Selective Effects of Baclofen on Use-Dependent Modulation of GABAB Inhibition after Tetraplegia

Abstract

Baclofen is a GABA B receptor agonist commonly used to relief spasticity related to motor disorders. The effects of baclofen on voluntary motor output are limited and not yet understood. Using noninvasive transcranial magnetic and electrical stimulation techniques, we examined electrophysiological measures probably involving GABA B (long-interval intracortical inhibition and the cortical silent period) and GABA A (short-interval intracortical inhibition) receptors, which are inhibitory effects mediated by subcortical and cortical mechanisms. We demonstrate increased active long-interval intracortical inhibition and prolonged cortical silent period during voluntary activity of an intrinsic finger muscle in humans with chronic incomplete cervical spinal cord injury (SCI) compared with age-matched controls, whereas resting long-interval intracortical inhibition was unchanged. However, long-term (ϳ6 years) use of baclofen decreased active long-interval intracortical inhibition to similar levels as controls but did not affect the duration of the cortical silent period. We found a correlation between signs of spasticity and long-interval intracortical inhibition in patients with SCI. Short-interval intracortical inhibition was decreased during voluntary contraction compared with rest but there was no effect of SCI or baclofen use. Together, these results demonstrate that baclofen selectively maintains use-dependent modulation of largely subcortical but not cortical GABA B neuronal pathways after human SCI. Thus, cortical GABA B circuits may be less sensitive to baclofen than spinal GABA B circuits. This may contribute to the limited effects of baclofen on voluntary motor output in subjects with motor disorders affected by spasticity.

Subcortical Control of Precision Grip after Human Spinal Cord Injury

“…Single unit recordings in primates showed that spinal interneurons exert postspike effects in hand muscles during a precision grip (Takei and Seki, 2010) in a task-dependent manner (Takei and Seki, 2013). Although lesions of the corticospinal tract at the cervical spinal cord level showed in most cases recovery of the ability to grasp with the index finger and thumb (Sasaki et al, 2004;Alstermark et al, 2011;Hoogewoud et al, 2013), likely related to time-dependent central compensatory mechanisms underlying the recovery of finger dexterity (Nishimura et al, , 2009Isa et al, 2013), the contribution of subcortical pathways to the control of precision grip in humans with subcortical damage due to incomplete spinal cord injury (SCI) remains unknown.…”

Transcranial Magnetic Stimulation to Investigate Motor Cortical Circuitry and Plasticity in Spinal Cord Injury

“…The duration of the SP during 25% of MVC increased in SCI groups irrespective of baclofen use compared with uninjured participants [51]. There was also no difference in the cSP between SCI participants who were or were not taking baclofen.…”

“…These data indicate that baclofen creates typical modulation of LICI circuitry in the SCI population and that baclofen appears to normalize LICI function following SCI. The limited amount of research done regarding the LICI circuit within the SCI population shows an increase in the GABA B mediated circuit compared to uninjured, however the presence of baclofen appears to alter function of this circuit to similar levels of uninjured [51] LICI holds much of the same methodological limitations as SICI due to the similarities in the way they are both elicited. Therefore, changes to the motor threshold and MEP amplitude can affect LICI data interpretation in SCI.…”

“…In controls, SAS targeting muscles of the lower limb facilitates spinal Hoffman reflexes [95][96][97] and their recruitment [95]. SAS targeting the FDI leads to increases in MEP amplitude that are attributed to changes in the corticospinal-motor neuron synapses and follows STDP principles [51]. SAS has been tested on the less impaired FDI muscle in incomplete chronic SCI and shown to be effective at facilitating MEPs, and increasing both index finger force and background EMG for 80 minutes following stimulation, effects that are attributed to STDP at corticospinal-spinal motor neuron synapses.…”

Relationship between intracortical inhibition and motor behavior; implications for incomplete spinal cord injury

“…Baclofen is one such agonist that reduces the magnitude of SICI via presynaptic inhibition of GABAA neuron populations by GABAB receptors [3,13,14] . This medication is commonly prescribed to patients following SCI to reduce spasticity.…”