Clinically Relevant Levels of 4-Aminopyridine Strengthen Physiological Responses in Intact Motor Circuits in Rats, Especially After Pyramidal Tract Injury

Abstract

Background. 4-Aminopyridine (4-AP) is a Food and Drug Administration–approved drug to improve motor function in people with multiple sclerosis. Preliminary results suggest the drug may act on intact neural circuits and not just on demyelinated ones. Objective. To determine if 4-AP at clinically relevant levels alters the excitability of intact motor circuits. Methods. In anesthetized rats, electrodes were placed over motor cortex and the dorsal cervical spinal cord for electrical stimulation, and electromyogram electrodes were inserted into biceps muscle to measure responses. The motor responses to brain and spinal cord stimulation were measured before and for 5 hours after 4-AP administration both in uninjured rats and rats with a cut lesion of the pyramidal tract. Blood was collected at the same time as electrophysiology to determine drug plasma concentration with a goal of 20 to 100 ng/mL. Results. We first determined that a bolus infusion of 0.32 mg/kg 4-AP was optimal: it produced on average 61.5 ± 1.8 ng/mL over the 5 hours after infusion. This dose of 4-AP increased responses to spinal cord stimulation by 1.3-fold in uninjured rats and 3-fold in rats with pyramidal tract lesion. Responses to cortical stimulation also increased by 2-fold in uninjured rats and up to 4-fold in the injured. Conclusion. Clinically relevant levels of 4-AP strongly augment physiological responses in intact circuits, an effect that was more robust after partial injury, demonstrating its broad potential in treating central nervous system injuries.

Paired motor cortex and cervical epidural electrical stimulation timed to converge in the spinal cord promotes lasting increases in motor responses

“…The nature of the descending output following cortical stimulation is likely corticospinal because it is a crossed response, and the response abolishes with pyramidal tract section (Sindhurakar et al . ).…”

Dexterity: A MATLAB-based analysis software suite for processing and visualizing data from tasks that measure arm or forelimb function

“…After a subject reached baseline, four consecutive sessions were collected. Then, the subject received a pyramidotomy, which is a unilateral cut injury to the corticospinal tract, as we have done previously (Brus-Ramer, Carmel, Chakrabarty, & Martin, 2007; Brus-Ramer, Carmel, & Martin, 2009; Carmel et al, 2010; Carmel, Kimura, & Martin, 2014; Sindhurakar et al, 2016; Sindhurakar et al, 2017). Testing was performed at 3, 7, 14, 21, 28, and 35 days after injury.…”

Motometrics: A Toolbox for Annotation and Efficient Analysis of Motor Evoked Potentials

“…All protocols were approved by the Institutional Animal Care and Use Committee of Weill Cornell Medicine. MEPs were evoked by stimulating forelimb area of motor cortex with epidural screw electrodes and recording from the contralateral biceps muscle with implanted EMG wires as described in Sindhurakar et al (2017). To modulate the MEP, low level (subthreshold) spinal cord stimulation was applied as described in Mishra et al (2017).…”

“…To assay the descending motor system, muscle responses to motor cortex stimulation are measured as the motor evoked potential (MEP) using electromyography (EMG). MEPs are used to measure changes in the motor system, due to neurological diseases or injury (Nitsche and Paulus, 2000; Buccino et al, 2005), and to measure the effects of therapy (Liepert et al, 1998; Sindhurakar et al, 2017). A characteristic of MEPs is that as stimulation strength is gradually increased, the MEP increases exponentially, then exhibits a linear relationship, and finally begins to saturate as stimulation intensity is increased (Devanne et al, 1997; Boroojerdi et al, 2001; Luft et al, 2001).…”