Derivation of Multivariate Syndromic Outcome Metrics for Consistent Testing across Multiple Models of Cervical Spinal Cord Injury in Rats

Abstract

Spinal cord injury (SCI) and other neurological disorders involve complex biological and functional changes. Well-characterized preclinical models provide a powerful tool for understanding mechanisms of disease; however managing information produced by experimental models represents a significant challenge for translating findings across research projects and presents a substantial hurdle for translation of novel therapies to humans. In the present work we demonstrate a novel ‘syndromic’ information-processing approach for capitalizing on heterogeneous data from diverse preclinical models of SCI to discover translational outcomes for therapeutic testing. We first built a large, detailed repository of preclinical outcome data from 10 years of basic research on cervical SCI in rats, and then applied multivariate pattern detection techniques to extract features that are conserved across different injury models. We then applied this translational knowledge to derive a data-driven multivariate metric that provides a common ‘ruler’ for comparisons of outcomes across different types of injury (NYU/MASCIS weight drop injuries, Infinite Horizons (IH) injuries, and hemisection injuries). The findings revealed that each individual endpoint provides a different view of the SCI syndrome, and that considering any single outcome measure in isolation provides a misleading, incomplete view of the SCI syndrome. This limitation was overcome by taking a novel multivariate integrative approach for leveraging complex data from preclinical models of neurological disease to identify therapies that target multiple outcomes. We suggest that applying this syndromic approach provides a roadmap for translating therapies for SCI and other complex neurological diseases.

Undirected compensatory plasticity contributes to neuronal dysfunction after severe spinal cord injury

“…Using a syndromic analysis (Ferguson et al, 2013) applied on a range of functional, electrophysiological and neuromorphological assessments, we provide statistical evidence that aberrant remodelling of denervated spinal circuits was in part responsible for the development of neuronal dysfunction in the chronic stage of SCI. Severely paralysed rats and humans exhibit similar neuronal dysfunction in the chronic stage of injury…”

“…Chronically denervated lumbosacral segments showed sprouting of myelinated primary afferent fibres, increased intraspinal axon density, enhanced bidirectional connectivity between distant spinal segments, and upregulation of the number of glutamatergic synaptic terminals. Using a syndromic analysis (Ferguson et al, 2011(Ferguson et al, , 2013, we established mechanistic relationships between this extensive anatomical reorganization, and the alteration of reflex behaviour and stepping capacities. These results suggested that injury-induced rewiring of denervated spinal segments formed aberrant sensorimotor circuits that caused abnormal reflex responses and recruited inappropriate combinations of neuronal networks during gait execution.…”

“…For this purpose, we applied a syndromic analysis (Ferguson et al, 2013) to all the computed variables (n = 55) in order to uncover causal links between neuronal dysfunction and Correlation between stepping capacities and the amplitude of the long-latency reflex response in chronically paralysed rats (n = 10).…”

“…Using a range of multifaceted assessments and novel syndromic analysis (Ferguson et al, 2013), we provide evidence suggesting that undirected compensatory plasticity contributes to the development of neuronal dysfunction in the chronic stage of severe SCI.…”

Noninvasive Reactivation of Motor Descending Control after Paralysis

“…At each stimulation site initiation (Initiate = response to stimulation alone) was first recorded followed by efforts to voluntarily oscillate (Voluntary) the limbs in a stepping-like fashion (rows 1-5). The lower limbs then were passively moved (Conditioning) in a stepping-like fashion for 3 min with and 3 min without stimulation (rows [6][7][8][9][10][11][12][13][14][15]. After each of these conditioning procedures the subject was asked to oscillate the limbs without stimulation.…”