Spinal plasticity in stroke patients after botulinum neurotoxin A injection in ankle plantar flexors

Abstract

The effect of botulinum neurotoxin A (BoNT-A) in stroke patients' upper limbs has been attributed to its peripheral action only. However, BoNT-A depressed recurrent inhibition of lumbar motoneurons, likely due to its retrograde transportation along motor axons affecting synapses to Renshaw cells. Because Renshaw cells control group Ia interneurons mediating reciprocal inhibition between antagonists, we tested whether this inhibition, particularly affected after stroke, could recover after BoNT-A. The effect of posterior tibial nerve (PTN) stimulation on tibialis anterior (TA) electromyogram (EMG) was investigated in 13 stroke patients during treadmill walking before and 1 month after BoNT-A injection in ankle plantar flexors. Before BoNT-A, PTN stimuli enhanced TA EMG all during the swing phase. After BoNT-A, the PTN-induced reciprocal facilitation in TA motoneurons was depressed at the beginning of swing and reversed into inhibition in midswing, but at the end of swing, the reciprocal facilitation was enhanced. This suggests that BoNT-A induced spinal plasticity leading to the recovery of reciprocal inhibition likely due to the withdrawal of inhibitory control from Renshaw cells directly blocked by the toxin. At the end of swing, the enhanced reciprocal facilitation might be due to BoNT-induced modification of peripheral afferent inputs. Therefore, both central and peripheral actions of BoNT-A can modify muscle synergies during walking: (1) limiting ankle muscle co-contraction in the transition phase from stance to swing, to assist dorsiflexion, and (2) favoring it from swing to stance, which blocks the ankle joint and thus assists the balance during the single support phase on the paretic limb.

The Expanding Therapeutic Utility of Botulinum Neurotoxins

“…This probably led to the decreased recurrent inhibition of the latter muscle [ 112 ]. A similar study obtained comparable findings [ 113 ], providing more evidence for a central action of BoNT in humans as a result of a putative neuronal retrograde transport.…”

Interneuronal Transfer and Distal Action of Tetanus Toxin and Botulinum Neurotoxins A and D in Central Neurons

“…However, this idea has been called into question by physicians utilizing this agent in human patients. For example, after peripheral injection of BoNT/A, reciprocal inhibition between agonist and antagonist muscles has been reported, raising the possibility that BoNT/A moves within networks of neurons to affect circuit function (Priori et al, 1995, Aymard et al, 2013, Marchand-Pauvert et al, 2013, CeballosBaumann et al, 1997, Giladi, 1997). Alternatively, the observed effects might be due to the compensatory reorganization and remodeling of neuronal networks upstream of the injection site, as a result of purely local effects on the initial uptake neurons (Berardelli and Curra, 2002, Curra et al, 2004, Gilio et al, 2000, Boroojerdi et al, 2003, Abbruzzese and Berardelli, 2006).…”

Dramatic neurological and biological effects by botulinum neurotoxin type A on SH-SY5Y neuroblastoma cells, beyond the blockade of neurotransmitter release

“…However, there has been evidence questioning this idea after physicians utilized this agent in human patients. For example, after peripheral injection of BoNT/A, the possibility that BoNT/A moves within networks of neurons to affect circuit function has been raised with the observation of reciprocal inhibition between agonist and antagonist muscles [4,32]. Secondly, subsequent to the purely local effects on the initial uptake neurons, upstream of the injection site has shown the compensatory reorganization and remodeling of neuronal networks [1,7,12].…”