Cervical dorsal root injuries that result in the deafferentation of the fingers can severely impair hand function, especially the execution of manual tasks that depend on continuous sensory feedback (i.e. the handling and identification of objects within reach). Surgical repair of such injuries is rarely, if ever, successful, and the recovery of dexterity is typically limited. Our studies in the adult macaque monkey show that somatosensory pathways undergo substantial reorganization following a dorsal root lesion, and that this reorganization contributes to the recovery of hand function (which is sometimes dramatic). Given that all manipulative tasks are inherently sensorimotor, it is now important that the 'motor'responses to the injury are understood. This forms the focus of the proposed investigations. The long term objectives are (1) to identify the structural and functional changes that occur in the sensorimotor pathways following deafferentation of the hand, that contribute to the spontaneous recovery of manual dexterity, and (2) to identify endogenous mechanisms that could be targeted therapeutically to promote functional recovery. In the proposed studies, a unique dorsal root lesion model will be used that allows us to select and block sensory input from a discrete part of the monkey hand (namely the thumb and index finger, and surrounding regions). Physiological and anatomical analyses will allow the determination of changes in the motor neuronal circuitry and this will be correlated with the behavioral deficit and recovery of manual dexterity over a period of several months.
The specific aims i n summary are as follows: 1. Do the corticospinal and other descending cortical motor pathways subserve voluntary hand movements following a dorsal root lesion? 2. Do the connections of the rubro-olivary- cerebello-cortical loop reorganize in response to the loss of sensory input following a cervical dorsal root lesion? This feedforward system is necessary to fine voluntary hand function in the higher primates and human, and its major sensory input from the digits is lost following a deafferentation injury, and 3. Do descending cortical fibers form new functional synapses (within the dorsal and ventral horn, cuneate nucleus and red nucleus), in response to a dorsal root lesion? EM analysis will be used to answer this question. The proposed work will contribute important new insight into the central neural mechanisms responsible for the behavioral adaptations that occur following a well defined deafferentation injury. The experimental design simulates aspects of the clinical condition of spinal root avulsion, and makes the study of the mechanistic changes in a complex system possible. The resulting findings will inform our understanding of the changes that occur in clinical injuries, and better enable the future development of effective treatments for people with avulsed root and other spinal and central nervous system injuries.

Public Health Relevance

Cervical spinal nerve injuries can result in a severe and permanent loss of hand function which is rarely repaired successfully by surgery. This disability can be accurately reproduced in the monkey in a controlled experimental model, which enables the analysis of the reorganized brain in the months following injury. Our current and proposed studies focus on examining factors that impede or promote the recovery of hand function, and our findings will enable the development of more effective treatments of cervical nerve and spinal injury

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS048425-08
Application #
8269942
Study Section
Motor Function, Speech and Rehabilitation Study Section (MFSR)
Program Officer
Ludwig, Kip A
Project Start
2004-04-01
Project End
2013-09-28
Budget Start
2012-07-01
Budget End
2013-09-28
Support Year
8
Fiscal Year
2012
Total Cost
$541,875
Indirect Cost
$208,008
Name
Stanford University
Department
Veterinary Sciences
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Darian-Smith, Corinna; Lilak, Alayna; Garner, Joseph et al. (2014) Corticospinal sprouting differs according to spinal injury location and cortical origin in macaque monkeys. J Neurosci 34:12267-79
Darian-Smith, Corinna; Lilak, Alayna; Alarcon, Christina (2013) Corticospinal sprouting occurs selectively following dorsal rhizotomy in the macaque monkey. J Comp Neurol 521:2359-72
Darian-Smith, Corinna; Hopkins, Stephanie; Ralston 3rd, Henry J (2010) Changes in synaptic populations in the spinal dorsal horn following a dorsal rhizotomy in the monkey. J Comp Neurol 518:103-17
Vessal, Mani; Darian-Smith, Corinna (2010) Adult neurogenesis occurs in primate sensorimotor cortex following cervical dorsal rhizotomy. J Neurosci 30:8613-23
Darian-Smith, Corinna (2009) Synaptic plasticity, neurogenesis, and functional recovery after spinal cord injury. Neuroscientist 15:149-65
Vessal, Mani; Aycock, Ari; Garton, Margaret Tess et al. (2007) Adult neurogenesis in primate and rodent spinal cord: comparing a cervical dorsal rhizotomy with a dorsal column transection. Eur J Neurosci 26:2777-94
Darian-Smith, Corinna; Ciferri, Melanie (2006) Cuneate nucleus reorganization following cervical dorsal rhizotomy in the macaque monkey: its role in the recovery of manual dexterity. J Comp Neurol 498:552-65
Darian-Smith, Corinna; Ciferri, Melanie M (2005) Loss and recovery of voluntary hand movements in the macaque following a cervical dorsal rhizotomy. J Comp Neurol 491:27-45