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.

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.

Amygdala atrophies in specific subnuclei in preclinical Alzheimer's disease.

INTRODUCTION: Magnetic resonance imaging (MRI) segmentation algorithms make it possible to study detailed medial temporal lobe (MTL) substructures as hippocampal subfields and amygdala subnuclei, offering opportunities to develop biomarkers for preclinical Alzheimer's disease (AD). METHODS: We identified the MTL substructures significantly associated with tau-positron emission tomography (PET) signal in 581 non-demented individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI-3). We confirmed our results in our UCLouvain cohort including 110 non-demented individuals by comparing volumes between individuals with different visual Braak's stages and clinical diagnosis. RESULTS: Four amygdala subnuclei (cortical, central, medial, and accessory basal) were associated with tau in amyloid beta-positive (Aß+) clinically normal (CN) individuals, while the global amygdala and hippocampal volumes were not. Using UCLouvain data, we observed that both Braak I-II and Aß+ CN individuals had smaller volumes in these subnuclei, while no significant difference was observed in the global structure volumes or other subfields. CONCLUSION: Measuring specific amygdala subnuclei, early atrophy may serve as a marker of temporal tauopathy in preclinical AD, identifying individuals at risk of progression. HIGHLIGHTS: Amygdala atrophy is not homogeneous in preclinical Alzheimer's disease (AD). Tau pathology is associated with atrophy of specific amygdala subnuclei, specifically, the central, medial, cortical, and accessory basal subnuclei. Hippocampal and amygdala volume is not associated with tau in preclinical AD. Hippocampus and CA1-3 volume is reduced in preclinical AD, regardless of tau.

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.

Neural bases of inhibitory control: Combining transcranial magnetic stimulation and magnetic resonance imaging in alcohol-use disorder patients.

Inhibitory control underlies the ability to inhibit inappropriate responses and involves processes that suppress motor excitability. Such motor modulatory effect has been largely described during action preparation but very little is known about the neural circuit responsible for its implementation. Here, we addressed this point by studying the degree to which the extent of preparatory suppression relates to brain morphometry. We investigated this relationship in patients suffering from severe alcohol use disorder (AUD) because this population displays an inconsistent level of preparatory suppression and major structural brain damage, making it a suitable sample to measure such link. To do so, 45 detoxified patients underwent a structural magnetic resonance imaging (MRI) and performed a transcranial magnetic stimulation (TMS) experiment, in which the degree of preparatory suppression was quantified. Besides, behavioral inhibition and trait impulsivity were evaluated in all participants. Overall, whole-brain analyses revealed that a weaker preparatory suppression was associated with a decrease in cortical thickness of a medial prefrontal cluster, encompassing parts of the anterior cingulate cortex and superior-frontal gyrus. In addition, a negative association was observed between the thickness of the supplementary area (SMA)/pre-SMA and behavioral inhibition abilities. Finally, we did not find any significant correlation between preparatory suppression, behavioral inhibition and trait impulsivity, indicating that they represent different facets of inhibitory control. Altogether, the current study provides important insight on the neural regions underlying preparatory suppression and allows highlighting that the excitability of the motor system represents a valuable read-out of upstream cognitive processes.

Mental fatigue correlates with depression of task-related network and augmented DMN activity but spares the reward circuit.

Long-lasting and demanding cognitive activity typically leads to mental fatigue (MF). Indirect evidence suggests that MF may be caused by altered motivational processes. Here, we hypothesized that if MF consists in an alteration of motivational states, brain functional changes induced by MF could specifically affect the brain motivation circuit. In order to test this hypothesis, we devised a functional neuroimaging protocol to detect altered brain activity in reward-related brain regions in relation to cognitively induced mental fatigue. Twenty-five healthy participants underwent a FATIGUE and a CONTROL session on different days. In the FATIGUE session, MF was induced by performing a demanding cognitive task (adapted Stroop task) during 90 min, whereas in the CONTROL session, participants were asked to read magazines for the same period of time. We measured the neural consequences of the MF induction during a working memory task (Missing Number task) while modulating extrinsic motivation with block-wise variations in monetary reward. We also tracked participants' momentary fatigue, anxiety state and intrinsic motivation prior to and following the MF inducement and measurement. Accuracy on the Missing Number Task was lower in the FATIGUE than in the CONTROL condition. Furthermore, subjective MF, but not its behavioral manifestations, was associated with hypoactivity of the task-evoked neural responses. Importantly, activity in regions modulated by reward showed no differences between FATIGUE and CONTROL sessions. In parallel, subjective MF correlated with increased on-task activity and resting-state functional connectivity in the default mode network. These results indicate that subjective mental fatigue is not associated with altered activity in the brain motivation circuit but rather with hypoactivity in task-specific brain regions as well as relative increases of activity and connectivity in the default mode network during and after the task.

Defining a Centiloid scale threshold predicting long-term progression to dementia in patients attending the memory clinic: an [18F] flutemetamol amyloid PET study.

PURPOSE: To evaluate cerebral amyloid-ß(Aß) pathology in older adults with cognitive complaints, visual assessment of PET images is approved as the routine method for image interpretation. In research studies however, Aß-PET semi-quantitative measures are associated with greater risk of progression to dementia; but until recently, these measures lacked standardization. Therefore, the Centiloid scale, providing standardized Aß-PET semi-quantitation, was recently validated. We aimed to determine the predictive values of visual assessments and Centiloids in non-demented patients, using long-term progression to dementia as our standard of truth. METHODS: One hundred sixty non-demented participants (age, 54-86) were enrolled in a monocentric [18F] flutemetamol Aß-PET study. Flutemetamol images were interpreted visually following the manufacturers recommendations. SUVr values were converted to the Centiloid scale using the GAAIN guidelines. Ninety-eight persons were followed until dementia diagnosis or were clinically stable for a median of 6 years (min = 4.0; max = 8.0). Twenty-five patients with short follow-up (median = 2.0 years; min = 0.8; max = 3.9) and 37 patients with no follow-up were excluded. We computed ROC curves predicting subsequent dementia using baseline PET data and calculated negative (NPV) and positive (PPV) predictive values. RESULTS: In the 98 participants with long follow-up, Centiloid = 26 provided the highest overall predictive value = 87% (NPV = 85%, PPV = 88%). Visual assessment corresponded to Centiloid = 40, which predicted dementia with an overall predictive value = 86% (NPV = 81%, PPV = 92%). Inclusion of the 25 patients who only had a 2-year follow-up decreased the PPV = 67% (NPV = 88%), reflecting the many positive cases that did not progress to dementia after short follow-ups. CONCLUSION: A Centiloid threshold = 26 optimally predicts progression to dementia 6 years after PET. Visual assessment provides similar predictive value, with higher specificity and lower sensitivity. TRIAL REGISTRATION: Eudra-CT number: 2011-001756-12.

Neural Responses to the Implicit Processing of Emotional Facial Expressions in Binge Drinking.

AIMS: Emotional processing is a crucial ability in human and impairments in the processing of emotions are considered as transdiagnostic processes in psychopathology. In alcohol use disorder, numerous studies have investigated emotional processing and showed emotional deficits related to the perpetuation of alcohol use. Recent studies have also explored this topic in binge drinking, but few studies are available. In this paper, we explored whether emotional difficulties in binge drinking may be extended to implicit emotion processing. METHODS: We compared 39 binge drinkers (BD) and 40 non-binge drinkers who performed a gender categorization task while faces represented emotional expressions of anger, fear, happiness and sadness. Emotional brain responses were assessed thanks to functional magnetic resonance imaging. Emotional versus non-emotional conditions were first contrasted in the whole sample and groups were then compared. RESULTS: Emotional condition led to differential activations than non-emotional condition, supporting the validity of the paradigm. Regarding group comparisons, BD exhibited higher activations in the left posterior cerebellum (anger processing) and the right anterior cingulate (fear processing) as well as lower activations in the left insula (happiness), the right post-central gyrus, the right cingulate gyrus and the right medial frontal gyrus (sadness processing). CONCLUSIONS: Beyond emotional identification, BD presented differential brain responses following the implicit processing of emotions. Emotional difficulties in binge drinking might be related to a more automatic/unconscious processing of emotions.

Respective influence of current alcohol consumption and duration of heavy drinking on brain morphological alterations in alcohol use disorder.

Numerous studies have explored the morphological differences of the brain between subjects with alcohol use disorder (AUD) and control subjects, but very few have investigated the impact of the duration of alcohol use disorder (DAD) and current level of alcohol consumption (CAC) within AUD subjects using magnetic resonance imaging (MRI). We compared the morphological MRI of 44 controls and 66 AUD subjects, recruited at the end of a detoxification program. Additional analyses within the AUD group determined which specific alterations were respectively associated with DAD and CAC using: (1) Bonferroni-corrected multivariable linear regressions to explore the DAD/CAC impact on brain volumes and (2) a general linear model (GLM module of FreeSurfer's Qdec) and Monte Carlo simulation to correct for multiple comparisons (P < 0.05) to explore the DAD/CAC impact on cortical thickness and volumes. Analyses were adjusted for age and tobacco use. CAC and DAD were significantly correlated (ρ = 0.25, P < 0.0001), and sensitivity analyses were conducted with and without both CAC and DAD included in the same model. While the AUD-control comparisons globally reproduced preexisting findings, within-AUD analyses found that CAC was inversely correlated with cortical thickness and gray matter volume in a bilateral dorsal band of the temporal lobe, including the fusiform and parahippocampal gyri. For DAD, only a left and more ventral temporal band that partially overlapped the CAC-associated area was found in cortical thickness analyses. No significant volumetric result was reached after a Bonferroni correction. CAC and, to a lesser extent, DAD were thus associated with specific, though partially overlapping, temporal surface-based signatures.

cTBS disruption of the supplementary motor area perturbs cortical sequence representation but not behavioural performance.

Neuroimaging studies have repeatedly emphasized the role of the supplementary motor area (SMA) in motor sequence learning, but interferential approaches have led to inconsistent findings. Here, we aimed to test the role of the SMA in motor skill learning by combining interferential and neuroimaging techniques. Sixteen subjects were trained on simple finger movement sequences for 4 days. Afterwards, they underwent two neuroimaging sessions, in which they executed both trained and novel sequences. Prior to entering the scanner, the subjects received inhibitory transcranial magnetic stimulation (TMS) over the SMA or a control site. Using multivariate fMRI analysis, we confirmed that motor training enhances the neural representation of motor sequences in the SMA, in accordance with previous findings. However, although SMA inhibition altered sequence representation (i.e. between-sequence decoding accuracy) in this area, behavioural performance remained unimpaired. Our findings question the causal link between the neuroimaging correlate of elementary motor sequence representation in the SMA and sequence generation, calling for a more thorough investigation of the role of this region in performance of learned motor sequences.

Hearing, feeling or seeing a beat recruits a supramodal network in the auditory dorsal stream.

Hearing a beat recruits a wide neural network that involves the auditory cortex and motor planning regions. Perceiving a beat can potentially be achieved via vision or even touch, but it is currently not clear whether a common neural network underlies beat processing. Here, we used functional magnetic resonance imaging (fMRI) to test to what extent the neural network involved in beat processing is supramodal, that is, is the same in the different sensory modalities. Brain activity changes in 27 healthy volunteers were monitored while they were attending to the same rhythmic sequences (with and without a beat) in audition, vision and the vibrotactile modality. We found a common neural network for beat detection in the three modalities that involved parts of the auditory dorsal pathway. Within this network, only the putamen and the supplementary motor area (SMA) showed specificity to the beat, while the brain activity in the putamen covariated with the beat detection speed. These results highlighted the implication of the auditory dorsal stream in beat detection, confirmed the important role played by the putamen in beat detection and indicated that the neural network for beat detection is mostly supramodal. This constitutes a new example of convergence of the same functional attributes into one centralized representation in the brain.

Persistent sparing of action conceptual processing in spite of increasing disorders of action production: A case against motor embodiment of action concepts.

In this study, we addressed the issue of whether the brain sensorimotor circuitry that controls action production is causally involved in representing and processing action-related concepts. We examined the three-year pattern of evolution of brain atrophy, action production disorders, and action-related concept processing in a patient (J.R.) diagnosed with corticobasal degeneration. During the period of investigation, J.R. presented with increasing action production disorders resulting from increasing bilateral atrophy in cortical and subcortical regions involved in the sensorimotor control of actions (notably, the superior parietal cortex, the primary motor and premotor cortex, the inferior frontal gyrus, and the basal ganglia). In contrast, the patient's performance in processing action-related concepts remained intact during the same period. This finding indicated that action concept processing hinges on cognitive and neural resources that are mostly distinct from those underlying the sensorimotor control of actions.

Prediction of Free and Cued Selective Reminding Test Performance Using Volumetric and Amyloid-Based Biomarkers of Alzheimer's Disease.

OBJECTIVES: Relatively few studies have investigated relationships between performance on clinical memory measures and indexes of underlying neuropathology related to Alzheimer's disease (AD). This study investigated predictive relationships between Free and Cued Selective Reminding Test (FCSRT) cue efficiency (CE) and free-recall (FR) measures and brain amyloid levels, hippocampal volume (HV), and regional cortical thickness. METHODS: Thirty-one older controls without memory complaints and 60 patients presenting memory complaints underwent the FCSRT, amyloid imaging using [F18]-flutemetamol positron emission tomography, and surface-based morphometry (SBM) using brain magnetic resonance imaging. Three groups were considered: patients with high (Aß+P) and low (Aß- P) amyloid load and controls with low amyloid load (Aß- C). RESULTS: Aß+P showed lower CE than both Aß- groups, but the Aß- groups did not differ significantly. In contrast, FR discriminated all groups. SBM analyses revealed that CE indexes were correlated with the cortical thickness of a wider set of left-lateralized temporal and parietal regions than FR. Regression analyses demonstrated that amyloid load and left HV independently predicted FCSRT scores. Moreover, CE indexes were predicted by the cortical thickness of some regions involved in early AD, such as the entorhinal cortex. CONCLUSIONS: Compared to FR measures, CE indexes appear to be more specific for differentiating persons on the basis of amyloid load. Both CE and FR performance were predicted independently by brain amyloid load and reduced left HV. However, CE performance was also predicted by the cortical thickness of regions known to be atrophic early in AD. (JINS, 2016, 22, 991-1004).

Neural substrates underlying stimulation-enhanced motor skill learning after stroke.

Motor skill learning is one of the key components of motor function recovery after stroke, especially recovery driven by neurorehabilitation. Transcranial direct current stimulation can enhance neurorehabilitation and motor skill learning in stroke patients. However, the neural mechanisms underlying the retention of stimulation-enhanced motor skill learning involving a paretic upper limb have not been resolved. These neural substrates were explored by means of functional magnetic resonance imaging. Nineteen chronic hemiparetic stroke patients participated in a double-blind, cross-over randomized, sham-controlled experiment with two series. Each series consisted of two sessions: (i) an intervention session during which dual transcranial direct current stimulation or sham was applied during motor skill learning with the paretic upper limb; and (ii) an imaging session 1 week later, during which the patients performed the learned motor skill. The motor skill learning task, called the 'circuit game', involves a speed/accuracy trade-off and consists of moving a pointer controlled by a computer mouse along a complex circuit as quickly and accurately as possible. Relative to the sham series, dual transcranial direct current stimulation applied bilaterally over the primary motor cortex during motor skill learning with the paretic upper limb resulted in (i) enhanced online motor skill learning; (ii) enhanced 1-week retention; and (iii) superior transfer of performance improvement to an untrained task. The 1-week retention's enhancement driven by the intervention was associated with a trend towards normalization of the brain activation pattern during performance of the learned motor skill relative to the sham series. A similar trend towards normalization relative to sham was observed during performance of a simple, untrained task without a speed/accuracy constraint, despite a lack of behavioural difference between the dual transcranial direct current stimulation and sham series. Finally, dual transcranial direct current stimulation applied during the first session enhanced continued learning with the paretic limb 1 week later, relative to the sham series. This lasting behavioural enhancement was associated with more efficient recruitment of the motor skill learning network, that is, focused activation on the motor-premotor areas in the damaged hemisphere, especially on the dorsal premotor cortex. Dual transcranial direct current stimulation applied during motor skill learning with a paretic upper limb resulted in prolonged shaping of brain activation, which supported behavioural enhancements in stroke patients.

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.].

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.

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.

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.

Identifying responders to vagus nerve stimulation based on microstructural features of thalamocortical tracts in drug-resistant epilepsy.

The mechanisms of action of Vagus Nerve Stimulation (VNS) and the biological prerequisites to respond to the treatment are currently under investigation. It is hypothesized that thalamocortical tracts play a central role in the antiseizure effects of VNS by disrupting the genesis of pathological activity in the brain. This pilot study explored whether in vivo microstructural features of thalamocortical tracts may differentiate Drug-Resistant Epilepsy (DRE) patients responding and not responding to VNS treatment. Eighteen patients with DRE (37.11 â€‹± â€‹10.13 years, 10 females), including 11 responders or partial responders and 7 non-responders to VNS, were recruited for this high-gradient multi-shell diffusion Magnetic Resonance Imaging (MRI) study. Using Diffusion Tensor Imaging (DTI) and multi-compartment models - Neurite Orientation Dispersion and Density Imaging (NODDI) and Microstructure Fingerprinting (MF), we extracted microstructural features in 12 subsegments of thalamocortical tracts. These characteristics were compared between responders/partial responders and non-responders. Subsequently, a Support Vector Machine (SVM) classifier was built, incorporating microstructural features and 12 clinical covariates (including age, sex, duration of VNS therapy, number of antiseizure medications, benzodiazepine intake, epilepsy duration, epilepsy onset age, epilepsy type - focal or generalized, presence of an epileptic syndrome - no syndrome or Lennox-Gastaut syndrome, etiology of epilepsy - structural, genetic, viral, or unknown, history of brain surgery, and presence of a brain lesion detected on structural MRI images). Multiple diffusion metrics consistently demonstrated significantly higher white matter fiber integrity in patients with a better response to VNS (pFDR < 0.05) in different subsegments of thalamocortical tracts. The SVM model achieved a classification accuracy of 94.12%. The inclusion of clinical covariates did not improve the classification performance. The results suggest that the structural integrity of thalamocortical tracts may be linked to therapeutic effectiveness of VNS. This study reveals the great potential of diffusion MRI in improving our understanding of the biological factors associated with the response to VNS therapy.

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.