Lumbar Spine fMRI to Quantify Efficacy of Spinal Cord Stimulation Therapy in Spinal Muscular Atrophy

321 

Abstract Submission 

Scott Ensel¹, Genis Prat-Ortega¹, Serena Donadio¹, Amy Boos², Luigi Borda³, Nikhil Verma³, Jonathan Ho¹, Daryl Fields⁴, Lee Fisher¹, Doug Weber³, Peter Gerszten⁵, Robert Friedlander⁴, Marco Capogrosso¹, Elvira Pirondini¹

¹University of Pittsburgh, Pittsburgh, PA, ²Department of Neurology, Pittsburgh, PA, ³Carnegie Mellon University, Pittsburgh, PA, ⁴Department of Neurological Surgery, Pittsburgh, PA, ⁵Department of Neurological Surgery, pittsburgh, PA

Scott Ensel  
University of Pittsburgh
Pittsburgh, PA

Genis Prat-Ortega  
University of Pittsburgh
Pittsburgh, PA

Serena Donadio  
University of Pittsburgh
Pittsburgh, PA

Amy Boos  
Department of Neurology
Pittsburgh, PA

Luigi Borda  
Carnegie Mellon University
Pittsburgh, PA

Nikhil Verma  
Carnegie Mellon University
Pittsburgh, PA

Jonathan Ho  
University of Pittsburgh
Pittsburgh, PA

Daryl Fields  
Department of Neurological Surgery
Pittsburgh, PA

Lee Fisher  
University of Pittsburgh
Pittsburgh, PA

Doug Weber  
Carnegie Mellon University
Pittsburgh, PA

Peter Gerszten  
Department of Neurological Surgery
pittsburgh, PA

Robert Friedlander  
Department of Neurological Surgery
Pittsburgh, PA

Marco Capogrosso  
University of Pittsburgh
Pittsburgh, PA

Elvira Pirondini  
University of Pittsburgh
Pittsburgh, PA

Spinal Muscular Atrophy (SMA) is a genetic disease that causes progressive dysfunction and death of spinal motor neurons, leading to motor deficits ranging from lower limb weakness (type 4) to severe muscle weakness with respiratory failure (type 1). Recent experiments in mice indicate that SMA motor deficits are due to motor neuron death and decreased firing rates in surviving motor neurons due to a maladaptive response to a loss in the excitatory Ia sensory synapses [1]. Epidural spinal cord stimulation (SCS) can selectively activate Ia sensory fibers; thus we hypothesize that targeted stimulation of Ia afferents via epidural SCS would increase inputs to the motor neurons, resulting in increased firing ability and improved leg functions through long-term stimulation effects (Figure 1A) [2-4]. To test the efficacy of our SCS therapy we quantified long term changes in motor neuron functions by performing functional magnetic resonance imaging (fMRI) of the lumbar spinal cord during active and passive mobilization of the knee joint pre- and post- SCS therapy (Figure 1B). Spinal cord fMRI is a rapidly growing field, but the lumbar spine has largely been ignored. Therefore, we leverage recently developed cervical spinal cord fMRI techniques to create a robust lumbar spine acquisition and processing paradigm, which can be applied to any clinical population [5-7].

Three participants were installed in a 3T Siemens Prisma scanner in a supine position. Participants completed three runs of active and three runs of passive knee mobilization each session (Figure 1B). Functional acquisitions were performed using a gradient-echo echo-planar sequence with a ZOOMit field-of-view imaging, with repetition time (TR) = 2.5 s, echo time (TE) = 34 ms, FOV = 48x144 mm, flip angle = 80°, image resolution = 1.0 mm x 1.0 mm x 3.0 mm, 32 axial slices were acquired per volume. Physiological data (respiratory and cardiac signals) were acquired during scans. A T2-weighted high-resolution anatomical image (sequence SPACE with a resolution of 0.4 mm x 0.4 mm x 0.8 mm, TR = 1.5 s, TE = 135 ms) was also acquired for registration and normalization using the spinal cord toolbox [8]. Active block conditions were compared to baseline rest periods using a second level fixed effects analysis (subject level) by combining the three runs of each session [9].

We report the Z-maps of the lumbar spinal cord fMRI during voluntary movements of the leg (Figure 2A), where we calculated both the number of activated voxels as well as the z-scores of the activations in all participants (Figure 2B). We calculated this activation in the spinal segments where the dorsal roots innervated by the quadriceps were located. In all subjects we observed an increase in the number of activated voxels as well as significantly higher z-scores indicating that after 4-weeks of SCS therapy there are long term improvement in motor neuron function. Interestingly, we observed a statistically significant increase in the number of active voxels and z-score also during passive movements suggesting an increased synaptic drive into the motor neurons. Overall, we found an increased response in the lumbar spinal cord motor neurons post-therapy as compared to pre-therapy in all three participants.

All participants physically improved during SCS treatments and these changes correlate with fMRI results, on both the active and passive tasks, showing an increased number of active voxels and higher voxel z-scores post SCS therapy. Our data shows that SCS is contributing to long term changes by increasing the firing rate of vulnerable motor neurons in patients with type 3 SMA resulting in improved leg motor functions and raise the possibility that SCS can provide a permanent treatment for people living with SMA. We also show that lumbar spine fMRI is viable, and this study demonstrates successful implementation of a fMRI acquisition protocol and analysis pipeline.

Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s) ¹

Activation (eg. BOLD task-fMRI) ²

Methods Development

BOLD fMRI

Degenerative Disease

FUNCTIONAL MRI

Movement Disorder

Spinal Cord

Treatment

Other - Spinal Cord Stimulation