RESUMEN
Spinal interneuron (IN) networks can facilitate respiratory motor recovery after spinal cord injury (SCI). We hypothesized that excitatory synaptic connectivity between INs located immediately caudal to unilateral cervical SCI would be most prevalent in a contra- to ipsilateral direction. Adult rats were studied following chronic C2 spinal cord hemisection (C2Hx) injury. Rats were anesthetized and ventilated and a multi-electrode array was used to simultaneously record INs on both sides of the C4-5 spinal cord. The temporal firing relationship between IN pairs was evaluated using cross-correlation with directionality of synaptic connections inferred based on electrode location. During baseline recordings, the majority of detectable excitatory IN connections occurred in a contra- to- ipsilateral direction. However, acute respiratory stimulation with hypoxia abolished this directionality, while simultaneously increasing the detectable inhibitory connections within the ipsilateral cord. We conclude that propriospinal networks caudal to SCI can display a contralateral-to-ipsilateral directionality of synaptic connections and that these connections are modulated by acute exposure to hypoxia.
Asunto(s)
Médula Cervical/lesiones , Médula Cervical/fisiología , Interneuronas/fisiología , Red Nerviosa/fisiología , Traumatismos de la Médula Espinal/fisiopatología , Potenciales de Acción/fisiología , Animales , Femenino , Nervio Frénico/fisiología , Ratas , Ratas Sprague-DawleyRESUMEN
Following spinal cord injury (SCI), intraspinal transplantation of neural progenitor cells (NPCs) harvested from the forebrain sub-ventricular zone (SVZ) can improve locomotor outcomes. Cervical SCI often results in respiratory-related impairments, and here we used an established model cervical SCI (C2 hemisection, C2Hx) to confirm the feasibility of mid-cervical transplantation of SVZ-derived NPCs and the hypothesis that that this procedure would improve spontaneous respiratory motor recovery. NPCs were isolated from the SVZ of enhanced green fluorescent protein (GFP) expressing neonatal rats, and then intraspinally delivered immediately caudal to an acute C2Hx lesion in adult non-GFP rats. Whole body plethysmography conducted at 4 and 8wks post-transplant demonstrated increased inspiratory tidal volume in SVZ vs. sham transplants during hypoxic (P=0.003) or hypercapnic respiratory challenge (P=0.019). Phrenic nerve output was assessed at 8wks post-transplant; burst amplitude recorded ipsilateral to C2Hx was greater in SVZ vs. sham rats across a wide range of conditions (e.g., quiet breathing through maximal chemoreceptor stimulation; P<0.001). Stereological analyses at 8wks post-injury indicated survival of ~50% of transplanted NPCs with ~90% of cells distributed in ipsilateral white matter at or near the injection site. Peak inspiratory phrenic bursting after NPC transplant was positively correlated with the total number of surviving cells (P<0.001). Immunohistochemistry confirmed an astrocytic phenotype in a subset of the transplanted cells with no evidence for neuronal differentiation. We conclude that intraspinal transplantation of SVZ-derived NPCs can improve respiratory recovery following high cervical SCI.
Asunto(s)
Ventrículos Laterales/citología , Nervio Frénico/fisiología , Trastornos Respiratorios/etiología , Traumatismos de la Médula Espinal/complicaciones , Traumatismos de la Médula Espinal/cirugía , 2',3'-Nucleótido Cíclico Fosfodiesterasas/metabolismo , Animales , Animales Recién Nacidos , Antígeno CD11b/metabolismo , Vértebras Cervicales , Modelos Animales de Enfermedad , Femenino , Proteína Ácida Fibrilar de la Glía/metabolismo , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Hipoxia , Masculino , Proteína Básica de Mielina/metabolismo , Células-Madre Neurales/metabolismo , Células-Madre Neurales/fisiología , Ratas , Ratas Sprague-Dawley , Ratas Transgénicas , Recuperación de la Función/fisiología , Trastornos Respiratorios/cirugíaRESUMEN
Intraspinal microstimulation (ISMS) using implanted electrodes can evoke locomotor movements after spinal cord injury (SCI) but has not been explored in the context of respiratory motor output. An advantage over epidural and direct muscle stimulation is the potential of ISMS to selectively stimulate components of the spinal respiratory network. The present study tested the hypothesis that medullary respiratory activity could be used to trigger midcervical ISMS and diaphragm motor unit activation in rats with cervical SCI. Studies were conducted after acute (hours) and subacute (5-21 days) C2 hemisection (C2Hx) injury in adult rats. Inspiratory bursting in the genioglossus (tongue) muscle was used to trigger a 250-ms train stimulus (100 Hz, 100-200 µA) to the ventral C4 spinal cord, targeting the phrenic motor nucleus. After both acute and subacute injury, genioglossus EMG activity effectively triggered ISMS and activated diaphragm motor units during the inspiratory phase. The ISMS paradigm also evoked short-term potentiation of spontaneous inspiratory activity in the previously paralyzed hemidiaphragm (i.e., bursting persisting beyond the stimulus period) in â¼70% of the C2Hx animals. We conclude that medullary inspiratory output can be used to trigger cervical ISMS and diaphragm activity after SCI. Further refinement of this method may enable "closed-loop-like" ISMS approaches to sustain ventilation after severe SCI.NEW & NOTEWORTHY We examined the feasibility of using intraspinal microstimulation (ISMS) of the cervical spinal cord to evoke diaphragm activity ipsilateral to acute and subacute hemisection of the upper cervical spinal cord of the rat. This proof-of-concept study demonstrated the efficacy of diaphragm activation, using an upper airway respiratory EMG signal to trigger ISMS at the level of the ipsilesional phrenic nucleus during acute and advanced postinjury intervals.
Asunto(s)
Diafragma/fisiopatología , Estimulación Eléctrica/métodos , Recuperación de la Función/fisiología , Traumatismos de la Médula Espinal/patología , Traumatismos de la Médula Espinal/terapia , Médula Espinal/fisiología , Análisis de Varianza , Animales , Fenómenos Biomecánicos , Biofisica , Médula Cervical , Modelos Animales de Enfermedad , Electromiografía , Femenino , Ratas , Ratas Sprague-DawleyRESUMEN
Midcervical spinal interneurons form a complex and diffuse network and may be involved in modulating phrenic motor output. The intent of the current work was to enable a better understanding of midcervical "network-level" connectivity by pairing the neurophysiological multielectrode array (MEA) data with histological verification of the recording locations. We first developed a method to deliver 100-nA currents to electroplate silver onto and subsequently deposit silver from electrode tips after obtaining midcervical (C3-C5) recordings using an MEA in anesthetized and ventilated adult rats. Spinal tissue was then fixed, harvested, and histologically processed to "develop" the deposited silver. Histological studies verified that the silver deposition method discretely labeled (50-µm resolution) spinal recording locations between laminae IV and X in cervical segments C3-C5. Using correlative techniques, we next tested the hypothesis that midcervical neuronal discharge patterns are temporally linked. Cross-correlation histograms produced few positive peaks (5.3%) in the range of 0-0.4 ms, but 21.4% of neuronal pairs had correlogram peaks with a lag of ≥0.6 ms. These results are consistent with synchronous discharge involving mono- and polysynaptic connections among midcervical neurons. We conclude that there is a high degree of synaptic connectivity in the midcervical spinal cord and that the silver-labeling method can reliably mark metal electrode recording sites and "map" interneuron populations, thereby providing a low-cost and effective tool for use in MEA experiments. We suggest that this method will be useful for further exploration of midcervical network connectivity.NEW & NOTEWORTHY We describe a method that reliably identifies the locations of multielectrode array (MEA) recording sites while preserving the surrounding tissue for immunohistochemistry. To our knowledge, this is the first cost-effective method to identify the anatomic locations of neuronal ensembles recorded with a MEA during acute preparations without the requirement of specialized array electrodes. In addition, evaluation of activity recorded from silver-labeled sites revealed a previously unappreciated degree of connectivity between midcervical interneurons.
Asunto(s)
Médula Cervical/citología , Médula Cervical/fisiología , Electroporación/métodos , Interneuronas/citología , Interneuronas/fisiología , Técnicas de Trazados de Vías Neuroanatómicas/métodos , Tinción con Nitrato de Plata/métodos , Potenciales de Acción , Animales , Microelectrodos , Neuronas Motoras/citología , Neuronas Motoras/fisiología , Vías Nerviosas/citología , Vías Nerviosas/fisiología , Nervio Frénico/citología , Nervio Frénico/fisiología , Ratas , Ratas Sprague-DawleyRESUMEN
Respiratory motor output after cervical spinal cord injury (cSCI) is profoundly influenced by spinal serotonin. We hypothesized that intraspinal transplantation of embryonic midline brainstem (MB) cells rich in serotonergic raphé neurons would improve respiratory outcomes after cSCI. One week after hemisection of the 2nd cervical segment (C2Hx) a suspension of either embryonic (E14) MB cells, fetal spinal cord cells (FSC), or media only (sham) was delivered to the dorsal C3 spinal cord of adult male rats. Six weeks later, ventilation was evaluated using plethysmography; phrenic nerve activity was evaluated in a subset of rats. Seven of 12 rats receiving MB-derived grafts had clear histological evidence of serotonin-positive neurons in the C3-4 dorsal white matter. The transplantations had no impact on baseline breathing patterns, but during a brief respiratory challenge (7% inspired CO2) rats with successful MB grafts had increased ventilation compared to rats with failed MB grafts, FSC or sham grafts. Recordings from the phrenic nerve ipsilateral to C2Hx also indicated increased output during respiratory challenge in rats with successful MB grafts. We conclude that intraspinal allografting of E14 MB cells can have a positive impact on respiratory motor recovery following high cSCI.
Asunto(s)
Trasplante de Células/métodos , Trastornos Respiratorios/etiología , Traumatismos de la Médula Espinal/complicaciones , Traumatismos de la Médula Espinal/cirugía , Potenciales de Acción , Animales , Modelos Animales de Enfermedad , Embrión de Mamíferos/citología , Lateralidad Funcional , Masculino , Bulbo Raquídeo/citología , Nervio Frénico/fisiopatología , Pletismografía , Ratas , Ratas Sprague-Dawley , Trastornos Respiratorios/terapia , Serotonina/metabolismo , Trasplante HomólogoRESUMEN
Anatomical evidence indicates that midcervical interneurons can be synaptically coupled with phrenic motoneurons. Accordingly, we hypothesized that interneurons in the C3-C4 spinal cord can display discharge patterns temporally linked with inspiratory phrenic motor output. Anesthetized adult rats were studied before, during, and after a 4-min bout of moderate hypoxia. Neuronal discharge in C3-C4 lamina I-IX was monitored using a multielectrode array while phrenic nerve activity was extracellularly recorded. For the majority of cells, spike-triggered averaging (STA) of ipsilateral inspiratory phrenic nerve activity based on neuronal discharge provided no evidence of discharge synchrony. However, a distinct STA phrenic peak with a 6.83 ± 1.1 ms lag was present for 5% of neurons, a result that indicates a monosynaptic connection with phrenic motoneurons. The majority (93%) of neurons changed discharge rate during hypoxia, and the diverse responses included both increased and decreased firing. Hypoxia did not change the incidence of STA peaks in the phrenic nerve signal. Following hypoxia, 40% of neurons continued to discharge at rates above prehypoxia values (i.e., short-term potentiation, STP), and cells with initially low discharge rates were more likely to show STP (P < 0.001). We conclude that a population of nonphrenic C3-C4 neurons in the rat spinal cord is synaptically coupled to the phrenic motoneuron pool, and these cells can modulate inspiratory phrenic output. In addition, the C3-C4 propriospinal network shows a robust and complex pattern of activation both during and following an acute bout of hypoxia.
Asunto(s)
Potenciales de Acción/fisiología , Vértebras Cervicales , Hipoxia/fisiopatología , Neuronas Motoras/fisiología , Nervio Frénico/fisiología , Animales , Masculino , Ratas , Ratas Sprague-Dawley , Médula Espinal/fisiopatologíaRESUMEN
Anatomical and neurophysiological evidence indicates that thoracic interneurons can serve a commissural function and activate contralateral motoneurons. Accordingly, we hypothesized that respiratory-related intercostal (IC) muscle electromyogram (EMG) activity would be only modestly impaired by a unilateral cervical spinal cord injury. Inspiratory tidal volume (VT) was recorded using pneumotachography and EMG activity was recorded bilaterally from the 1st to 2nd intercostal space in anesthetized, spontaneously breathing rats. Studies were conducted at 1-3 days, 2 wks or 8 wks following C2 spinal cord hemisection (C2HS). Data were collected during baseline breathing and a brief respiratory challenge (7% CO(2)). A substantial reduction in inspiratory intercostal EMG bursting ipsilateral to the lesion was observed at 1-3 days post-C2HS. However, a time-dependent return of activity occurred such that by 2 wks post-injury inspiratory intercostal EMG bursts ipsilateral to the lesion were similar to age-matched, uninjured controls. The increases in ipsilateral intercostal EMG activity occurred in parallel with increases in VT following the injury (R=0.55; P<0.001). We conclude that plasticity occurring within a "crossed-intercostal" circuitry enables a robust, spontaneous recovery of ipsilateral intercostal activity following C2HS in rats.
Asunto(s)
Inhalación/fisiología , Músculos Intercostales/fisiología , Plasticidad Neuronal/fisiología , Recuperación de la Función/fisiología , Traumatismos de la Médula Espinal/fisiopatología , Animales , Vértebras Cervicales , Músculos Intercostales/inervación , Masculino , Ratas , Ratas Sprague-Dawley , Mecánica Respiratoria/fisiologíaRESUMEN
The present study was performed to establish an anatomical context for studies of phrenic motor function in mouse models of central nervous system trauma and disease. Application of cholera toxin ß-subunit to the diaphragm of adult C57BL/6 mice revealed a columnar organization of phrenic motoneurons (PhMNs) which extended from rostral C3 to C6. Injection of Miniruby into the ventrolateral medulla revealed decussating, anterogradely labeled axons in the cervical spinal cord. In addition, application of the transneuronal tracer pseudorabies virus (PRV) to the right hemidiaphragm demonstrated a population of putative pre-phrenic interneurons at the level of the infected PhMN pool. These neuroanatomical features of the mouse phrenic nucleus are consistent with those described in other species and provide a foundation for studies of neuroplasticity and repair in relation to a functionally and anatomically identified spinal network.
Asunto(s)
Neuronas Motoras/fisiología , Nervio Frénico/fisiología , Animales , Biotina/análogos & derivados , Toxina del Cólera/toxicidad , Dextranos , Colorantes Fluorescentes , Inmunohistoquímica , Ratones , Ratones Endogámicos C57BL , Red Nerviosa/citología , Red Nerviosa/fisiología , Plasticidad Neuronal/fisiología , Nervio Frénico/citología , Rodaminas , Médula Espinal/patologíaRESUMEN
In this paper we review respiratory recovery following C2 spinal cord hemisection (C2HS) and introduce evidence for ipsilateral (IL) and contralateral (CL) phrenic motor neuron (PhrMN) synchrony post-C2HS. Rats have rapid, shallow breathing after C2HS but ventilation ( logical or (E)) is maintained. logical or (E) deficits occur during hypercapnic challenge reflecting reduced tidal volume (VT), but modest recovery occurs by 12 wks post-injury. IL PhrMN activity recovers in a time-dependent manner after C2HS, and neuroanatomical evidence suggests that this may involve both mono- and polysynaptic pathways. Accordingly, we used cross-correlation to examine IL and CL PhrMN synchrony after C2HS. Uninjured rats showed correlogram peaks consistent with synchronous activity and common synaptic input. Correlogram peaks were absent at 2 wks post-C2HS, but by 12 wks 50% of rats showed peaks occurring with a 1.1+/-0.19ms lag from zero on the abscissa. These data are consistent with prolonged conduction time to IL (vs. CL) PhrMNs and the possibility of polysynaptic inputs to IL PhrMNs after chronic C2HS.
Asunto(s)
Lateralidad Funcional/fisiología , Recuperación de la Función/fisiología , Mecánica Respiratoria/fisiología , Traumatismos de la Médula Espinal/patología , Animales , Vértebras Cervicales/patología , Modelos Animales de Enfermedad , Humanos , Neuronas Motoras/fisiología , Nervio Frénico/patología , Traumatismos de la Médula Espinal/fisiopatologíaRESUMEN
We examined the potential contribution of ventromedial (VM) tissue sparing to respiratory recovery following chronic (1 mo) unilateral C2 spinal cord injury (SCI) in rats. Preserved white matter ipsilateral to the injury was quantitatively expressed relative to contralateral white matter. The ipsilateral-to-contralateral white matter ratio was 0 after complete C2 hemisection (C2HS) and 0.23+/-0.04 with minimal VM sparing. Inspiratory (breath min(-1)) and phrenic frequency (burst min(-1)), measured by plethysmography (conscious rats) and phrenic neurograms (anesthetized rats) respectively, were both lower with minimal VM sparing (p<0.05 vs. C2HS). Tidal volume also was greater in minimal VM sparing rats during a hypercapnic challenge (p<0.05 vs. C2HS). In other C2 hemilesioned rats with more extensive VM matter sparing (ipsilateral-to-contralateral white matter ratio=0.55+/-0.05), respiratory deficits were indicated at 1 mo post-injury by reduced ventilation during hypercapnic challenge (p<0.05 vs. uninjured). Anterograde (ventral respiratory column-to-spinal cord) neuroanatomical tracing studies showed that descending respiratory projections from the brainstem are present in VM tissue. We conclude that even relatively minimal sparing of VM tissue after C2 hemilesion can alter respiratory outcomes. In addition, respiratory deficits can emerge in the adult rat after high cervical SCI even when relatively extensive VM sparing occurs.
Asunto(s)
Neuronas Motoras/fisiología , Recuperación de la Función/fisiología , Mecánica Respiratoria/fisiología , Traumatismos de la Médula Espinal/patología , Traumatismos de la Médula Espinal/fisiopatología , Animales , Vértebra Cervical Axis , Masculino , Vías Nerviosas , Nervio Frénico/citología , Nervio Frénico/fisiología , Pletismografía , Ratas , Ratas Sprague-Dawley , Índice de Severidad de la EnfermedadRESUMEN
Female sex hormones influence the neural control of breathing and may impact neurologic recovery from spinal cord injury. We hypothesized that respiratory recovery after C2 spinal hemisection (C2HS) differs between males and females and is blunted by prior ovariectomy (OVX) in females. Inspiratory tidal volume (VT), frequency (fR), and ventilation (VE) were quantified during quiet breathing (baseline) and 7% CO2 challenge before and after C2HS in unanesthetized adult rats via plethysmography. Baseline breathing was similarly altered in all rats (reduced VT, elevated fR) but during hypercapnia females had relatively higher VT (i.e. compared to pre-injury) than male or OVX rats (p<0.05). Phrenic neurograms recorded in anesthetized rats indicated that normalized burst amplitude recorded ipsilateral to C2HS (i.e. the crossed phrenic phenomenon) is greater in females during respiratory challenge (p<0.05 vs. male and OVX). We conclude that sex differences in recovery of VT and phrenic output are present at 2 weeks post-C2HS. These differences are consistent with the hypothesis that ovarian sex hormones influence respiratory recovery after cervical spinal cord injury.
Asunto(s)
Nervio Frénico/fisiología , Ventilación Pulmonar/fisiología , Recuperación de la Función/fisiología , Trastornos Respiratorios/complicaciones , Traumatismos de la Médula Espinal/complicaciones , Análisis de Varianza , Animales , Vértebras Cervicales , Estradiol/sangre , Potenciales Evocados/fisiología , Femenino , Lateralidad Funcional/fisiología , Masculino , Análisis por Apareamiento , Nervio Frénico/fisiopatología , Pletismografía Total , Progesterona/sangre , Ratas , Trastornos Respiratorios/fisiopatología , Factores Sexuales , Traumatismos de la Médula Espinal/fisiopatología , Estadísticas no ParamétricasRESUMEN
Following C2 spinal hemisection (C2HS) in adult rats, ipsilateral phrenic motoneuron (PhMN) recovery occurs through a time-dependent activation of latent, crossed-spinal collaterals (i.e., spontaneous crossed phrenic phenomenon; sCPP) from contralateral bulbospinal axons. Ventilation is maintained during quiet breathing after C2HS, but the ability to increase ventilation during a respiratory stimulation (e.g. hypercapnia) is impaired. We hypothesized that long-term expression of the sCPP would correspond to a progressive normalization in ventilatory patterns during respiratory challenge. Breathing was assessed via plethsymography in unanesthetized animals and phrenic motor output was measured in urethane-anesthetized, paralyzed and vagotomized rats. At 2-week post-C2HS, minute ventilation (VE) was maintained during baseline (room air) conditions as expected but was substantially blunted during hypercapnic challenge (68+/-3% of VE in uninjured, weight-matched rats). However, by 12 weeks the spinal-lesioned rats achieved a hypercapnic VE response that was 85+/-7% of control (p=0.017 vs. 2 wks). These rats also exhibited augmented breaths (AB's) or "sighs" more frequently (p<0.05) than controls; however, total AB volume was significantly less than control at 2- and 12-week post-injury (69+/-4% and 80+/-5%, p<0.05, respectively). We also noted that phrenic neurograms demonstrated a consistent delay in onset of the ipsilateral vs. contralateral inspiratory phrenic burst at 2-12-week post-injury. Finally, the ipsilateral phrenic response to respiratory challenge (hypoxia) was greater, though not normalized, at 4-12- vs. 2-week post-injury. We conclude that recovery of ventilation deficits occurs over 2-12-week post-C2HS; however, intrinsic neuroplasticity remains insufficient to concurrently restore a normal level of ipsilateral phrenic output.
Asunto(s)
Ventilación Pulmonar , Recuperación de la Función/fisiología , Traumatismos de la Médula Espinal/fisiopatología , Análisis de Varianza , Animales , Análisis de los Gases de la Sangre , Plexo Cervical/patología , Modelos Animales de Enfermedad , Lateralidad Funcional , Hipercapnia/etiología , Hipercapnia/fisiopatología , Masculino , Neuronas Motoras/fisiología , Pletismografía , Ratas , Ratas Sprague-Dawley , Traumatismos de la Médula Espinal/patología , Factores de TiempoRESUMEN
The mechanisms by which chronic cervical spinal cord injury alters respiratory function and plasticity are not well understood. We speculated that spinal hemisection at C(2) would alter the respiratory pattern controlled by vagal mechanisms. Expired volume (V(E)) and respiratory rate (RR) were measured in anesthetized control and C(2)-hemisected rats at 1 and 2 mo postinjury. C(2) hemisection altered the pattern of breathing at both postinjury time intervals. Injured rats utilized a higher RR and lower V(E) to maintain the same minute ventilation as control rats. After bilateral vagotomy, the pattern of breathing in injured rats was not different from controls. The frequency of augmented breaths was higher in injured rats at 2 mo postinjury before vagotomy; however, the V(E) of augmented breaths was not different between groups. In conclusion, C(2) hemisection alters the pattern of breathing at 1 and 2 mo postinjury via vagal mechanisms.
Asunto(s)
Respiración , Traumatismos de la Médula Espinal/fisiopatología , Animales , Vértebras Cervicales , Femenino , Ratas , Ratas Sprague-Dawley , Fenómenos Fisiológicos Respiratorios , Traumatismos de la Médula Espinal/patología , Vagotomía , Nervio Vago/fisiopatologíaRESUMEN
Because some bulbospinal respiratory premotor neurons have bilateral projections to the phrenic nuclei, we investigated whether changes in contralateral phrenic motoneuron function would occur after unilateral axotomy via C(2) hemisection. Phrenic neurograms were recorded under baseline conditions and during hypercapnic and hypoxic challenge in C(2) hemisected, normal, and sham-operated rats at 1 and 2 months after injury. The rats were anesthetized, vagotomized, and mechanically ventilated. No group differences were seen in contralateral neurograms at 1 month after injury. At 2 months, however, there was a statistically significant decrease in respiratory rate (RR) at normocapnia, an elevated RR during hypoxia, and an attenuated increase in phrenic neurogram amplitude during hypercapnia in the C(2)-hemisected animals. To test whether C(2) hemisection had induced a supraspinal change in respiratory motor drive, we recorded ipsilateral and contralateral hypoglossal neurograms during hypercapnia. As with the phrenic motor function data, no change in hypoglossal output was evident until 2 months had elapsed when hypoglossal amplitudes were significantly decreased bilaterally. Last, the influence of serotonin-containing neurons on the injury-induced change in phrenic motoneuron function was examined in rats treated with the serotonin neurotoxin, 5,7-dihydroxytryptamine. Pretreatment with 5,7-dihydroxytryptamine prevented the effects of C(2) hemisection on contralateral phrenic neurogram amplitude and normalized the change in RR during hypoxia. The results of this study show novel neuroplastic changes in segmental and brainstem respiratory motor output after C(2) hemisection that coincided with the spontaneous recovery of some ipsilateral phrenic function. Some of these effects may be modulated by serotonin-containing neurons.
Asunto(s)
Tronco Encefálico/fisiopatología , Respiración , Sistema Respiratorio/fisiopatología , Traumatismos de la Médula Espinal/fisiopatología , Médula Espinal/fisiopatología , 5,7-Dihidroxitriptamina/administración & dosificación , Inhibidores de Captación Adrenérgica/farmacología , Animales , Axotomía , Tronco Encefálico/efectos de los fármacos , Tronco Encefálico/patología , Modelos Animales de Enfermedad , Femenino , Lateralidad Funcional , Hipercapnia/fisiopatología , Nervio Hipogloso/fisiopatología , Hipoxia/fisiopatología , Inyecciones Intraventriculares , Neuronas Motoras/efectos de los fármacos , Plasticidad Neuronal/efectos de los fármacos , Nervio Frénico/efectos de los fármacos , Nervio Frénico/fisiopatología , Ratas , Respiración/efectos de los fármacos , Respiración Artificial , Sistema Respiratorio/efectos de los fármacos , Sistema Respiratorio/inervación , Serotoninérgicos/administración & dosificación , Organismos Libres de Patógenos Específicos , Médula Espinal/patología , Traumatismos de la Médula Espinal/patología , VagotomíaRESUMEN
Transplantation of fetal spinal cord (FSC) tissue has demonstrated significant potential in animal models for achieving partial anatomical and functional restoration following spinal cord injury (SCI). To determine whether this strategy can eventually be translated to humans with SCI, a pilot safety and feasibility study was initiated in patients with progressive posttraumatic syringomyelia (PPTS). A total of eight patients with PPTS have been enrolled to date, and this report presents findings for the first two patients through 18 months postoperative. The study design included detailed assessments of each subject at multiple pre- and postoperative time points. Outcome data were then compared with each subject's own baseline. The surgical protocol included detethering, cyst drainage, and implantation of 6-9-week postconception human FSC tissue. Immunosuppression with cyclosporine was initiated a few days prior to surgery and continued for 6 months postoperatively. Key outcome measures included: serial magnetic resonance imaging (MRI) exams, standardized measures of neurological impairment and functional disability, detailed pain assessment, and extensive neurophysiological testing. Through 18 months, the first two patients have been stable neurologically and the MRIs have shown evidence of solid tissue at the graft sites, without evidence of donor tissue overgrowth. Although it is still too soon to draw any firm conclusions, the findings from the initial two patients in this study suggest that intraspinal grafting of human FSC tissue is both feasible and safe.
Asunto(s)
Trasplante de Tejido Fetal , Traumatismos de la Médula Espinal/cirugía , Médula Espinal/trasplante , Siringomielia/cirugía , Adulto , Estudios de Factibilidad , Estudios de Seguimiento , Humanos , Terapia de Inmunosupresión , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Dimensión del Dolor , Proyectos Piloto , Médula Espinal/patología , Traumatismos de la Médula Espinal/complicaciones , Traumatismos de la Médula Espinal/patología , Siringomielia/etiología , Siringomielia/patología , Resultado del TratamientoRESUMEN
The feasibility and safety of a procedure involving fetal spinal cord tissue transplantation in patients with syringomyelia was assessed using a neurophysiological protocol designed to quantitate peripheral nerve function, spinal cord reflex excitability, and spinal cord conduction pathways essential for somatosensory evoked potentials. We report here data obtained before and for 18 months following the transplantation procedure performed on the first two patients in this study. The neurophysiological assessment protocols included measures of cortical and spinal cord evoked potentials, H-reflex excitability, and peripheral nerve conduction. Prior to the procedure, both patients had significant deficits on some of the neurophysiological measures, for example, lower extremity cortical evoked potentials. However, robust measures of intact pathways, such as upper extremity cortical evoked potentials, were also observed preoperatively in both patients. Thus, it was anticipated that conduction in these intact pathways could be at risk either from complications from the transplantation procedure and/or from continued expansion of the syrinx. Following the transplantation procedure, no negative changes were observed in any of the neurophysiological measures in either patient. In addition, patient 1 showed a decrease in the rate potentiation of tibial H-reflexes on the right side and an increase in the response probability of left tibial H-reflexes. The results of this postoperative longitudinal assessment provide a first-level demonstration of the safety of the intraspinal neural tissue transplantation procedure. However, the consideration of safety is currently limited to the grafting procedure itself, since the long-term fates of the donor tissue in these two patients remain to be shown more definitively.
Asunto(s)
Potenciales Evocados Somatosensoriales , Trasplante de Tejido Fetal , Médula Espinal/trasplante , Siringomielia/fisiopatología , Siringomielia/cirugía , Potenciales de Acción , Estudios de Factibilidad , Estudios de Seguimiento , Reflejo H , Humanos , Nervio Mediano/fisiología , Conducción Nerviosa , Nervio Tibial/fisiologíaRESUMEN
A variety of central nervous system injuries, diseases, and developmental deficits can lead to motor disorders that present complex mixtures of symptoms. Those that have a fundamental similarity characterized by the appearance of exaggerated velocity-dependent resistance to the lengthening of skeletal muscles are called spasticity. Reports based on clinical observations of motor disorders have and continue to provide the essential database of information regarding the range and distribution of unifying and discordant features of spasticity. Laboratory investigations employing animal models of motor disorders following experimental lesions of the central nervous system have reproduced some of the neurophysiologic changes that accompany injury of the central nervous system in humans. Those experimental lesions produced by spinal cord contusion/compression reproduce many of the histopathologic features displayed in traumatic injury of the human spinal cord as well. Studies using this model have revealed not only changes in reflex threshold and amplitude but also alterations in fundamental rate-modulation processes that regulate reflex excitability during repetitive stimulation. This report characterizes insights obtained from a laboratory investigation in search of fundamental mechanisms that contribute to the development of spasticity and provides a vantage point for understanding therapeutic strategies for treatment of spasticity.
Asunto(s)
Modelos Animales de Enfermedad , Espasticidad Muscular/etiología , Espasticidad Muscular/fisiopatología , Compresión de la Médula Espinal/complicaciones , Traumatismos de la Médula Espinal/complicaciones , Animales , Canales de Calcio/efectos de los fármacos , Canales de Calcio/metabolismo , Antagonistas del GABA/farmacología , Humanos , Interneuronas/fisiología , Neuronas Aferentes/efectos de los fármacos , Neuronas Aferentes/metabolismo , Compuestos Organofosforados/farmacología , Terminales Presinápticos/efectos de los fármacos , Terminales Presinápticos/metabolismo , Receptores de GABA-A/efectos de los fármacos , Receptores de GABA-A/metabolismoRESUMEN
The present study was conducted to determine the pattern of activation of the anterolateral abdominal muscles during the cough reflex. Electromyograms (EMGs) of the rectus abdominis, external oblique, internal oblique, transversus abdominis, and parasternal muscles were recorded along with gastric pressure in anesthetized cats. Cough was produced by mechanical stimulation of the lumen of the intrathoracic trachea or larynx. The pattern of EMG activation of these muscles during cough was compared with that during graded expiratory threshold loading (ETL; 1-30 cmH(2)O). ETL elicited differential recruitment of abdominal muscle EMG activity (transversus abdominis > internal oblique > rectus abdominis congruent with external oblique). In contrast, both laryngeal and tracheobronchial cough resulted in simultaneous activation of all four anterolateral abdominal muscles with peak EMG amplitudes 3- to 10-fold greater than those observed during the largest ETL. Gastric pressures during laryngeal and tracheobronchial cough were at least eightfold greater than those produced by the largest ETL. These results suggest that, unlike their behavior during expiratory loading, the anterolateral abdominal muscles act as a unit during cough.