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Principal Investigator: CORINNA DARIAN-SMITH
Organization: STANFORD UNIVERSITY
Fiscal Year: 2024
Award: $591,219
Funding agency: National Institute of Neurological Disorders and Stroke
Project Summary/Abstract
The toll of spinal cord injury on people and society is substantial, and particularly so when hand function
is impaired and independence lost. We use well defined spinal cord injury (SCI) models in nonhuman
primates and rodents to delineate the responses of major ascending and descending tracts, that
reorganize post-injury and that mediate the recovery of hand function. Our past work shows that spinal
injuries that remove sensory input from the opposing digits, can cause an initial deficit in hand function,
from which monkeys recover over weeks and months post-lesion. This recovery occurs despite the
permanent loss of most of the original sensory innervation to the hand. We have shown that spared
primary motor (M1) and somatosensory (S1) cortical subdivisions of the corticospinal tract (CST) sprout
extensively and bilaterally beyond their normal terminal territory within the cord following a
deafferentation injury, but only when the injury involves the central nervous system. Similar responses
can be demonstrated in rats which indicates the response is robust and conserved across mammalian
species. In this grant, we will address some major gaps that remain in our understanding of the
recovery process. We will do this by determining what happens at the neuronal circuit level, at the
periphery, and following a more clinically relevant lesion involving both sensory and motor components.
Our main focus is on monkeys, where our findings are directly translational, and on sub-chronic and
chronic time points following injury. These are times when patients are more accessible to intervention,
and the chronic time point in particular is poorly understood. Our specific aims in summary are as
follows: 1. What happens to the central neuronal circuitry following a deafferentation injury? Here we
will target the major inputs to the spinal cord (from the hand and cortex) and their connections, to
assess how they reorganize to mediate the recovery of hand function. 2. How do peripheral nerves and
receptors compensate for lost innervation to support significant recovery of sensation in the hand? 3.
How does the addition of a small motor component to our lesion model, alter the recovery process and
underlying connections? The lesion models to be used are particularly well defined, and involve
peripheral and central, as well as sensory and motor components, which makes them clinically relevant.
We use behavioral, electrophysiological, and a range of neuroanatomical techniques (including high
resolution confocal microscopy), as well as powerful multifactorial statistical modeling to assess
changes. Our findings will improve our understanding of the changes that occur in clinical injuries, and
better enable the future development of effective treatments for people with spinal cord injury. Findings
will be set in a broader context of behavioral recovery and system wide neuronal responses.
Terms: <Address><Afferent Neurons><Allelism Test><Anatomic Sites><Anatomic structures><Anatomy><Animals><Behavior><Behavioral><Bilateral><Brain><Brain Nervous System><Brain Stem><Brainstem><CNS Nervous System><Central Nervous System><Cervical><Chronic><Clinical><Common Rat Strains><Compensation><Complementation Test><Confocal Microscopy><Corticospinal Tracts><Data><Deafferentation><Deafferentation procedure><Development><Digit><Digit structure><Electron Microscopy><Electrophysiology><Electrophysiology (science)><Encephalon><Esthesia><Evoked Potentials><Fingers><Future><Genetic Complementation Test><Goals><Grant><Hand><Hand functions><Human><Hypersensitivity skin testing><Impairment><Individual><Injury><Intervention><Intervention Strategies><Lesion><Macaca><Macaque><Maps><Measures><Mediating><Medulla Spinalis><Modeling><Modern Man><Monkeys><Motivation><Motor><Motor Pathways><Nerve><Nerve Cells><Nerve Conduction><Nerve Fibers><Nerve Unit><Neural Cell><Neural Conduction><Neuranatomies><Neuranatomy><Neuraxis><Neuroanatomies><Neuroanatomy><Neurocyte><Neurons><Neurophysiology / Electrophysiology><Pathway interactions><Patients><Peripheral><Peripheral Nerves><Peripheral Nervous System><Persons><Population><Primates><Primates Mammals><Probabilistic Models><Probability Models><Process><Rat><Rats Mammals><Rattus><Receptor Protein><Recovery><Recovery of Function><Reproducibility><Research><Resolution><Rodent><Rodentia><Rodents Mammals><Role><SCI Patients><Sensation><Sensory><Sensory Neurons><Shapes><Skin><Skin Tests><Societies><Specificity><Spinal Cord><Spinal Cord Trauma><Spinal Injuries><Spinal Trauma><Spinal cord injured><Spinal cord injury><Spinal cord injury patients><Statistical Models><Synapses><Synaptic><System><Techniques><Thumb><Thumb structure><Time><Tracer><Trans Test><Traumatic Myelopathy><Using hands><Work><behavior response><behavioral response><clinical relevance><clinically relevant><complementation analysis><complementation approach><confocal imaging><develop therapy><developmental><effective therapy><effective treatment><electrophysiological><experiment><experimental research><experimental study><experiments><functional recovery><hand dysfunction><hand function impairment><hand function rehabilitation><hand function restoration><hand impairment><hand rehab><hand rehabilitation><hands><hypersensitivity test><immunologic skin test><impairment in hand function><improve hand function><improved><improvement in hand function><indexing><injuries><innervation><insight><intervention development><interventional strategy><nerve supply><neural mechanism><neuromechanism><neuronal><neuronal circuit><neuronal circuitry><non-human primate><nonhuman primate><novel><pathway><receptor><recover hand function><recovery of hand function><resolutions><response><restore hand function><sensory input><social role><somatosensory><spine injury><statistical linear mixed models><statistical linear models><synapse><therapy development><therapy optimization><treatment development><treatment optimization><vertebral injury>