Preclinical evidence supporting the clinical development of central pattern generator-modulating therapies for chronic spinal cord-injured patients

Abstract

Ambulation or walking is one of the main gaits of locomotion. In terrestrial animals, it may be defined as a series of rhythmic and bilaterally coordinated movement of the limbs which creates a forward movement of the body. This applies regardless of the number of limbs—from arthropods with six or more limbs to bipedal primates. These fundamental similarities among species may explain why comparable neural systems and cellular properties have been found, thus far, to control in similar ways locomotor rhythm generation in most animal models. The aim of this article is to provide a comprehensive review of the known structural and functional features associated with central nervous system (CNS) networks that are involved in the control of ambulation and other stereotyped motor patterns—specifically Central Pattern Generators (CPGs) that produce basic rhythmic patterned outputs for locomotion, micturition, ejaculation, and defecation. Although there is compelling evidence of their existence in humans, CPGs have been most studied in reduced models including in vitro isolated preparations, genetically-engineered mice and spinal cord-transected animals. Compared with other structures of the CNS, the spinal cord is generally considered as being well-preserved phylogenetically. As such, most animal models of spinal cord-injured (SCI) should be considered as valuable tools for the development of novel pharmacological strategies aimed at modulating spinal activity and restoring corresponding functions in chronic SCI patients.

Spinal Cord Stimulation and Augmentative Control Strategies for Leg Movement after Spinal Paralysis in Humans

“…A recently completed clinical trial in SCI individuals ( cf . clinicaltrials.gov, NCT01484184) provided preliminary evidence for the efficacy of a drug combination specifically designed to activate the spinal locomotor circuitry . Finally, SCS can have beneficial effects upon bladder, bowel, and sexual function below the lesion level as recently rediscovered ( cf .…”

“…In quadrupedal mammals, such central pattern generators for hindlimb control are situated in the lumbar spinal cord and can be activated by tonic electrical stimulation . Indirect evidence has suggested that functional circuitry with the capacity to generate rhythmic motor output also exists within the human lumbar spinal cord . Epidural stimulation applied over the posterior structures of the lumbar spinal cord (Figure A) at 25–50 Hz was shown to induce rhythmic activity in the legs of paralyzed individuals lying supine, some of which could result in involuntary smooth and coordinated flexion–extension movements at hip, knee, and ankle (Figure B) .…”

Tonic and Rhythmic Spinal Activity Underlying Locomotion

“…Pharmacological modulation of the state-dependency of neuronal circuits represents a promising approach for enabling locomotion. When the researcher attempts to neuromodulate the physiological state of the spinal circuitry by means of epidural electrical stimulation or pharmacological treatment of the spinal cord aimed at performing central pattern generator-modulating therapies [13], he/she should bear in mind their diffuse nature and a potential effect on various elementary interneuronal spinal networks [10]. Future research will focus on how these treatments can tune the physiological state of the spinal cord to activate the CPG circuitry and to respond appropriately to proprioceptive input and provide the control of both posture and locomotion [9].…”

“…It is also worth noting that most synapses are inhibitory (see, for instance, [11]) and contribute to maintain network stability, select/activate neurons of a particular elementary spinal network and avoid an excessive motor reaction [12]. In addition, there are various neuromodulators involved in the control of locomotion ( [8,13]) that affect the physiological state and plasticity of the spinal locomotor circuitry [5].…”

Stretching adversely modulates locomotor capacity following spinal cord injury via activation of nociceptive afferents.

“…Although it is not feasible to directly test for CPG in the human spinal cord, for example, with intracellular recordings due to the obvious invasive nature of these methods, the indirect evidence for the presence of a locomotor CPG in humans is substantial. First, given the strong evidence for CPG in every mammalian spinal cord tested and the fact that the spinal cord is one of the most well preserved structures phylogenetically it is more logical to argue for the existence of the CPG in humans than against it [119,140]. Second, human infants (3-6 months old) can generate "stepping" before the emergence of locomotor behavior given an appropriate proprioceptive stimulus [133,141].…”