RESUMEN
A spinal cord injury interrupts the communication between the brain and the region of the spinal cord that produces walking, leading to paralysis1,2. Here, we restored this communication with a digital bridge between the brain and spinal cord that enabled an individual with chronic tetraplegia to stand and walk naturally in community settings. This brain-spine interface (BSI) consists of fully implanted recording and stimulation systems that establish a direct link between cortical signals3 and the analogue modulation of epidural electrical stimulation targeting the spinal cord regions involved in the production of walking4-6. A highly reliable BSI is calibrated within a few minutes. This reliability has remained stable over one year, including during independent use at home. The participant reports that the BSI enables natural control over the movements of his legs to stand, walk, climb stairs and even traverse complex terrains. Moreover, neurorehabilitation supported by the BSI improved neurological recovery. The participant regained the ability to walk with crutches overground even when the BSI was switched off. This digital bridge establishes a framework to restore natural control of movement after paralysis.
Asunto(s)
Interfaces Cerebro-Computador , Encéfalo , Terapia por Estimulación Eléctrica , Rehabilitación Neurológica , Traumatismos de la Médula Espinal , Médula Espinal , Caminata , Humanos , Encéfalo/fisiología , Terapia por Estimulación Eléctrica/instrumentación , Terapia por Estimulación Eléctrica/métodos , Cuadriplejía/etiología , Cuadriplejía/rehabilitación , Cuadriplejía/terapia , Reproducibilidad de los Resultados , Médula Espinal/fisiología , Traumatismos de la Médula Espinal/complicaciones , Traumatismos de la Médula Espinal/rehabilitación , Traumatismos de la Médula Espinal/terapia , Caminata/fisiología , Pierna/fisiología , Rehabilitación Neurológica/instrumentación , Rehabilitación Neurológica/métodos , MasculinoRESUMEN
Holoprosencephaly (HPE) is the most common congenital cerebral malformation in humans, characterized by impaired forebrain cleavage and midline facial anomalies. It presents a high heterogeneity, both in clinics and genetics. We have developed a novel targeted next-generation sequencing (NGS) assay and screened a cohort of 257 HPE patients. Mutations with high confidence in their deleterious effect were identified in approximately 24% of the cases and were held for diagnosis, whereas variants of uncertain significance were identified in 10% of cases. This study provides a new classification of genes that are involved in HPE. SHH, ZIC2, and SIX3 remain the top genes in term of frequency with GLI2, and are followed by FGF8 and FGFR1. The three minor HPE genes identified by our study are DLL1, DISP1, and SUFU. Here, we demonstrate that fibroblast growth factor signaling must now be considered a major pathway involved in HPE. Interestingly, several cases of double mutations were found and argue for a polygenic inheritance of HPE. Altogether, it supports that the implementation of NGS in HPE diagnosis is required to improve genetic counseling.
Asunto(s)
Factores de Crecimiento de Fibroblastos/genética , Holoprosencefalia/genética , Mutación , Femenino , Predisposición Genética a la Enfermedad , Proteínas Hedgehog/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Masculino , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos , Análisis de Secuencia de ADN/métodos , Transducción de SeñalRESUMEN
Tonic receptors convey stimulus duration and intensity and are implicated in homeostatic control. However, how tonic homeostatic signals are generated and how they reconfigure neural circuits and modify animal behavior is poorly understood. Here we show that Caenorhabditis elegans O(2)-sensing neurons are tonic receptors that continuously signal ambient [O(2)] to set the animal's behavioral state. Sustained signaling relied on a Ca(2+) relay involving L-type voltage-gated Ca(2+) channels, the ryanodine and the inositol-1,4,5-trisphosphate receptors. Tonic activity evoked continuous neuropeptide release, which helps elicit the enduring behavioral state associated with high [O(2)]. Sustained O(2) receptor signaling was propagated to downstream neural circuits, including the hub interneuron RMG. O(2) receptors evoked similar locomotory states at particular O(2) concentrations, regardless of previous d[O(2)]/dt. However, a phasic component of the URX receptors' response to high d[O(2)]/dt, as well as tonic-to-phasic transformations in downstream interneurons, enabled transient reorientation movements shaped by d[O(2)]/dt. Our results highlight how tonic homeostatic signals can generate both transient and enduring behavioral change.
Asunto(s)
Proteínas de Caenorhabditis elegans/fisiología , Células Quimiorreceptoras/fisiología , Actividad Motora/fisiología , Red Nerviosa/fisiología , Oxígeno/fisiología , Transducción de Señal/fisiología , Animales , Animales Modificados Genéticamente , Caenorhabditis elegans , Señalización del Calcio/fisiologíaRESUMEN
Information capture by photoreceptors ultimately limits the quality of visual processing in the brain. Using conventional sharp microelectrodes, we studied how locust photoreceptors encode random (white-noise, WN) and naturalistic (1/f stimuli, NS) light patterns in vivo and how this coding changes with mean illumination and ambient temperature. We also examined the role of their plasma membrane in shaping voltage responses. We found that brightening or warming increase and accelerate voltage responses, but reduce noise, enabling photoreceptors to encode more information. For WN stimuli, this was accompanied by broadening of the linear frequency range. On the contrary, with NS the signaling took place within a constant bandwidth, possibly revealing a 'preference' for inputs with 1/f statistics. The faster signaling was caused by acceleration of the elementary phototransduction current--leading to bumps--and their distribution. The membrane linearly translated phototransduction currents into voltage responses without limiting the throughput of these messages. As the bumps reflected fast changes in membrane resistance, the data suggest that their shape is predominantly driven by fast changes in the light-gated conductance. On the other hand, the slower bump latency distribution is likely to represent slower enzymatic intracellular reactions. Furthermore, the Q(10)s of bump duration and latency distribution depended on light intensity. Altogether, this study suggests that biochemical constraints imposed upon signaling change continuously as locust photoreceptors adapt to environmental light and temperature conditions.