Combined in vivo MRI assessment of locus coeruleus and nucleus basalis of Meynert integrity in amnestic Alzheimer's disease, suspected-LATE and frontotemporal dementia.

BACKGROUND: The locus coeruleus (LC) and the nucleus basalis of Meynert (NBM) are altered in early stages of Alzheimer's disease (AD). Little is known about LC and NBM alteration in limbic-predominant age-related TDP-43 encephalopathy (LATE) and frontotemporal dementia (FTD). The aim of the present study is to investigate in vivo LC and NBM integrity in patients with suspected-LATE, early-amnestic AD and FTD in comparison with controls. METHODS: Seventy-two participants (23 early amnestic-AD patients, 17 suspected-LATE, 17 FTD patients, defined by a clinical-biological diagnosis reinforced by amyloid and tau PET imaging, and 15 controls) underwent neuropsychological assessment and 3T brain MRI. We analyzed the locus coeruleus signal intensity (LC-I) and the NBM volume as well as their relation with cognition and with medial temporal/cortical atrophy. RESULTS: We found significantly lower LC-I and NBM volume in amnestic-AD and suspected-LATE in comparison with controls. In FTD, we also observed lower NBM volume but a slightly less marked alteration of the LC-I, independently of the temporal or frontal phenotype. NBM volume was correlated with the global cognitive efficiency in AD patients. Strong correlations were found between NBM volume and that of medial temporal structures, particularly the amygdala in both AD and FTD patients. CONCLUSIONS: The alteration of LC and NBM in amnestic-AD, presumed-LATE and FTD suggests a common vulnerability of these structures to different proteinopathies. Targeting the noradrenergic and cholinergic systems could be effective therapeutic strategies in LATE and FTD.

Association of abnormal explicit sense of agency with cerebellar impairment in myoclonus-dystonia.

Non-motor aspects in dystonia are now well recognized. The sense of agency, which refers to the experience of controlling one's own actions, has been scarcely studied in dystonia, even though its disturbances can contribute to movement disorders. Among various brain structures, the cerebral cortex, the cerebellum, and the basal ganglia are involved in shaping the sense of agency. In myoclonus dystonia, resulting from a dysfunction of the motor network, an altered sense of agency may contribute to the clinical phenotype of the condition. In this study, we compared the explicit and implicit sense of agency in patients with myoclonus dystonia caused by a pathogenic variant of SGCE (DYT-SGCE) and control participants. We utilized behavioural tasks to assess the sense of agency and performed neuroimaging analyses, including structural, resting-state functional connectivity, and dynamic causal modelling, to explore the relevant brain regions involved in the sense of agency. Additionally, we examined the relationship between behavioural performance, symptom severity, and neuroimaging findings. We compared 19 patients with DYT-SGCE and 24 healthy volunteers. Our findings revealed that patients with myoclonus-dystonia exhibited a specific impairment in explicit sense of agency, particularly when implicit motor learning was involved. However, their implicit sense of agency remained intact. These patients also displayed grey-matter abnormalities in the motor cerebellum, as well as increased functional connectivity between the cerebellum and pre-supplementary motor area. Dynamic causal modelling analysis further identified reduced inhibitory effects of the cerebellum on the pre-supplementary motor area, decreased excitatory effects of the pre-supplementary motor area on the cerebellum, and increased self-inhibition within the pre-supplementary motor area. Importantly, both cerebellar grey-matter alterations and functional connectivity abnormalities between the cerebellum and pre-supplementary motor area were found to correlate with explicit sense of agency impairment. Increased self-inhibition within the pre-supplementary motor area was associated with less severe myoclonus symptoms. These findings highlight the disruption of higher-level cognitive processes in patients with myoclonus-dystonia, further expanding the spectrum of neurological and psychiatric dysfunction already identified in this disorder.

Association between superior longitudinal fasciculus, motor recovery, and motor outcome after stroke: a cohort study.

Introduction: Parieto-frontal interactions are mediated by the superior longitudinal fasciculus (SLF) and are crucial to integrate visuomotor information and mediate fine motor control. In this study, we aimed to characterize the relation of white matter integrity of both parts of the SLF (SLF I and SLF II) to both motor outcome and recovery and its evolution over time in stroke patients with upper limb motor deficits. Materials and methods: Fractional anisotropy (FA) values over the SLF I, SLF II, and corticospinal tract (CST) and upper limb motor performance evaluated by both the upper limb Fugl-Meyer Assessment score and maximum grip strength were measured for 16 patients at 3 weeks, 6 weeks, and 12 weeks poststroke. FA changes were assessed over time using repeated-measures Friedman ANOVA, and correlations between motor recovery, motor outcome at 12 weeks, and FA values in the CST, SLF I, and SLF II at 3 weeks were performed using Spearman's rank-order correlation. Results: FA values in the affected hemisphere's SLF I and SLF II at 3 weeks correlated with motor recovery at 12 weeks when assessed by the Fugl-Meyer Assessment for upper limb extremity (rho: 0.502, p: 0.04 and rho: 0.510, p: 0.04, respectively) but not when assessed by grip strength. FA values in the SLF I and SLF II were not correlated with motor outcomes. FA values in the SLF II in the affected hemisphere changed significantly over time (p: 0.016). Conclusion: Both SLF I and SLF II appeared to participate in poststroke motor recovery of complex movements but not in the motor outcome. These results argue that visually/spatially oriented motor tasks as well as more complex motor tasks using parietal associative areas should be used for poststroke rehabilitation strategies.

Fixel-Based Analysis Reveals Whole-Brain White Matter Abnormalities in Cervical Dystonia.

BACKGROUND: Cervical dystonia (CD) is a form of isolated focal dystonia typically associated to abnormal head, neck, and shoulder movements and postures. The complexity of the clinical presentation limits the investigation of its pathophysiological mechanisms, and the neural networks associated to specific motor manifestations are still the object of debate. OBJECTIVES: We investigated the morphometric properties of white matter fibers in CD and explored the networks associated with motor symptoms, while regressing out nonmotor scores. METHODS: Nineteen patients affected by CD and 21 healthy controls underwent diffusion-weighted magnetic resonance imaging. We performed fixel-based analysis, a novel method evaluating fiber orientation within specific fiber bundles, and compared fiber morphometric properties between groups. Moreover, we correlated fiber morphometry with the severity of motor symptoms in patients. RESULTS: Compared to controls, patients exhibited decreased white matter fibers in the right striatum. Motor symptom severity negatively correlated with white matter fibers passing through inferior parietal areas and the head representation area of the motor cortex. CONCLUSIONS: Abnormal white matter integrity at the basal ganglia level may affect several functional networks involved, for instance, in motor preparation and execution, visuomotor coordination, and multimodal integration. This may result in progressive maladaptive plasticity, culminating in overt symptoms of dystonia. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Cerebellar and basal ganglia structural connections in humans: Effect of aging and relation with memory and learning.

Introduction: The cerebellum and basal ganglia were initially considered anatomically distinct regions, each connected via thalamic relays which project to the same cerebral cortical targets, such as the motor cortex. In the last two decades, transneuronal viral transport studies in non-human primates showed bidirectional connections between the cerebellum and basal ganglia at the subcortical level, without involving the cerebral cortical motor areas. These findings have significant implications for our understanding of neurodevelopmental and neurodegenerative diseases. While these subcortical connections were established in smaller studies on humans, their evolution with natural aging is less understood. Methods: In this study, we validated and expanded the previous findings of the structural connectivity within the cerebellum-basal ganglia subcortical network, in a larger dataset of 64 subjects, across different age ranges. Tractography and fixel-based analysis were performed on the 3 T diffusion-weighted dataset using Mrtrix3 software, considering fiber density and cross-section as indicators of axonal integrity. Tractography of the well-established cerebello-thalamo-cortical tract was conducted as a control. We tested the relationship between the structural white matter integrity of these connections with aging and with the performance in different domains of Addenbrooke's Cognitive Examination. Results: Tractography analysis isolated connections from the dentate nucleus to the contralateral putamen via the thalamus, and reciprocal tracts from the subthalamic nucleus to the contralateral cerebellar cortex via the pontine nuclei. Control tracts of cerebello-thalamo-cortical tracts were also isolated, including associative cerebello-prefrontal tracts. A negative linear relationship was found between the fiber density of both the ascending and descending cerebellum-basal ganglia tracts and age. Considering the cognitive assessments, the fiber density values of cerebello-thalamo-putaminal tracts correlated with the registration/learning domain scores. In addition, the fiber density values of cerebello-frontal and subthalamo-cerebellar (Crus II) tracts correlated with the cognitive assessment scores from the memory domain. Conclusion: We validated the structural connectivity within the cerebellum-basal ganglia reciprocal network, in a larger dataset of human subjects, across wider age range. The structural features of the subcortical cerebello-basal ganglia tracts in human subjects display age-related neurodegeneration. Individual morphological variability of cerebellar tracts to the striatum and prefrontal cortex was associated with different cognitive functions, suggesting a functional contribution of cerebellar tracts to cognitive decline with aging. This study offers new perspectives to consider the functional role of these pathways in motor learning and the pathophysiology of movement disorders involving the cerebellum and striatum.

Neuromelanin-Sensitive Magnetic Resonance Imaging Changes in the Locus Coeruleus/Subcoeruleus Complex in Patients with Typical and Atypical Parkinsonism.

BACKGROUND: The locus coeruleus/subcoeruleus complex (LC/LsC) is a structure comprising melanized noradrenergic neurons. OBJECTIVE: To study the LC/LsC damage across Parkinson's disease (PD) and atypical parkinsonism in a large group of subjects. METHODS: We studied 98 healthy control subjects, 47 patients with isolated rapid eye movement sleep behavior disorder (RBD), 75 patients with PD plus RBD, 142 patients with PD without RBD, 19 patients with progressive supranuclear palsy (PSP), and 19 patients with multiple system atrophy (MSA). Twelve patients with MSA had proven RBD. LC/LsC signal intensity was derived from neuromelanin magnetic resonance imaging using automated software. RESULTS: The signal intensity was reduced in all parkinsonian syndromes compared with healthy control subjects, except in PD without RBD. The signal intensity decreased as age increased. Moreover, the signal intensity was lower in MSA than in isolated RBD and PD without RBD groups. In PD, the signal intensity correlated negatively with the percentage of REM sleep without atonia. There were no differences in signal intensity between PD plus RBD, PSP, and MSA. CONCLUSIONS: Neuromelanin signal intensity was reduced in all parkinsonian disorders, except in PD without RBD. The presence of RBD in parkinsonian disorders appears to be associated with lower neuromelanin signal intensity. Furthermore, lower LC/LsC signal changes in PSP could be partly caused by the effect of age. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Interpretable deep learning for the prognosis of long-term functional outcome post-stroke using acute diffusion weighted imaging.

Advances in deep learning can be applied to acute stroke imaging to build powerful and explainable prediction models that could supersede traditionally used biomarkers. We aimed to evaluate the performance and interpretability of a deep learning model based on convolutional neural networks (CNN) in predicting long-term functional outcome with diffusion-weighted imaging (DWI) acquired at day 1 post-stroke. Ischemic stroke patients (n = 322) were included from the ASTER and INSULINFARCT trials as well as the Pitié-Salpêtrière registry. We trained a CNN to predict long-term functional outcome assessed at 3 months with the modified Rankin Scale (dichotomized as good [mRS ≤ 2] vs. poor [mRS ≥ 3]) and compared its performance to two logistic regression models using lesion volume and ASPECTS. The CNN contained an attention mechanism, which allowed to visualize the areas of the brain that drove prediction. The deep learning model yielded a significantly higher area under the curve (0.83 95%CI [0.78-0.87]) than lesion volume (0.78 [0.73-0.83]) and ASPECTS (0.77 [0.71-0.83]) (p < 0.05). Setting all classifiers to the specificity as the deep learning model (i.e., 0.87 [0.82-0.92]), the CNN yielded a significantly higher sensitivity (0.67 [0.59-0.73]) than lesion volume (0.48 [0.40-0.56]) and ASPECTS (0.50 [0.41-0.58]) (p = 0.002). The attention mechanism revealed that the network learned to naturally attend to the lesion to predict outcome.

In Vivo 2-Hydroxyglutarate Monitoring With Edited MR Spectroscopy for the Follow-up of IDH-Mutant Diffuse Gliomas: The IDASPE Prospective Study.

BACKGROUND AND OBJECTIVES: D-2-hydroxyglutarate (2HG) characterizes IDH-mutant gliomas and can be detected and quantified with edited MRS (MEGA-PRESS). In this study, we investigated the clinical, radiologic, and molecular parameters affecting 2HG levels. METHODS: MEGA-PRESS data were acquired in 71 patients with glioma (24 untreated, 47 treated) on a 3 T system. Eighteen patients were followed during cytotoxic (n = 12) or targeted (n = 6) therapy. 2HG was measured in tumor samples using gas chromatography coupled to mass spectrometry (GCMS). RESULTS: MEGA-PRESS detected 2HG with a sensitivity of 95% in untreated patients and 62% in treated patients. Sensitivity depended on tumor volume (>27 cm3; p = 0.02), voxel coverage (>75%; p = 0.002), and expansive presentation (defined by equal size of T1 and FLAIR abnormalities, p = 0.04). 2HG levels were positively correlated with IDH-mutant allelic fraction (p = 0.03) and total choline levels (p < 0.001) and were higher in IDH2-mutant compared with IDH1 R132H-mutant and non-R132H IDH1-mutant patients (p = 0.002). In patients receiving IDH inhibitors, 2HG levels decreased within a few days, demonstrating the on-target effect of the drug, but 2HG level decrease did not predict tumor response. Patients receiving cytotoxic treatments showed a slower decrease in 2HG levels, consistent with tumor response and occurring before any tumor volume change on conventional MRI. At progression, 1p/19q codeleted gliomas, but not the non-codeleted, showed detectable in vivo 2HG levels, pointing out to different modes of progression characterizing these 2 entities. DISCUSSION: MEGA-PRESS edited MRS allows in vivo monitoring of 2-hydroxyglutarate, confirming efficacy of IDH inhibition and suggests different patterns of tumor progression in astrocytomas compared with oligodendrogliomas.

Clinically Meaningful Magnetic Resonance Endpoints Sensitive to Preataxic Spinocerebellar Ataxia Types 1 and 3.

OBJECTIVE: This study was undertaken to identify magnetic resonance (MR) metrics that are most sensitive to early changes in the brain in spinocerebellar ataxia type 1 (SCA1) and type 3 (SCA3) using an advanced multimodal MR imaging (MRI) protocol in the multisite trial setting. METHODS: SCA1 or SCA3 mutation carriers and controls (n = 107) underwent MR scanning in the US-European READISCA study to obtain structural, diffusion MRI, and MR spectroscopy data using an advanced protocol at 3T. Morphometric, microstructural, and neurochemical metrics were analyzed blinded to diagnosis and compared between preataxic SCA (n = 11 SCA1, n = 28 SCA3), ataxic SCA (n = 14 SCA1, n = 37 SCA3), and control (n = 17) groups using nonparametric testing accounting for multiple comparisons. MR metrics that were most sensitive to preataxic abnormalities were identified using receiver operating characteristic (ROC) analyses. RESULTS: Atrophy and microstructural damage in the brainstem and cerebellar peduncles and neurochemical abnormalities in the pons were prominent in both preataxic groups, when patients did not differ from controls clinically. MR metrics were strongly associated with ataxia symptoms, activities of daily living, and estimated ataxia duration. A neurochemical measure was the most sensitive metric to preataxic changes in SCA1 (ROC area under the curve [AUC] = 0.95), and a microstructural metric was the most sensitive metric to preataxic changes in SCA3 (AUC = 0.92). INTERPRETATION: Changes in cerebellar afferent and efferent pathways underlie the earliest symptoms of both SCAs. MR metrics collected with a harmonized advanced protocol in the multisite trial setting allow detection of disease effects in individuals before ataxia onset with potential clinical trial utility for subject stratification. ANN NEUROL 2022.

NigraNet: An automatic framework to assess nigral neuromelanin content in early Parkinson's disease using convolutional neural network.

BACKGROUND: Parkinson's disease (PD) demonstrates neurodegenerative changes in the substantia nigra pars compacta (SNc) using neuromelanin-sensitive (NM)-MRI. As SNc manual segmentation is prone to substantial inter-individual variability across raters, development of a robust automatic segmentation framework is necessary to facilitate nigral neuromelanin quantification. Artificial intelligence (AI) is gaining traction in the neuroimaging community for automated brain region segmentation tasks using MRI. OBJECTIVE: Developing and validating AI-based NigraNet, a fully automatic SNc segmentation framework allowing nigral neuromelanin quantification in patients with PD using NM-MRI. METHODS: We prospectively included 199 participants comprising 144 early-stage idiopathic PD patients (disease duration = 1.5 ± 1.0 years) and 55 healthy volunteers (HV) scanned using a 3 Tesla MRI including whole brain T1-weighted anatomical imaging and NM-MRI. The regions of interest (ROI) were delineated in all participants automatically using NigraNet, a modified U-net, and compared to manual segmentations performed by two experienced raters. The SNc volumes (Vol), volumes corrected by total intracranial volume (Cvol), normalized signal intensity (NSI) and contrast-to-noise ratio (CNR) were computed. One-way GLM-ANCOVA was performed while adjusting for age and sex as covariates. Diagnostic performance measurement was assessed using the receiver operating characteristic (ROC) analysis. Inter and intra-observer variability were estimated using Dice similarity coefficient (DSC). The agreements between methods were tested using intraclass correlation coefficient (ICC) based on a mean-rating, two-way, mixed-effects model estimates for absolute agreement. Cronbach's alpha and Bland-Altman plots were estimated to assess inter-method consistency. RESULTS: Using both methods, Vol, Cvol, NSI and CNR measurements differed between PD and HV with an effect of sex for Cvol and CNR. ICC values between the methods demonstrated optimal agreement for Cvol and CNR (ICC > 0.9) and high reproducibility (DSC: 0.80) was also obtained. The SNc measurements also showed good to excellent consistency values (Cronbach's alpha > 0.87). Bland-Altman plots of agreement demonstrated no association of SNc ROI measurement differences between the methods and ROI average measurements while confirming that 95 % of the data points were ranging between the limits of mean difference (d ± 1.96xSD). Percentage changes between PD and HV were -27.4 % and -17.7 % for Vol, -30.0 % and -22.2 % for Cvol, -15.8 % and -14.4 % for NSI, -17.1 % and -16.0 % for CNR for automatic and manual measurements respectively. Using automatic method, in the entire dataset, we obtained the areas under the ROC curve (AUC) of 0.83 for Vol, 0.85 for Cvol, 0.79 for NSI and 0.77 for CNR whereas in the training dataset of 0.96 for Vol, 0.95 for Cvol, 0.85 for NSI and 0.85 for CNR. Disease duration correlated negatively with NSI of the patients for both the automatic and manual measurements. CONCLUSIONS: We presented an AI-based NigraNet framework that utilizes a small MRI training dataset to fully automatize the SNc segmentation procedure with an increased precision and more reproducible results. Considering the consistency, accuracy and speed of our approach, this study could be a crucial step towards the implementation of a time-saving non-rater dependent fully automatic method for studying neuromelanin changes in clinical settings and large-scale neuroimaging studies.

Regional Selectivity of Neuromelanin Changes in the Substantia Nigra in Atypical Parkinsonism.

BACKGROUND: Neurodegeneration in the substantia nigra pars compacta (SNc) in parkinsonian syndromes may affect the nigral territories differently. OBJECTIVE: The objective of this study was to investigate the regional selectivity of neurodegenerative changes in the SNc in patients with Parkinson's disease (PD) and atypical parkinsonism using neuromelanin-sensitive magnetic resonance imaging (MRI). METHODS: A total of 22 healthy controls (HC), 38 patients with PD, 22 patients with progressive supranuclear palsy (PSP), 20 patients with multiple system atrophy (MSA, 13 with the parkinsonian variant, 7 with the cerebellar variant), 7 patients with dementia with Lewy body (DLB), and 4 patients with corticobasal syndrome were analyzed. volume and signal-to-noise ratio (SNR) values of the SNc were derived from neuromelanin-sensitive MRI in the whole SNc. Analysis of signal changes was performed in the sensorimotor, associative, and limbic territories of the SNc. RESULTS: SNc volume and corrected volume were significantly reduced in PD, PSP, and MSA versus HC. Patients with PSP had lower volume, corrected volume, SNR, and contrast-to-noise ratio than HC and patients with PD and MSA. Patients with PSP had greater SNR reduction in the associative region than HC and patients with PD and MSA. Patients with PD had reduced SNR in the sensorimotor territory, unlike patients with PSP. Patients with MSA did not differ from patients with PD. CONCLUSIONS: This study provides the first MRI comparison of the topography of neuromelanin changes in parkinsonism. The spatial pattern of changes differed between PSP and synucleinopathies. These nigral topographical differences are consistent with the topography of the extranigral involvement in parkinsonian syndromes. © 2022 International Parkinson and Movement Disorder Society.

Deep Learning-Based Neuromelanin MRI Changes of Isolated REM Sleep Behavior Disorder.

BACKGROUND: Isolated REM sleep behavior disorder (iRBD) is considered a prodromal stage of parkinsonism. Neurodegenerative changes in the substantia nigra pars compacta (SNc) in parkinsonism can be detected using neuromelanin-sensitive MRI. OBJECTIVE: To investigate SNc neuromelanin changes in iRBD patients using fully automatic segmentation. METHODS: We included 47 iRBD patients, 134 early Parkinson's disease (PD) patients and 55 healthy volunteers (HVs) scanned at 3 Tesla. SNc regions-of-interest were delineated automatically using convolutional neural network. SNc volumes, volumes corrected by total intracranial volume, signal-to-noise ratio (SNR) and contrast-to-noise ratio were computed. One-way general linear models (GLM) analysis of covariance (ANCOVA) was conducted while adjusting for age and sex. RESULTS: All SNc measurements differed significantly between the three groups (except SNR in iRBD). Changes in iRBD were intermediate between those in PD and HVs. CONCLUSIONS: Using fully automated SNc segmentation method and neuromelanin-sensitive imaging, iRBD patients showed neurodegenerative changes in the SNc at a lower level than in PD patients. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Cerebello-Motor Paired Associative Stimulation and Motor Recovery in Stroke: a Randomized, Sham-Controlled, Double-Blind Pilot Trial.

Cerebellum is a key structure for functional motor recovery after stroke. Enhancing the cerebello-motor pathway by paired associative stimulation (PAS) might improve upper limb function. Here, we conducted a randomized, double-blind, sham-controlled pilot trial investigating the efficacy of a 5-day treatment of cerebello-motor PAS coupled with physiotherapy for promoting upper limb motor function compared to sham stimulation. The secondary objectives were to determine in the active treated group (i) whether improvement of upper limb motor function was associated with changes in corticospinal excitability or changes in functional activity in the primary motor cortex and (ii) whether improvements were correlated to the structural integrity of the input and output pathways. To that purpose, hand dexterity and maximal grip strength were assessed along with TMS recordings and multimodal magnetic resonance imaging, before the first treatment, immediately after the last one and a month later. Twenty-seven patients were analyzed. Cerebello-motor PAS was effective compared to sham in improving hand dexterity (p: 0.04) but not grip strength. This improvement was associated with increased activation in the ipsilesional primary motor cortex (p: 0.04). Moreover, the inter-individual variability in clinical improvement was partly explained by the structural integrity of the afferent (p: 0.06) and efferent pathways (p: 0.02) engaged in this paired associative stimulation (i.e., cortico-spinal and dentato-thalamo-cortical tracts). In conclusion, cerebello-motor-paired associative stimulation combined with physiotherapy might be a promising approach to enhance upper limb motor function after stroke.Clinical Trial Registration URL: http://www.clinicaltrials.gov . Unique identifier: NCT02284087.

Cerebellum Dysfunction in Patients With PRRT2-Related Paroxysmal Dyskinesia.

BACKGROUND AND OBJECTIVES: The main culprit gene for paroxysmal kinesigenic dyskinesia, characterized by brief and recurrent attacks of involuntary movements, is PRRT2. The location of the primary dysfunction associated with paroxysmal dyskinesia remains a matter of debate and may vary depending on the etiology. While striatal dysfunction has often been implicated in these patients, evidence from preclinical models indicates that the cerebellum could also play a role. We aimed to investigate the role of the cerebellum in the pathogenesis of PRRT2-related dyskinesia in humans. METHODS: We enrolled 22 consecutive right-handed patients with paroxysmal kinesigenic dyskinesia with a pathogenic variant of PRRT2 and their matched controls. Participants underwent a multimodal neuroimaging protocol. We recorded anatomic and diffusion-weighted MRI, as well as resting-state fMRI, during which we tested the aftereffects of sham and repetitive transcranial magnetic stimulation applied to the cerebellum on endogenous brain activity. We quantified the structural integrity of gray matter using voxel-based morphometry, the structural integrity of white matter using fixel-based analysis, and the strength and direction of functional cerebellar connections using spectral dynamic causal modeling. RESULTS: Patients with PRRT2 had decreased gray matter volume in the cerebellar lobule VI and in the medial prefrontal cortex, microstructural alterations of white matter in the cerebellum and along the tracts connecting the cerebellum to the striatum and the cortical motor areas, and dysfunction of cerebellar motor pathways to the striatum and the cortical motor areas, as well as abnormal communication between the associative cerebellum (Crus I) and the medial prefrontal cortex. Cerebellar stimulation modulated communication within the motor and associative cerebellar networks and tended to restore this communication to the level observed in healthy controls. DISCUSSION: Patients with PRRT2-related dyskinesia have converging structural alterations of the motor cerebellum and related pathways with a dysfunction of cerebellar output toward the cerebello-thalamo-striato-cortical network. We hypothesize that abnormal cerebellar output is the primary dysfunction in patients with a PRRT2 pathogenic variant, resulting in striatal dysregulation and paroxysmal dyskinesia. More broadly, striatal dysfunction in paroxysmal dyskinesia might be secondary to aberrant cerebellar output transmitted by thalamic relays in certain disorders. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov identifier: NCT03481491.

The sooner the better: clinical and neural correlates of impulsive choice in Tourette disorder.

Reward sensitivity has been suggested as one of the central pathophysiological mechanisms in Tourette disorder. However, the subjective valuation of a reward by introduction of delay has received little attention in Tourette disorder, even though it has been suggested as a trans-diagnostic feature of numerous neuropsychiatric disorders. We aimed to assess delay discounting in Tourette disorder and to identify its brain functional correlates. We evaluated delayed discounting and its brain functional correlates in a large group of 54 Tourette disorder patients and 31 healthy controls using a data-driven approach. We identified a subgroup of 29 patients with steeper reward discounting, characterised by a higher burden of impulse-control disorders and a higher level of general impulsivity compared to patients with normal behavioural performance or to controls. Reward discounting was underpinned by resting-state activity of a network comprising the orbito-frontal, cingulate, pre-supplementary motor area, temporal and insular cortices, as well as ventral striatum and hippocampus. Within this network, (i) lower connectivity of pre-supplementary motor area with ventral striatum predicted a higher impulsivity and a steeper reward discounting and (ii) a greater connectivity of pre-supplementary motor area with anterior insular cortex predicted steeper reward discounting and more severe tics. Overall, our results highlight the heterogeneity of the delayed reward processing in Tourette disorder, with steeper reward discounting being a marker of burden in impulsivity and impulse control disorders, and the pre-supplementary motor area being a hub region for the delay discounting, impulsivity and tic severity.

Effect of Intermittent Theta Burst Stimulation on the Neural Processing of Emotional Stimuli in Healthy Volunteers.

BACKGROUND: Intermittent theta burst stimulation (iTBS) is a form of repetitive transcranial magnetic stimulation that has shown to be effective in treatment-resistant depression. Through studying the effect of iTBS on healthy subjects, we wished to attain a greater understanding of its impact on the brain. Our objective was to assess whether 10 iTBS sessions altered the neural processing of emotional stimuli, mood and brain anatomy in healthy subjects. METHODS: In this double-blind randomized sham-controlled study, 30 subjects received either active iTBS treatment (10 sessions, two sessions a day) or sham treatment over the left dorsolateral prefrontal cortex. Assessments of mood, structural magnetic resonance imaging (MRI) and functional MRI (fMRI) were performed before and after iTBS sessions. During the fMRI, three different categories of stimuli were presented: positive, negative and neutral photographs. RESULTS: This study showed that, during the presentation of negative stimuli (compared with neutral stimuli), 10 sessions of iTBS increased activity in the left anterior insula. However, iTBS did not induce any change in mood, regional gray matter volume or cortical thickness. CONCLUSIONS: iTBS modifies healthy subjects' brain activity in a key region that processes emotional stimuli. (AFSSAPS: ID-RCB 2010A01032-37).

The spatiotemporal changes in dopamine, neuromelanin and iron characterizing Parkinson's disease.

In Parkinson's disease, there is a progressive reduction in striatal dopaminergic function, and loss of neuromelanin-containing dopaminergic neurons and increased iron deposition in the substantia nigra. We tested the hypothesis of a relationship between impairment of the dopaminergic system and changes in the iron metabolism. Based on imaging data of patients with prodromal and early clinical Parkinson's disease, we assessed the spatiotemporal ordering of such changes and relationships in the sensorimotor, associative and limbic territories of the nigrostriatal system. Patients with Parkinson's disease (disease duration < 4 years) or idiopathic REM sleep behaviour disorder (a prodromal form of Parkinson's disease) and healthy controls underwent longitudinal examination (baseline and 2-year follow-up). Neuromelanin and iron sensitive MRI and dopamine transporter single-photon emission tomography were performed to assess nigrostriatal levels of neuromelanin, iron, and dopamine. For all three functional territories of the nigrostriatal system, in the clinically most and least affected hemispheres separately, the following was performed: cross-sectional and longitudinal intergroup difference analysis of striatal dopamine and iron, and nigral neuromelanin and iron; in Parkinson's disease patients, exponential fitting analysis to assess the duration of the prodromal phase and the temporal ordering of changes in dopamine, neuromelanin or iron relative to controls; and voxel-wise correlation analysis to investigate concomitant spatial changes in dopamine-iron, dopamine-neuromelanin and neuromelanin-iron in the substantia nigra pars compacta. The temporal ordering of dopaminergic changes followed the known spatial pattern of progression involving first the sensorimotor, then the associative and limbic striatal and nigral regions. Striatal dopaminergic denervation occurred first followed by abnormal iron metabolism and finally neuromelanin changes in the substantia nigra pars compacta, which followed the same spatial and temporal gradient observed in the striatum but shifted in time. In conclusion, dopaminergic striatal dysfunction and cell loss in the substantia nigra pars compacta are interrelated with increased nigral iron content.

Longitudinal Changes in Neuromelanin MRI Signal in Parkinson's Disease: A Progression Marker.

BACKGROUND: Development of reliable and accurate imaging biomarkers of dopaminergic cell neurodegeneration is necessary to facilitate therapeutic drug trials in Parkinson's disease (PD). Neuromelanin-sensitive MRI techniques have been effective in detecting neurodegeneration in the substantia nigra pars compacta (SNpc). The objective of the current study was to investigate longitudinal neuromelanin signal changes in the SNpc in PD patients. METHODS: In this prospective, longitudinal, observational case-control study, we included 140 PD patients and 64 healthy volunteers divided into 2 cohorts. Cohort I included 99 early PD patients (disease duration, 1.5 ± 1.0 years) and 41 healthy volunteers analyzed at baseline (V1), where 79 PD patients and 32 healthy volunteers were rescanned after 2.0 ± 0.2 years of follow-up (V2). Cohort II included 41 progressing PD patients (disease duration, 9.3 ± 3.7 years) and 23 healthy volunteers at V1, where 30 PD patients were rescanned after 2.4 ± 0.5 years of follow-up. Subjects were scanned at 3 T MRI using 3-dimensional T1-weighted and neuromelanin-sensitive imaging. Regions of interest were delineated manually to calculate SN volumes, volumes corrected by total intracranial volume, signal-to-noise ratio, and contrast-to-noise ratio. RESULTS: Results showed (1) significant reduction in volume and volume corrected by total intracranial volume between visits, greater in progressing PD than nonsignificant changes in healthy volunteers; (2) no significant effects of visit for signal intensity (signal-to-noise ratio); (3) significant interaction in volume between group and visit; (4) greater volume corrected by total intracranial volume at baseline in female patients and greater decrease in volume and increase in the contrast-to-noise ratio in progressing female PD patients compared with male patients; and (5) correlations between neuromelanin SN changes and disease severity and duration. CONCLUSIONS: We observed a progressive and measurable decrease in neuromelanin-based SN signal and volume in PD, which might allow a direct noninvasive assessment of progression of SN loss and could represent a target biomarker for disease-modifying treatments. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Multiparametric in vivo analyses of the brain and spine identify structural and metabolic biomarkers in men with adrenomyeloneuropathy.

OBJECTIVE: Progressive myelopathy causes severe handicap in men with adrenomyeloneuropathy (AMN), an X-linked disorder due to ABCD1 pathogenic variants. At present, treatments are symptomatic but disease-modifying therapies are under evaluation. Given the small effect size of clinical scales in AMN, biomarkers with higher effect size are needed. Here we used high-resolution magnetic resonance techniques to identify non-invasive in vivo biomarkers of the brain and spine with high effect sizes. METHODS: We performed a multiparametric imaging and spectroscopy study in 23 male patients with AMN (age: 44 ± 11) and 23 male controls (age: 43 ± 11) of similar age and body-mass index. We combined (i) macrostructural analyses of the spine, using cross-sectional area (CSA) and magnetization transfer ratio (MTR), (ii) microstructural analyses of the spine and the brain, using diffusion tensor and the newly developed fixel-based analysis, and (iii) advanced metabolic analyses of the spine using metabolite cycling coupled to a semi-LASER sequences. RESULTS: Macrostructural alterations (decrease in CSA and MTR) were observed in patients at all spinal cord levels studied (C1-T2 for CSA and C1-C5 for MTR) (p < 0.001). Microstructural alterations were observed in the spine and brain on diffusion tensor and fixel-based metrics though the latter showed higher effect sizes. Metabolic alterations were observed in patients as a decreased total N-acetylaspartate/myo-inositol ratio (p < 0.001). Overall, MTR showed the highest effect size. CONCLUSION: This cross-sectional study supports the use of multiparametric techniques that elucidate the structural, microstructural and metabolic alterations in AMN. These outcome measures should be tested longitudinally and in clinical trials.