Spinal stimulation of the upper lumbar spinal cord modulates urethral sphincter activity in rats after spinal cord injury.

After spinal cord injury (SCI), the neurogenic bladder is observed to develop asynchronous bladder and external urethral sphincter (EUS) contractions in a condition known as detrusor-sphincter dyssnergia (DSD). Activation of the EUS spinal controlling center located at the upper lumbar spinal cord may contribute to reduce EUS dyssynergic contractions and decrease urethral resistance during voiding. However, this mechanism has not been well studied. This study aimed at evaluating the effects of epidural stimulation (EpS) over the spinal EUS controlling center (L3) in combination with a serotonergic receptor agonist on EUS relaxation in naive rats and chronic (6-8 wk) T8 SCI rats. Cystometrogram and EUS electromyography (EMG) were obtained before and after the intravenous administration of 5HT-1A receptor agonist and antagonist. The latency, duration, frequency, amplitude, and area under curve of EpS-evoked EUS EMG responses were analyzed. EpS on L3 evoked an inhibition of EUS tonic contraction and an excitation of EUS intermittent bursting/relaxation correlating with urine expulsion in intact rats. Combined with a 5HT-1A receptor agonist, EpS on L3 evoked a similar effect in chronic T8 SCI rats to reduce urethral contraction (resistance). This study examined the effect of facilitating the EUS spinal controlling center to switch between urine storage and voiding phases by using EpS and a serotonergic receptor agonist. This novel approach of applying EpS on the EUS controlling center modulates EUS contraction and relaxation as well as reduces urethral resistance during voiding in chronic SCI rats with DSD.

Movement rehabilitation after spinal cord injuries: emerging concepts and future directions.

Considerable inroads are being made into developing new treatments for spinal cord injury (SCI) which aim to facilitate functional recovery, including locomotion. Research on rehabilitative strategies following SCI using animal models has demonstrated that regaining and maintaining motor function, such as standing or stepping, is governed by principles of skill acquisition. Mechanisms key to learning motor tasks, including retention and transfer of skill, feedback and conditions of practice, all have examples in the SCI animal literature, although the importance of many concepts may often be overlooked. Combinatorial strategies which include physical rehabilitation are beginning to yield promising results. However, the effects of molecular-cellular interventions including chondroitinaseABC, anti-NogoA, foetal stem cell transplantation, etc., are still poorly understood with reference to the changes made to spinal plasticity by training and exercise. Studies that investigate the interplay between rehabilitation and other treatments have had mixed results; it appears likely that precise timings of different interventions will help to maximize recovery of function. Understanding how the time-course of injury and different rehabilitative and treatment modalities might factor into spinal plasticity will be critical in future therapeutic interventions.

Enhanced motor function by training in spinal cord contused rats following radiation therapy.

Weight-bearing stepping, without supraspinal re-connectivity, can be attained by treadmill training in an animal whose spinal cord has been completely transected at the lower thoracic level. Repair of damaged tissue and of supraspinal connectivity/circuitry following spinal cord injury in rat can be achieved by specific cell elimination with radiation therapy of the lesion site delivered within a critical time window, 2-3 weeks postinjury. Here we examined the effects of training in the repaired spinal cord following clinical radiation therapy. Studies were performed in a severe rat spinal cord contusion injury model, one similar to fracture/crush injuries in humans; the injury was at the lower thoracic level and the training was a combined hindlimb standing and stepping protocol. Radiotherapy, in a similar manner to that reported previously, resulted in a significant level of tissue repair/preservation at the lesion site. Training in the irradiated group, as determined by limb kinematics tests, resulted in functional improvements that were significant for standing and stepping capacity, and yielded a significant direct correlation between standing and stepping performance. In contrast, the training in the unirradiated group resulted in no apparent beneficial effects, and yielded an inverse correlation between standing and stepping performance, e.g., subject with good standing showed poor stepping capacity. Further, without any training, a differential functional change was observed in the irradiated group; standing capacity was significantly inhibited while stepping showed a slight trend of improvement compared with the unirradiated group. These data suggest that following repair by radiation therapy the spinal circuitries which control posture and locomotor were modified, and that the beneficial functional modulation of these circuitries is use dependent. Further, for restoring beneficial motor function following radiotherapy, training seems to be crucial.

Transformation of nonfunctional spinal circuits into functional states after the loss of brain input.

After complete spinal cord transections that removed all supraspinal inputs in adult rats, combinations of serotonergic agonists and epidural electrical stimulation were able to acutely transform spinal networks from nonfunctional to highly functional and adaptive states as early as 1 week after injury. Using kinematics, physiological and anatomical analyses, we found that these interventions could recruit specific populations of spinal circuits, refine their control via sensory input and functionally remodel these locomotor pathways when combined with training. The emergence of these new functional states enabled full weight-bearing treadmill locomotion in paralyzed rats that was almost indistinguishable from voluntary stepping. We propose that, in the absence of supraspinal input, spinal locomotion can emerge from a combination of central pattern-generating capability and the ability of these spinal circuits to use sensory afferent input to control stepping. These findings provide a strategy by which individuals with spinal cord injuries could regain substantial levels of motor control.

Changes in the exercise activation of diencephalic and brainstem cardiorespiratory areas after training.

The purpose of this study was to determine whether exercise training changes the extent or pattern of activation of areas in the central nervous system (CNS) involved in cardiorespiratory control. Rats that spontaneously trained on running wheels for 80-100 days were compared to rats that were not provided an opportunity to exercise. Selected brain regions including the hypothalamic and mesencephalic locomotor regions, and ventrolateral medulla were studied using c-Fos-like immunocytochemistry. A single test bout of exercise evoked significantly less activation as indicated by Fos labeling in the posterior (caudal) hypothalamic area, periaqueductal gray, nucleus of the tractus solitarius and the rostral ventrolateral medulla of the trained rats when compared to sedentary rats. These results are consistent with the concept that the nervous system changes its responses to a given level of exercise after training. These changes may also be related to perceived exertion.