The Traumatic Brain Injury (TBI) Research Forum was founded in 2011 by The Defense and Veterans Brain Injury Center and the Polytrauma System of and is supported by the Western Blind Rehabilitation Center at the Veterans Affairs Palo Alto Health Care System. Its goal is to increase awareness of recent innovations in TBI Research during March, in recognition of Brain Injury Awareness Month. The Forum is hosted annually to help disseminate knowledge gained through TBI Research to both researchers and clinicians alike, as well as provide networking opportunities. The Forum attracts over 100 attendees annually from the Northern California VA hospitals and other nearby states as well as local academic and community hospitals involved in TBI research.
ABILITY’s chief health editor Tom Chappell, MD, spoke with Maheen Adamson, PhD, about the forum and her research.
Dr. Tom Chappell: I understand our own Casey Mims, in ABILITY Magazine’s Sales Dept., is speaking at the Stanford forum on TBI. And you heading up that program?
Dr. Maheen Adamson: Yes. It’s actually at the Veterans Affairs Palo Alto, which is right next to Stanford. We are connected with Stanford very heavily, so it’s a traumatic brain injury research forum that happens every year. I’m the director for research for the Defense and Veterans Brain Injury Center (DVBIC). I’m also on the faculty at Stanford. We bring in community from the VA as well as Stanford. It’s a research forum that highlights research on a chosen topic. This year our topic is brain stimulation, which is what I do. I have about three clinical trials that I’m running in brain stimulation and neuroimaging. I’ve invited about three people from different communities; faculty members, to talk about brain stimulation. And I invited Casey to see a patient’s perspective, because she has gone through some of it.
Dr. Chappell: You’re dealing with people with TBI mainly?
Dr. Adamson: Yes. I can tell you a little bit about myself. I’m a research scientist, a neuroscientist. I study the brain. I’m a clinical associate professor in neurosurgery and psychiatry at Stanford, and I’m also at the VA Palo Alto, where I work with the Department of Defense. I’m the head of research at the VA Palo Alto. I’m within the department of Veterans Affairs that deal with body trauma, which is basically injury to the body. We’ve got spinal cord injury, brain injury; so basically the rehabilitation department, which is why I’m talking to you guys, because I think your magazine is absolutely amazing.
It’s the rehab department, and because I’m a scientist, all my research is based on the entire spectrum of traumatic brain injury, so basically the incidents of traumatic brain injury in the military – such as blast force concussion, motor vehicle accidents, and then you look at different techniques that can improve the diagnostic capabilities; we look at genetic factors, how that works with post-traumatic syndrome, and then we’re ready to try to treat them. I use brain stimulation, which is magnetic in our case. We look at how we might actually help with treatment of the symptoms that affect the patients. So, the whole spectrum of the patient’s condition, as well as management of their rehabilitation.
Dr. Chappell: The stimulation techniques are all non-invasive?
Dr. Adamson: The one that I use is non-invasive. It’s called repetitive transcranial magnetic stimulation (TMS). It’s not direct current (electricity), so it’s not electroconvulsive therapy. Basically, it’s a big machine that costs a lot of money, and it’s electromagnetic; basically, it creates an electromagnetic field over your skull and turns it into electrical energy. So yes, it’s non-invasive. It has some “invasive” qualities associated with it, for example if the patient has seizures.
Dr. Adamson: It’s basically a commercially available machine. There are a lot of companies that sell one. They are designed to stimulate a certain site in the brain for specifically either depression or a couple of other problems. But, the idea is that that machine is an electromagnetic coil on top of your skull, and it creates large magnetic field over your skull for a short duration, and then it penetrates (like “ray beam”) the skull with electrical energy that stimulates the neurons talk to each other, so it’s non-invasive in that way. If you are prone to seizures and you are on anti-seizure medications, then you may have a higher risk of seizures during this treatment. Thus, we make sure that no one is entering the studies who are on seizure medications or has those type of problems.
Dr. Chappell: Are you able to direct electromagnetic energy to focal areas of the brain?
Dr. Adamson: There are a lot of different techniques. The one that I just described to you is RTMS, which is “Repetitive Transcranial Magnetic Stimulation,” and we are targeting it to an area that’s been approved by FDA. And the way we find the area in the brain is, we have another little machine that attaches to the primary machine which allows us to insert the MRI scan of the patient. This allows us to localize the exact spot in the brain based on either gray or white matter, or an actual image of blood flow to really target the area you want to stimulate. The stimulation site has to be pretty exact, and although a lot of research is being done in this area right now, we’ve come a really long way.
Dr. Chappell: What are your typical target sites in the brain?
Dr. Adamson: Right now, the ones I work on and the ones that a lot of people are working on are in the dorsolateral prefrontal cortex. A lot of the problems in traumatic brain injury are associated with “executive function” (which our frontal lobes are most responsible for). It’s also the area that’s responsible for depression. It’s also the area that’s responsible for anxiety. so if you stimulate it, it has all these downstream effects and it can actually take care of a lot of different things. So it’s kind of a big area in the brain that many researchers are targeting.
But, a lot of clinics are also looking into other areas of the brain, like parietal. I have a grant proposal for a study that’s under review currently in which I want to look at parietal lobe memory changes. I want to look at right dorsolateral prefrontal cortex for PTSD (post-traumatic stress disorder). Other researchers are targeting motor-control areas of the brain for pain and also dorsolateral prefrontal cortex on the left side, which is an FDA-approved site for pain. So, there’s a lot of research under way. It’s a very thriving field right now.
Dr. Chappell: Are you able to construct or direct the focus of the electromagnetic energy? Are you able to control the size of the focus of the energy in any way? Is it much more general than that?
Dr. Adamson: It depends on what your protocol is. I use high frequency; I use 10Hz, which is supposed to be excitatory, so it excites the neurons. You can change the intervals. You can do short intervals or long intervals. There’s a lot of research that goes behind that. You can really manipulate the intervals. And obviously you manipulate it based on review scientific papers and talking to experts in the field. Then, you have to get it approved by the IRB (Interval Review Board) and all that kind of stuff. Then if you want to inhibit certain areas of the brain, then you use low frequency stimulation, for example 1Hz. In people with epilepsy or schizophrenia, investigators have used inhibitory, the 1HZ as opposed to 10Hz. You want the neurons to calm down their activity.
Dr. Chappell: That’s modulating frequency and intensity and so forth. What about focusing anatomically, on specific areas of the brain? Are you able to focus the energy, say on a 1cm spherical area of the brain?
Dr. Adamson: Once you locate the site with the MRI – based navigator, that’s the site you’re going to stimulate.
Dr. Chappell: How can you focus only on that site?
Dr. Adamson: The tool that I told you about, the neural navigation, it’s a machine that hooks up with the stimulation machine. It’s MRI-guided stimulation. Whenever your arm is moving with the coil, you can see it on the screen, on the MRI, so you can see where you’re stimulating. But, it doesn’t give you a real-time information that this is where your stimulation is, and then you also mark it on the head with an EEG cap. So there’s all kinds of accurate techniques that we’re doing. And I’m not saying we’re there yet, but I think we’re much better than we were five years ago. I’ve got data that show that the procedure is changing functional connectivity in the area of the brain where the electromagnetic energy is focused. So, once we mark the area where we stimulate, and once the protocol is done, the treatment is done; we can then perform an analysis from that point where we stimulated and see downstream (in terms of neural pathways or connected areas of the brain) what has changed in terms of blood flow response.
Dr. Chappell: Blood flow response, meaning functional MRI?
Dr. Adamson: That’s exactly what I’m talking about. We analyze functional connectivity at the beginning of the treatment, we do it after the treatment, and then we do it six months later to see if the effects are still there.
Dr. Chappell: I’m a neurosurgeon, so that’s why I was asking those questions. You’re familiar, I take it, with stereotactic radiosurgery and those sorts of things?
Dr. Adamson: Yes.
Dr. Chappell: I was trying to draw analogies to that in terms of volume of stimulation and target of stimulation.
Dr. Adamson: Totally makes sense. In fact, there is a company that does TMS that’s trying to do image-guided TMS for neurosurgeons right now. I think it’s a start-up and they’re working with our Stanford neurosurgery department.
Dr. Chappell: So you’re working with also post-traumatic stress disorder?
Dr. Adamson: Post-traumatic stress disorder, I am not working with it per se, but if you work with TBI, you kind of have to work with PTSD. You can’t get away from it. It is not an outcome in my study in the sense that I’m not stimulating and saying that I’m going to reduce the symptoms on PTSD scales, but a large population of my TBI patients have PTSD. And they have depression, because I work with depression, and there’s considerable co-morbidity. I look for PTSD effects on cognition, and the issue with PTSD is that the symptoms tend to over-power everything else that might be going on. Even if you—if you don’t randomize subjects based on PTSD, but say instead use a CAP (Clinically – Administered PTSD) score or a PCL (PTSD Check List) score, it will overwhelm the analysis. So we have to study PTSD, whether we like it or not.
Dr. Chappell: What are your end points, then?
Dr. Adamson: I did my post-doc in cognitive neuroscience and cognitive aging and Alzheimer’s disease. So, I’m very interested in cognition. My colleagues have been using RTMS in studies for treating depression. The psychiatry department is really big at Stanford for using it in depression. We at VA Palo Alto did the first scientific paper that came out in 2018 looking at the effects of RTMS on major depressive disorder. People are using it for PTSD and anxiety. I used it for executive function and now I’m using it also with paired associative memory tasks. So, I’m looking at memory and executive function. My end points are cognition and I also look at quality of life and other things like that.
Dr. Chappell: So, you’re writing these papers and you have outcomes from the different protocols that you’ve created?
Dr. Adamson: Yes, I have looked at all of these outcomes. I have hypotheses-driven outcomes; like I have the primary hypotheses and then I have secondary hypotheses. My primary hypotheses are usually cognitive, and my secondary hypotheses are either molecular-based or imaging-based, and I do a ton of cognitive measures in order to see the co-morbidities in PTSD, along with anxiety, and looking at all the different NIH common data elements that are typically reported for traumatic brain injury.
Dr. Chappell: So in layman’s terms, what can you say about where we are now in this research and where things can go in the very near future?
Dr. Adamson: Oh, boy! I think we’re just at the tip of the iceberg, and I don’t say that in order to save my job! (laughter) It’s—the field is just becoming exciting. Five years ago, when I was finishing my post-doc, I used to have to argue with people to say, “No, I don’t believe in the 5cm rule,” which is basically, you go from the midline of the skull and you target the treatment to the dorsolateral prefrontal cortex. In those days, people were doing TMS or whatever, but people were also starting to do neural navigation. And so I think in the field of TMS, one of the biggest things that’s happening is, people are looking at different parts in the brain. They’re not just on the surface of the brain, but people are also looking deeper in the brain. Deep brain stimulation is big, but also looking at trying to get at different areas in the brain with ultrasound, maybe focused ultrasoundm, and things like that. So, brain stimulation is really taking off.
Also, focusing on a particular area and more tightly focusing the treatment on a smaller area of the brain is one of the biggest things that is currently going on in TMS, and looking at how to navigate to the right spot. I think you were asking exactly the right question, because that’s where the field is going. Three years ago it was a big deal to look at structurally navigated targets, so you could do an MRI scan and use that imaging data for structural navigation. The study I just started right now, I’m doing functional navigation, which is basically, you can an fMRI (functional MRI) and you navigate to the site that you want to stimulate based on an active focus in the individual person’s connectivity matrix. These are all things that are happening based on the concept of precision medicine, like you do the baseline assessment and everything has to be applied to the individual’s specific characteristics. So, I think the field is really exciting, and I think we need to really study the co-morbidities and strive for really good outcomes, because I feel like some of the outcomes are very subtle and do not detect the full effects of the treatment; and also we don’t do a lot of follow-up, so a lot of the changes in the brain may happen six months, for example, after you’ve stimulated it. If you don’t assess the patient six months later, you won’t know. These are just some of the thoughts.
Dr. Chappell: Are you doing phase I trials? Are they larger cohorts? How does that work?
Dr. Adamson: I had a clinical trial phase I with the VA that just ended. I am now doing a DOD trial, which is on a much larger grant. I just got funded today for another one, which is another VA trial that I’ll be doing with pain as an outcome. Pain is another thing I’m interested in. Pain is one of the biggest problems in TBI patients as well. We’re all testing different outcomes with similar protocols. The thing I’d really like to do in my research studies is more imaging and measuring molecular biomarkers to really see the mechanisms of change in the brain after treatment with TMS. I also have data for blood biomarkers like brain-derived neurotropic factor and other myokines that change with TMS. I’ve got three trials that are happening right now.
Dr. Chappell: What are the treatment protocols like? Is it a one-time treatment? Several treatments over the course of several days?
Dr. Adamson: The FDA-approved protocol that we follow is 20 treatments, three treatments per day over the course of two weeks. Each treatment is 20 minutes long. That’s the hard part, because a lot of the patients around here have to work and they can’t come in every day, especially 3 times a day. So, we have to somehow fly some of our patients in from other areas. Since I don’t study patients with severe TBI, also TMS and severe TBI is controversial; you won’t get permission from IRB to do it at this point. I look at mild and moderate TBI, and mild and moderate are usually people, if they’re under the age of 65 or 70, they’re all working. It gets to be a little harrowing trying to get patients to be part of the study.
Dr. Chappell: How long have you decided to follow these patients? It sounds like you do need to follow them out pretty far in these studies.
Dr. Adamson: So far I’ve done six months, and then I have tried to get funding for one year. The idea is, if you do other devices, like there are all these different devices you can use to stimulate using the vagus nerve and that kind of thing; these are commercially available items that can be used any time. But with TMS, it’s like, if you figure out that after a year the effect goes down, either by looking at an outcome measure or functional connectivity, then you might give a booster treatment or something like that. But nobody’s really figured that out yet.