Botulinum Toxin as a Neuro-Relearning Drug Tool in Motor Paralytic Disorders

Abstract

The clinical use of Botulinum toxin (BoTx) in motor paralytic disorders until now is limited to spasticity relief in isolated spastic muscle/s. This paper advocates that BoTx should be used as a neuro-relearning tool that can significantly improve recovery in motor paralytic disorders. BoTx generates redundant numbers of synapses at motor endplates and at spinal motoneuron-interneurons. It facilitates muscle activity-dependent synapse competition at these two sites. Redundancy and competition-based selection of synaptic connections are naturally occurring learning-related plasticity events during infant motor learning-now familiarly known as competitive-learning. Thus when injected in small doses to multiple muscles of a paralyzed limb, BoTx can recreate and replay those competitive-learning processes in the learningresistant paralyzed brain centers. Computational modeling, humanoid robot, and animal studies reveal that motor re) learning can be significantly faster if competitive-learning mechanisms are employed in the paralyzed system. A treatment protocol is presented that aims to keep the paralyzing effects of BoTx minimized while prolonging relearning duration. Recent clinical studies strongly attest that small-dose; multi-muscle, repeat regimens improve function. The principal objective of the present paper is that future multi-muscle clinical studies will take note of the relearning properties of BoTx and make full utilization of this therapeutic effect.Key Words: Botulinum toxin, cerebral palsy, motor paralysis, spinal cord injury, stroke, traumatic brain injury (TBI). THE TWO FACES OF BOTXBotulinum toxin (BoTx) is being extensively used in the treatment of a variety of disorders e.g. spasticity relief in skeletal muscles, in glandular disorders e.g. hyperhidrosis and sialorrhoea, and in urological disorders e.g. bladdersphincter dyssynergia, besides many others. In motor paralytic disorders, the clinical use of BoTx until now is limited to spasticity relief in isolated, spastic muscle/s. This paper advocates that BoTx should be used as a neuro-relearning tool that can significantly improve recovery in motor paralytic disorders. Botulinum toxin (BoTx) has two distinct, but closely inter-related function facets. First is its acetylcholine release-blocking property that relieves spasticity by paralyzing that overactive muscle. This beneficial effect is temporary however, for as the effects of the toxin vanes off the spasticity returns [1-3]. The second is its extensive plasticityinducing property. BoTx generates profound transient plasticity at motor endplates, spinal motoneuron soma-dendrites, spinal interneurons, and cerebral sensory-motor cortex. This includes motoneuron soma size plasticity, dendro-dendritic coupling, new synapses formation, synapse competition, modifications of excitation-inhibition, motoneuron firing frequency, reflex response, long-latency polysynaptic pathways, cortical maps reorganizations etc among others [4]. Interesting to note, this widespread structural and functional BoTx pla...

Restoring Motor functions in Spinal cord injury, Hemiplegic Cerebral Palsy, and Stroke by Botulinum toxin-induced Synaptic Competitive-Learning Therapy

“…The beneficial effect of BoTx in spasticity relief is generally attributed to its Ach release blocking action at the motor terminals, the altered afferent signals from the injected muscle on to its synergistsantagonists, and the sensory plasticity at spinal and supra-spinal levels [1][2][3]. It should be stated however, that the far-reaching actions of BoTx at the motor system have been overlooked for far too long [4][5][6]. BoTx causes extensive sprouting of intramuscular motor axons, resulting in transient hyper-innervation (polyneuronal) of the injected muscle [4,6,[8][9][10].…”

“…It should be stated however, that the far-reaching actions of BoTx at the motor system have been overlooked for far too long [4][5][6]. BoTx causes extensive sprouting of intramuscular motor axons, resulting in transient hyper-innervation (polyneuronal) of the injected muscle [4,6,[8][9][10]. The motor units in that muscle start sharing each other's territories and thus the average size of motor unit becomes larger.…”

“…Botulinum toxin (BoTx) is well known as a popular drug of choice for spasticity relief [1][2][3]. Recent research shows that BoTx has synaptic competitive-learning (SCL) restoring properties that act at neuromuscular, spinal cord, and central nervous sensory-motor centers [4][5][6]. Contemporary research in sensory-motor cognitive systems indicate that in SCI, HCP,and stroke the motor paresis/ paralysis, and spasticity is caused by partial/complete disruption of all SCL mechanisms in the injured and denervated target neuron centers synaptic fields [5][6][7].…”

“…Recent research shows that BoTx has synaptic competitive-learning (SCL) restoring properties that act at neuromuscular, spinal cord, and central nervous sensory-motor centers [4][5][6]. Contemporary research in sensory-motor cognitive systems indicate that in SCI, HCP,and stroke the motor paresis/ paralysis, and spasticity is caused by partial/complete disruption of all SCL mechanisms in the injured and denervated target neuron centers synaptic fields [5][6][7]. In the intact brain-cord, SCL is naturallyendowed, that controls-regulates all sensory-motor learn-registerrecall-(motor) execute functions, and memory storage functions during development and throughout adult life.…”

“…SCL consists of an initial redundant numbers of synaptic connections, muscles activitydependent, competition-based selection of appropriate connections and pruning of inappropriate ones. Basic science research shows that BoTx has SCL-restoring properties that act transiently (weeks) at neuromuscular synapses, spinal cord motoneuron pools and the motor cortex [4][5][6][7]. Until now BoTx use in motor paralytic disorders is limited to spasticity/overactivity relief in isolated limb muscles and in dyssynergic bladder-sphincters.…”