Blair Calancie - US grants

In a previous study a novel reflex was described in subjects who had suffered spinal cord injury (SCI) at or cephalad to the sixth cervical root (C6; neurological level) and who had not recovered significant motor function below this level (Calancie, 1991). In response to electrical stimulation of the tibial and/or posterior tibial nerves in the lower extremity, short-latency motor responses were evoked form distal muscle groups in the upper extremity, particularly intrinsic hand muscles and wrist extensors. Conversely, subjects with clinically-identical injuries at the acute stage but who subsequently recovered some function below C6 did not demonstrate such responses, nor did able-bodied control subjects. The proposed study will investigate the origin of these reflexes, in that they might reflect either: 1) pre-existing neural circuitry which is ineffectual under ordinary circumstances but which becomes functionally possible reflecting aberrant CNS regenerative sprouting. Our preliminary studies indicate that these reflexes develop after the neural lesion, and are due to sprouting from axotomized lower extremity afferent axons which innervate motoneurons of the caudal cervical enlargement. If this is correct, we will have demonstrated a capacity for CNS plasticity previously unrecognized in the adult human spinal cord, and which may well bear upon future strategies to promote regeneration. Furthermore, based on our previous study that the development of such reflex activity bodes poorly for functional recovery, we will attempt to implement a therapeutic program in the acute SCI stage which is designed to minimize the development of these interlimb reflexes, which if successful may result in greater functional recovery than these individual experience on their own (which is almost none). Experiments will be conducted over a 5 year period, and will include subjects with acute and subacute (<1 year) injury (n= 50 subjects) and chronic (>1 year) cervical SCI (n = 100 subjects). We will make repeated measures on the same individuals. The discharge properties of upper extremity single motor units (SMU) recruited by various lower extremity stimuli (muscle twitch, tendon ta, light touch, heat, cold, hair pulls, skin vibration, electric shocks) will be a major focus of investigation. Properties of the sensory afferents and spinal cord long tracts mediating these reflexes will also be examined carefully. The extent and magnitude of upper extremity reflexes at different stages after SCI will be quantified as an indicator of whether or not the applied therapy is affecting spinal cord reflex organization. Similarly, a standardized test of muscle and sensation will be given to acute SCI research subjects to correlate these behavioral measures with the electrophysiological measures which we obtain.

DESCRIPTION: (Applicant's Abstract) Little is known about the mechanisms within the spinal cord which allow some persons with spinal cord injury to recover significant function, while others do not. We propose to conduct a series of electrophysiological and behavioral measures on persons with acute spinal cord injury who are admitted to Jackson Memorial Hospital. Subjects will be studied as many as 12 times after injury, in order to accurately define the time-course of any neurologic improvement or alteration seen. Approximately 150 subjects will be enrolled over a 5 year period. Clinical strength (through manual muscle test) and muscle electrical activity (EMG) will be recorded from multiple muscles of the arms and legs for persons with injury to the cervical spine, or from the legs in persons with injury to the thoracic or thoracolumbar spine. In addition to voluntary contractions, non-invasive magnetic stimulation of the brain will be used in some subjects to cause contractions of muscles made weak by the spinal cord injury. The size of the evoked EMG response, the time at which the response occurs, and the intensity of brain stimulation needed to cause a response will be determined for each muscle, to provide objective measures of conduction in spinal cord motor tracts. Reflex responses will be measured to estimate spinal cord excitability, and magnetic resonance images of the region of damage will be obtained at 3, 12, and 24 months after injury in a subset of individuals who have recovered some voluntary movement in the legs, in order to match changes in tissue properties (e.g. edema, myelination) with clinical function. In addition to providing valuable scientific information not currently available, this project will benefit attempts to implement clinical trials of treatment interventions for spinal cord injury - trials which are now being seriously considered and for which animal studies are underway. Specifically, the information gained from the successful completion of studies proposed herein will: 1) provide some sense of a given subjects's potential for spontaneous recovery of volitional motor activity and its time-course, to help establish whether there is an optimal time post-injury to apply whatever interventions are developed; 2) contribute towards the development of objective measures for prognosis; 3) develop criteria to select the most appropriate candidates for a particular intervention; and 4) guide decisions regarding which type of intervention might be most advantageous for a certain type of injury.

Fundamental strategies first adopted in major centers 20 years ago for the physical rehabilitation of persons with sub-acute or chronic spinal cord injury (SCI) have changed little since that time. One novel method of gait rehabilitation involves the use of an overhead support point and a harness. This body weight support' (BWS) strategy has been combined with treadmill-based gait training in several centers throughout the world, with what are claimed to be dramatic results; we also have seen marked improvement in function in our subjects trained in this manner from preliminary studies. It is speculated that this form of training may enhance output of a 'central pattern generator' of stepping movement from circuitry intrinsic to the subject's spinal cord. However, published studies of this type have been limited in their ability to form strong conclusions due to small sample size, inadequate control interventions, and/or limited outcome measures. In particular, only limited attention has been paid to the role that training-induced physical conditioning might play in mediating the functional improvements reported. This study will address these weaknesses to determine whether BWS-gait training is more effective than conventional rehabilitation therapy in improving functional gait in person's with neurologically-incomplete spinal cord injury. Two populations will be studied: persons with chronic SCI (greater than 1 year post-injury), and persons with sub-acute SCI (2 - 8 months post-injury). For the chronic SCI study, subjects will be randomly assigned to one of 3 groups: body weight support and treadmill-based training, body weight support and overground training, and conventional rehabilitation therapy. This design allows us to directly compare whether treadmill-based training, and its inherent advantage of providing highly-rhythmic input to the subject's legs, is superior to overground-based training, and its inherent advantage of allowing use of assistive devices, thereby replicating a more 'natural' training condition. Training sessions will typically last up to 1 hour/session, at a frequency of 3 sessions per week for a 13 week period. Persons with sub-acute injury will be randomized to receive either BWS-treadmill training, or conventional rehabilitation. All subjects will be evaluated with a battery of functional, metabolic and neurophysiologic measures prior to the onset of training, and during the week after training has been completed. The primary outcome measure will be average maximum overground walking velocity without body weight support but with the use of passive assistive devices. Secondary measures will concentrate on function (balance, mobility), fitness (work capacity, strength, gait efficiency), and spinal cord neurophysiology (motor conduction, reflex excitability). These studies will allow us to determine whether the functional improvements associated with BWS-based training are due to neurologic adaptation within the spinal cord, or reflect an increased work capacity secondary to fitness training; both possibilities have important implications with respect to optimizing therapy for persons with spinal cord injury.

[unreadable] DESCRIPTION (provided by applicant): Surgery involving the thoracic spine sometimes requires the implantation of metal rods to stabilize and fuse the vertebrae. One increasingly-popular method of anchoring these rods is to place large bone screws through the pedicles that connect the `back' part of each vertebra (i.e. the lamina) with its `front' part (i.e. the body), and then connecting the rods to these implanted screws. Typically a narrow `awl' (or pedicle finder) is forced through the pedicle (creating the pedicle track), and then a screw is placed along this track. Ideally the screw should be fully- contained within bone, but if it `misses' towards the midline (i.e. medially) at any level within the thoracic spine, it may hit and injure the spinal cord. The goal of this study is to develop a new intra-operative monitoring (IOM) test of spinal cord conduction to prevent medial malplacement of thoracic pedicle screws, thereby preventing spinal cord injury. In the first of 2 Specific Aims, we will establish the relationship between the amount of energy needed to electrically stimulate spinal cord and nerve roots through the pedicle track (i.e. prior to screw implantation) and the position of that screw relative to the pedicle, once the screw is placed. We anticipate that pedicle tracks which have broken through the bone of the medial pedicle wall will lead to spinal cord stimulation with weak current intensities. We will retrospectively develop rules to tell us when it is safe to put a screw in a particular pedicle track. In Specific Aim #2, we will apply these rules in a prospective manner to actively prevent screw malplacement during surgery in new subjects. Moreover, we will randomize these subjects into two cohorts. In one group we will actively stimulate through a modified pedicle finder while the surgeon is making a pedicle track, to provide immediate feedback to the surgeon if the orientation of the pedicle track needs to change. We anticipate that there will be fewer cases of medially-malplaced thoracic pedicle screws in subjects studied in Specific Aim #2 compared to those tested with the protocol from Specific Aim #1. Moreover we expect that those subjects who receive active stimulation through the pedicle finder will have the lowest incidence of medial screw malplacement of all subjects tested. By the end of this study period, we will have developed and validated a novel form of intra- operative monitoring for thoracic pedicle screw placement. Not only will this test lower the risk of spinal cord injury, but it will also lower the numbers of subjects who require additional surgery to revise screw placements that " while not causing spinal cord injury per se" are still encroaching upon the canal space enough that they would eventually lead to symptoms if left in place. PUBLIC HEALTH RELEVANCE: Surgery to the thoracic spine to treat deformity or trauma places the spinal cord at relatively high risk for injury, particularly when screws are implanted into the pedicles of the spine. This project will develop a novel method to prevent accidental screw placement into the spinal cord, thereby preventing spinal cord injury. [unreadable] [unreadable] [unreadable]