Digital Gait Measures Capture 1-Year Progression in Early-Stage Spinocerebellar Ataxia Type 2.

BACKGROUND: With disease-modifying drugs in reach for cerebellar ataxias, fine-grained digital health measures are highly warranted to complement clinical and patient-reported outcome measures in upcoming treatment trials and treatment monitoring. These measures need to demonstrate sensitivity to capture change, in particular in the early stages of the disease. OBJECTIVE: Our aim is to unravel gait measures sensitive to longitudinal change in the-particularly trial-relevant-early stage of spinocerebellar ataxia type 2 (SCA2). METHODS: We performed a multicenter longitudinal study with combined cross-sectional and 1-year interval longitudinal analysis in early-stage SCA2 participants (n = 23, including nine pre-ataxic expansion carriers; median, ATXN2 CAG repeat expansion 38 ± 2; median, Scale for the Assessment and Rating of Ataxia [SARA] score 4.8 ± 4.3). Gait was assessed using three wearable motion sensors during a 2-minute walk, with analyses focused on gait measures of spatio-temporal variability that have shown sensitivity to ataxia severity (eg, lateral step deviation). RESULTS: We found significant changes for gait measures between baseline and 1-year follow-up with large effect sizes (lateral step deviation P = 0.0001, effect size rprb = 0.78), whereas the SARA score showed no change (P = 0.67). Sample size estimation indicates a required cohort size of n = 43 to detect a 50% reduction in natural progression. Test-retest reliability and minimal detectable change analysis confirm the accuracy of detecting 50% of the identified 1-year change. CONCLUSIONS: Gait measures assessed by wearable sensors can capture natural progression in early-stage SCA2 within just 1 year-in contrast to a clinical ataxia outcome. Lateral step deviation represents a promising outcome measure for upcoming multicenter interventional trials, particularly in the early stages of cerebellar ataxia. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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.

Cerebellar Transcranial Alternating Current Stimulation in Essential Tremor Patients with Thalamic Stimulation: A Proof-of-Concept Study.

Essential tremor (ET) is a disabling condition resulting from a dysfunction of cerebello-thalamo-cortical circuitry. Deep brain stimulation (DBS) or lesion of the ventral-intermediate thalamic nucleus (VIM) is an effective treatment for severe ET. Transcranial cerebellar brain stimulation has recently emerged as a non-invasive potential therapeutic option. Here, we aim to investigate the effects of high-frequency non-invasive cerebellar transcranial alternating current stimulation (tACS) in severe ET patients already operated for VIM-DBS. Eleven ET patients with VIM-DBS, and 10 ET patients without VIM-DBS and matched for tremor severity, were included in this double-blind proof-of-concept controlled study. All patients received unilateral cerebellar sham-tACS and active-tACS for 10 min. Tremor severity was blindly assessed at baseline, without VIM-DBS, during sham-tACS, during and at 0, 20, 40 min after active-tACS, using kinetic recordings during holding posture and action ('nose-to-target') task and videorecorded Fahn-Tolosa-Marin (FTM) clinical scales. In the VIM-DBS group, active-tACS significantly improved both postural and action tremor amplitude and clinical (FTM scales) severity, relative to baseline, whereas sham-tACS did not, with a predominant effect for the ipsilateral arm. Tremor amplitude and clinical severity were also not significantly different between ON VIM-DBS and active-tACS conditions. In the non-VIM-DBS group, we also observed significant improvements in ipsilateral action tremor amplitude, and clinical severity after cerebellar active-tACS, with a trend for improved postural tremor amplitude. In non-VIM-DBS group, sham- active-tACS also decreased clinical scores. These data support the safety and potential efficacy of high-frequency cerebellar-tACS to reduce ET amplitude and severity.

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.

Behavioral Differences Across Theta Burst Stimulation Protocols. A Study on the Sense of Agency in Healthy Humans.

BACKGROUND: Theta burst stimulation (TBS) is a non-invasive brain stimulation method. Various stimulation protocols have been proposed, for instance, stimulation at 50 Hz with pattern at 5 Hz, or at 30 Hz with pattern at 6 Hz. To identify better stimulation parameters for behavioral applications, we investigated the effects of 50-Hz continuous TBS (cTBS) on the sense of agency (SoA), and compared them with a previously published study with 30-Hz cTBS. METHODS: Based on power analysis from a previous sample using two applications of 30-Hz cTBS, we recruited 20 healthy subjects in a single-blind, Vertex-controlled, randomized, crossover trial. Participants were stimulated with one application of 50-Hz cTBS over the right posterior parietal cortex (rPPC), a key area for agency processing, and the vertex, in a random order. A behavioral task targeting the SoA was done before and after stimulation. After controlling for baseline differences across samples, we studied the effect of stimulation in the two protocols separately. RESULTS: Compared to the previously published 30-Hz protocol, 50-Hz cTBS over the rPPC did not reveal significant changes in the SoA, similar to sham Vertex stimulation. CONCLUSION: One application of 50-Hz cTBS was not sufficient to elicit behavioral effects, compared to two applications of 30-Hz cTBS, as previously described. This may be due to a mechanism of synaptic plasticity, consolidated through consecutive stimulation cycles. Our results are relevant for future studies aiming at modulating activity of the rPPC in cognitive domains other than agency, and in patients affected by abnormal agency, who could benefit from treatment options based on TBS.

Trans-Spinal Direct Current Stimulation for Managing Primary Orthostatic Tremor.

BACKGROUND: Primary orthostatic tremor (POT) is a rare disorder, characterized by 13 to 18 Hz tremor in the legs when standing and is often refractory to medical treatment. Epidural spinal cord stimulation has been proposed as an alternative treatment. However, this approach is invasive, which limits its application. OBJECTIVE: Trans-spinal direct current stimulation (tsDCS) is a non-invasive method to modulate spinal cord circuits. The aim of this proof-of-concept study was to investigate the potential beneficial effect of tsDCS in POT. METHODS: We conducted a double-blind, sham-controlled study in 16 patients with POT. In two separate visits, patients received sham tsDCS first followed by active (either cathodal or anodal) tsDCS. The primary outcome was the change in time in standing position. Secondary outcomes comprised quantitative assessment of tremor, measurement of corticospinal excitability including short-latency afferent inhibition, and clinical global impression-improvement (CGI-I). Measurements were made at baseline, after sham tsDCS, 0-30 min, and 30-60 min after active conditions. RESULTS: Cathodal-tsDCS reduced tremor amplitude and frequency and lowered corticospinal excitability whereas anodal-tsDCS reduced tremor frequency only. CGI-I scores positively correlated with the time in standing position after both active tsDCS conditions. CONCLUSION: A single session of tsDCS can improve instability in POT. This opens a new vista for experimental treatment options using multiple sessions of spinal DC stimulation. © 2021 International Parkinson and Movement Disorder Society.

Prediction of motor recovery after stroke: being pragmatic or innovative?

PURPOSE OF REVIEW: This review considers both pragmatic and cutting-edge approaches for predicting motor stroke recovery over the period 2017-2019. It focuses on the predictive value of clinical scores and biomarkers including Transcranial Magnetic Stimulation (TMS) and MRI as well as more innovative alternatives. RECENT FINDINGS: Clinical scores combined with corticospinal tract (CST) integrity as assessed by both TMS-induced motor-evoked potential (MEP) and MRI predict motor recovery with an accuracy of about 75%. Therefore, research on novel biomarkers is still needed to improve the accuracy of these models. SUMMARY: Up to date, there is no consensus about which predictive models should be used in clinical routine. Decision trees, such as the PREP2 algorithm are probably the easiest approach to operationalize the translation of predictive models from bench to bedside. However, external validation is still needed to implement current models.

Elucidating the Structural and Functional Correlates of Upper-Limb Poststroke Motor Impairment.

Background and Purpose- Many studies have attempted to bring to light the neural correlates of poststroke motor impairment, but few have used multimodal approach to explain it. The aim of this study was to elucidate neural structural and functional correlates of upper limb motor impairment by combining electrophysiological, anatomic, and functional neuroimaging data. Methods- Forty ischemic stroke patients (median [min-max] age: 63 [33-82] years, time poststroke: 3.5 [1.1-58] months) with unilateral upper limb weakness were included. The upper limb motor impairment was defined by a motor composite score. Simple linear analysis followed by multiple linear regression analysis were performed to identify which variables (corticospinal excitability, laterality indices within the primary motor cortex or corticospinal [CST], and corpus callosum tracts integrity) were the best explaining factors of upper limb motor impairment. Results- There was a significant correlation between the resting motor threshold ratio and CST damage (r= -0.50 [95% CI, -0.70 to -0.22]; P<0.001) as well as the motor-evoked potentials amplitude (r= -0.73 [95% CI, -0.85 to -0.54]; P<0.001). Only the resting motor threshold ratio was retained by the multiple regression model and explained half of the variance (49%; P<0.001) of the upper limb motor impairment after stroke. Conclusions- The implementation of quantitative neurophysiological measurements such as the resting motor threshold as a surrogate marker of impairment could be considered in neurorehabilitation trials.

Redundancy Among Parameters Describing the Input-Output Relation of Motor Evoked Potentials in Healthy Subjects and Stroke Patients.

Background: Transcranial magnetic stimulation (TMS) is widely used to probe corticospinal excitability through Motor Evoked Potential (MEP) amplitude measurements. The input-output (I/O) curve is a sigmoid-shaped relation between the MEP amplitude at incremented TMS intensities. The aim of this study was to examine the relationships between seven parameters derived from the sigmoid function. Methods: Principal Component Analysis and Spearman's rank correlation matrices were used to determine if the seven I/O curve parameters capture similar or, conversely, different aspects of the corticospinal excitability in 24 healthy subjects and 40 stroke survivors with a hand motor impairment. Results: Maximum amplitude (MEPmax), peak slope, area under the I/O curve (AUC), and MEP amplitude recorded at 140% of the resting motor threshold showed strong linear relationships with each other (ρ > 0.72, p < 0.001). Results were found to be similar in healthy subjects and in both hemispheres of stroke patients. Our results did not support an added benefit of sampling entire I/O curves in both healthy subjects and stroke patients, with the exception of S50, the stimulus intensity needed to obtain half of MEPmax amplitude. Conclusions: This demonstrates that MEP elicited at a single stimulus intensity allows to capture the same characteristics of the corticospinal excitability as measured by the AUC, MEPmax and the peak slope, which may be of interest in both clinical and research settings. However, it is still necessary to plot I/O curves if an effect or a difference is expected at S50.

The supplementary motor area modulates interhemispheric interactions during movement preparation.

The execution of coordinated hand movements requires complex interactions between premotor and primary motor areas in the two hemispheres. The supplementary motor area (SMA) is involved in movement preparation and bimanual coordination. How the SMA controls bimanual coordination remains unclear, although there is evidence suggesting that the SMA could modulate interhemispheric interactions. With a delayed-response task, we investigated interhemispheric interactions underlying normal movement preparation and the role of the SMA in these interactions during the delay period of unimanual or bimanual hand movements. We used functional MRI and transcranial magnetic stimulation in 22 healthy volunteers (HVs), and then in two models of SMA dysfunction: (a) in the same group of HVs after transient disruption of the right SMA proper by continuous transcranial magnetic theta-burst stimulation; (b) in a group of 22 patients with congenital mirror movements (CMM), whose inability to produce asymmetric hand movements is associated with SMA dysfunction. In HVs, interhemispheric connectivity during the delay period was modulated according to whether or not hand coordination was required for the forthcoming movement. In HVs following SMA disruption and in CMM patients, interhemispheric connectivity was modified during the delay period and the interhemispheric inhibition was decreased. Using two models of SMA dysfunction, we showed that the SMA modulates interhemispheric interactions during movement preparation. This unveils a new role for the SMA and highlights its importance in coordinated movement preparation.

Individual recovery profiles of manual dexterity, and relation to corticospinal lesion load and excitability after stroke -a longitudinal pilot study.

OBJECTIVES: In this longitudinal pilot study, we investigated how manual dexterity recovery was related to corticospinal tract (CST) injury and excitability, in six patients undergoing conventional rehabilitation. METHODS: Key components of manual dexterity, namely finger force control, finger tapping rate and independence of finger movements, were quantified. Structural MRI was obtained to calculate CST lesion load. CST excitability was assessed by measuring rest motor threshold (RMT) and the amplitude of motor evoked potentials (MEPs) using transcranial magnetic stimulation (TMS). Measurements were obtained at two weeks, three and six months post-stroke. RESULTS: At six months post-stroke, complete recovery of hand gross motor impairment (i.e., maximal Fugl-Meyer score for hand) had occurred in three patients and four patients had recovered ability to accurately control finger force. However, tapping rate and independence of finger movements remained impaired in all six patients at six months. Recovery in hand gross motor impairment and finger force control occurred in patients with smaller CST lesion load and almost complete recovery of CST excitability, although RMT or MEP size remained slightly altered in the stroke-affected hemisphere compared to the unaffected hemisphere. The two patients with poorest recovery showed persistent absence of MEPs and greatest structural injury to CST. DISCUSSION: The findings support good motor recovery being overall correlated with smaller CST lesion, and with almost complete recovery of CST excitability. However, impairment of manual dexterity persisted despite recovery in gross hand movements and grasping abilities, suggesting involvement of additional brain structures for fine manual tasks.

Furosemide Unmasks Inhibitory Dysfunction after Spinal Cord Injury in Humans: Implications for Spasticity.

Spasticity after spinal cord injury has considerable quality of life implications, impacts on rehabilitation efforts and necessitates long-term multi-disciplinary pharmacological and non-pharmacological management. The potassium chloride co-transporter (KCC2) plays a central role in intracellular chloride homeostasis and the inhibitory function of mature neurons. Animal studies consistently have demonstrated a downregulation of KCC2 activity after spinal cord transection, causing a shift from the inhibitory action of gamma-aminobutyric acid and glycine to an excitatory effect. Furosemide, a recognized KCC2 antagonist in animals, blocks the formation of inhibitory post-synaptic potentials in spinal motoneurons without affecting excitatory post-synaptic potentials. Based on observations in animals studies, we hypothesized that furosemide may be used to unmask KCC2 downregulation after spinal cord injury in humans, which contributes to reflex hyperexcitability. We have shown previously that furosemide reduces both pre-synaptic and post-synaptic inhibition in healthy subjects without altering monosynaptic excitatory transmission. These findings provide evidence that furosemide may be used in humans to evaluate inhibitory synapses in the spinal cord. In this present study, we show that furosemide fails to modulate both pre- and post-synaptic inhibitions relayed to soleus spinal motor neurons in persons with spinal cord injury. The lack of furosemide effect after spinal cord injury suggests KCC2 dysfunction in humans, resulting in reduced inhibitory synaptic transmission in spinal neurons. Our findings suggest that KCC2 dysfunction may be an important etiological factor in hyperreflexia after spinal cord injury. These observations may pave the way to novel therapeutic strategies against spasticity centered on chloride homeostasis.

Does Resting Motor Threshold Predict Motor Hand Recovery After Stroke?

Background: Resting Motor threshold (rMT) is one of the measurement obtained by Transcranial Magnetic Stimulation (TMS) that reflects corticospinal excitability. As a functional marker of the corticospinal pathway, the question arises whether rMT is a suitable biomarker for predicting post-stroke upper limb function. To that aim, we conducted a systematic review of relevant studies that investigated the clinical significance of rMT in stroke survivors by using correlations between upper limb motor scores and rMT. Methods: Studies that reported correlations between upper limb motor function and rMT as a measure of corticospinal excitability in distal arm muscle were identified via a literature search in stroke patients. Two authors extracted the data using a home-made specific form. Subgroup analyses were carried out with patients classified with respect to time post-stroke onset (early vs. chronic stage) and stroke location (cortical, subcortical, or cortico-subcortical). Methodological quality of the study was also evaluated by a published checklist. Results: Eighteen studies with 22 groups (n = 508 stroke patients) were included in this systematic review. Mean methodological quality score was 14.75/24. rMT was often correlated with motor function or hand dexterity (n = 15/22, 68%), explaining on average 31% of the variance of the motor score. Moreover, the results did not seem impacted if patients were examined at the early or chronic stages of stroke. Two findings could not be properly interpreted: (i) the fact that the rMT is an independent predictor of motor function as several confounding factors are well-established, and, (ii) whether the stroke location impacts this prediction. Conclusion: Most of the studies found a correlation between rMT and upper limb motor function after stroke. However, it is still unclear if rMT is an independent predictor of upper limb motor function when taking into account for age, time post stroke onset and level of corticospinal tract damage as confounding factors. Clear-cut conclusions could not be drawn at that time but our results suggest that rMT could be a suitable candidate although future investigations are needed. Systematic Review Registration Number: (https://www.crd.york.ac.uk/prospero/): ID 114317.

Repetitive sessions of tDCS to improve naming in post-stroke aphasia: Insights from an individual patient data (IPD) meta-analysis.

OBJECTIVES: Small clinical trials reported that repetitive sessions of tDCS could improve naming abilities in post-stroke aphasia. However, systematic meta-analyses found no effect, but all of these analyses pooled data from both single and repetitive sessions at the group level. The aim of this paper was to perform a meta-analysis based on individual patient data to explore the effects of repetitive tDCS sessions on naming in post-stroke aphasia and in prespecified subgroups. METHODS: We searched for published sham-controlled trials using the keywords "aphasia OR language" AND "transcranial direct current stimulation OR tDCS" AND "stroke". We computed an active and sham improvement ratio by dividing the difference between naming scores after and before the active or sham sessions, respectively, by the total number of picture items. Because of heterogeneity (I2 = 66%, p: 0.002), we used random-effects models to estimate the standardized mean difference (SMD) for the naming outcome. We then analyzed subgroups according to number of sessions, polarity, side/location of the active electrode, post-stroke delay, aphasia severity and comprehension disorders. RESULTS: Seven eligible studies were identified, including 68 chronic stroke patients. tDCS was beneficial on naming ability (35% ±34% in the active vs. 25% ±37% in the sham condition). An SMD of 0.8 (95% CI: 0.27-1.33) was found for the naming outcome. Additionally, there was a dose-dependent effect (5 vs. >5 sessions). We also demonstrated a prevalence of anodal vs. cathodal condition and left vs. right targeting electrode. Finally, repetitive sessions were beneficial regardless of the severity of aphasia, comprehension disorders or post-stroke delay. CONCLUSION: Repetitive sessions of tDCS are likely to be valuable in enhancing naming accuracy in post-stroke aphasia.

Mutations in the netrin-1 gene cause congenital mirror movements.

Netrin-1 is a secreted protein that was first identified 20 years ago as an axon guidance molecule that regulates midline crossing in the CNS. It plays critical roles in various tissues throughout development and is implicated in tumorigenesis and inflammation in adulthood. Despite extensive studies, no inherited human disease has been directly associated with mutations in NTN1, the gene coding for netrin-1. Here, we have identified 3 mutations in exon 7 of NTN1 in 2 unrelated families and 1 sporadic case with isolated congenital mirror movements (CMM), a disorder characterized by involuntary movements of one hand that mirror intentional movements of the opposite hand. Given the diverse roles of netrin-1, the absence of manifestations other than CMM in NTN1 mutation carriers was unexpected. Using multimodal approaches, we discovered that the anatomy of the corticospinal tract (CST) is abnormal in patients with NTN1-mutant CMM. When expressed in HEK293 or stable HeLa cells, the 3 mutated netrin-1 proteins were almost exclusively detected in the intracellular compartment, contrary to WT netrin-1, which is detected in both intracellular and extracellular compartments. Since netrin-1 is a diffusible extracellular cue, the pathophysiology likely involves its loss of function and subsequent disruption of axon guidance, resulting in abnormal decussation of the CST.

Anatomical and functional correlates of cortical motor threshold of the dominant hand.

BACKGROUND: Resting Motor threshold (rMT) provides information about cortical motor excitability. Interestingly, the influences of the structural or functional variability of the motor system on the rMT inter-individual variability have been poorly investigated. OBJECTIVE/HYPOTHESIS: To investigate relationships between rMT and measures of brain structures and function of the motor system. The hypothesis is that cortical excitability not only depends on the primary motor cortex (M1) but also on the integration of information originating from its vicinity such as premotor (PMd and SMA) and post-central (S1) cortices. METHODS: We measured brain structures, including grey and white matter properties (cortical volume and fiber coherence respectively), and functional interaction (resting-state functional connectivity-FC) in areas contributing to the corticospinal tract axons, i. e, M1, S1, SMA and PMd in the dominant hemisphere of 21 healthy subjects. RESULTS: The rMT was inversely correlated with the FC between PMd and M1 (r = -0.496, 95%CI: -0.764; -0.081; p = 0.02) and the grey matter volume of the dominant hemisphere (r = -0.463, 95%CI: -0.746; -0.039; p = 0.03). The multiple regression analysis model retained the FC between M1 and PMd (coefficient: -25 ± 9) as well as the grey matter volume of the dominant hemisphere (coefficient: -0.15 ± 0.06) explaining 44% of the variance of the rMT (p: 0.005). When adding age and coil-to-cortex distance, two factors known to influence rMT, the model reached a R2 of 75% (p: 0.0001). CONCLUSIONS: These results underline the major role of the PMd and the cortico-cortical connections toward M1 in the excitation of the corticospinal fibers likely through trans-synaptic pathways.

Non cell-autonomous role of DCC in the guidance of the corticospinal tract at the midline.

DCC, a NETRIN-1 receptor, is considered as a cell-autonomous regulator for midline guidance of many commissural populations in the central nervous system. The corticospinal tract (CST), the principal motor pathway for voluntary movements, crosses the anatomic midline at the pyramidal decussation. CST fails to cross the midline in Kanga mice expressing a truncated DCC protein. Humans with heterozygous DCC mutations have congenital mirror movements (CMM). As CMM has been associated, in some cases, with malformations of the pyramidal decussation, DCC might also be involved in this process in human. Here, we investigated the role of DCC in CST midline crossing both in human and mice. First, we demonstrate by multimodal approaches, that patients with CMM due to DCC mutations have an increased proportion of ipsilateral CST projections. Second, we show that in contrast to Kanga mice, the anatomy of the CST is not altered in mice with a deletion of DCC in the CST. Altogether, these results indicate that DCC controls CST midline crossing in both humans and mice, and that this process is non cell-autonomous in mice. Our data unravel a new level of complexity in the role of DCC in CST guidance at the midline.

Saccadic eye movements as markers of schizophrenia spectrum: Exploration in at-risk mental states.

Schizophrenia is a neurodevelopmental disease with cognitive and motor impairments. Motor dysfunctions, such as eye movements or Neurological Soft Signs (NSS), are proposed as endophenotypic markers. Antisaccade (AS) and memory-guided saccades (MGS), two markers of inhibitory control mechanism, are altered in both patients with schizophrenia and their relatives, although these tools may have different sensitivities. Recently, emphasis has been put on identifying markers predictive of psychosis transition in subjects with ultra-high-risk psychosis in order to develop targeted prevention. This study investigates AS and MGS in 46 patients with schizophrenia, 23 ultra-high-risk subjects, and 39 full siblings compared to 47 healthy volunteers. NSS were assessed as a marker of abnormal neurodevelopment. The results revealed more errors in MGS in patients, ultra-high-risk subjects and siblings, than in controls, and more specifically ultra-high-risk subjects with high NSS scores. By contrast, the error rate in AS was significantly higher only in patients with schizophrenia compared to controls. These findings suggest that MGS could be more accurate to detect deficient inhibitory processes as a marker of vulnerability before the onset of schizophrenia. The use of the different paradigms (AS, MGS) revealed distinct profiles depending on the stage of the disease, indicating that some alterations could be pure endophenotypic markers of vulnerability for schizophrenia, while others could be markers of the disease progression.