RESUMEN
Paralyzed muscles can be reanimated following spinal cord injury (SCI) using a brain-computer interface (BCI) to enhance motor function alone. Importantly, the sense of touch is a key component of motor function. Here, we demonstrate that a human participant with a clinically complete SCI can use a BCI to simultaneously reanimate both motor function and the sense of touch, leveraging residual touch signaling from his own hand. In the primary motor cortex (M1), residual subperceptual hand touch signals are simultaneously demultiplexed from ongoing efferent motor intention, enabling intracortically controlled closed-loop sensory feedback. Using the closed-loop demultiplexing BCI almost fully restored the ability to detect object touch and significantly improved several sensorimotor functions. Afferent grip-intensity levels are also decoded from M1, enabling grip reanimation regulated by touch signaling. These results demonstrate that subperceptual neural signals can be decoded from the cortex and transformed into conscious perception, significantly augmenting function.
Asunto(s)
Retroalimentación Sensorial/fisiología , Percepción del Tacto/fisiología , Tacto/fisiología , Adulto , Interfaces Cerebro-Computador/psicología , Mano/fisiopatología , Fuerza de la Mano/fisiología , Humanos , Masculino , Corteza Motora/fisiología , Movimiento/fisiología , Traumatismos de la Médula Espinal/fisiopatologíaRESUMEN
CNS injury often severs axons. Scar tissue that forms locally at the lesion site is thought to block axonal regeneration, resulting in permanent functional deficits. We report that inhibiting the generation of progeny by a subclass of pericytes led to decreased fibrosis and extracellular matrix deposition after spinal cord injury in mice. Regeneration of raphespinal and corticospinal tract axons was enhanced and sensorimotor function recovery improved following spinal cord injury in animals with attenuated pericyte-derived scarring. Using optogenetic stimulation, we demonstrate that regenerated corticospinal tract axons integrated into the local spinal cord circuitry below the lesion site. The number of regenerated axons correlated with improved sensorimotor function recovery. In conclusion, attenuation of pericyte-derived fibrosis represents a promising therapeutic approach to facilitate recovery following CNS injury.
Asunto(s)
Cicatriz/patología , Traumatismos de la Médula Espinal/patología , Animales , Axones/fisiología , Axones/efectos de la radiación , Modelos Animales de Enfermedad , Potenciales Evocados/efectos de la radiación , Matriz Extracelular/metabolismo , Fibrosis , Luz , Ratones , Ratones Transgénicos , Pericitos/citología , Pericitos/metabolismo , Estimulación Luminosa , Tractos Piramidales/fisiología , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/genética , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Recuperación de la Función , Regeneración , Corteza Sensoriomotora/fisiología , Traumatismos de la Médula Espinal/fisiopatologíaRESUMEN
A spinal cord injury interrupts pathways from the brain and brainstem that project to the lumbar spinal cord, leading to paralysis. Here we show that spatiotemporal epidural electrical stimulation (EES) of the lumbar spinal cord1-3 applied during neurorehabilitation4,5 (EESREHAB) restored walking in nine individuals with chronic spinal cord injury. This recovery involved a reduction in neuronal activity in the lumbar spinal cord of humans during walking. We hypothesized that this unexpected reduction reflects activity-dependent selection of specific neuronal subpopulations that become essential for a patient to walk after spinal cord injury. To identify these putative neurons, we modelled the technological and therapeutic features underlying EESREHAB in mice. We applied single-nucleus RNA sequencing6-9 and spatial transcriptomics10,11 to the spinal cords of these mice to chart a spatially resolved molecular atlas of recovery from paralysis. We then employed cell type12,13 and spatial prioritization to identify the neurons involved in the recovery of walking. A single population of excitatory interneurons nested within intermediate laminae emerged. Although these neurons are not required for walking before spinal cord injury, we demonstrate that they are essential for the recovery of walking with EES following spinal cord injury. Augmenting the activity of these neurons phenocopied the recovery of walking enabled by EESREHAB, whereas ablating them prevented the recovery of walking that occurs spontaneously after moderate spinal cord injury. We thus identified a recovery-organizing neuronal subpopulation that is necessary and sufficient to regain walking after paralysis. Moreover, our methodology establishes a framework for using molecular cartography to identify the neurons that produce complex behaviours.
Asunto(s)
Neuronas , Parálisis , Traumatismos de la Médula Espinal , Médula Espinal , Caminata , Animales , Humanos , Ratones , Neuronas/fisiología , Parálisis/genética , Parálisis/fisiopatología , Parálisis/terapia , Médula Espinal/citología , Médula Espinal/fisiología , Médula Espinal/fisiopatología , Traumatismos de la Médula Espinal/genética , Traumatismos de la Médula Espinal/fisiopatología , Traumatismos de la Médula Espinal/terapia , Caminata/fisiología , Estimulación Eléctrica , Región Lumbosacra/inervación , Rehabilitación Neurológica , Análisis de Secuencia de ARN , Perfilación de la Expresión GénicaRESUMEN
Spinal cord injury (SCI) induces haemodynamic instability that threatens survival1-3, impairs neurological recovery4,5, increases the risk of cardiovascular disease6,7, and reduces quality of life8,9. Haemodynamic instability in this context is due to the interruption of supraspinal efferent commands to sympathetic circuits located in the spinal cord10, which prevents the natural baroreflex from controlling these circuits to adjust peripheral vascular resistance. Epidural electrical stimulation (EES) of the spinal cord has been shown to compensate for interrupted supraspinal commands to motor circuits below the injury11, and restored walking after paralysis12. Here, we leveraged these concepts to develop EES protocols that restored haemodynamic stability after SCI. We established a preclinical model that enabled us to dissect the topology and dynamics of the sympathetic circuits, and to understand how EES can engage these circuits. We incorporated these spatial and temporal features into stimulation protocols to conceive a clinical-grade biomimetic haemodynamic regulator that operates in a closed loop. This 'neuroprosthetic baroreflex' controlled haemodynamics for extended periods of time in rodents, non-human primates and humans, after both acute and chronic SCI. We will now conduct clinical trials to turn the neuroprosthetic baroreflex into a commonly available therapy for people with SCI.
Asunto(s)
Barorreflejo , Biomimética , Hemodinámica , Prótesis e Implantes , Traumatismos de la Médula Espinal/fisiopatología , Traumatismos de la Médula Espinal/terapia , Animales , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Vías Nerviosas , Primates , Ratas , Ratas Endogámicas Lew , Sistema Nervioso Simpático/citología , Sistema Nervioso Simpático/fisiologíaRESUMEN
AIM: After spinal cord injuries (SCIs), patients may develop either detrusor-sphincter dyssynergia (DSD) or urinary incontinence, depending on the level of the spinal injury. DSD and incontinence reflect the loss of coordinated neural control among the detrusor muscle, which increases bladder pressure to facilitate urination, and urethral sphincters and pelvic floor muscles, which control the bladder outlet to restrict or permit bladder emptying. Transcutaneous magnetic stimulation (TMS) applied to the spinal cord after SCI reduced DSD and incontinence. We defined, within a mathematical model, the minimum neuronal elements necessary to replicate neurogenic dysfunction of the bladder after a SCI and incorporated into this model the minimum additional neurophysiological features sufficient to replicate the improvements in bladder function associated with lumbar TMS of the spine in patients with SCI. METHODS: We created a computational model of the neural circuit of micturition based on Hodgkin-Huxley equations that replicated normal bladder function. We added interneurons and increased network complexity to reproduce dysfunctional micturition after SCI, and we increased the density and complexity of interactions of both inhibitory and excitatory lumbar spinal interneurons responsive to TMS to provide a more diverse set of spinal responses to intrinsic and extrinsic activation of spinal interneurons that remains after SCI. RESULTS: The model reproduced the re-emergence of a spinal voiding reflex after SCI. When we investigated the effect of monophasic and biphasic TMS at two frequencies applied at or below T10, the model replicated the improved coordination between detrusor and external urethral sphincter activity that has been observed clinically: low-frequency TMS (1 Hz) within the model normalized control of voiding after SCI, whereas high-frequency TMS (30 Hz) enhanced urine storage. CONCLUSION: Neuroplasticity and increased complexity of interactions among lumbar interneurons, beyond what is necessary to simulate normal bladder function, must be present in order to replicate the effects of SCI on control of micturition, and both neuronal and network modifications of lumbar interneurons are essential to understand the mechanisms whereby TMS reduced bladder dysfunction after SCI.
Asunto(s)
Traumatismos de la Médula Espinal , Micción , Traumatismos de la Médula Espinal/fisiopatología , Humanos , Micción/fisiología , Modelos Neurológicos , Estimulación de la Médula Espinal/métodos , Vejiga Urinaria/fisiopatología , Vejiga Urinaria/inervación , Simulación por Computador , Biología Computacional , Médula Espinal/fisiopatologíaRESUMEN
When the foot dorsum contacts an obstacle during locomotion, cutaneous afferents signal central circuits to coordinate muscle activity in the four limbs. Spinal cord injury disrupts these interactions, impairing balance and interlimb coordination. We evoked cutaneous reflexes by electrically stimulating left and right superficial peroneal nerves before and after two thoracic lateral hemisections placed on opposite sides of the cord at 9- to 13-week interval in seven adult cats (4 males and 3 females). We recorded reflex responses in ten hindlimb and five forelimb muscles bilaterally. After the first (right T5-T6) and second (left T10-T11) hemisections, coordination of the fore- and hindlimbs was altered and/or became less consistent. After the second hemisection, cats required balance assistance to perform quadrupedal locomotion. Short-latency reflex responses in homonymous and crossed hindlimb muscles largely remained unaffected after staggered hemisections. However, mid- and long-latency homonymous and crossed responses in both hindlimbs occurred less frequently after staggered hemisections. In forelimb muscles, homolateral and diagonal mid- and long-latency response occurrence significantly decreased after the first and second hemisections. In all four limbs, however, when present, short-, mid- and long-latency responses maintained their phase-dependent modulation. We also observed reduced durations of short-latency inhibitory homonymous responses in left hindlimb extensors early after the first hemisection and delayed short-latency responses in the right ipsilesional hindlimb after the first hemisection. Therefore, changes in cutaneous reflex responses correlated with impaired balance/stability and interlimb coordination during locomotion after spinal cord injury. Restoring reflex transmission could be used as a biomarker to facilitate locomotor recovery. KEY POINTS: Cutaneous afferent inputs coordinate muscle activity in the four limbs during locomotion when the foot dorsum contacts an obstacle. Thoracic spinal cord injury disrupts communication between spinal locomotor centres located at cervical and lumbar levels, impairing balance and limb coordination. We investigated cutaneous reflexes during quadrupedal locomotion by electrically stimulating the superficial peroneal nerve bilaterally, before and after staggered lateral thoracic hemisections of the spinal cord in cats. We showed a loss/reduction of mid- and long-latency responses in all four limbs after staggered hemisections, which correlated with altered coordination of the fore- and hindlimbs and impaired balance. Targeting cutaneous reflex pathways projecting to the four limbs could help develop therapeutic approaches aimed at restoring transmission in ascending and descending spinal pathways.
Asunto(s)
Miembro Posterior , Locomoción , Músculo Esquelético , Reflejo , Traumatismos de la Médula Espinal , Animales , Gatos , Miembro Posterior/inervación , Miembro Posterior/fisiología , Miembro Posterior/fisiopatología , Masculino , Femenino , Traumatismos de la Médula Espinal/fisiopatología , Reflejo/fisiología , Locomoción/fisiología , Músculo Esquelético/inervación , Músculo Esquelético/fisiología , Músculo Esquelético/fisiopatología , Piel/inervación , Vértebras Torácicas , Miembro Anterior/fisiopatología , Miembro Anterior/fisiología , Estimulación EléctricaRESUMEN
During quadrupedal locomotion, interactions between spinal and supraspinal circuits and somatosensory feedback coordinate forelimb and hindlimb movements. How this is achieved is not clear. To determine whether forelimb movements modulate hindlimb cutaneous reflexes involved in responding to an external perturbation, we stimulated the superficial peroneal nerve in six intact cats during quadrupedal locomotion and during hindlimb-only locomotion (with forelimbs standing on stationary platform) and in two cats with a low spinal transection (T12-T13) during hindlimb-only locomotion. We compared cutaneous reflexes evoked in six ipsilateral and four contralateral hindlimb muscles. Results showed similar occurrence and phase-dependent modulation of short-latency inhibitory and excitatory responses during quadrupedal and hindlimb-only locomotion in intact cats. However, the depth of modulation was reduced in the ipsilateral semitendinosus during hindlimb-only locomotion. Additionally, longer-latency responses occurred less frequently in extensor muscles bilaterally during hindlimb-only locomotion, whereas short-latency inhibitory and longer-latency excitatory responses occurred more frequently in the ipsilateral and contralateral sartorius anterior, respectively. After spinal transection, short-latency inhibitory and excitatory responses were similar to both intact conditions, whereas mid- or longer-latency excitatory responses were reduced or abolished. Our results in intact cats and the comparison with spinal-transected cats suggest that the absence of forelimb movements suppresses inputs from supraspinal structures and/or cervical cord that normally contribute to longer-latency reflex responses in hindlimb extensor muscles.NEW & NOTEWORTHY During quadrupedal locomotion, the coordination of forelimb and hindlimb movements involves central circuits and somatosensory feedback. To demonstrate how forelimb movement affects hindlimb cutaneous reflexes during locomotion, we stimulated the superficial peroneal nerve in intact cats during quadrupedal and hindlimb-only locomotion as well as in spinal-transected cats during hindlimb-only locomotion. We show that forelimb movement influences the modulation of hindlimb cutaneous reflexes, particularly the occurrence of long-latency reflex responses.
Asunto(s)
Miembro Anterior , Miembro Posterior , Locomoción , Músculo Esquelético , Reflejo , Traumatismos de la Médula Espinal , Animales , Gatos , Miembro Posterior/fisiología , Miembro Anterior/fisiología , Reflejo/fisiología , Locomoción/fisiología , Músculo Esquelético/fisiología , Traumatismos de la Médula Espinal/fisiopatología , Movimiento/fisiología , Femenino , Masculino , Piel/inervaciónRESUMEN
On demand and localized treatment for excessive muscle tone after spinal cord injury (SCI) is currently not available. Here, we examine the reduction in leg hypertonus in a person with mid-thoracic, motor complete SCI using a commercial transcutaneous electrical stimulator (TES) applied at 50 or 150 Hz to the lower back and the possible mechanisms producing this bilateral reduction in leg tone. Hypertonus of knee extensors without and during TES, with both cathode (T11-L2) and anode (L3-L5) placed over the spinal column (midline, MID) or 10 cm to the left of midline (lateral, LAT) to only active underlying skin and muscle afferents, was simultaneously measured in both legs with the pendulum test. Spinal reflexes mediated by proprioceptive (H-reflex) and cutaneomuscular reflex (CMR) afferents were examined in the right leg opposite to the applied LAT TES. Hypertonus disappeared in both legs but only during thoracolumbar TES, and even during LAT TES. The marked reduction in tone was reflected in the greater distance both lower legs first dropped to after being released from a fully extended position, increasing by 172.8% and 94.2% during MID and LAT TES, respectively, compared with without TES. Both MID and LAT (left) TES increased H-reflexes but decreased the first burst, and lengthened the onset of subsequent bursts, in the cutaneomuscular reflex of the right leg. Thoracolumbar TES is a promising method to decrease leg hypertonus in chronic, motor complete SCI without activating spinal cord structures and may work by facilitating proprioceptive inputs that activate excitatory interneurons with bilateral projections that in turn recruit recurrent inhibitory neurons.NEW & NOTEWORTHY We present proof of concept that surface stimulation of the lower back can reduce severe leg hypertonus in a participant with motor complete, thoracic spinal cord injury (SCI) but only during the applied stimulation. We propose that activation of skin and muscle afferents from thoracolumbar transcutaneous electrical stimulation (TES) may recruit excitatory spinal interneurons with bilateral projections that in turn recruit recurrent inhibitory networks to provide on demand suppression of ongoing involuntary motoneuron activity.
Asunto(s)
Hipertonía Muscular , Traumatismos de la Médula Espinal , Vértebras Torácicas , Humanos , Pierna/fisiopatología , Hipertonía Muscular/fisiopatología , Hipertonía Muscular/etiología , Hipertonía Muscular/terapia , Músculo Esquelético/fisiopatología , Piel/inervación , Traumatismos de la Médula Espinal/fisiopatología , Traumatismos de la Médula Espinal/terapia , Traumatismos de la Médula Espinal/complicaciones , Raíces Nerviosas Espinales/fisiopatología , Raíces Nerviosas Espinales/fisiología , Estimulación Eléctrica Transcutánea del Nervio/métodosRESUMEN
Spinal Cord Injury (SCI) disrupts critical autonomic pathways responsible for the regulation of the immune function. Consequently, individuals with SCI often exhibit a spectrum of immune dysfunctions ranging from the development of damaging pro-inflammatory responses to severe immunosuppression. Thus, it is imperative to gain a more comprehensive understanding of the extent and mechanisms through which SCI-induced autonomic dysfunction influences the immune response. In this review, we provide an overview of the anatomical organization and physiology of the autonomic nervous system (ANS), elucidating how SCI impacts its function, with a particular focus on lymphoid organs and immune activity. We highlight recent advances in understanding how intraspinal plasticity that follows SCI may contribute to aberrant autonomic activity in lymphoid organs. Additionally, we discuss how sympathetic mediators released by these neuron terminals affect immune cell function. Finally, we discuss emerging innovative technologies and potential clinical interventions targeting the ANS as a strategy to restore the normal regulation of the immune response in individuals with SCI.
Asunto(s)
Vías Autónomas , Traumatismos de la Médula Espinal , Traumatismos de la Médula Espinal/inmunología , Traumatismos de la Médula Espinal/fisiopatología , Humanos , Animales , Vías Autónomas/inmunología , Sistema Nervioso Autónomo/fisiopatología , Sistema Nervioso Autónomo/inmunologíaRESUMEN
In humans and other adult mammals, axon regeneration is difficult in axotomized neurons. Therefore, spinal cord injury (SCI) is a devastating event that can lead to permanent loss of locomotor and sensory functions. Moreover, the molecular mechanisms of axon regeneration in vertebrates are not very well understood, and currently, no effective treatment is available for SCI. In striking contrast to adult mammals, many nonmammalian vertebrates such as reptiles, amphibians, bony fishes and lampreys can spontaneously resume locomotion even after complete SCI. In recent years, rapid progress in the development of next-generation sequencing technologies has offered valuable information on SCI. In this review, we aimed to provide a comparison of axon regeneration process across classical model organisms, focusing on crucial genes and signalling pathways that play significant roles in the regeneration of individually identifiable descending neurons after SCI. Considering the special evolutionary location and powerful regenerative ability of lamprey and zebrafish, they will be the key model organisms for ongoing studies on spinal cord regeneration. Detailed study of SCI in these model organisms will help in the elucidation of molecular mechanisms of neuron regeneration across species.
Asunto(s)
Traumatismos de la Médula Espinal , Regeneración de la Medula Espinal , Vertebrados , Animales , Traumatismos de la Médula Espinal/fisiopatología , Vertebrados/fisiología , Regeneración de la Medula Espinal/fisiología , Lampreas , Humanos , Regeneración Nerviosa/fisiologíaRESUMEN
Spinal cord injury (SCI) often leads to cell death, vascular disruption, axonal signal interruption, and permanent functional damage. Currently, there are no clearly effective therapeutic options available for SCI. Considering the inhospitable SCI milieu typified by ischemia, hypoxia, and restricted neural regeneration, a novel injectable hydrogel system containing conductive black phosphorus (BP) nanosheets within a lipoic acid-modified chitosan hydrogel matrix (LAMC) is explored. The incorporation of tannic acid (TA)-modified BP nanosheets (BP@TA) into the LAMC hydrogel matrix significantly improved its conductivity. Further, by embedding a bicyclodextrin-conjugated tazarotene drug, the hydrogel showcased amplified angiogenic potential in vitro. In a rat model of complete SCI, implantation of LAMC/BP@TA hydrogel markedly improved the recovery of motor function. Immunofluorescence evaluations confirmed that the composite hydrogel facilitated endogenous angiogenesis and neurogenesis at the injury site. Collectively, this work elucidates an innovative drug-incorporated hydrogel system enriched with BP, underscoring its potential to foster vascular and neural regeneration.
Asunto(s)
Hidrogeles , Regeneración Nerviosa , Fósforo , Traumatismos de la Médula Espinal , Traumatismos de la Médula Espinal/tratamiento farmacológico , Traumatismos de la Médula Espinal/fisiopatología , Animales , Hidrogeles/química , Hidrogeles/farmacología , Regeneración Nerviosa/efectos de los fármacos , Fósforo/química , Ratas , Ratas Sprague-Dawley , Nanoestructuras/química , Neovascularización Fisiológica/efectos de los fármacos , InyeccionesRESUMEN
One cannot survive without regularly urinating and defecating. People with neurologic injury (spinal cord injury, traumatic brain injury, stroke) or disease (multiple sclerosis, Parkinson's disease, spina bifida) and many elderly are unable to voluntarily initiate voiding. The great majority of them require bladder catheters to void urine and "manual bowel programs" with digital rectal stimulation and manual extraction to void stool. Catheter-associated urinary tract infections frequently require hospitalization, whereas manual bowel programs are time consuming (1 to 2 hours) and stigmatizing and cause rectal pain and discomfort. Laxatives and enemas produce defecation, but onset and duration are unpredictable, prolonged, and difficult to control, which can produce involuntary defecation and fecal incontinence. Patients with spinal cord injury (SCI) consider recovery of bladder and bowel function a higher priority than recovery of walking. Bladder and bowel dysfunction are a top reason for institutionalization of elderly. Surveys indicate that convenience, rapid onset and short duration, reliability and predictability, and efficient voiding are priorities of SCI individuals. Despite the severe, unmet medical need, there is no literature regarding on-demand, rapid-onset, short-duration, drug-induced voiding therapies. This article provides in-depth discussion of recent discovery and development of two candidates for on-demand voiding therapies. The first, [Lys3,Gly8,-R-γ-lactam-Leu9]-NKA(3-10) (DTI-117), a neurokinin2 receptor agonist, induces both urination and defecation after systemic administration. The second, capsaicin (DTI-301), is a transient receptor potential cation channel subfamily V member 1 (TRPV1) receptor agonist that induces defecation after intrarectal administration. The review also presents clinical studies of a combination drug therapy administered via iontophoresis and preclinical studies of neuromodulation devices that induce urination and defecation. SIGNIFICANCE STATEMENT: A safe and effective, on-demand, rapid-onset, short-duration, drug-induced, voiding therapy could eliminate or reduce need for bladder catheters, manual bowel programs, and colostomies in patient populations that are unable to voluntarily initiate voiding. People with spinal injury place more importance on restoring bladder and bowel control than restoring their ability to walk. This paradigm-changing therapy would reduce stigmatism and healthcare costs while increasing convenience and quality of life.
Asunto(s)
Micción , Humanos , Micción/fisiología , Micción/efectos de los fármacos , Traumatismos de la Médula Espinal/terapia , Traumatismos de la Médula Espinal/fisiopatología , Animales , Defecación/fisiología , Defecación/efectos de los fármacosRESUMEN
Substantial clinical and preclinical evidence indicates that transient receptor potential vanilloid 1 (TRPV1) receptors are expressed on terminals of colorectal chemoreceptors and mechanoreceptors and are involved in various rectal hypersensitivity disorders with common features of colorectal overactivity. These stimulatory properties of TRPV1 receptors on colorectal function suggested that brief stimulation of TRPV1 might provide a means of pharmacologically activating the colorectum to induce defecation in patients with an "unresponsive" colorectum. The current studies explored the basic features of TRPV1 receptor-induced contractions of the colorectum in anesthetized rats with and without acute spinal cord injury (aSCI). Cumulative concentration-response curves to intrarectal (IR) capsaicin (CAP) solutions (0.003%-3.0%) were performed in anesthetized aSCI and spinal intact rats. CAP produced an "inverted U," cumulative concentration-response curve with a threshold for inducing colorectal contractions at 0.01% and a peak response at 0.1% and slight decreases in responses up to 3%. Decreases in responses with concentrations >0.1% are due to a rapid desensitization (i.e., ≤30 minutes) of TRPV1 receptors to each successive dose. Desensitization appeared fully recovered within 24 hours in spinal intact rats. Colorectal contractions were completely blocked by atropine, indicating a reflexogenic activation of parasympathetic neurons, and responses were completely unaffected by a neurokinin 2 receptor antagonist, indicating that release of neurokinin A from afferent terminals and subsequent direct contractions of the smooth muscle was not involved. IR administration of three other TRPV1 receptor agonists produced similar results as CAP. SIGNIFICANCE STATEMENT: Individuals with spinal cord injury often lose control of defecation. Time-consuming bowel programs using digital stimulation of the rectum are used to empty the bowel. This study shows that intrarectal administration of the transient receptor potential vanilloid 1 (TRPV1) receptor agonist, capsaicin, can induce rapid-onset, short-duration colorectal contractions capable of inducing defecation in spinal cord injured and intact rats. Therefore, TRPV1 agonists show promise as potential therapeutics to induce defecation in individuals with neurogenic bowel.
Asunto(s)
Capsaicina , Colon , Contracción Muscular , Ratas Sprague-Dawley , Canales Catiónicos TRPV , Animales , Masculino , Ratas , Canales Catiónicos TRPV/agonistas , Canales Catiónicos TRPV/metabolismo , Capsaicina/farmacología , Colon/efectos de los fármacos , Colon/metabolismo , Contracción Muscular/efectos de los fármacos , Traumatismos de la Médula Espinal/fisiopatología , Traumatismos de la Médula Espinal/metabolismo , Recto/efectos de los fármacos , Recto/inervación , Relación Dosis-Respuesta a Droga , Anestesia , Factores de TiempoRESUMEN
BACKGROUND: The traumatic spinal cord injury (SCI) can cause immediate multi-faceted function loss or paralysis. Microglia, as one of tissue resident macrophages, has been reported to play a critical role in regulating inflammation response during SCI processes. And transplantation with M2 microglia into SCI mice promotes recovery of motor function. However, the M2 microglia can be easily re-educated and changed their phenotype due to the stimuli of tissue microenvironment. This study aimed to find a way to maintain the function of M2 microglia, which could exert an anti-inflammatory and pro-repair role, and further promote the repair of spinal cord injury. METHODS: To establish a standard murine spinal cord clip compression model using Dumont tying forceps. Using FACS, to sort microglia from C57BL/6 mice or CX3CR1GFP mice, and further culture them in vitro with different macrophage polarized medium. Also, to isolate primary microglia using density gradient centrifugation with the neonatal mice. To transfect miR-145a-5p into M2 microglia by Lipofectamine2000, and inject miR-145a-5p modified M2 microglia into the lesion sites of spinal cord for cell transplanted therapy. To evaluate the recovery of motor function in SCI mice through behavior analysis, immunofluorescence or histochemistry staining, Western blot and qRT-PCR detection. Application of reporter assay and molecular biology experiments to reveal the mechanism of miR-145a-5p modified M2 microglia therapy on SCI mice. RESULTS: With in vitro experiments, we found that miR-145a-5p was highly expressed in M2 microglia, and miR-145a-5p overexpression could suppress M1 while promote M2 microglia polarization. And then delivery of miR-145a-5p overexpressed M2 microglia into the injured spinal cord area significantly accelerated locomotive recovery as well as prevented glia scar formation and neuron damage in mice, which was even better than M2 microglia transplantation. Further mechanisms showed that overexpressed miR-145a-5p in microglia inhibited the inflammatory response and maintained M2 macrophage phenotype by targeting TLR4/NF-κB signaling. CONCLUSIONS: These findings indicate that transplantation of miR-145a-5p modified M2 microglia has more therapeutic potential for SCI than M2 microglia transplantation from epigenetic perspective.
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Ratones Endogámicos C57BL , MicroARNs , Microglía , Recuperación de la Función , Traumatismos de la Médula Espinal , Animales , Traumatismos de la Médula Espinal/terapia , Traumatismos de la Médula Espinal/fisiopatología , Traumatismos de la Médula Espinal/patología , MicroARNs/metabolismo , MicroARNs/genética , Microglía/metabolismo , RatonesRESUMEN
Spinal-cord injury (SCI) is a severe condition that can lead to limb paralysis and motor dysfunction, and its pathogenesis is not fully understood. The objective of this study was to characterize the differential gene expression and molecular mechanisms in the spinal cord of mice three days after spinal cord injury. By analyzing RNA sequencing data, we identified differentially expressed genes and discovered that the immune system and various metabolic processes play crucial roles in SCI. Additionally, we identified UHRF1 as a key gene that plays a significant role in SCI and found that SCI can be improved by suppressing UHRF1. These findings provide important insights into the molecular mechanisms of SCI and identify potential therapeutic targets that could greatly contribute to the development of new treatment strategies for SCI.
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Proteínas Potenciadoras de Unión a CCAAT , Traumatismos de la Médula Espinal , Ubiquitina-Proteína Ligasas , Animales , Traumatismos de la Médula Espinal/fisiopatología , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ratones , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Proteínas Potenciadoras de Unión a CCAAT/genética , Actividad Motora/fisiología , Ratones Endogámicos C57BL , Recuperación de la Función/fisiología , Femenino , Médula Espinal/metabolismo , Médula Espinal/patología , Regulación de la Expresión GénicaRESUMEN
Older patients with spinal cord injury (SCI) have different features with regard to neurological characteristics after injury. Recent large-scale longitudinal population-based studies showed that individuals with SCI are at a higher risk of developing dementia than non-SCI patients, indicating that SCI is a potential risk factor for dementia. Aging is known to potentiate inflammation and neurodegeneration at the injured site leading to impaired recovery from SCI. However, no research has been aimed at studying the mechanisms of SCI-mediated cognitive impairment in the elderly. The present study examined neurobehavioral and molecular changes in the brain and the underlying mechanisms associated with brain dysfunction in aged C57BL/6 male mice using a contusion SCI model. At 2 months post-injury, aged mice displayed worse performance in locomotor, cognitive and depressive-like behavioral tests compared to young adult animals. Histopathology in injured spinal cord tissue was exacerbated in aged SCI mice. In the brain, transcriptomic analysis with NanoString neuropathology panel identified activated microglia and dysregulated autophagy as the most significantly altered pathways by both age and injury. These findings were further validated by flow cytometry, which demonstrated increased myeloid and lymphocytes infiltration at both the injured site and brain of aged mice. Moreover, SCI in aged mice altered microglial function and dysregulated autophagy in microglia, resulting in worsened neurodegeneration. Taken together, our data indicate that old age exacerbates neuropathological changes in both the injured spinal cord and remote brain regions leading to poorer functional outcomes, at least in part, through altered inflammation and autophagy function.
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Envejecimiento , Autofagia , Encéfalo , Inflamación , Ratones Endogámicos C57BL , Traumatismos de la Médula Espinal , Animales , Masculino , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/complicaciones , Traumatismos de la Médula Espinal/fisiopatología , Ratones , Autofagia/fisiología , Encéfalo/metabolismo , Envejecimiento/metabolismo , Inflamación/metabolismo , Microglía/metabolismo , Transducción de Señal/fisiología , Modelos Animales de Enfermedad , Médula Espinal/metabolismoRESUMEN
The aim of this work is to determine the effect of upper-body high intensity interval training (HIIT) on cardiometabolic risks in individuals with chronic paraplegia. Twenty-seven individuals (14 females, 13 males, mean ± SD age: 46 ± 9 years) with chronic paraplegia (spinal cord injury between T2 and L5 >1-year post-injury) took part in a randomized controlled trial and were included in the final analysis. Participants in the HIIT group (n = 18) performed â¼30 min of arm crank exercise (60 s intervals at 80%-90% peak heart rate) four times per week, for 6 weeks. Participants in the control (CON) group (n = 9) were asked to maintain their habitual diet and physical activity patterns over the study period. Outcome measures were taken at baseline and follow-up. The primary outcome measures were fasting insulin, peak power output (PPO) and peak aerobic capacity ( V Ì O 2 peak ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}{\mathrm{peak}}}}$ ). Secondary outcome measures included body composition, postprandial glycaemic control, fasting blood lipids, inflammatory biomarkers and resting blood pressure. Differences between groups were assessed by ANCOVA, using baseline values as a covariate. PPO was higher in the HIIT (101 W, 97-106) compared to the CON (90 W, 83-96) group at follow-up (P = 0.006). There were no differences in fasting insulin (P = 0.415) or relative V Ì O 2 peak ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}{\mathrm{peak}}}}$ (P = 0.417). Postprandial Matsuda insulin sensitivity index (ISIMatsuda) was higher in the HIIT (5.42, 4.69-6.15) compared to the CON (3.75, 2.46-5.04) group at follow-up (P = 0.036). Six weeks of upper-body HIIT increased PPO and ISIMatsuda, with no other beneficial effect on cardiometabolic component risks in persons with chronic paraplegia. HIGHLIGHTS: What is the central question of this study? What is the effect of upper-body high intensity interval training (HIIT) on cardiometabolic component risks in individuals with chronic paraplegia? What is the main finding and its importance? Six weeks of upper-body HIIT increased PPO and improved insulin sensitivity, but had no beneficial effect on other cardiometabolic component risks in persons with chronic paraplegia. The large effect size observed for insulin sensitivity may be important in terms of reducing the risk of type-2 diabetes in this population.
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Entrenamiento de Intervalos de Alta Intensidad , Paraplejía , Humanos , Masculino , Femenino , Paraplejía/fisiopatología , Entrenamiento de Intervalos de Alta Intensidad/métodos , Persona de Mediana Edad , Adulto , Traumatismos de la Médula Espinal/fisiopatología , Glucemia/metabolismo , Insulina/sangre , Presión Sanguínea/fisiología , Composición Corporal/fisiología , Consumo de Oxígeno/fisiología , Enfermedades Cardiovasculares/prevención & control , Enfermedades Cardiovasculares/fisiopatología , Factores de Riesgo Cardiometabólico , Frecuencia Cardíaca/fisiologíaRESUMEN
The spinal cord facilitates communication between the brain and the body, containing intrinsic systems that work with lower motor neurons (LMNs) to manage movement. Spinal cord injuries (SCIs) can lead to partial paralysis and dysfunctions in muscles below the injury. While traditionally this paralysis has been attributed to disruptions in the corticospinal tract, a growing body of work demonstrates LMN damage is a factor. Motor units, comprising the LMN and the muscle fibers with which they connect, are essential for voluntary movement. Our understanding of their changes post-SCI is still emerging, but the health of motor units is vital, especially when considering innovative SCI treatments like nerve transfer surgery. This review seeks to collate current literature on how SCI impact motor units and explore neuromuscular clinical implications and treatment avenues. SCI reduced motor unit number estimates, and surviving motor units had impaired signal transmission at the neuromuscular junction, force-generating capacity, and excitability, which have the potential to recover chronically, yet the underlaying mechanisms are unclear. Furthermore, electrodiagnostic evaluations can aid in assessing the health lower and upper motor neurons, identify suitable targets for nerve transfer surgeries, and detect patients with time sensitive injuries. Lastly, many electrodiagnostic abnormalities occur in both chronic and acute SCI, yet factors contributing to these abnormalities are unknown. Future studies are required to determine how motor units adapt following SCI and the clinical implications of these adaptations.
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Traumatismos de la Médula Espinal , Traumatismos de la Médula Espinal/fisiopatología , Traumatismos de la Médula Espinal/complicaciones , Humanos , Neuronas Motoras/fisiología , Unión Neuromuscular/fisiopatología , Animales , Músculo Esquelético/fisiopatologíaRESUMEN
Spinal cord injury (SCI) is a complex problem in modern medicine. Fibroblast activation and fibroscarring after SCI impede nerve recovery. Non-coding RNA plays an important role in the progression of many diseases, but the study of its role in the progression of spinal fibrosis is still emerging. Here, we investigated the function of circular RNAs, specifically antisense to the cerebellar degeneration-related protein 1 (CDR1as), in spinal fibrosis and characterized its molecular mechanism and pathophysiology. The presence of CDR1as in the spinal cord was verified by sequencing and RNA expression assays. The effects of inhibition of CDR1as on scar formation, inflammation and nerve regeneration after spinal cord injury were investigated in vivo and in vitro. Further, gene expression of miR-7a-5p and protein expression of transforming Growth Factor Beta Receptor II (TGF-ßR2) were measured to evaluate their predicted interactions with CDR1as. The regulatory effects and activation pathways were subsequently verified by miR-7a-5p inhibitor and siCDR1as. These results indicate that CDR1as/miR-7a-5p/TGF-ßR2 interactions may exert scars and nerves functions and suggest potential therapeutic targets for treating spinal fibrotic diseases.
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Fibrosis , MicroARNs , ARN Circular , ARN Largo no Codificante , Transducción de Señal , Traumatismos de la Médula Espinal , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/genética , Traumatismos de la Médula Espinal/fisiopatología , Animales , MicroARNs/genética , MicroARNs/metabolismo , ARN Circular/genética , ARN Circular/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Médula Espinal/metabolismo , Médula Espinal/patología , Proteínas Smad/metabolismo , Proteínas Smad/genética , Regeneración Nerviosa , Femenino , Masculino , Receptor Tipo II de Factor de Crecimiento Transformador beta/genética , Receptor Tipo II de Factor de Crecimiento Transformador beta/metabolismo , Ratones Endogámicos C57BL , Ratones , Recuperación de la FunciónRESUMEN
The experience of empathy for pain is underpinned by sensorimotor and affective dimensions which, although interconnected, are at least in part behaviorally and neurally distinct. Spinal cord injuries (SCI) induce a massive, below-lesion level, sensorimotor body-brain disconnection. This condition may make it possible to test whether sensorimotor deprivation alters specific dimensions of empathic reactivity to observed pain. To explore this issue, we asked SCI people with paraplegia and healthy controls to observe videos of painful or neutral stimuli administered to a hand (intact) or a foot (deafferented). The stimuli were displayed by means of a virtual reality set-up and seen from a first person (1PP) or third person (3PP) visual perspective. A number of measures were recorded ranging from explicit behaviors like explicit verbal reports on the videos, to implicit measures of muscular activity (like EMG from the corrugator and zygomatic muscles that may represent a proxy of sensorimotor empathy) and of autonomic reactivity (like the electrodermal response and Respiratory Sinus Arrhythmia that may represent a general proxy of affective empathy). While no across group differences in explicit verbal reports about the pain stimuli were found, SCI people exhibited reduced facial muscle reactivity to the stimuli applied to the foot (but not the hand) seen from the 1PP. Tellingly, the corrugator activity correlated with SCI participants' neuropathic pain. There were no across group differences in autonomic reactivity suggesting that SCI lesions may affect sensorimotor dimensions connected to empathy for pain.