearing aid use, the frequent associated vestibular dysfunction or neurocognitive impairment. Another important weakness highlighted by this review concern the lack of papers about postlingual deafness, whereas it represents most of the deaf population. Further studies are needed to better understand these issues, and finally try to improve deafness rehabilitation.

Neural Correlates of Healthy Sustained Vowel Phonation Tasks: A Systematic Review and Meta-Analysis of Neuroimaging Studies.

OBJECTIVE: This review of the methodology and results of studies involving a sustained vowel phonation task during functional Magnetic Resonance Imaging (fMRI) aims to contribute to the identification of brain regions involved in phonation for healthy subjects. DATA SOURCES: This review was performed using the PubMed electronic database. REVIEW METHODS: A review was conducted, according to PRISMA guidelines, between September and November 2020, using the following search term pairs: "fMRI and Phonation" and "fMRI and Voice." Activation likelihood estimation analysis was performed. A qualitative analysis was also performed to specify the frequency of activation of each region, as well as the various activation clusters within a single region. RESULTS: Seven studies were included and analyzed. Five of the seven studies were selected for the activation likelihood estimation meta-analysis which revealed significant convergent activation for only one cluster located in the left precentral gyrus (BA4). A qualitative review provides an overview of brain activation. Primary motor and premotor areas were the only activated areas in all studies included. Other regions previously considered to be implicated in phonation were often activated in sustained vowel phonation tasks. Additionally, areas generally associated with articulation or language also showed activation. CONCLUSION: Methodological recommendations are suggested to isolate the phonatory component and reduce variability between future studies. Based on the qualitative analysis, this review does not support a distinction between regions more related to phonation and regions more related to articulation. Further research is required seeking to isolate the vocal component and to improve insight into human brain network involved in phonation.

Evidence of Motor Skill Learning in Acute Stroke Patients Without Lesions to the Thalamus and Internal Capsule.

BACKGROUND: It is currently unknown whether motor skill learning (MSkL) with the paretic upper limb is possible during the acute phase after stroke and whether lesion localization impacts MSkL. Here, we investigated MSkL in acute (1-7 days post) stroke patients compared with healthy individuals (HIs) and in relation to voxel-based lesion symptom mapping. METHODS: Twenty patients with acute stroke and 35 HIs were trained over 3 consecutive days on a neurorehabilitation robot measuring speed, accuracy, and movement smoothness variables. Patients used their paretic upper limb and HI used their nondominant upper limb on an MSkL task involving a speed/accuracy trade-off. Generalization was evaluated on day 3. All patients underwent a 3-dimensional magnetic resonance imaging used for VSLM. RESULTS: Most patients achieved MSkL demonstrated by day-to-day retention and generalization of the newly learned skill on day 3. When comparing raw speed/accuracy trade-off values, HI achieved larger MSkL than patients. However, relative speed/accuracy trade-off values showed no significant differences in MSkL between patients and HI on day 3. In patients, MSkL progression correlated with acute motor and cognitive impairments. The voxel-based lesion symptom mapping showed that acute vascular damage to the thalamus or the posterior limb of the internal capsule reduced MSkL. CONCLUSIONS: Despite worse motor performance for acute stroke patients compared with HI, most patients were able to achieve MSkL with their paretic upper limb. Damage to the thalamus and posterior limb of the internal capsule, however, reduced MSkL. These data show that MSkL could be implemented into neurorehabilitation during the acute phase of stroke, particularly for patients without lesions to the thalamus and posterior limb of the internal capsule. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01519843.

Evidence of Altered Functional Connectivity at Rest in the Writing Network of Children with Dyslexia.

AIM: Handwriting abilities in children with dyslexia (DYS) are not well documented in the current literature, and the presence of graphomotor impairment in addition to spelling impairment in dyslexia is controversial. Using resting-state functional connectivity (RSFC), the present study aims to answer the following question: are there markers of graphomotor impairment at rest in DYS children? METHOD: The participants were children with DYS and typically developing (TD) children (n = 32) from French-speaking primary schools (Mage = 9.3 years). The behavioural evaluation consisted of spelling and handwriting measures. Participants underwent a resting-state fMRI scan. RESULTS: Analyses of RSFC focused on a brain region responsible for graphomotor processes-the graphemic/motor frontal area (GMFA). The RSFC between the GMFA and all other voxels of the brain was measured. Whole-brain ANOVAs were run to compare RSFC in DYS and TD children. The results demonstrated reduced RSFC in DYS compared to TD between the GMFA and brain areas involved in both spelling processes and motor-related processes. CONCLUSIONS: For the first time, this study highlighted a disruption of the writing network in DYS. By identifying functional markers of both spelling and handwriting deficits at rest in young DYS participants, this study supports the presence of graphomotor impairment in dyslexia.

Evidence of graphomotor dysfunction in children with dyslexia: A combined behavioural and fMRI experiment.

AIM: Children with dyslexia (DYS) have a deficit in spelling (i.e., central processes of writing), and past experiments have suggested that they also frequently experience difficulties in handwriting (i.e., motor peripheral processes of writing) compared with typically developing children (TD). However, the presence of handwriting difficulties in dyslexia is controversial. This experiment aimed to better understand the writing difficulties in DYS children, investigating both the central and peripheral processes of writing and combining cognitive and neuroimaging data. METHOD: Participants were 14 DYS and 14 TD (Mage = 9.5) children. They were assessed on behavioural measures (i.e., spelling, handwriting and manual dexterity). Structural and functional magnetic resonance imaging (MRI) data were collected. The fMRI task was a word-dictation task performed using pencil and paper and a head coil mirror providing visual feedback. RESULTS: Behavioural results revealed a clear spelling deficit and poorer handwriting in DYS than in TD. DYS and TD performed equally in handwriting speed and gross manual dexterity. fMRI data were analysed with an ROI approach using nine central ROIs and 10 peripheral ROIs, which constitute the writing network identified in past literature. fMRI results revealed less brain activation in both central and peripheral ROIs in DYS. The main peripheral differences were located in right lobule VI of the cerebellum. Structural data strengthened the presence of bilateral cerebellar abnormalities in dyslexia. CONCLUSION: The present findings constitute a first piece of evidence that children with dyslexia's writing difficulties are not limited to the central processes of writing (i.e., spelling) and that they extend to the peripheral processes of writing (i.e., handwriting). This experiment is the first study to use an fMRI handwriting task to investigate DYS's writing abilities. These results encourage researchers to continue investigating DYS's spelling and handwriting difficulties with a neuroimaging approach. Future experiments are needed to determine whether the functional and structural anomalies observed are consequences of deviant literacy development or whether they could have a causal role in dyslexia.