Establishing a Novel Neural Tissue Deformation Biomarker for Type 1 Chiari Malformation

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Project Summary Untreated Type 1 Chiari malformation (CM1) is a devastating neurological disorder that can be treated by a high risk and costly brain operation. Since the decision to operate is often based on common symptoms, such as headache, along with a single imaging measure of cerebellar tonsil position that is commonly recognized as inadequate, the concern for under- and especially over-treatment is high. The CM1 public critically needs a biomarker that better reflects CM1 pathophysiology, allowing physicians a more accurate surgical selection. This proposal seeks to replace the simplistic CM1 diagnostic measure of cerebellar tonsil descent with a novel MRI-based biomarker that quantifies intrinsic cardiac-induced stretching and compression (deformation) of the brain and spinal cord. Our central hypothesis is that quantification of dynamic deformation within specific central nervous system tissue regions will be a biomarker to help appropriately select people with >5 mm tonsillar descent for surgical treatment. It is not possible to quantify neural tissue stress or pressure noninvasively. However, tissue deformation can be measured noninvasively with phase contrast (PC) MRI or displacement encoding with stimulated echoes (DENSE). Our preliminary data and publications show strong evidence for the importance of neural tissue deformation assessment in CM1 and confirmed DENSE sequence optimization and measurement reliability in the brain. Additionally, all members of our research team have received multiple research grants focused on CM1 and worked together in multiple funded CM1 projects. To test our hypothesis, in Aim 1, we will compare symptomatic CM1 patients, prior to surgery (N=20), to healthy controls (N=20) using dynamic deformation parameters (bulk motion, compression, tension, and shear) obtained at the spinal cord, brain stem, and cerebellar tonsils using PC MRI and DENSE. This aim will establish dynamic deformation parameters as a biomarker for symptomatic CM1. In Aim 2, we will compare neural tissue deformation in symptomatic CM1 patients (N=20) to asymptomatic subjects with >6 mm tonsillar descent below the foramen magnum (N=20). This aim will establish dynamic deformation as a biomarker that mitigates CM1 false-positive diagnosis. In Aim 3, we will determine how surgical treatment of CM1 alters neural tissue deformation and its correlation with symptom improvement. This aim will allow understanding of how deformation relates to surgical success. Our long-term goal is to develop advanced MR imaging and analysis techniques to form a CM1 biomechanics analysis tool-set that can be used clinically and applied in a multicenter study that will aid early detection, more precise diagnosis, and clinical management of CM1.