Depression: Epidural Prefrontal Cortical Stimulation
Guest: Dr. Ziad Nahas -Psychiatry & Behavioral Sciences, MUSC
Host: Dr. Linda Austin – Psychiatry, MUSC
Dr. Linda Austin: Dr. Ziad Nahas is Associate Professor in the Department of Psychiatry & Behavioral Sciences, as well as the Department of Neurosciences, here at the Medical University of South Carolina. Dr. Nahas, you’ve headed up, recently, a stunningly exciting clinical project. This is a project that was funded by NARSAD (National Alliance for Research on Schizophrenia and Depression), and was a collaborative effort between Psychiatry, Neurosurgery, Anesthesia, and the GCRC (General Clinical Research Center). Let’s take this sort of step by step, because it’s complex to understand, but so interesting. First of all, the overall point of this study was to do brain stimulation for severely depressed patients. So, tell us about the patients themselves. How many were there, and how depressed were these patients?
Dr. Ziad Nahas: Well, we’re obviously dealing with a fairly small but very disabled group of patients, for whom this may ultimately apply, even in the future. These patients had what we label in clinical terms treatment-resistant depression. That typically entails that they had to show failure with a number of treatments, whether it was drug therapy, electroconvulsive therapy, or a combination, to be eligible in the study. Our criterion was to have a minimum of four failed treatments in a current depressive episode.
Dr. Linda Austin: You brought these patients, one by one, into the operating room. They were under, initially, light anesthesia, I understand. What happened next with the patients?
Dr. Ziad Nahas: Well, the premise behind the therapy was to try to target, and stimulate part of the front of the brain that’s important in governing mood and socialization. We know that there are different areas that have different functions. They’re obviously part of a connected network in the brain. And so, we intended to implant these patients with paddles that would deliver electrical stimulation to the lateral part of the front of the brain.
Dr. Linda Austin: The side part of the front of the brain, kind of over the temple, sort of, or above?
Dr. Ziad Nahas: A little bit, yes, over the temple area; a little bit, like, at the end of your eyebrows, and around your forehead; in the middle.
Dr. Linda Austin: So, the first step, then, was to drill tiny holes in the skull. What happened then?
Dr. Ziad Nahas: Well, previous to getting the patient in the operating room, we’d done substantial work to make sure that we could identify this brain region well on their MRIs; their brain images. And we imported all of that to the operating room so that it would help guide the surgeon to be very accurate in their placement. So, the first part of the procedure was, after we’d drilled those tiny holes in the skull, behind the hairline; so, ultimately, they will not be visible, esthetically, we inserted these paddles to the right places. We had four of those, two on each side the head.
Dr. Linda Austin: Now, just to ask a question, the paddles, then, were they resting on the surface of the brain? Is that right? Or, were they actually under the brain tissue itself?
Dr. Ziad Nahas: No. It’s an excellent question. The brain is involved with yet another sheet [layer], which we call the dura. So, what we purposely did was, essentially, insert these paddles between the bone and the dura, so there was a little bit of space left before we hit the surface of the brain. And that would actually make the procedure even safer, because we’re not risking damaging the brain, directly, by directly touching the tissue.
Dr. Linda Austin: The four paddles were, how big, Dr. Nahas?
Dr. Ziad Nahas: Each one would be about two inches long. And on each paddle, there were four smaller discs, which would be the independent electrode by which we deliver the stimulus.
Dr. Linda Austin: So, now the patient has these paddles implanted. And the patient, at this point, is actually conscious. What did you do next?
Dr. Ziad Nahas: We lifted all sedation to make sure that they’d be as alert as possible. Obviously, they’d been through three hours of surgery and were fairly exhausted. And we wanted to test, right there, whether we would have any signal, whether our targets were relevant to, ultimately, how things would turn out.
For an antidepressant to work, I think it should not only alleviate depressive symptoms, but allow patients to disengage from their attention to negative things that overwhelm them. So, we set out to test exactly that, first in the OR. The patient had a laptop, and they had trained previously to insert a series of questions about their subjective experiences: Do they feel sad, emotionally settled, anxious, depressed, etc.? And we delivered, without the patient’s knowledge, different settings. In fact, sometimes we didn’t delivery any stimulation at all and still asked the patient whether or not they perceived any changes in their mood, or their attention.
What was fairly remarkable to us was that, taken as a group, there was a distinct effect of our stimulation on alleviating sadness, temporarily, as well as temporarily relieving anxiety. In a couple of patients, they actually noticed, specifically, an increased attention, as if the room was a little bit brighter. And, although that was not a universal experience, we had one other patient that had absolutely no response in the OR. It was a very encouraging sign that we were at least in the right vicinity and, possibly, we could then begin our true test of the antidepressant effect of this therapy by administering it chronically over days, and weeks, and months.
Dr. Linda Austin: So, at that point, then, after you knew that the placement; or at least with four of the five, you were pretty sure from those kind of short-term, very temporary, responses, was right, patients were then put to sleep. What did you do then?
Dr. Ziad Nahas: The wires, that I mentioned, that connected these paddles to the external stimulator now had to be tunneled. They had to be connected under the skin to two battery generators that are, essentially, implanted in the interior part of the chest wall.
Dr. Linda Austin: So, in other words, just kind of close to the collar bone? Is that right?
Dr. Ziad Nahas: Correct. Close to the collar bone, a little bit like a heart pacemaker, except that, obviously, the wires are connected to stimulate the brain, and not the heart.
Dr. Linda Austin: And, what happened then?
Dr. Ziad Nahas: The patients were sent to recover. On average, they stayed in the hospital for about three days. We were a little extra cautious and didn’t want to send them [home] too early. We did a CT scan to confirm our placement, that we were in the right place, and we discharged the patient with the stimulation off, completely. We allowed them two to three weeks to recover and then we brought them back to my lab, where we began a series of testing, much more elaborate than what we did in the OR, obviously, as we didn’t have the constraint of time anymore, to figure out what would work best for them, at least immediately. And if we didn’t have any response, then we went to theoretical, preset, settings. If we didn’t see any effect, we just went with something. And we, essentially, turned the patients on an on/off cycle, coming in four times a day for about half an hour, and asked them to keep us informed. We continued seeing them, essentially, weekly and then monthly, until the end of the acute phase, which was about seven months.
Dr. Linda Austin: And, what was the response on their depression?
Dr. Ziad Nahas: So, keep in mind, these patients had been sick, on average, for about 20 years with recurrent severe depression. And the length of their depressive episodes coming into our study had been several years. One particular patient had been stuck in his depression for about four and a half years and had failed over eight treatments. So, the expectations were very modest.
We began seeing gradual changes in their depression as it was measured objectively. There are certain scales that we use in research to try to gauge that, as well as our subjective measure, where we ask the patient to fill out certain forms; they do it themselves. And, essentially, by seven months of this stimulation coming on and off, on and off, chronically and repeatedly, without much change in their medication otherwise, we had about a 56 percent drop in their depression scores. Subjectively, they were reporting, as a group, 60 percent improvement. What is tangibly unique is that where we started off with five very disabled, and ill, patients, three of them were reporting being symptom-free by seven months. One of them had about a 40 percent response, and unfortunately this patient did not have much of a clinical benefit.
Dr. Linda Austin: Now, was that fifth patient the same one who did not respond initially in the operating room, or a different patient?
Dr. Ziad Nahas: It’s actually a different one, which brings up a very important question. In this early stage, we obviously don’t have what we call a good prognosticator. What we wanted to test in the OR was not necessarily whether we were in the right place, but were we in the right place functionally? We made it very clear, as we were implanting these, that we were anatomically exactly where we decided to go. The question was whether or not, functionally, it would make a difference.
Dr. Linda Austin: Now, how long can the patients keep these stimulation devices in place?
Dr. Ziad Nahas: Well, the material they’re made of is fairly durable. It won’t corrode. It will stay as long as there aren’t any particular malfunctions. The batteries, however, are obviously dependent on how much we use them. They could probably go for one to four years before they would need to be replaced. It’s all dependent on much energy we’re using and the frequency of stimulation. We’re so early in this research phase that we, obviously, haven’t yet stumbled on the optimal setting to try to maximize efficiency and efficacy.
Dr. Linda Austin: But it’s so incredibly exciting. So, what is the next phase of this research?
Dr. Ziad Nahas: Well, the next phase is securing more funding. I think what we’ve shown, so far, that we have a novel therapy that is safe and has a potential to treat patients. We tested it under what we call open conditions, where the patients knew they were getting the therapy. We didn’t do a double-blind, placebo-controlled study. And, for us to begin to feel more comfortable about our result, we have to begin thinking about double-blind, well-controlled conditions, and then really put it to the test.
Dr. Linda Austin: This is such exciting research. Congratulations to you and your team. You must be absolutely thrilled. I’m just astounded by this. It’s a wonderful step forward.
Dr. Ziad Nahas: Thank you for the opportunity to share this.
Dr. Linda Austin: Thank you.
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