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Acute intermittent hypoxia (AIH) is an emerging technique for enhancing neuroplasticity and motor function in respiratory and limb musculature. Thus far, AIH-induced improvements in strength have been reported for upper and lower limb muscles after chronic incomplete cervical spinal cord injury (iSCI), but the underlying mechanisms have been elusive. We used high-density surface EMG (HDsEMG) to determine if motor unit discharge behaviour is altered after 15 × 60 s exposures to 9% inspired oxygen, interspersed with 21% inspired oxygen (AIH), compared to breathing only 21% air (SHAM). We recorded HDsEMG from the biceps and triceps brachii of seven individuals with iSCI during maximal elbow flexion and extension contractions, and motor unit spike trains were identified using convolutive blind source separation. After AIH, elbow flexion and extension torque increased by 54% and 59% from baseline (P = 0.003), respectively, whereas there was no change after SHAM. Across muscles, motor unit discharge rates increased by â¼4 pulses per second (P = 0.002) during maximal efforts, from before to after AIH. These results suggest that excitability and/or activation of spinal motoneurons is augmented after AIH, providing a mechanism to explain AIH-induced increases in voluntary strength. Pending validation, AIH may be helpful in conjunction with other therapies to enhance rehabilitation outcomes after incomplete spinal cord injury, due to these enhancements in motor unit function and strength. KEY POINTS: Acute intermittent hypoxia (AIH) causes increases in muscular strength and neuroplasticity in people living with chronic incomplete spinal cord injury (SCI), but how it affects motor unit discharge rates is unknown. Motor unit spike times were identified from high-density surface electromyograms during maximal voluntary contractions and tracked from before to after AIH. Motor unit discharge rates were increased following AIH. These findings suggest that AIH can facilitate motoneuron function in people with incomplete SCI.
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Impaired spinal cord vascular function contributes to numerous neurological pathologies, making it important to be able to noninvasively characterize these changes. Here, we propose a functional magnetic resonance imaging (fMRI)-based method to map spinal cord vascular reactivity (SCVR). We used a hypercapnic breath-holding task, monitored with end-tidal CO2 (PETCO2), to evoke a systemic vasodilatory response during concurrent blood oxygenation level-dependent (BOLD) fMRI. SCVR amplitude and hemodynamic delay were mapped at the group level in 27 healthy participants as proof-of-concept of the approach, and then in two highly-sampled participants to probe feasibility/stability of individual SCVR mapping. Across the group and the highly-sampled individuals, a strong ventral SCVR amplitude was initially observed without accounting for local regional variation in the timing of the vasodilatory response. Shifted breathing traces (PETCO2) were used to account for temporal differences in the vasodilatory response across the spinal cord, producing maps of SCVR delay. These delay maps reveal an earlier ventral and later dorsal response and demonstrate distinct gray matter regions concordant with territories of arterial supply. The SCVR fMRI methods described here enable robust mapping of spatiotemporal hemodynamic properties of the human spinal cord. This noninvasive approach has exciting potential to provide early insight into pathology-driven vascular changes in the cord, which may precede and predict future irreversible tissue damage and guide the treatment of several neurological pathologies involving the spine.
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Upper extremity motor paradigms during spinal cord functional magnetic resonance imaging (fMRI) can provide insight into the functional organization of the cord. Hand-grasping is an important daily function with clinical significance, but previous studies of similar squeezing movements have not reported consistent areas of activity and are limited by sample size and simplistic analysis methods. Here, we study spinal cord fMRI activation using a unimanual isometric hand-grasping task that is calibrated to participant maximum voluntary contraction (MVC). Two task modeling methods were considered: (1) a task regressor derived from an idealized block design (Ideal) and (2) a task regressor based on the recorded force trace normalized to individual MVC (%MVC). Across these two methods, group motor activity was highly lateralized to the hemicord ipsilateral to the side of the task. Activation spanned C5-C8 and was primarily localized to the C7 spinal cord segment. Specific differences in spatial distribution are also observed, such as an increase in C8 and dorsal cord activity when using the %MVC regressor. Furthermore, we explored the impact of data quantity and spatial smoothing on sensitivity to hand-grasp motor task activation. This analysis shows a large increase in number of active voxels associated with the number of fMRI runs, sample size, and spatial smoothing, demonstrating the impact of experimental design choices on motor activation.
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Actividad Motora , Médula Espinal , Humanos , Actividad Motora/fisiología , Médula Espinal/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Extremidad Superior/fisiología , Fuerza de la ManoRESUMEN
Upper extremity motor paradigms during spinal cord functional magnetic resonance imaging (fMRI) can provide insight into the functional organization of the cord. Hand-grasping is an important daily function with clinical significance, but previous studies of similar squeezing movements have not reported consistent areas of activity and are limited by sample size and simplistic analysis methods. Here, we study spinal cord fMRI activation using a unimanual isometric hand-grasping task that is calibrated to participant maximum voluntary contraction (MVC). Two task modeling methods were considered: (1) a task regressor derived from an idealized block design (Ideal) and (2) a task regressor based on the recorded force trace normalized to individual MVC (%MVC). Across these two methods, group motor activity was highly lateralized to the hemicord ipsilateral to the side of the task. Activation spanned C5-C8 and was primarily localized to the C7 spinal cord segment. Specific differences in spatial distribution are also observed, such as an increase in C8 and dorsal cord activity when using the %MVC regressor. Furthermore, we explored the impact of data quantity and spatial smoothing on sensitivity to hand-grasp motor task activation. This analysis shows a large increase in number of active voxels associated with the number of fMRI runs, sample size, and spatial smoothing, demonstrating the impact of experimental design choices on motor activation.
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Acute intermittent hypoxia (AIH) is an emerging technique for facilitating neural plasticity in individuals with chronic incomplete spinal cord injury (iSCI). A single sequence of AIH enhances hand grip strength and ankle plantarflexion torque, but underlying mechanisms are not yet clear. We sought to examine how AIH-induced changes in magnitude and spatial distribution of the electromyogram (EMG) of the biceps and triceps brachii contributes to improved strength. Seven individuals with iSCI visited the laboratory on two occasions, and received either AIH or Sham AIH intervention in a randomized order. AIH consisted of 15 brief (â¼60s) periods of low oxygen (fraction of inspired O2 = 0.09) alternating with 60s of normoxia, whereas Sham AIH consisted of repeated exposures to normoxic air. High-density surface EMG of biceps and triceps brachii was recorded during maximal elbow flexion and extension. We then generated spatial maps which distinguished active muscle regions prior to and 60 min after AIH or Sham AIH. After an AIH sequence, elbow flexion and extension forces increased by 91.7 ± 88.4% and 51.7 ± 57.8% from baseline, respectively, whereas there was no difference after Sham AIH. Changes in strength were associated with an altered spatial distribution of EMG and increased root mean squared EMG amplitude in both biceps and triceps brachii muscles. These data suggest that altered motor unit activation profiles may underlie improved volitional strength after a single dose of AIH and warrant further investigation using single motor unit analysis techniques to further elucidate mechanisms of AIH-induced plasticity.
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Fuerza de la Mano , Traumatismos de la Médula Espinal , Humanos , Electromiografía , Hipoxia , Músculos , OxígenoRESUMEN
BACKGROUND: The Graded Redefined Assessment of Strength, Sensation, and Prehension (GRASSP V1.0) was developed in 2010 as a 3-domain assessment for upper extremity function after tetraplegia (domains: Strength, Sensibility, and Prehension). A remote version (rGRASSP) was created in response to the growing needs of the field of Telemedicine. OBJECTIVE: The purpose of this study was to assess the psychometric properties of rGRASSP, establishing concurrent validity and inter-rater reliability. METHODS: Individuals with tetraplegia (n = 61) completed 2 visits: 1 in-person and 1 remote. The first visit was completed in-person to administer the GRASSP, and the second visit was conducted remotely to administer the rGRASSP. The rGRASSP was scored both by the administrator of the rGRASSP (Examiner 1), and a second assessor (Examiner 2) to establish inter-rater reliability. Agreement between the in-person and remote GRASSP evaluations was assessed using the intraclass correlation coefficient (ICC) and Bland-Altman agreement plots. RESULTS: The remote GRASSP demonstrated excellent concurrent validity with the GRASSP (left hand intraclass correlation coefficient (ICC) = .96, right ICC = .96). Concurrent validity for the domains was excellent for strength (left ICC = .96, right ICC = .95), prehension ability (left ICC = .94, right ICC = .95), and prehension performance (left ICC = .92, right ICC = .93), and moderate for sensibility (left ICC = .59, right ICC = .68). Inter-rater reliability for rGRASSP total score was high (ICC = .99), and remained high for all 4 domains. Bland-Altman plots and limits of agreements support these findings. CONCLUSIONS: The rGRASSP shows strong concurrent validity and inter-rater reliability, providing a psychometrically sound remote assessment for the upper extremity in individuals with tetraplegia.
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Traumatismos de la Médula Espinal , Humanos , Reproducibilidad de los Resultados , Cuadriplejía , Extremidad Superior , Sensación/fisiologíaRESUMEN
Peripheral nerve interfaces are frequently used in experimental neuroscience and regenerative medicine for a wide variety of applications. Such interfaces can be sensors, actuators, or both. Traditional methods of peripheral nerve interfacing must either tether to an external system or rely on battery power that limits the time frame for operation. With recent developments of wireless, battery-free, and fully implantable peripheral nerve interfaces, a new class of devices can offer capabilities that match or exceed those of their wired or battery-powered precursors. This paper describes methods to (i) surgically implant and (ii) wirelessly power and control this system in adult rats. The sciatic and phrenic nerve models were selected as examples to highlight the versatility of this approach. The paper shows how the peripheral nerve interface can evoke compound muscle action potentials (CMAPs), deliver a therapeutic electrical stimulation protocol, and incorporate a conduit for the repair of peripheral nerve injury. Such devices offer expanded treatment options for single-dose or repeated dose therapeutic stimulation and can be adapted to a variety of nerve locations.
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Terapia por Estimulación Eléctrica , Nervios Periféricos , Animales , Suministros de Energía Eléctrica , Terapia por Estimulación Eléctrica/métodos , Nervios Periféricos/fisiología , Nervios Periféricos/cirugía , Nervio Frénico , Prótesis e Implantes , Ratas , Tecnología InalámbricaRESUMEN
PURPOSE OF REVIEW: We have known for many decades that animals that sustain injuries to the neuraxis, which result in respiratory impairment, are able to develop rapid neural compensation for these injuries. This compensation, which is linked to the systemic hypoxia resulting from damage to the respiratory apparatus, is a potent manifestation of neural plasticity. Hypoxia-induced plasticity is also applicable to somatic neural systems that regulate motor activity in extremity muscles. We report on recent developments in our understanding of the mechanisms underlying this seemingly beneficial action of acute intermittent hypoxia (AIH). RECENT FINDINGS: AIH improves breathing in animal models of spinal cord injury, and increases strength and endurance in individuals with incomplete spinal injuries. The role of AIH as a therapeutic intervention remains to be confirmed but it has proved to be well tolerated for use in humans with no adverse effects reported to date. The effects of AIH emerge rapidly and persist for several hours raising the possibility that the intervention may serve as a priming mechanism for facilitating rehabilitation and promoting recovery after neurologic injury in man. SUMMARY: AIH is emerging as a potent and relatively inexpensive modality for inducing neuroplasticity, so it may prove feasible to use AIH in a clinical setting.
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Hipoxia , Traumatismos de la Médula Espinal , Animales , Sistema Nervioso Central , Humanos , Plasticidad Neuronal , Recuperación de la Función , Médula EspinalRESUMEN
Spinal cord injuries (SCI) disrupt neural pathways between the brain and spinal cord, causing impairment of motor function and loss of independent mobility. Spontaneous plasticity in spared neural pathways improves function but is often insufficient to restore normal function. One unique approach to augment plasticity in spinal synaptic pathways is acute intermittent hypoxia (AIH), meaning brief exposure to mild bouts of low oxygen, interspersed with normoxia. While the administration of AIH elicits rapid plasticity and enhances volitional somatic motor output in the lower-limbs of people with incomplete SCI, it is not known if AIH-induced neuroplasticity is equally prevalent in spinal motor pathways regulating upper-extremity motor-function. In addition, how long the motor effects are retained following AIH has not yet been established. The goal of this research was to investigate changes in hand strength and upper-limb function elicited by episodic hypoxia, and to establish how long these effects were sustained in persons with incomplete cervical SCI. We conducted a randomized, blinded, placebo-controlled and cross-over design study consisting of a single AIH or sham AIH session in 14 individuals with chronic, incomplete cervical SCI. In a subset of six participants, we also performed a second protocol to determine the cumulative effects of repetitive AIH (i.e., two consecutive days). In both protocols, hand dynamometry and clinical performance tests were performed pre- and post-exposure. We found that a single AIH session enhanced bilateral grip and pinch strength, and that this effect peaked ~3 h post-intervention. The strength change was substantially higher after AIH versus sham AIH. These findings demonstrate the potential of AIH to improve upper-extremity function in persons with chronic SCI, although follow-up studies are needed to investigate optimal dosage and duration of effect.
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Médula Cervical/lesiones , Fuerza de la Mano/fisiología , Hipoxia , Traumatismos de la Médula Espinal/terapia , Extremidad Superior/fisiología , Adulto , Estudios Cruzados , Femenino , Humanos , Hipoxia/metabolismo , Masculino , Persona de Mediana Edad , Plasticidad Neuronal/fisiología , Desempeño Psicomotor/fisiología , Recuperación de la Función/fisiología , Método Simple Ciego , Traumatismos de la Médula Espinal/metabolismo , Factores de Tiempo , Resultado del Tratamiento , Extremidad Superior/inervaciónRESUMEN
Objective. To test the hypothesis that an anti-inflammatory corticosteroid drug enhances spinal motor plasticity induced by acute intermittent hypoxia (AIH) in persons with chronic incomplete spinal cord injury (iSCI). Methods. Fourteen subjects with incomplete spinal cord injury (ASIA level C or D; mean age = 46 years) participated in a randomized, double-blinded, crossover, and placebo-controlled study. Subjects received either 60 mg oral prednisolone or a matching placebo, 1 hour before administration of AIH (15, 60-second hypoxic exposures; fraction of inspired oxygen [FiO2] = 0.09). Changes in voluntary ankle strength, lower extremity electromyograms (EMG), and serum inflammatory biomarkers were quantified. Results. Maximal ankle plantarflexion torque was significantly higher following prednisolone + AIH versus placebo + AIH (mean difference [MD] 9, 11, and 7 newton meter [Nâm] at 30, 60, and 120 minutes post-AIH, respectively; all Ps <.02). Soleus surface EMG during maximal voluntary contraction was also significantly increased following prednisolone + AIH (MD 3.5, P = .02 vs placebo + AIH), while activity of other leg muscles remained unchanged. Individuals had significantly higher levels of the anti-inflammatory serum biomarker interleukin-10 after prednisolone versus placebo (P = .004 vs placebo + AIH). Conclusions. Pretreatment with prednisolone increased the capacity for AIH-induced functional motor plasticity, suggesting that suppression of inflammation enhances the efficacy of AIH administration in individuals with spinal cord injury. Clinical trial registration number: NCT03752749.
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Antiinflamatorios/farmacología , Hipoxia , Rehabilitación Neurológica/métodos , Plasticidad Neuronal , Prednisolona/farmacología , Traumatismos de la Médula Espinal/terapia , Adulto , Tobillo/fisiopatología , Antiinflamatorios/administración & dosificación , Enfermedad Crónica , Estudios Cruzados , Método Doble Ciego , Electromiografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Plasticidad Neuronal/efectos de los fármacos , Plasticidad Neuronal/fisiología , Prednisolona/administración & dosificación , Traumatismos de la Médula Espinal/sangre , Traumatismos de la Médula Espinal/inmunología , Traumatismos de la Médula Espinal/fisiopatología , Resultado del TratamientoRESUMEN
Human spinal cord injuries (SCI) disrupt the pathways between brain and spinal cord, resulting in substantial impairment and loss of function. Currently, we do not have the ability to precisely quantify the "functional" level of motor injury. The aim of this study is to determine if high-density surface electromyography imaging (SEI) can be used to characterize the location and extent of the spinal lesion. SEI is a safe and non-invasive technique, which uses several electrodes to provide a map of muscle activity. We applied the SEI technique to characterize muscle activity in individuals with chronic incomplete cervical SCI. Surface electromyogram signals (sEMG) from Biceps Brachii (BB) were recorded at submaximal levels (20%, 40%, and 60%) of maximum voluntary contractions (MVC) during isometric elbow flexion, shoulder flexion, and elbow abduction in two individuals with SCI. Through time-domain analysis of the collected data, we detected signs of de-innervation and re-innervations by analyzing the innervation zones (IZ) on the left and right BB muscles. We found that the distribution of IZs was different between the two sides. In addition, analysis of sEMG data collected at rest (no voluntary contraction) showed evidence of superficial active motor units that were active during rest (in the absence of spasms). These findings highlight the potential of SEI technique as a potential clinical tool to quantitatively describe the extent of the damage to motor spinal circuitry, and provide added precision to the clinical examinations and radiological findings.
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Médula Cervical/lesiones , Médula Cervical/fisiopatología , Electromiografía/métodos , Traumatismos de la Médula Espinal/fisiopatología , Adulto , Brazo/fisiología , Codo/fisiopatología , Electrodos , Electromiografía/instrumentación , Humanos , Contracción Isométrica/fisiología , Masculino , Persona de Mediana Edad , Músculo Esquelético/inervación , Músculo Esquelético/fisiología , Músculo Esquelético/fisiopatología , Descanso , Hombro/fisiologíaRESUMEN
Extended culture of neural stem/progenitor cells facilitates in vitro analyses to understand their biology while enabling expansion of cell populations to adequate numbers prior to transplantation. Identifying approaches to refine this process, to augment the production of all CNS cell types (i.e., neurons), and to possibly contribute to therapeutic cell therapy protocols is a high research priority. This report describes an easily applied in vivo "pre-conditioning" stimulus which can be delivered to awake, non-anesthetized animals. Thus, it is a non-invasive and non-stressful procedure. Specifically described are the procedures for exposing mouse or rat pups (aged postnatal day 1-8) to a brief (40-80 min) period of intermittent hypoxia (AIH). The procedures included in this video protocol include calibration of the whole-body plethysmography chamber in which pups are placed during AIH and the technical details of AIH exposure. The efficacy of this approach to elicit tissue-level changes in the awake animal is demonstrated through the enhancement of subsequent in vitro expansion and neuronal differentiation in cells harvested from the subventricular zone (SVZ). These results support the notion that tissue level changes across multiple systems could be observed following AIH, and support the continued optimization and establishment of AIH as a priming or conditioning modality for therapeutic cell populations.
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Hipoxia/patología , Ventrículos Laterales/citología , Células-Madre Neurales/citología , Neuronas/citología , Animales , Animales Recién Nacidos , Técnicas de Cultivo de Célula/métodos , Células Cultivadas , Hipoxia/metabolismo , Ratones , RatasRESUMEN
In vitro exposure of neural progenitor cell (NPC) populations to reduced O(2) (e.g. 3% versus 20%) can increase their proliferation, survival and neuronal differentiation. Our objective was to determine if an acute (<1hr), in vivo exposure to intermittent hypoxia (AIH) alters expansion and/or differentiation of subsequent in vitro cultures of NPC from the subventricular zone (SVZ). Neonatal C57BL/6 mice (postnatal day 4) were exposed to an AIH paradigm (20×1 minute; alternating 21% and 10% O(2)). Immediately after AIH, SVZ tissue was isolated and NPC populations were cultured and assayed either as neurospheres (NS) or as adherent monolayer cells (MASC). AIH markedly increased the capacity for expansion of cultured NS and MASC, and this was accompanied by increases in a proliferation maker (Ki67), MTT activity and hypoxia-inducible factor-1α (HIF-1α) signaling in NS cultures. Peptide blockade experiments confirmed that proteins downstream of HIF-1α are important for both proliferation and morphological changes associated with terminal differentiation in NS cultures. Finally, immunocytochemistry and Western blotting experiments demonstrated that AIH increased expression of the neuronal fate determination transcription factor Pax6 in SVZ tissue, and this was associated with increased neuronal differentiation in cultured NS and MASC. We conclude that in vivo AIH exposure can enhance the viability of subsequent in vitro SVZ-derived NPC cultures. AIH protocols may therefore provide a means to "prime" NPC prior to transplantation into the injured central nervous system.