RESUMEN
BACKGROUND: Abnormal sensory processing, including temporal discrimination threshold, has been described in various dystonic syndromes. OBJECTIVE: To investigate visual sensory processing in DYT-SGCE and identify its structural correlates. METHODS: DYT-SGCE patients without DBS (DYT-SGCE-non-DBS) and with DBS (DYT-SGCE-DBS) were compared to healthy volunteers in three tasks: a temporal discrimination threshold, a movement orientation discrimination, and movement speed discrimination. Response times attributed to accumulation of sensory visual information were computationally modelized, with µ parameter indicating sensory mean growth rate. We also identified the structural correlates of behavioral performance for temporal discrimination threshold. RESULTS: Twenty-four DYT-SGCE-non-DBS, 13 DYT-SGCE-DBS, and 25 healthy volunteers were included in the study. In DYT-SGCE-DBS, the discrimination threshold was higher in the temporal discrimination threshold (P = 0.024), with no difference among the groups in other tasks. The sensory mean growth rate (µ) was lower in DYT-SGCE in all three tasks (P < 0.01), reflecting a slower rate of sensory accumulation for the visual information in these patients independent of DBS. Structural imaging analysis showed a thicker left primary visual cortex (P = 0.001) in DYT-SGCE-non-DBS compared to healthy volunteers, which also correlated with lower µ in temporal discrimination threshold (P = 0.029). In DYT-SGCE-non-DBS, myoclonus severity also correlated with a lower µ in the temporal discrimination threshold task (P = 0.048) and with thicker V1 on the left (P = 0.022). CONCLUSION: In DYT-SGCE, we showed an alteration of the visual sensory processing in the temporal discrimination threshold that correlated with myoclonus severity and structural changes in the primary visual cortex. © 2019 International Parkinson and Movement Disorder Society.
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Trastornos Distónicos/fisiopatología , Trastornos del Movimiento/fisiopatología , Movimiento/fisiología , Percepción Visual/fisiología , Adulto , Trastornos Distónicos/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trastornos del Movimiento/patología , Mioclonía/patología , Mioclonía/fisiopatologíaRESUMEN
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.
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Isquemia Encefálica/diagnóstico por imagen , Cuerpo Calloso/diagnóstico por imagen , Potenciales Evocados Motores/fisiología , Corteza Motora/diagnóstico por imagen , Tractos Piramidales/diagnóstico por imagen , Accidente Cerebrovascular/diagnóstico por imagen , Extremidad Superior/fisiopatología , Adulto , Anciano , Anciano de 80 o más Años , Isquemia Encefálica/fisiopatología , Imagen de Difusión Tensora , Femenino , Neuroimagen Funcional , Fuerza de la Mano , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Accidente Cerebrovascular/fisiopatología , Estimulación Magnética TranscranealRESUMEN
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.
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Lateralidad Funcional/fisiología , Intención , Corteza Motora/diagnóstico por imagen , Corteza Motora/fisiología , Movimiento/fisiología , Desempeño Psicomotor/fisiología , Adolescente , Adulto , Potenciales Evocados Motores/fisiología , Femenino , Voluntarios Sanos , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Trastornos del Movimiento/diagnóstico por imagen , Trastornos del Movimiento/fisiopatología , Estimulación Magnética Transcraneal/métodos , Adulto JovenRESUMEN
BACKGROUND: Evidence from mice suggests that brain infiltrating immune cells contribute to neurodegeneration, and we previously identified a deleterious lymphocyte infiltration in Parkinson's disease mice. However, this remains controversial for monocytes, due to artifact-prone techniques used to distinguish them from microglia. Our aim was to reassess this open question, by taking advantage of the recent recognition that chemokine receptors CCR2 and CX3CR1 can differentiate between inflammatory monocytes and microglia, enabling to test whether CCR2+ monocytes infiltrate the brain during dopaminergic (DA) neurodegeneration and whether they contribute to neuronal death. This revealed unexpected insights into possible regulation of monocyte-attracting CCL2 induction. METHODS: We used acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mice and assessed monocyte infiltration by combining laser microdissection-guided chemokine RNA profiling of the substantia nigra (SN) with immunohistochemistry and CCR2-GFP reporter mice. To determine contribution to neuronal loss, we used CCR2-deletion and CCL2-overexpression, to reduce and increase CCR2+ monocyte infiltration, and CX3CR1-deletion to assess a potential implication in CCL2 regulation. RESULTS: Nigral chemokine profiling revealed early CCL2/7/12-CCR2 axis induction, suggesting monocyte infiltration in MPTP mice. CCL2 protein showed early peak induction in nigral astrocytes, while CCR2-GFP mice revealed early but limited nigral monocyte infiltration. However, blocking infiltration by CCR2 deletion did not influence DA neuronal loss. In contrast, transgenic astrocytic CCL2 over-induction increased CCR2+ monocyte infiltration and DA neuronal loss in MPTP mice. Surprisingly, CCL2 over-induction was also detected in MPTP intoxicated CX3CR1-deleted mice, which are known to present increased DA neuronal loss. Importantly, CX3CR1/CCL2 double-deletion suggested that increased neurotoxicity was driven by astrocytic CCL2 over-induction. CONCLUSIONS: We show that CCR2+ monocytes infiltrate the affected CNS, but at the level observed in acute MPTP mice, this does not contribute to DA neuronal loss. In contrast, the underlying astrocytic CCL2 induction seemed to be tightly controled, as already moderate CCL2 over-induction led to increased neurotoxicity in MPTP mice, likely due to the increased CCR2+ monocyte infiltration. Importantly, we found evidence suggesting that during DA neurodegeneration, this control was mediated by microglial CX3CR1 signaling, which protects against such neurotoxic CCL2 over-induction by astrocytes, thus hinting at an endogenous mechanism to limit neurotoxic effects of the CCL2-CCR2 axis.
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Astrocitos/metabolismo , Movimiento Celular/efectos de los fármacos , Quimiocina CCL2/metabolismo , Intoxicación por MPTP/patología , Microglía/metabolismo , Receptores de Interleucina-8A/deficiencia , Animales , Astrocitos/efectos de los fármacos , Antígeno CD11b/metabolismo , Proteínas de Unión al Calcio/metabolismo , Movimiento Celular/genética , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Lipopolisacáridos/farmacología , Intoxicación por MPTP/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas de Microfilamentos/metabolismo , Microglía/efectos de los fármacos , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Receptores CCR2/genética , Receptores CCR2/metabolismo , Receptores de Interleucina-8A/genética , Sustancia Negra/efectos de los fármacos , Sustancia Negra/patología , Factores de Tiempo , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Congenital mirror movements (CMM) are characterized by involuntary movements of one side of the body that mirror intentional movements on the opposite side. CMM reflect dysfunctions and structural abnormalities of the motor network and are mainly inherited in an autosomal-dominant fashion. Recently, heterozygous mutations in DCC, the gene encoding the receptor for netrin 1 and involved in the guidance of developing axons toward the midline, have been identified but CMM are genetically heterogeneous. By combining genome-wide linkage analysis and exome sequencing, we identified heterozygous mutations introducing premature termination codons in RAD51 in two families with CMM. RAD51 mRNA was significantly downregulated in individuals with CMM resulting from the degradation of the mutated mRNA by nonsense-mediated decay. RAD51 was specifically present in the developing mouse cortex and, more particularly, in a subpopulation of corticospinal axons at the pyramidal decussation. The identification of mutations in RAD51, known for its key role in the repair of DNA double-strand breaks through homologous recombination, in individuals with CMM reveals a totally unexpected role of RAD51 in neurodevelopment. These findings open a new field of investigation for researchers attempting to unravel the molecular pathways underlying bimanual motor control in humans.
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Anomalías Congénitas/genética , Discinesias/genética , Trastornos del Movimiento/genética , Recombinasa Rad51/genética , Axones , Receptor DCC , Roturas del ADN de Doble Cadena , Reparación del ADN , Regulación hacia Abajo , Exoma/genética , Salud de la Familia , Heterogeneidad Genética , Estudio de Asociación del Genoma Completo/métodos , Haploinsuficiencia , Heterocigoto , Recombinación Homóloga/genética , Humanos , Corteza Motora/anomalías , Mutación/genética , Factores de Crecimiento Nervioso/genética , Netrina-1 , Linaje , ARN Mensajero/genética , Receptores de Superficie Celular/genética , Proteínas Supresoras de Tumor/genéticaRESUMEN
A large body of evidence points to a role of basal ganglia dysfunction in the pathophysiology of dystonia, but recent studies indicate that cerebellar dysfunction may also be involved. The cerebellum influences sensorimotor adaptation by modulating sensorimotor plasticity of the primary motor cortex. Motor cortex sensorimotor plasticity is maladaptive in patients with writer's cramp. Here we examined whether putative cerebellar dysfunction in dystonia is linked to these patients' maladaptive plasticity. To that end we compared the performances of patients and healthy control subjects in a reaching task involving a visuomotor conflict generated by imposing a random deviation (-40° to 40°) on the direction of movement of the mouse/cursor. Such a task is known to involve the cerebellum. We also compared, between patients and healthy control subjects, how the cerebellum modulates the extent and duration of an ongoing sensorimotor plasticity in the motor cortex. The cerebellar cortex was excited or inhibited by means of repeated transcranial magnetic stimulation before artificial sensorimotor plasticity was induced in the motor cortex by paired associative stimulation. Patients with writer's cramp were slower than the healthy control subjects to reach the target and, after having repeatedly adapted their trajectories to the deviations, they were less efficient than the healthy control subjects to perform reaching movement without imposed deviation. It was interpreted as impaired washing-out abilities. In healthy subjects, cerebellar cortex excitation prevented the paired associative stimulation to induce a sensorimotor plasticity in the primary motor cortex, whereas cerebellar cortex inhibition led the paired associative stimulation to be more efficient in inducing the plasticity. In patients with writer's cramp, cerebellar cortex excitation and inhibition were both ineffective in modulating sensorimotor plasticity. In patients with writer's cramp, but not in healthy subjects, behavioural parameters reflecting their capacity for adapting to the rotation and for washing-out of an earlier adaptation predicted the efficacy of inhibitory cerebellar conditioning to influence sensorimotor plasticity: the better the online adaptation, the smaller the influence of cerebellar inhibitory stimulation on motor cortex plasticity. Altered cerebellar encoding of incoming afferent volleys may result in decoupling the motor component from the afferent information flow, and also in maladjusted sensorimotor calibration. The loss of cerebellar control over sensorimotor plasticity might also lead to building up an incorrect motor program to specific adaptation tasks such as writing.
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Enfermedades Cerebelosas/complicaciones , Trastornos Distónicos/etiología , Trastornos Distónicos/patología , Corteza Motora/fisiopatología , Plasticidad Neuronal/fisiología , Adaptación Fisiológica/fisiología , Adolescente , Adulto , Anciano , Biofisica , Electromiografía , Potenciales Evocados Motores/fisiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Músculo Esquelético/inervación , Músculo Esquelético/fisiopatología , Inhibición Neural/fisiología , Desempeño Psicomotor/fisiología , Tractos Piramidales/fisiopatología , Tiempo de Reacción/fisiología , Estadística como Asunto , Estimulación Magnética Transcraneal , Grabación en Video , Adulto JovenRESUMEN
Mirror movements are involuntary symmetrical movements of one side of the body that mirror voluntary movements of the other side. Congenital mirror movement disorder is a rare condition characterized by mirror movements that persist throughout adulthood in subjects with no other clinical abnormalities. The affected individuals have mirror movements predominating in the muscles that control the fingers and are unable to perform purely unimanual movements. Congenital mirror movement disorder thus provides a unique paradigm for studying the lateralization of motor control. We conducted a multimodal, controlled study of patients with congenital mirror movements associated with RAD51 haploinsufficiency (n = 7, mean age 33.3 ± 16.8 years) by comparison with age- and gender-matched healthy volunteers (n = 14, mean age 33.9 ± 16.1 years). We showed that patients with congenital mirror movements induced by RAD51 deficiency had: (i) an abnormal decussation of the corticospinal tract; (ii) abnormal interhemispheric inhibition and bilateral cortical activation of primary motor areas during intended unimanual movements; and (iii) an abnormal involvement of the supplementary motor area during both unimanual and bimanual movements. The lateralization of motor control thus requires a fine interplay between interhemispheric communication and corticospinal wiring. This fine interplay determines: (i) the delivery of appropriate motor plans from the supplementary motor area to the primary motor cortex; (ii) the lateralized activation of the primary motor cortex; and (iii) the unilateral transmission of the motor command to the limb involved in the intended movement. Our results also unveil an unexpected function of RAD51 in corticospinal development of the motor system.
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Discinesias/fisiopatología , Vías Eferentes/fisiopatología , Mano/fisiopatología , Corteza Motora/fisiopatología , Recombinasa Rad51/genética , Adolescente , Adulto , Discinesias/congénito , Discinesias/genética , Potenciales Evocados Motores , Femenino , Lateralidad Funcional/fisiología , Haploinsuficiencia/genética , Humanos , Magnetoencefalografía , Masculino , Persona de Mediana Edad , Imagen Multimodal , Estimulación Magnética Transcraneal , Adulto JovenRESUMEN
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.
RESUMEN
Parkinson disease (PD) is a neurodegenerative disorder characterized by a loss of dopamine-containing neurons. Mounting evidence suggests that dopaminergic cell death is influenced by the innate immune system. However, the pathogenic role of the adaptive immune system in PD remains enigmatic. Here we showed that CD8+ and CD4+ T cells but not B cells had invaded the brain in both postmortem human PD specimens and in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD during the course of neuronal degeneration. We further demonstrated that MPTP-induced dopaminergic cell death was markedly attenuated in the absence of mature T lymphocytes in 2 different immunodeficient mouse strains (Rag1-/- and Tcrb-/- mice). Importantly, similar attenuation of MPTP-induced dopaminergic cell death was seen in mice lacking CD4 as well as in Rag1-/- mice reconstituted with FasL-deficient splenocytes. However, mice lacking CD8 and Rag1-/- mice reconstituted with IFN-gamma-deficient splenocytes were not protected. These data indicate that T cell-mediated dopaminergic toxicity is almost exclusively arbitrated by CD4+ T cells and requires the expression of FasL but not IFNgamma. Further, our data may provide a rationale for targeting the adaptive arm of the immune system as a therapeutic strategy in PD.
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Encéfalo , Linfocitos T CD4-Positivos/inmunología , Degeneración Nerviosa , Enfermedad de Parkinson , Trastornos Parkinsonianos , Anciano , Anciano de 80 o más Años , Animales , Encéfalo/citología , Encéfalo/inmunología , Encéfalo/patología , Linfocitos T CD4-Positivos/citología , Muerte Celular/fisiología , Modelos Animales de Enfermedad , Dopamina/metabolismo , Proteína Ligando Fas/genética , Proteína Ligando Fas/metabolismo , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Humanos , Sistema Inmunológico/fisiología , Interferón gamma/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Degeneración Nerviosa/inmunología , Degeneración Nerviosa/patología , Neuronas/citología , Neuronas/metabolismo , Neuronas/patología , Enfermedad de Parkinson/inmunología , Enfermedad de Parkinson/patología , Trastornos Parkinsonianos/inmunología , Trastornos Parkinsonianos/patologíaRESUMEN
BACKGROUND: Recent neuroimaging studies point to a possible pathophysiological role of cerebellar dysfunction in dystonia. The authors investigated the association between sensorimotor adaptation, cerebellar dysfunction and the myoclonus-dystonia phenotype. METHODS: The authors prospectively analysed reactive saccade adaptation in a genetically homogeneous group of 14 patients with DYT11 dystonia owing to a mutation of the SGCE gene. The authors used a backward reactive saccade adaptation task, a well-characterised experimental oculomotor paradigm involving the cerebellum. The principle of this paradigm is to simulate a spatial error in saccade generation by systematically shifting a visual target during saccade execution. Repetition of this systematic error induces a gradual decrease in the initial saccade amplitude, reflecting an adaptive phenomenon. RESULTS: Saccade adaptation was significantly lower in the DYT11 patients than in healthy controls (mean value: 8.9%±4.5% vs 21.6%±4.5%; p=8.3×10(-6)). The time course of adaptation also differed between the patients and controls (p=0.002), reflecting the slower saccadic adaptation in the patients. CONCLUSIONS: This study provides the first neurophysiological evidence of cerebellar dysfunction in DYT11 dystonia and supports a role of cerebellar dysfunction in the myoclonus-dystonia phenotype.
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Enfermedades Cerebelosas/genética , Enfermedades Cerebelosas/fisiopatología , Trastornos Distónicos/genética , Trastornos Distónicos/fisiopatología , Retroalimentación Sensorial/fisiología , Movimientos Sacádicos/genética , Movimientos Sacádicos/fisiología , Sarcoglicanos/genética , Adolescente , Cerebelo/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Examen Neurológico , FenotipoAsunto(s)
Discinesias/genética , Genes DCC/genética , Niño , Discinesias/fisiopatología , Femenino , Humanos , Mutación , LinajeRESUMEN
Myoclonus-dystonia (MD) is a syndrome characterized by myoclonus of subcortical origin and dystonia, frequently associated with psychiatric comorbidities. The motor and psychiatric phenotypes of this syndrome likely result from cortico-striato-thamalo-cerebellar-cortical pathway dysfunction. We hypothesized that reactive and proactive inhibitory control may be altered in these patients. Using the Stop Signal Task, we assessed reactive and proactive inhibitory control in MD patients with (n = 12) and without (n = 21) deep brain stimulation of the globus pallidus interna and compared their performance to matched healthy controls (n = 24). Reactive inhibition was considered as the ability to stop an already initiated action and measured using the stop signal reaction time. Proactive inhibition was assessed through the influence of several consecutive GO or STOP trials on decreased response time or inhibitory process facilitation. The proactive inhibition was solely impaired in unoperated MD patients. Patients with deep brain stimulation showed impairment in reactive inhibition, independent of presence of obsessive-compulsive disorders. This impairment in reactive inhibitory control correlated with intrinsic severity of myoclonus (i.e. pre-operative score). The results point to a dissociation in reactive and proactive inhibitory control in MD patients with and without deep brain stimulation of the globus pallidus interna.
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Trastornos Distónicos/fisiopatología , Adulto , Estimulación Encefálica Profunda/métodos , Trastornos Disociativos/fisiopatología , Distonía/fisiopatología , Femenino , Globo Pálido/fisiopatología , Humanos , Inhibición Psicológica , Masculino , Mioclonía/fisiopatología , Inhibición Proactiva , Tiempo de Reacción/fisiología , Inhibición Reactiva , Transmisión Sináptica , Adulto JovenRESUMEN
The regulatory circuits that orchestrate mammalian myoblast cell fusion during myogenesis are poorly understood. The transcriptional activity of FoxO1a directly regulates this process, yet the molecular mechanisms governing FoxO1a activity during muscle cell differentiation remain unknown. Here we show an autoregulatory loop in which FoxO1a directly activates transcription of the cyclic GMP-dependent protein kinase I (cGKI) gene and where the ensuing cGKI activity phosphorylates FoxO1a and abolishes its DNA binding activity. These findings establish the FoxO1a-to-cGKI pathway as a novel feedback loop that allows the precise tuning of myoblast fusion. Interestingly, this pathway appears to operate independently of muscle cell differentiation programs directed by myogenic transcription factors.
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Proteínas Quinasas Dependientes de GMP Cíclico/metabolismo , Mioblastos/citología , Mioblastos/metabolismo , Factores de Transcripción/metabolismo , Secuencia de Aminoácidos , Animales , Diferenciación Celular , Fusión Celular , Células Cultivadas , Proteínas Quinasas Dependientes de GMP Cíclico/antagonistas & inhibidores , Proteínas Quinasas Dependientes de GMP Cíclico/genética , ADN/metabolismo , Proteína Forkhead Box O1 , Factores de Transcripción Forkhead , Humanos , Ratones , Datos de Secuencia Molecular , Fosforilación , Unión Proteica , Alineación de Secuencia , Transducción de Señal , Factores de Transcripción/química , Factores de Transcripción/genética , Transcripción Genética/genéticaRESUMEN
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.
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Orientación del Axón , Receptor DCC/fisiología , Tractos Piramidales/patología , Tractos Piramidales/fisiopatología , Adulto , Anciano , Animales , Axones/metabolismo , Cuerpo Calloso/metabolismo , Receptor DCC/genética , Potenciales Evocados Motores , Femenino , Mano/inervación , Mano/fisiopatología , Humanos , Masculino , Ratones Transgénicos , Persona de Mediana Edad , Corteza Motora/fisiopatología , Movimiento , Neocórtex/metabolismo , Estimulación Magnética TranscranealRESUMEN
BACKGROUND: Based on the hypothesis of a brain energy deficit, we investigated the safety and efficacy of triheptanoin on paroxysmal episodes in patients with alternating hemiplegia of childhood due to ATP1A3 mutations. METHODS: We conducted a randomized, double-blind, placebo-controlled crossover study of triheptanoin, at a target dose corresponding to 30% of daily calorie intake, in ten patients with alternating hemiplegia of childhood due to ATP1A3 mutations. Each treatment period consisted of a 12-week fixed-dose phase, separated by a 4-week washout period. The primary outcome was the total number of paroxysmal events. Secondary outcomes included the number of paroxysmal motor-epileptic events; a composite score taking into account the number, severity and duration of paroxysmal events; interictal neurological manifestations; the clinical global impression-improvement scale (CGI-I); and safety parameters. The paired non-parametric Wilcoxon test was used to analyze treatment effects. RESULTS: In an intention-to-treat analysis, triheptanoin failed to reduce the total number of paroxysmal events (p = 0.646), including motor-epileptic events (p = 0.585), or the composite score (p = 0.059). CGI-I score did not differ between triheptanoin and placebo periods. Triheptanoin was well tolerated. CONCLUSIONS: Triheptanoin does not prevent paroxysmal events in Alternating hemiplegia of childhood. We show the feasibility of a randomized placebo-controlled trial in this setting. TRIAL REGISTRATION: The study has been registered with clinicaltrials.gov ( NCT002408354 ) the 03/24/2015.
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Hemiplejía/tratamiento farmacológico , Triglicéridos/uso terapéutico , Adolescente , Estudios Cruzados , Suplementos Dietéticos , Método Doble Ciego , Femenino , Humanos , Masculino , Adulto JovenRESUMEN
OBJECTIVE: To evaluate the efficacy and safety of zonisamide in patients with myoclonus-dystonia. METHODS: We conducted a randomized, double-blind, placebo-controlled crossover trial of zonisamide (300 mg/d) in 24 patients with myoclonus-dystonia. Each treatment period consisted of a 6-week titration phase followed by a 3-week fixed-dose phase. The periods were separated by a 5-week washout period. The co-primary outcomes were action myoclonus severity (section 4 of the Unified Myoclonus Rating Scale [UMRS 4]) and myoclonus-related functional disability (UMRS 5). Secondary outcomes included dystonia severity, assessed with the movement and disability subscales of the Burke-Fahn-Marsden-Dystonia Rating Scale (BFM), the Clinical Global Impression-Improvement scale (CGI), and safety measures. Wilcoxon signed-rank tests for paired data were used to analyze treatment effects. RESULTS: Twenty-three patients (11 men, 12 women) were analyzed in the intention-to-treat analysis. Zonisamide significantly improved both action myoclonus (median improvement [95% confidence limits] -5 [-9.25 to -1.44], p = 0.003) and myoclonus-related functional disability (median improvement [95% confidence limits] -2 [-2.58 to -2.46], p = 0.007) compared to placebo. Zonisamide also significantly improved dystonia (BFM movement) compared to placebo (median improvement [95% confidence limits] -3 [-8.46 to 0.03], p = 0.009). No difference was found between zonisamide and placebo with respect to the CGI (median improvement [95% confidence limits] -1 [-1.31 to 0.09], p = 0.1). Zonisamide was well-tolerated. CONCLUSIONS: Zonisamide is well-tolerated and effective on the motor symptoms of myoclonus-dystonia. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that zonisamide improves myoclonus and related disability in patients with myoclonus-dystonia.
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Fármacos del Sistema Nervioso Central/uso terapéutico , Trastornos Distónicos/tratamiento farmacológico , Isoxazoles/uso terapéutico , Adolescente , Adulto , Fármacos del Sistema Nervioso Central/efectos adversos , Fármacos del Sistema Nervioso Central/sangre , Estudios Cruzados , Evaluación de la Discapacidad , Método Doble Ciego , Trastornos Distónicos/sangre , Trastornos Distónicos/genética , Femenino , Humanos , Isoxazoles/efectos adversos , Isoxazoles/sangre , Masculino , Sarcoglicanos/genética , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Adulto Joven , ZonisamidaRESUMEN
IMPORTANCE: Myoclonus-dystonia (M-D) is a clinical syndrome characterized by a combination of myoclonic jerks and mild to moderate dystonia. The syndrome is related to ε-sarcoglycan (SGCE) gene mutations in about half the typical cases. Whether the M-D phenotype reflects a primary dysfunction of the cerebellothalamocortical pathway or of the striatopallidothalamocortical pathway is unclear. The exact role of an additional cortical dysfunction in the pathogenesis of M-D is also unknown. OBJECTIVE: To clarify the neurophysiological features of M-D and discuss whether M-D due to SGCE deficiency differs from other primary dystonias. DESIGN, SETTING, AND PARTICIPANTS: We studied a referred sample of 12 patients with M-D (mean [SD] age, 28.8 [6.2] years; age range, 19-38 years; 5 women) belonging to 11 unrelated families with a proven mutation or deletion of the SGCE gene and a group of 12 age- and sex-matched healthy control individuals. Every participant underwent 3 sessions exploring the excitability of the primary motor cortex, the response of the primary motor cortex to a plasticity-inducing protocol, and the cerebellar-dependent eye-blink classic conditioning (EBCC). The clinical evaluation of patients included the Unified Myoclonus Rating Scale and Burke-Fahn-Marsden Dystonia Rating Scale. EXPOSURE: Myoclonus-dystonia with a proven SGCE mutation. MAIN OUTCOMES AND MEASURES: We measured resting and active motor thresholds, and short-interval intracortical inhibition and facilitation. The plasticity of the motor cortex was evaluated before and for 30 minutes after 600 pulses of rapid paired associative stimulation. The cerebellar functioning was evaluated with the number of conditioned responses during the 6 blocks of EBCC and 1 extinction block. All data were compared between the 2 groups. For patients, correlations were explored between electrophysiological data and clinical scores. RESULTS: We found lower membrane excitability of the corticocortical axons and normal intracortical γ-aminobutyric acid inhibition in contrast with what has been described in other forms of primary dystonia. Myoclonus-dystonia patients also shared some common pathophysiological features of dystonia, including enhanced responsiveness of the motor cortex to plasticity induction and abnormal response to cerebellar conditioning as tested by EBCC. CONCLUSIONS AND RELEVANCE: Specific underlying dysfunctions are associated with the very particular clinical phenotype of M-D and make it a unique entity that stands apart from other primary dystonias.