Wednesday, April 2, 2025
4/2/2025
Impairment of Spinal Development in Cerebral Palsy - Quinlan, Katharina Project Summary This project pursues the hypothesis that in individuals with spastic cerebral palsy (CP), primary afferent depolarization (PAD), a type of presynaptic modulation of Ia afferents, contributes to hypertonia, hyperreflexia and reflex irradiation. We have recently shown that spontaneous tonic activity of nociceptors contributes to PAD. Recent evidence from a large animal model of CP shows nociceptor sprouting is present along with more PAD and reflex irradiation. We propose parallel studies in people with and without CP and rabbits after prenatal hypoxia-ischemia (HI) at 70% gestation. The rabbit HI model shows hallmarks of spastic CP including cell death in the cortex, white matter injury, thinning of the corticospinal tracts, muscle stiffness, hyperreflexia, reflex irradiation, and changes in muscle architecture consistent with spastic CP. This study will investigate mechanisms by which nociceptive afferent expansion influences PAD in rabbits and humans and tests the effectiveness of transcutaneous nerve stimulation (TENS) to reduce spasticity in both rabbits and people. AIM 1: Compare nociceptive drive to GABAaxo neurons and PAD in HI/CP. Corticospinal innervation of spinal GABAaxo neurons is weakened by developmental injury. We hypothesize that this results in expanded nociceptor innervation of GABAaxo neurons and increased amplitude of nociceptor driven PAD, which then increases intersegmental Ia afferent conduction and reflex irradiation. Therefore, PAD will be measured in people with CP using conditioning of the H reflex by CST and other sensory pathways known to activate PAD, and using the in vitro rabbit spinal cord, stimulation of sensory and descending pathways and pharmacology. Expected outcome: Nociceptor-driven PAD and reflex irradiation will be larger in HI/CP. AIM 2: Quantify nociceptive synaptic contacts onto GABAaxo neurons in HI/CP. Nociceptive expansion occurs in CP/HI, potentially increasing synapses onto GABAaxo neurons, consistent with Aim 1. We hypothesize in HI/CP, additional synapses between nociceptors and GABAaxo neurons are concomitant with fewer CST contacts. We will quantify CGRP+ - GAD2+ contacts in rabbits and postmortem human tissue and CST-GAD2+ contacts using dye labeling and immunohistochemistry (IHC) in rabbits. Expected outcome: Nociceptor expansion in CP/HI will extend onto GABAaxo neurons driving aberrant PAD. AIM 3: Therapeutic blockade of nociceptors. TENS appears to reduce nociceptor neurotransmission, possibly via opioid and 5HT1D receptors. We hypothesize that in CP/ HI, use of lumbosacral TENS will reduce nociceptor-driven PAD, hyperreflexia, and reflex irradiation through a mechanism involving activation of spinal opioid and 5HT1D receptors, possibly through activation of a brainstem pathway. Lumbosacral TENS will be tested in rabbits and humans for its ability to reduce spasticity. In rabbits, mechanisms of action of TENS will be pharmacologically dissected in vivo intrathecally and in vitro to determine involvement of 1) 5HT1D 2) α5GABAA and 3) opioid receptors. Expected outcome: TENS will reduce reflex irradiation / spasticity.
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