Spinal cord functional connectivity as a biomarker of spinal cord dysfunction

Project Summary / Abstract This proposal aims to (1) develop and evaluate functional magnetic resonance imaging (fMRI) methods to non- invasively detect functional networks in the human cervical spinal cord at 7 Tesla, and (2) characterize spinal cord network dysfunction in patients with relapsing remitting multiple sclerosis (MS). Nearly all MS patients have focal lesions throughout the spinal cord, yet the majority of studies do not investigate disease progression in the clinically eloquent yet largely unexplored spinal cord. Currently, no imaging technique can predict disability progression referable to the spinal cord, severely limiting the development of new treatments to slow or halt the advancement of central nervous system diseases affecting the spinal cord. Thousands of blood oxygenation level dependent (BOLD) fMRI studies over two decades have provided a wealth of knowledge on the functional architecture of healthy brains and have explored how brain networks may be altered through aging, injury, or disease. We have published that spontaneous BOLD fluctuations also exist in the spinal cord, and have demonstrated that, like the brain, spinal cord activity at rest is organized into distinct, synchronized functional networks. In the spinal cord, ventral and dorsal resting state networks reflect function of the motor and sensory pathways, respectively. The precise functioning of the spinal cord in normal and pathological populations, however, remains poorly understood even though studies of connectivity and spinal cord plasticity using methods other than MRI have been topics of intense research for over two decades. The scarcity of spinal cord fMRI studies mainly reflects the technical difficulties of performing fMRI in the spinal cord, a general lack of appropriate methods and coils, and the need for higher spatial resolution and greater sensitivity for imaging the spinal cord compared to the brain. We hypothesize that resting state spinal cord networks are impaired in MS patients with spinal cord lesions, and spinal cord network dysfunction as measured by resting state fMRI predicts disease progression in this cohort of MS patients. This proposal will therefore develop an updated 7 Tesla acquisition protocol for high-resolution spinal cord MRI with significant improvements to both data quality and spatial coverage (Aim 1); validate the new protocol by quantifying within- and between-session reproducibility of spinal cord connectivity in healthy subjects (Aim 2); and measure the reproducibility of spinal cord connectivity in MS patients, and quantify the predictive ability of baseline spinal cord functional connectivity on disease progression (worsening of Expanded Disability Status Scale metrics) after 24 months (Aim 3). Upon completion, we will understand the role of spinal cord functional connectivity as a novel technology that is complementary to established anatomical and functional methods currently used to study the brain and spinal cord. These techniques may also be used to investigate functional changes in spinal cord injury and other diseases of the central nervous system such as transverse myelitis, primary progressive MS, and amyotrophic lateral sclerosis.

Project Summary / Abstract This proposal aims to (1) develop and evaluate functional magnetic resonance imaging (fMRI) methods to non- invasively detect functional networks in the human cervical spinal cord at 7 Tesla, and (2) characterize spinal cord network dysfunction in patients with relapsing remitting multiple sclerosis (MS). Nearly all MS patients have focal lesions throughout the spinal cord, yet the majority of studies do not investigate disease progression in the clinically eloquent yet largely unexplored spinal cord. Currently, no imaging technique can predict disability progression referable to the spinal cord, severely limiting the development of new treatments to slow or halt the advancement of central nervous system diseases affecting the spinal cord. Thousands of blood oxygenation level dependent (BOLD) fMRI studies over two decades have provided a wealth of knowledge on the functional architecture of healthy brains and have explored how brain networks may be altered through aging, injury, or disease. We have published that spontaneous BOLD fluctuations also exist in the spinal cord, and have demonstrated that, like the brain, spinal cord activity at rest is organized into distinct, synchronized functional networks. In the spinal cord, ventral and dorsal resting state networks reflect function of the motor and sensory pathways, respectively. The precise functioning of the spinal cord in normal and pathological populations, however, remains poorly understood even though studies of connectivity and spinal cord plasticity using methods other than MRI have been topics of intense research for over two decades. The scarcity of spinal cord fMRI studies mainly reflects the technical difficulties of performing fMRI in the spinal cord, a general lack of appropriate methods and coils, and the need for higher spatial resolution and greater sensitivity for imaging the spinal cord compared to the brain. We hypothesize that resting state spinal cord networks are impaired in MS patients with spinal cord lesions, and spinal cord network dysfunction as measured by resting state fMRI predicts disease progression in this cohort of MS patients. This proposal will therefore develop an updated 7 Tesla acquisition protocol for high-resolution spinal cord MRI with significant improvements to both data quality and spatial coverage (Aim 1); validate the new protocol by quantifying within- and between-session reproducibility of spinal cord connectivity in healthy subjects (Aim 2); and measure the reproducibility of spinal cord connectivity in MS patients, and quantify the predictive ability of baseline spinal cord functional connectivity on disease progression (worsening of Expanded Disability Status Scale metrics) after 24 months (Aim 3). Upon completion, we will understand the role of spinal cord functional connectivity as a novel technology that is complementary to established anatomical and functional methods currently used to study the brain and spinal cord. These techniques may also be used to investigate functional changes in spinal cord injury and other diseases of the central nervous system such as transverse myelitis, primary progressive MS, and amyotrophic lateral sclerosis.