Strategies to augment volitional and reflex function may improve locomotor capacity following incomplete spinal cord injury

Many studies highlight the remarkable plasticity demonstrated by spinal circuits following an incomplete spinal cord injury (SCI). Such plasticity can contribute to improvements in volitional motor recovery, such as walking function, although similar mechanisms underlying this recovery may also contribute to the manifestation of exaggerated responses to afferent input, or spastic behaviors. Rehabilitation interventions directed toward augmenting spinal excitability have shown some initial success in improving locomotor function. However, the potential effects of these strategies on involuntary motor behaviors may be of concern. In this article, we provide a brief review of the mechanisms underlying recovery of volitional function and exaggerated reflexes, and the potential overlap between these changes. We then highlight findings from studies that explore changes in spinal excitability during volitional movement in controlled conditions, as well as altered kinematic and behavioral performance during functional tasks. The initial focus will be directed toward recovery of reflex and volitional behaviors following incomplete SCI, followed by recent work elucidating neurophysiological mechanisms underlying patterns of static and dynamic muscle activation following chronic incomplete SCI during primarily single-joint movements. We will then transition to studies of locomotor function and the role of altered spinal integration following incomplete SCI, including enhanced excitability of specific spinal circuits with physical and pharmacological interventions that can modulate locomotor output. The effects of previous and newly developed strategies will need to focus on changes in both volitional function and involuntary spastic reflexes for the successful translation of effective therapies to the clinical setting

A Novel Cable-Driven Robotic Training Improves Locomotor Function in Individuals Post-Stroke

A novel cable-driven robotic gait training system has been tested to improve the locomotor function in individuals post stroke. Seven subjects with chronic stroke were recruited to participate in this 6 weeks robot-assisted treadmill training paradigm. A controlled assistance force was applied to the paretic leg at the ankle through a cable-driven robotic system. The force was applied from late stance to mid-swing during treadmill training. Body weight support was provided as necessary to prevent knee buckling or toe drag. Subjects were trained 3 times a week for 6 weeks. Overground gait speed, 6 minute walking distance, and balance were evaluated at pre, post 6 weeks robotic training, and at 8 weeks follow up. Significant improvements in gait speed and 6 minute walking distance were obtained following robotic treadmill training through a cable-driven robotic system. Results from this study indicate that it is feasible to improve the locomotor function in individuals post stroke through a flexible cable-driven robot

Digestive and locomotor capacity show opposing responses to changing food availability in an ambush predatory fish

Metabolic rates vary widely within species, but little is known about how variation in the “floor” (i.e. standard metabolic rate in ectotherms; SMR) and “ceiling” (maximum metabolic rate; MMR) for an individual's aerobic scope (AS) are linked with the digestive and locomotor function. Any links among metabolic traits and aspects of physiological performance may also be modulated by fluctuations in food availability. This study followed changes in SMR, MMR, and digestive and locomotor capacity in Southern catfish (Silurus meridionalis) throughout 15 days of food deprivation and 15 days of refeeding. Individuals down-regulated SMR during food deprivation and showed only a 10% body mass decrease during this time. While critical swim speed (Ucrit), was robust to food-deprivation, digestive function decreased after fasting with a reduced peak oxygen uptake during specific dynamic action (SDA) and prolonged SDA duration. During refeeding, individuals displayed rapid growth and digestive function recovered to pre-fasting levels. However, refed fish showed a lower Ucrit than would be expected for their increased body length and in comparison to measures at the start of the study. Reduced swimming ability may be a consequence of compensatory growth: growth rate was negatively correlated with changes in Ucrit during refeeding. Southern catfish down-regulate digestive function to reduce energy expenditure during food deprivation, but regain digestive capacity during refeeding, potentially at the cost of decreased swimming performance. The plasticity of maintenance requirements suggests that SMR is a key fitness trait for in this ambush predator. Shifts in trait correlations with food availability suggest that the potential for correlated selection may depend on context

Epilepsy, Behavioral Abnormalities, and Physiological Comorbidities in Syntaxin-Binding Protein 1 (STXBP1) Mutant Zebrafish.

Mutations in the synaptic machinery gene syntaxin-binding protein 1, STXBP1 (also known as MUNC18-1), are linked to childhood epilepsies and other neurodevelopmental disorders. Zebrafish STXBP1 homologs (stxbp1a and stxbp1b) have highly conserved sequence and are prominently expressed in the larval zebrafish brain. To understand the functions of stxbp1a and stxbp1b, we generated loss-of-function mutations using CRISPR/Cas9 gene editing and studied brain electrical activity, behavior, development, heart physiology, metabolism, and survival in larval zebrafish. Homozygous stxbp1a mutants exhibited a profound lack of movement, low electrical brain activity, low heart rate, decreased glucose and mitochondrial metabolism, and early fatality compared to controls. On the other hand, homozygous stxbp1b mutants had spontaneous electrographic seizures, and reduced locomotor activity response to a movement-inducing "dark-flash" visual stimulus, despite showing normal metabolism, heart rate, survival, and baseline locomotor activity. Our findings in these newly generated mutant lines of zebrafish suggest that zebrafish recapitulate clinical phenotypes associated with human syntaxin-binding protein 1 mutations

Interventions to Reduce Spasticity and Improve Function in People With Chronic Incomplete Spinal Cord Injury: Distinctions Revealed by Different Analytical Methods.

Background. Spinal cord injury (SCI) results in impaired function, and ankle joint spasticity is a common secondary complication. Different interventions have been trialed with variable results. Objective. We investigated the effects of pharmacological and physical (locomotor training) interventions on function in people living with incomplete motor function loss caused by SCI and used different analytical techniques to understand whether functional levels affect recovery with different interventions. Methods. Participants with an incomplete SCI were assigned to 3 groups: no intervention, Lokomat, or tizanidine. Outcome measures were the 10-m walk test, 6-minute walk test, and the Timed Up and Go. Participants were classified in 2 ways: (1) based on achieving an improvement above the minimally important difference (MID) and (2) using growth mixture modeling (GMM). Functional levels of participants who achieved the MID were compared and random coefficient regression (RCR) was used to assess recovery in GMM classes. Results. Overall, walking speed and endurance improved, with no difference between interventions. Only a small number of participants achieved the MID. Both MID and GMM-RCR analyses revealed that tizanidine improved endurance in high-functioning participants. GMM-RCR classification also showed that speed and mobility improved after locomotor training. Conclusions. Improvements in function were achieved in a limited number of people with SCI. Using the MID and GMM techniques, differences in responses to interventions between high-and low-functioning participants could be identified. These techniques may, therefore, have potential to be used for characterizing therapeutic effects resulting from different interventions

Chronic thoracic hemisection spinal cord injury in adult rats induces a progressive decline in transmission from uninjured fibers to lumbar motoneurons

Although most spinal cord injuries are anatomically incomplete, only limited functional recovery has been observed in people and rats with partial lesions. To address why surviving fibers cannot mediate more complete recovery, we evaluated the physiological and anatomical status of spared fibers after unilateral hemisection (HX) of thoracic spinal cord in adult rats. We made intracellular and extracellular recordings at L5 (below HX) in response to electrical stimulation of contralateral white matter above (T6) and below (L1) HX. Responses from T6 displayed reduced amplitude, increased latency and elevated stimulus threshold in the fibers across from HX, beginning 1-2 weeks after HX. Ultrastructural analysis revealed demyelination of intact axons contralateral to the HX, with a time course similar to the conduction changes. Behavioral studies indicated partial recovery which arrested when conduction deficits began. These findings suggest a chronic pathological state in intact fibers and necessity for prompt treatment to minimize it

Effects of methamphetamine on locomotor activity and thalamic gene expression in leptin-deficient obese mice

Leptin is an adipose-derived hormone that regulates energy balance. Leptin receptors are expressed in extrahypothalamic sites and several reports showed that leptin can influence feeding and locomotor behavior via direct actions on dopaminergic neurons. The leptin deficient mouse (ob/ob) has been used as an animal model of blunted leptin action, and presents with obesity and mild type 2 diabetes. We used ob/ob mice to study the effect of repeated 7-day methamphetamine (METH) administration analyzing locomotion, behavioral sensitization, and somatosensory thalamic mRNA expression of voltage-gated calcium channels and glutamatergic receptors using RT-PCR. We observed reduced METH-mediated responses in ob/ob mice associated with enhanced in mRNA expression of key voltage-gated and glutamate receptors in the somatosensory thalamus. Results described here are important for understanding the control of locomotion and thalamocortical excitability by leptin.Fil: Gonzalez, Betina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; ArgentinaFil: Gonzalez, Candela Rocio. Universidad Maimónides. Área de Investigaciones Biomédicas y Biotecnológicas. Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y de Diagnóstico; ArgentinaFil: Bisagno, Veronica. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; ArgentinaFil: Urbano Suarez, Francisco Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentin

Development of bipedal and quadrupedal locomotion in humans from a dynamical systems perspective

The first phase in the development 0f locomotion, pr,öary variability would occur in normal fetuses and infants, and those with Uner Tan syndrome. The neural networks for quadrupedal locomotion have apparently been transmitted epigenetically through many species since about 400 MYA.\ud The second phase is the neuronal selection process. During infancy, the most effective motor pattern(s) and their associated neuronal group(s) are selected through experience.\ud The third phase, secondary or adaptive variability, starts to bloom at two to three years of age and matures in adolescence. This third phase may last much longer in some patients with Uner Tan syndrome, with a considerably delay in selection of the well-balanced quadrupedal locomotion, which may emerge very late in adolescence in these cases

Role of dopamine D1-like receptors in methamphetamine locomotor responses of D2 receptor knockout mice

Behavioral sensitization to psychostimulants manifests as an increased locomotor response with repeated administration. Dopamine systems are accepted to play a fundamental role in sensitization, but the role of specific dopamine receptor subtypes has not been completely defined. This study used the combination of dopamine D2 receptor-deficient mice and a D1-like antagonist to examine dopamine D1 and D2 receptor involvement in acute and sensitized locomotor responses to methamphetamine. Absence of the dopamine D2 receptor resulted in attenuation of the acute stimulant effects of methamphetamine. Mutant and wild-type mice exhibited sensitization that lasted longer within the time period of the challenge test in the mutant animals. Pretreatment with the D1-like receptor antagonist SCH 23390 produced more potent reductions in the acute and sensitized locomotor responses to methamphetamine in D2 receptor-deficient mice than in wild-type mice; however, the expression of locomotor sensitization when challenged with methamphetamine alone was equivalently attenuated by previous treatment with SCH 23390. These data suggest that dopamine D2 receptors play a key role in the acute stimulant and sensitizing effects of methamphetamine and act in concert with D1-like receptors to influence the acquisition of methamphetamine-induced behavioral sensitization, traits that may influence continued methamphetamine use.Fil: Kelly, M. A.. Oregon Health And Science University; Estados UnidosFil: Low, M. J.. Oregon Health And Science University; Estados UnidosFil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular; ArgentinaFil: Phillips, T. J.. Oregon Health And Science University; Estados Unido

The likely effects of thermal climate change on vertebrate skeletal muscle mechanics with possible consequences for animal movement and behaviour

Climate change can involve alteration in the local temperature that an animal is exposed to, which in turn may affect skeletal muscle temperature. The underlying effects of temperature on the mechanical performance of skeletal muscle can affect organismal performance in key activities, such as locomotion and fitness-related behaviours, including prey capture and predator avoidance. The contractile performance of skeletal muscle is optimized within a specific thermal range. An increased muscle temperature can initially cause substantial improvements in force production, faster rates of force generation, relaxation, shortening, and production of power output. However, if muscle temperature becomes too high, then maximal force production and power output can decrease. Any deleterious effects of temperature change on muscle mechanics could be exacerbated by other climatic changes, such as drought, altered water, or airflow regimes that affect the environment the animal needs to move through. Many species will change their location on a daily, or even seasonal basis, to modulate the temperature that they are exposed to, thereby improving the mechanical performance of their muscle. Some species undergo seasonal acclimation to optimize muscle mechanics to longer-term changes in temperature or undergo dormancy to avoid extreme climatic conditions. As local climate alters, species either cope with the change, adapt, avoid extreme climate, move, or undergo localized extinction events. Given that such outcomes will be determined by organismal performance within the thermal environment, the effects of climate change on muscle mechanics could have a major impact on the ability of a population to survive in a particular location