Shocking Results Need Validation
Paralysis recovery results published in April 2014 about a groundbreaking clinical research study using epidural spinal stimulation treatment on four young men living with chronic complete paraplegia ignited hope around the world that there would soon be a treatment for paralysis recovery. Harkema/Edgerton 2014 Study Results
Proof of Concept to Validation
The next step in the clinical research process was to validate the findings reported by the University of Louisville team by replicating them at an independent medical center using a phase IIb clinical trial.
Having just entered this field of paralysis recovery research little more than a year earlier, our governance team at Jack Jablonski Foundation expected one of the ‘leading’ funders in the field of paralysis recovery research to take the necessary next step on this validation study.
After more than a year passed, we stopped waiting for someone else to lead.
In the summer of 2015 Jack Jablonski Foundation approached a leading neurosurgeon, Dr. Kendall Lee, at Mayo Clinic about taking on the required replication study. Dr. Lee agreed and we began funding that study a few months later. The first results were reported in 2017.
Doubters to Champions
In 2015, not one person on the Mayo Clinic research team believed that spinal stimulation treatment would restore function in a person living with complete chronic paralysis. They say skepticism is critical to scientific research.
The Mayo Clinic research team agreed in 2015 to complete a Phase IIb clinical trial replicating the paralysis recovery breakthroughs pioneered at the University of Louisville by Drs. Reggie Edgerton and Susan Harkema. In medical journal reports published in 2011 (Lancet) and 2014 (Nature), Drs Harkema and Edgerton demonstrated paralysis recovery results using spinal stimulation treatment with four young men living with chronic complete paraplegia.
Replication of these results at an independent medical center was essential to validating them. Why, because the neurosurgical textbooks used in every medical school in the world said those results were impossible. It was considered established medical fact that paralysis was permanent.
Based upon this pervasive assumption that paralysis was permanent, the Mayo Clinic research team was convinced there must be another explanation for those recovery results. They agreed to take on the task of replicating the procedures used in the earlier clinical trials in the expectation that they would discover ‘another’ explanation for the paralysis recovery results demonstrated by Rob Summers and the other three young men after receiving spinal stimulation treatment.
Instead, the research team from Mayo Clinic discovered that spinal stimulation treatment works.
In 2017, Mayo Clinic published the results of their replication trial. The first participant in the replication study, Jered Chinnock, responded immediately to the treatment.
Meet the Research Team
This video (see link below) was published online June 01, 2017 in Mayo Clinic Research Results: Mayo Proceedings at the time the first results of the replication study were published in a medical journal (Mayo Proceedings, see journal article reproduced below).
The results of this Phase IIb replication study were published in four more medical journals through 2021 (see these other journals reports below: 2018, 2019, 2020, and 2021).
Epidural stimulation enables motor function after chronic paraplegia
The goal of this project is to replicate a study that was performed by UCLA and the University of Louisville. This is the first paper to show that, in the same patient, within the first two weeks following epidural stimulation, the patient was able to recover volitional control over the leg, as well as standing.
“Dr. Edgerton’s team showed us the ropes of how to program the epidural electrical stimulator so we could replicate what they’d achieved in their studies,” says Dr. Peter Grahn. “During our first programming session, the subject moved his leg using his own intent. When we observed this ability, everyone in the room gasped.”
In this video presentation, the team describes the early results of their replication of the pioneering paralysis recovery breakthrough achieved by Drs. Reggie Edgerton and Susan Harkema at the University of Louisville just a few years earlier. See the video: https://www.mayoclinic.org/medical-professionals/videos/epidural-stimulation-enables-motor-function-after-chronic-paraplegia/vid-20433506
KENDALL LEE: Hello, my name is Dr. Kendall Lee. I’m the director of engineering here at the Mayo Clinic. My team and I were truly excited to be presenting this paper to you that is coming out of the Mayo Clinic proceedings, entitled Enabling Task-Specific Volitional Motor Function via Spinal Cord Neural Modulation in a Human with Paraplegia. We’re very excited to present this paper. This paper was done in collaboration with Dr. Reggie Egerton’s team at UCLA, as well as Dr. Kristen Zhao’s team here at the Mayo Clinic.
Meet Jered Chinnock, the first participant in the Mayo Clinic replication & validation clinical trial. Click the image to see video of his progress and hear more of his story.
The trial demonstrated use of epidural electrical stimulation in a patient who has complete thoracic spinal cord injury, ASIA A, meaning that it was both motor and sensory complete, that the patient using epidural stimulation was able to get volitional movement control back of his lower extremities.
Description of the Mayo Clinic Replication Clinical Trial
Published online in 2015 at Mayo Clinic Clinical Trials.
ABOUT THIS STUDY. This is a feasibility study to test the use of epidural electrical spinal stimulation (EESS) to restore volitional function previously lost due to spinal cord injury. Previous studies conducted in animal models, performed elsewhere and here at Mayo Clinic, have shown that direct electrical stimulation of the spinal cord increases the excitability of spared neuronal connections within the site of injury, thereby enhancing signal transmission and allowing recovery of previously lost volitional function. Recently, epidural electrical stimulation of the lumbosacral spinal cord in four individuals with spinal cord injury (SCI) has restored motor and autonomic function below the level of injury. Despite positive results, further translational research is needed to validate these findings. The goal of this proposal is to perform epidural stimulation to restore volitional function in patients with SCI. In two patients, we will implant an epidural stimulator onto the dorsal aspect of the lumbosacral spinal cord dura mater. Patients will undergo a structured program of daily physical rehabilitation, treadmill step training, and epidural stimulation to recover motor, sensory, and autonomic function.
Using EESS to enable volitional movement after chronic complete paralysis. In the Mayo Clinic Neurorecovery Program study on epidural stimulation to regain movement, people with complete paralysis of the legs resulting from spinal cord injuries are implanted with epidural stimulators — devices commonly used to treat pain.
The study aims to replicate promising findings from the University of Louisville and the University of California, Los Angeles. In combination with intense rehabilitative therapy (locomotor therapy or activity-based therapy), stimulation from the epidural stimulator allowed some intentional movement of participants’ previously paralyzed legs, and participants were able to stand unassisted.
Replicating this breakthrough in spinal cord injury treatment is only one step in advancing the science of epidural stimulation. Further research is critically needed to understand why epidural stimulation has worked, which patients will respond to epidural stimulation, and whether the enormous amount of rehabilitation that has been shown to be effective can be reduced.
TESS-ESS Characterization after SCI. The Mayo Clinic Neurorecovery Program seeks to improve the scientific understanding of how two electrical stimulation techniques, one which delivers electricity to the skin surface over the spine (transcutaneous electrical spinal stimulation—TESS) and another which is implanted onto the dura mater of the spinal cord (epidural electrical stimulation—EES), facilitate spinal circuitry to enable function after SCI.
Medical Journal Report #1
Enabling Task-Specific Volitional Motor Functions via Spinal Cord Neuromodulation in a Human with Paraplegia
By Peter J Grahn, Igor A Lavrov, Dimitry G Sayenko, Meegan G Van Straaten, Megan L Gill, Jeffrey A Strommen, Jonathan S Calvert, Dina I Drubach, Lisa A Beck, Margaux B Linde, Andrew R Thoreson, Cesar Lopez, Aldo A Mendez, Parag N Gad, Yury P Gerasimenko, V Reggie Edgerton, Kristin D Zhao, Kendall H Lee
Mayo Clinic Proceedings | April 2017
Abstract. We report a case of chronic traumatic paraplegia in which epidural electrical stimulation (EES) of the lumbosacral spinal cord enabled (1) volitional control of task-specific muscle activity, (2) volitional control of rhythmic muscle activity to produce steplike movements while side-lying, (3) independent standing, and (4) while in a vertical position with body weight partially supported, voluntary control of steplike movements and rhythmic muscle activity. This is the first time that the application of EES enabled all of these tasks in the same patient within the first 2 weeks (8 stimulation sessions total) of EES therapy.
Medical Journal Report #2
Neuromodulation of lumbosacral spinal networks enables independent stepping after complete paraplegia
By Megan L Gill, Peter J Grahn, Jonathan S Calvert, Margaux B Linde, Igor A Lavrov, Jeffrey A Strommen, Lisa A Beck, Dimitry G Sayenko, Meegan G Van Straaten, Dina I Drubach, Daniel D Veith, Andrew R Thoreson, Cesar Lopez, Yury P Gerasimenko, V Reggie Edgerton, Kendall H Lee, Kristin D Zhao
Nature Medicine | November 2018
Abstract. Spinal sensorimotor networks that are functionally disconnected from the brain because of spinal cord injury (SCI) can be facilitated via epidural electrical stimulation (EES) to restore robust, coordinated motor activity in humans with paralysis. Previously, we reported a clinical case of complete sensorimotor paralysis of the lower extremities in which EES restored the ability to stand and the ability to control step-like activity while side-lying or suspended vertically in a body-weight support system (BWS). Since then, dynamic task-specific training in the presence of EES, termed multimodal rehabilitation (MMR), was performed for 43 weeks and resulted in bilateral stepping on a treadmill, independent from trainer assistance or BWS. Additionally, MMR enabled independent stepping over ground while using a front-wheeled walker with trainer assistance at the hips to maintain balance. Furthermore, MMR engaged sensorimotor networks to achieve dynamic performance of standing and stepping. To our knowledge, this is the first report of independent stepping enabled by task-specific training in the presence of EES by a human with complete loss of lower extremity sensorimotor function due to SCI.
Medical Journal Report #3
Electrophysiological Guidance of Epidural Electrode Array Implantation over the Human Lumbosacral Spinal Cord to Enable Motor Function after Chronic Paralysis
By Jonathan S Calvert, Peter J Grahn, Jeffrey A Strommen, Igor A Lavrov, Lisa A Beck, Megan L Gill, Margaux B Linde, Desmond A Brown, Meegan G Van Straaten, Daniel D Veith, Cesar Lopez, Dimitry G Sayenko, Yury P Gerasimenko, V Reggie Edgerton, Kristin D Zhao, Kendall H Lee
Journal of Neurotrauma | April 2019
Abstract. Epidural electrical stimulation (EES) of the spinal cord has been shown to restore function after spinal cord injury (SCI). Characterization of EES-evoked motor responses has provided a basic understanding of spinal sensorimotor network activity related to EES-enabled motor activity of the lower extremities. However, the use of EES-evoked motor responses to guide EES system implantation over the spinal cord and their relation to post-operative EES-enabled function in humans with chronic paralysis attributed to SCI has yet to be described. Herein, we describe the surgical and intraoperative electrophysiological approach used, followed by initial EES-enabled results observed in 2 human subjects with motor complete paralysis who were enrolled in a clinical trial investigating the use of EES to enable motor functions after SCI. The 16-contact electrode array was initially positioned under fluoroscopic guidance. Then, EES-evoked motor responses were recorded from select leg muscles and displayed in real time to determine electrode array proximity to spinal cord regions associated with motor activity of the lower extremities. Acceptable array positioning was determined based on achievement of selective proximal or distal leg muscle activity, as well as bilateral muscle activation. Motor response latencies were not significantly different between intraoperative recordings and post-operative recordings, indicating that array positioning remained stable. Additionally, EES enabled intentional control of step-like activity in both subjects within the first 5 days of testing. These results suggest that the use of EES-evoked motor responses may guide intraoperative positioning of epidural electrodes to target spinal cord circuitry to enable motor functions after SCI.
Medical Journal Report #4
Epidural Electrical Stimulation of the Lumbosacral Spinal Cord Improves Trunk Stability During Seated Reaching in Two Humans with Severe Thoracic Spinal Cord Injury
By Megan Gill, Margaux Linde, Kalli Fautsch, Rena Hale, Cesar Lopez, Daniel Veith, Jonathan Calvert, Lisa Beck, Kristin Garlanger, Reggie Edgerton, Dimitry Sayenko, Igor Lavrov, Andrew Thoreson, Peter Grahn, and Kristin Zhao
Frontiers in Systems Neuroscience | November 2020
Abstract. Background: Quality of life measurements indicate that independent performance of activities of daily living, such as reaching to manipulate objects, is a high priority of individuals living with motor impairments due to spinal cord injury (SCI). In a small number of research participants with SCI, electrical stimulation applied to the dorsal epidural surface of the spinal cord, termed epidural spinal electrical stimulation (ES), has been shown to improve motor functions, such as standing and stepping. However, the impact of ES on seated reaching performance, as well as the approach to identifying stimulation parameters that improve reaching ability, have yet to be described. Objective: Herein, we characterize the effects of ES on seated reaching performance in two participants with chronic, complete loss of motor and sensory functions below thoracic-level SCI. Additionally, we report the effects of delivering stimulation to discrete cathode/anode locations on a 16-contact electrode array spanning the lumbosacral spinal segments on reach distance while participants were seated on a mat and/or in their wheelchair. Methods: Two males with mid-thoracic SCI due to trauma, each of which occurred more than 3 years prior to study participation, were enrolled in a clinical trial at Mayo Clinic, Rochester, MN, USA. Reaching performance was assessed, with and without ES, at several time points throughout the study using the modified functional reach test (mFRT). Altogether, participant 1 performed 1,164 reach tests over 26-time points. Participant 2 performed 480 reach tests over 17-time points. Results: Median reach distances during ES were higher for both participants compared to without ES. Forward reach distances were greater than lateral reach distances in all environments, mat, or wheelchair, for both participants. Stimulation delivered in the caudal region of the array resulted in improved forward reach distance compared to stimulation in the rostral region. For both participants, when stimulation was turned off, no significant changes in reach distance were observed throughout the study.
Conclusion: ES enhanced seated reaching-performance of individuals with chronic SCI. Additionally, electrode configurations delivering stimulation in caudal regions of the lumbosacral spinal segments may improve reaching ability compared to rostral regions.
Medical Journal Report #5
Impact of long-term epidural electrical stimulation enabled task-specific training on secondary conditions of chronic paraplegia in two humans
By Lisa Beck, Daniel Veith, Margaux Linde, Megan Gill, Jonathan Calvert, Peter Grahn, Kristin Garlanger, Douglas Husmann, Igor Lavrov, Dimitry Sayenko, Jeffrey Strommen, Kendall Lee, Kristin Zhao
Journal of Spinal Cord Medicine |September 2021
Abstract. Introduction: Spinal cord injury (SCI) often results in chronic secondary health conditions related to autonomic and metabolic dysfunction. Epidural electrical stimulation (EES) combined with task-specific training has been shown to enable motor function in individuals with chronic paralysis. The reported effects of EES on secondary health conditions, such as bladder function and body composition, are limited. We report the impact of EES on SCI-related secondary health changes in bladder function and body composition. Methods: Two participants with motor and sensory complete SCI performed 6 months of rehabilitation without EES followed by 12 months of task-specific training with EES after implantation of a 16-electrode array on the surface of the lumbosacral spinal cord. Participants performed three days of training per week in the laboratory, and additionally performed task-specific activities with EES at home during this time frame. Changes in bladder and body composition were recorded via clinically available testing of neurogenic bladder functionality and dual-energy X-ray absorptiometry, respectively. Results: In one participant, we observed an increase in episodes of urinary incontinence with worsening bladder compliance and pressures at the end of the study. Bone mineral density changes were insignificant in both participants; however, one participant showed a substantial increase in lean mass (+9.1 kg; 6 months of training) via redistribution of body fat through an android/gynoid ratio reduction (-0.15; 6 months of training). Conclusion: EES optimized for standing and stepping may negatively impact neurogenic bladder functionality. Close monitoring of bladder health is imperative to prevent undesirable bladder compliance, which can lead to upper urinary tract deterioration. Conversely, EES may serve as an adjunct tool with regular exercise modalities to improve body composition through activation of musculature innervated by spinal segments that are below the SCI.