Good afternoon, everyone. Thank you for joining the Stereotactic and Functional Surgery Session. This is going to be a really great session. We have a roster of very cutting-edge presentations on things ranging from recovery after spinal cord injury to blood-brain-barrier opening. We're going to start with our Guildenberg Award winner. And this is going to be Dr. David Darrow. And he's going to be talking about restoration of voluntary movement with spinal cord stimulation in two patients with paraplegia. We hope both are working. So I'm David Darrow. I'm a fifth-year resident at the University of Minnesota. And I'm going to talk about the outcomes from our first two patients in the East End trial where we used spinal cord stimulation to restore volitional movement and autonomic function. I do have some disclosures, mostly for me begging St. Jude, or now Abbott, for devices. And today I will be discussing off-label use of these devices, not FDA-approved. It's been about 10 years now since there was a serendipitous discovery that if you apply spinal cord stimulation below the lesion of patients with thoracic paraplegia, motor and or sensory complete, that you see the ability to regain some volitional movement and control of their legs despite not having moved in those patients up to four years. And this has really changed the paradigm of how we think about complete spinal cord injury. And for me, it really opened up the opportunity for looking at the narrative of spinal cord injury from the perspective of neuromodulation, this being the only positive finding or potentially positive finding in the history of spinal cord injury. So we know for a long time that there are intact supraspinal connections that pass through the lesion in spinal cord injury, but we never knew how to functionally restore them or that it was even possible. And so we believe that these intact supraspinal connections that make it through the lesion are then facilitated by changing the milieu of the segmental portion of the spinal cord with spinal cord stimulation by placing the electrode down by the segments of the spinal cord that correspond to the lower motor neuron, the roots that go to the legs. So in our study, we wanted to do broad inclusion criteria. As the previous patients were all really young, healthy males right before spinal cord injury and had significant amount of rehabilitation before and after being implanted. So our study involved no rehabilitation, made it easy on patients by being able to just come for monthly visits. And I involved an adaptive Bayesian optimization of the parameter space. In order to facilitate spinal cord stim optimization for volitional movement, despite the fact that we were also very interested in autonomic function, but it's certainly much easier to track volitional movement, in a very broad, generalizable patient population. Our patients are all adults with true thoracic lesions, full upper arm strength and intact segmental reflexes, meaning no lower motor neuron injury, and they had to be healthy enough not to have increased risk of infection or make it through the surgery. And in our study, we have two main arms that are very similar, but one specifically identifies patients with significant cardiovascular dysautonomia. And we separate them and just do extra testing on those patients with tilt table. They follow up every month for a formal assessment with SEMG. And in the first two patients, the one on the left is our first one, T8 AISA, and the one on the right is AISA T4. And when we were considering these patients, they met our inclusion-exclusion criteria, but we did not think it would work in them. They have severe myelomalacia and almost transected cords. But it turns out it did work. And in our task, we have six tasks that are really simple, bilateral hip and knee flexion extension, right then left, and bilateral ankle flexion, dorsal flexion with surface SEMG. And you can see with the stimulator on, we get activity corresponding to the flexion and extension period of those tasks. But the proof is really in the video. I can do a lot of quantitative assessments that show it, but once you see it, unfortunately, you can't hear the audio, but it's me telling her to lift her leg and then drop her leg again. Turn up the audio, please. And lift her leg and drop her leg again, and she has control of this. And it looks like it stopped, so she's really holding it up there. But we're able to do this, and she has it under control. But if you can imagine being this patient that has no sensory function, trying to control your leg without having any feedback is tricky. So if you look at a summary statistic for these patients and you look at the change in the SEMG power after removing all stimulation artifacts, we have a very significant change in overall power for both patients. The p-value is times 10 to the minus 9 with both t-tests and rank sum. And you can actually break it down further by muscle group and are able to see significant changes across each muscle group relative strengths in terms of recovery for each of the patients. So we can really narrow down just within the first five appointments. And all the patients undergo cardiovascular screening, and in the first patient we saw no significant dysautonomia until table testing. And in the second patient on the right, you can see a significant increase in the heart rate and then also a reduction in blood pressure just during those 10 minutes. And then we do ambulatory blood pressure monitoring to also tell what's going on at home, and we see the normal diurnal variation for patient one at night and no real variation for patient two, indicating a lack of sympathetic input. And we took the second patient and now have done a lot of tilt table testing, and we measured beat-by-beat blood pressure changes during tilt, and we see that when her blood pressure drops significantly from, you know, 100s or 90s over 70s all the way down to 70s over 40s, and she has cognitive problems at that time that are apparent under cognitive testing, we turn on sham stimulation where we direct the current more towards the volitional nerve roots or the nerve roots that are engaged with the legs, and we see no effect. And then when we change the anatomic target to the higher portion of the thoracic cord where there are sympathetic centers, we see an immediate restoration within minutes of the normal blood pressure while still tilted, and we also see an improvement in cognitive function. We see the corresponding changes in cerebral blood flow, and we also see the corresponding changes in cardiac contractility, indicating a significant sympathetic effect. And she does have significant cognitive changes that return to baseline or actually higher when the stimulation is on. Now, I don't have any videos of bowel, bladder, and sexual function, but we did see significant changes in both patients. We see return of bowel-bladder synergy so that you have to urinate before you defecate. We see in the first patient she has almost no incontinence anymore, and in the second patient now has restored volitional urination, and she can empty her bladder until all the way about 100 cc's on command, and we see a big significant change in bowel regimen from 90 or 120 minutes down to 30 minutes. The most surprising finding is that in the second patient we see restoration of sexual function, namely orgasm with sexual intercourse. That's been a consistent finding across all of her follow-up visits. So in conclusion, we see that in our first two patients, spinal cord stimulation does seem to restore volitional movement in variable ways, depending on muscle atrophy and things, but in both patients it immediately posts up. We see that spinal cord stimulation with our method also appears to restore autonomic function. If you target the right centers. And it does not affect the cardiovascular function of the patient that has no dysautonomia. And spinal cord stimulation may restore bowel-bladder and sexual function in some of these patients, so it's quite a significant finding. And the important thing is that this is in severe patients, the furthest out that's been reported from injury, and in female patients in their fifth and sixth decade of life. And just to acknowledge my team, Dr. Samadani and Dr. Parr and Dr. Park for all supporting me, especially Dr. Samadani, and my team, Dr. Balser and Caleb Hoover, our collaborators up in Canada, Dr. Phillips and Krasikoff, and my long-term collaborator, Dr. Nedoff in the BME department. Please email me with any questions. Thank you. Thank you.

Dr. David Darrow

University of Minnesota

East End trial

spinal cord stimulation

paraplegia