Diffusion MRI Biomarkers of Peripheral Nerve Trauma

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PROJECT SUMMARY Peripheral nerve damage following trauma results in catastrophic loss of sensorimotor function if not treated in a timely manner. In severe cases, surgical repair is required to regain function, but outcomes remain subopti- mal (with a failure rate reaching 40%). While electrodiagnostics are valuable indicators of nerve function and muscle denervation, they are often challenging to interpret early post-injury, limiting our ability to determine if surgical intervention is warranted. After surgery, it can also take many months for electrodiagnostics to indicate whether axons are sprouting across the repair site and regenerating toward their motor or sensory target. In both cases, this often results in a “wait and watch” approach that relies on the clinical manifestations of rein- nervation (e.g., the return of sensorimotor function), which ultimately delays clinical decision-making and in- creases the likelihood of permanent muscle atrophy, sensory loss, and the formation of painful neuromas. Giv- en these limitations, a biomarker that monitors nerve regeneration throughout the recovery process would im- prove sensorimotor outcomes by allowing for the earlier identification of i) nerves that require surgery and ii) failed repairs after surgery, even guiding re-operation (when necessary) in the latter case. Diffusion tensor im- aging (DTI) is an MRI method that yields indices (e.g., fractional anisotropy, FA) sensitive to nerve pathologies. We previously demonstrated that i) FA values from ex vivo rat nerves relate to axon density and behavioral outcomes following trauma and surgical repair and ii) FA values from human nerves report on failed surgeries, successful reoperations, and injury severity. While promising, larger-scale studies are required for clinical vali- dation given the heterogeneous nature of traumatic nerve injuries. Furthermore, we know that DTI lacks speci- ficity in the presence of concurrent edema and de/regeneration early after trauma. In line with these challeng- es, our overarching goal is to move nerve diffusion biomarkers toward clinical trial readiness by i) developing advanced diffusion methods with increased pathological specificity to regeneration; ii) demonstrating con- sistency across MRI vendors/sites; iii) and providing clinical validation by expanding to a larger-scale, multi-site study to evaluate whether pre- and post-surgical diffusion MRI predicts clinical outcomes. This multi-PI project represents a unique collaboration between scientists with expertise in advanced peripheral nerve MRI and world-class peripheral nerve surgeons. We will use the complementary technical and clinical expertise of the team to identify novel diffusion-based biomarkers based on the spherical mean technique (SMT) and opti- mize/evaluate performance. We hypothesize that SMT parameters predict surgical outcomes with higher levels of sensitivity and specificity than both DTI and standard clinical methods. If successful, these SMT-based bi- omarkers will allow physicians to recommend surgical interventions and detect failed repairs earlier than is cur- rently possible. Once established, these methods will also likely be of clinical utility in proximal injuries, where the prognosis for recovery is currently poor due to the prolonged time required to detect failed regeneration.