Longitudinal Assessment of Spinal Cord Structural Plasticity Using DTI in SCI Patients

This study will apply novel magnetic resonance imaging (MRI) techniques to investigation of spinal cord injury (SCI) to learn how nerve fibers repair and neural cells regain ability to control muscle during the rehabilitation. The information gained will be helpful for physicians to make more accurate diagnosis of SCI, predict injury recovery and movement restoration, and develop more effective treatment plans.

Today, the International Standards for the Neurological Classification of Spinal Cord Injury (ISNSCI) , which includes tests of motor and cutaneous sensory function, and Spinal Cord Independence Measure (SCIM) are the gold standards for neurological classification of spinal cord injury (SCI). These standard measures have very important applications in the rehabilitation of SCI as primary clinical and outcome measures. Despite the importance and usefulness of their applications, these standard measures have their limitations. For example, ISNSCI, intended to be a clinical classification system, is subjective and relatively insensitive to incremental neurophysiological and functional changes during both acute and chronic stages of recovery. Moreover, the ISNSCI cannot evaluate the spinal cord (SC) function bellow the neurological level. For some patients such as children and patients with concomitant brain injuries, reliable evaluation cannot be completed due to their limited cognitive engagement in the evaluation process. Magnetic resonance imaging (MRI) has been proposed as a more objective tool to help clinicians make prognosis. However, recent study showed that conventional clinical MRI does not correlate well with scores measured with ISNSCI.

Diffusion Tensor Imaging (DTI) is an advanced MRI tool capable of probing white matter integrity information through measuring directional diffusion of water molecules, thus providing more microscopic details than conventional MRI. Recent findings suggest that DTI is a promising, non-invasive and objective tool for evaluating and monitoring structural changes within white matter axon pathways after SCI. Our preliminary data showed significant deviation of DTI indices from normative values of healthy subjects in a SCI patient whose conventional T2 scans appeared to be normal (see preliminary data section). A likely explanation for this observed alteration of DTI indices is degeneration and demyelization in descending axonal pathways. Although DTI has been used in animal models to measure the evolution of the injury in the SC and showed great promise in detection of pathological changes in SC, no longitudinal DTI data obtained from human SC are available to indicate sensitivity of DTI technique in detecting SCI progression or recovery. Is DTI capable of detecting structural changes taking place in the SC over the course of rehabilitation in individuals with SCI? Will these measured DTI parameters correlate with ISNSCI-based scores? The fundamental hypothesis of the current study is that rehabilitation can facilitate SC fiber tract repair along with spontaneous adaptations following the injury to help reconnect some of the injured nerve fibers with motoneurons controlling muscles and this will in turn improve the motoneuron activity to promote muscular function, and all these changes can be detected by the proposed longitudinal DTI protocols and standard clinical tools for motor function evaluation. The expected results gained by this longitudinal study would support the application of DTI in monitoring plastic changes in the injured SC and the DTI-derived measures could potentially aid clinicians make more objective diagnosis of the injury and estimate its progression, which are critical in planning targeted therapies. However, it is out of the scope of this proposal to distinguish contributions to structural changes occurring in the SC between spontaneous and treatment factors. Because it is unethical to not treat patients, this limitation cannot be overcome in the current human study. Given the primary focus of the study being longitudinal tracking of SC structural changes using neuroimaging rather than determining relative contributions to these changes by spontaneous recovery and treatment, the limitation should not significantly influence the quality of our study. To test the hypothesis, the investigators propose the following Specific Aims.

Aim 1: Track SC structural changes in patients with incomplete SCI (iSCI) using DTI. Each patient in the proposed study will be scanned covering entire cervical region of the SC using a DTI sequence at baseline, 2 weeks, 1 month, 3 month and 6 month after start of standard rehabilitation intervention. DTI indices (see methods for details) will be quantified and compared across all time points. Previous longitudinal brain DTI human and animal studies suggest that DTI is sensitive to detect brain whiter matter structural changes 24 hours (animal study) and 3 months (unpublished human DTI results by PI's group) after brain injury, and 6 month after initial scan in patients with Amyotrophic lateral sclerosis(ALS) (DTI data were only available 6 months after initial scan in this study). The investigators hypothesize that the proposed DTI protocol will be able to capture structural changes in SCI during its recovery course.

Aim 2: Correlate the SC plasticity manifested by changes in DTI indices with clinical assessments of injury and sensorimotor function. Quantitative DTI indices will be correlated to clinical diagnoses of SCI and clinical evaluations of upper and lower limb sensorimotor function of the patients. It is hypothesized that the DTI index of SCI will significantly be correlated with clinical diagnosis and scores of upper and lower sensorimotor function. The DTI parameter holds great promise to be a biomarker of SCI and is expected to have prognostic value in predicting functional outcome of a rehabilitation program.

Eligibility Criteria:
Inclusion Criteria:

* SCI due to single event traumatic injury; C4-T12 neurological level of injury, AIS grade B,C or D;
* currently medically stable;
* no history of seizure;
* spasticity at a score of 2 or lower assessed using Modified Ashworth Assessment of the upper and lower extremities;
* able to give informed consent;
* to stay still in the MR scanner for \~30 min.

Exclusion Criteria:

* MRI contraindications;
* younger than 18 and older than 75 years (this age range will limit contributions from nervous system development and aging to results of the study);
* history of epilepsy and other neurological diseases and trauma;
* drug and alcohol abuse;
* multi injury levels;
* severe craniocerebral injury and
* presence of non-MRI-safe post-operative hardware in the spine or brain.