Hello, everybody. My name is Dave Brody. I'm a professor of neurology at Uniformed Services University and the director of the Center for Neuroscience and Regenerative Medicine, as well as running a lab at the NIH and the NINDS. Today, I've got an opportunity to talk to you about our work on Individualized Resting State fMRI-Guided Transcranial Magnetic Stimulation Treatment for Depressive Symptoms in Military Traumatic Brain Injury Patients. It's a great honor to be invited. I think this is going to be a lot of fun. First, my disclosures. These are my disclosures. I don't have any conflicts of interest. The objectives today are to understand the relationship between depression, post-traumatic stress disorder, and traumatic brain injury in military service members injured in wartime. A second objective is to appreciate the role of individualized resting state fMRI in guiding transcranial magnetic stimulation treatment for depressive symptoms in the context of traumatic brain injury. I'd also like to start with the who's who. There has been an enormous number of people who've participated in the studies that I'm going to tell you about over the next 40, 45 minutes or so, and I really want to make sure that I give them credit up front. Two people deserve a special mention. First is Christine McDonald, my collaborator for more than a decade at Washington University, who led many of the studies that were performed at the hospital and Washington University in St. Louis over many, many years. And the second is Dr. Sean Siddiqui, a psychiatrist with whom I worked while I was at Washington University, who was really the brains behind the idea of the resting state fMRI guided transcranial magnetic stimulation. I owe both Dr. McDonald and Dr. Siddiqui a great debt of gratitude for the opportunity to collaborate with them and all their teams during the time that I have worked on this project. So the first part of our talk today is going to describe some research studies on U.S. military personnel with blast-related and non-blast-related traumatic brain injury. This is Landstuhl Regional Medical Center in Landstuhl, Germany, and a lot of the work that we did occurred at Landstuhl, and I will tell you more about that. For geographical orientation, the wars in Iraq and Afghanistan involved triage activities in which a large number of injured U.S. military service members were evacuated from theater to Landstuhl, Germany, which is where the largest triage center for the central command area was located. So we went to Landstuhl, we brought our technology to Landstuhl because that was the right place to be to study our military service members. I also had an opportunity in 2011 to travel to Afghanistan to participate with the Gray team in studying the concussion care in theater at the concussion care centers that occurred in that location. This is me in Kandahar, that's Osama bin Laden's headquarters there in the background, and I'll tell you about some of the work that was done at warrior recovery centers and other concussion clinics like this in Afghanistan. Concussion care in theater, just to give you guys a little bit of background, included at that time in 2011 scheduled sleep, non-narcotic pain medications, concussion education, strict regulation of caffeine use, acupuncture, physical therapy, and a host of other really high quality therapies. We were really impressed with the quality of care we saw in theater. So the first research study that I'm going to tell you about involves assessment of clinical outcomes in concussive blast-related versus non-blast-related traumatic brain injury. At the time, one of the really big questions was, is there something fundamentally different about the effects of blast injury versus non-blast injuries? We still haven't fully solved that problem, but I'm going to show you some of the data that we obtained and published in 2014. This was a perspective study of patients that had blast plus impact TBI or non-blast TBI, and we also had blast-exposed controls who were evacuated for other reasons. These were people who had been exposed to blast during the time of their wartime service, but didn't have, didn't meet criteria for traumatic brain injury, were evacuated for other things, other types of injuries or illnesses. And then again, non-blast-exposed controls, again, that were evacuated to launch stool for other injuries or other illnesses. They were all evacuated to launch stool. None of them were made in theater in this first study. So the objective was to determine similarities and differences in clinical outcomes between blast and non-blast TBI. We had these two control groups, importantly, as well. So this was the first outcome measure, which was the global six to 12-month outcome. How were they doing six to 12 months later? And this is on the left axis, on the y-axis is the GASI, the Glasgow Outcome Scale Extended. This is a very simple global measure of overall function. So eight is completely normal. Everything is completely fine, back to normal. Seven is still some symptoms, but not having a disability. Six and five are different levels of moderate disability, and four is a severe disability. Three is also a severe disability. Two is a vegetative state, and one is dead. Luckily, we did not have anyone from our studies who was at the lowest levels of severe disability, vegetative, or dead. So what you can see from this is that the non-blast-exposed controls here, most of them made a good recovery, were in the good outcome category. Some of them had moderate disability, and I remember even the controls were evacuated from theater because they were sick or injured. So they were not healthy controls, they were other injury or other illness controls. And same thing with the blast-exposed controls in this second group. But as you notice, it was just a little worse, and we'll get back to that in a second. This is not statistically significant here, but we'll get back to that in a minute. Now the interesting part, the non-blast TBI patients and the blast-plus-impact TBI patients all had substantially higher level of moderate disability. Many of them still had good outcomes, but more of them had the moderate disability category than anything else, and these are the averages here. Now one note that I do want to point out is we call these blast-plus-impact TBI. It was very, very, very unusual to be anyone who had a pure blast injury. Almost everyone who had a blast injury also had an impact injury. That is to say, they may have been blown up, but then their vehicle crashed and they struck their head, or they had a lot of rotational acceleration, or they were blown up and then something collapsed on them, or they were blown up and thrown across a space and crashed into something. So just about every blast injury was also accompanied by impact. We screened through thousands and thousands of service members in a separate paper and only found a few, about five, that had pure blast injury. So the relevant comparison, non-blast TBI versus blast-plus-impact TBI, and we did not find a difference in this global outcome between those two groups. Next, we looked in a more granular fashion at neurological test performance abnormalities. We did a battery of neuropsychological tests and we asked how many abnormalities were there, meaning two standard deviations or more below the mean on the tests, and what we found was that both the blast-plus-impact TBI patients and the non-blast TBI patients had more neuropsychological test abnormalities than would be expected by chance. They were further off to the right in the distribution of number of abnormalities. Now, lots of normal people could have one test abnormality just by chance. That's the definition of two standard deviations is that there's going to be some that occur by chance when you do a large enough battery of tests, but to having two or more, that was much more common in the injured group than in the non-blast group or the non-injured groups. We next looked at the headache severity measures using an outcome called the MIDUS score, where a higher MIDUS score indicates a higher burden of migraine headache, and again, both the non-blast TBI and the blast-plus TBI had higher burden of headache than the controls, but there was no difference between the non-blast TBI and blast-plus-impact TBI. Next, we looked at the CAHPS score as a measure of post-traumatic stress disorder. Again, higher indicates worse, and we found the same basic phenomenon, that the TBI patients had higher CAHPS scores than the controls, but no difference between non-blast and blast-plus-impact. Now, here, there was a statistically significant difference, as in the headache group, between the blast-exposed controls and the non-blast-exposed controls. This was interesting. The blast-exposed controls are somewhere intermediate between the non-blast-exposed controls and the traumatic brain injury patients. And then finally, we looked at the depression severity using the MADRIS, the Montgomery, Ashburn Depression Rating Scale, and found a similar phenomenon, that the non-blast TBI and blast-plus-impact TBI were similar to each other and higher than the controls. So the general theme here was that the two types of injury, non-blast TBI and blast-plus-impact TBI, were quite similar to each other on these outcome assessments performed 6 to 12 months after injury. We did some assessments of what could be underlying some of the activity, some of the interventions. And so, one of the things that was quite interesting at the time was a measure called the combat exposure severity. Higher indicates more activities involving combat. Now, here, the blast-exposed controls were quite a bit higher than the non-blast-exposed controls, and the blast-plus-impact TBI subjects were quite a bit higher than the non-blast TBI subjects. So combat exposure intensity was not the strong driver of the outcomes that you saw on the previous slide. And in fact, the correlations between combat exposure scale and CAPS were actually quite weak and non-significant in the TBI group. Now, in the control group, there was a significant relationship, and you can see that it's really driven by the blast-exposed controls. You can see that in the black circles representing the blast-exposed controls, there's a trend that as the increase in combat exposure severity, there's higher CAPS scores. So what this is telling us is that there's a difference in the correlations between combat exposure and post-traumatic stress. There is a correlation in the controls, but there is not a correlation in the TBI group, suggesting that there's something different fundamentally about post-traumatic stress symptoms in the TBI group compared with the control group. In this paper, we also did a multivariate analysis of clinical outcomes, and we found that the strongest drivers or the strongest correlates of overall clinical outcome, remember that Glasgow outcome score extended that I showed a few slides ago, were the severity of the depressive symptoms, the number of neuropsychological abnormalities, and more weakly, the intensity of the headache. In another model where we included the TBI versus control as a factor, the severity of the depressive symptoms and the number of neuropsychological abnormalities still stood out. All throughout, the severity of the depressive symptoms was the strongest overall correlate of the global outcome, the Glasgow outcome score extended score. And this theme of the severity of depressive symptoms is going to come back over and over again. This is one of the first hints that depression would be one of the major domains in which we are going to intervene. And that's a foreshadowing of some of the work that's going to come later with regard to transcranial magnetic stimulation. So the summary of this group is that both TBI groups had higher rates of moderate to severe overall disability. Self-recorded combat exposure intensity was higher in the blastless impact TBI group than in the non-blast TBI group. Global outcomes, headache severity, neuropsychological performance of PTSD, severity, and depression were indistinguishable between the TBI groups. One potential interpretation is that the TBI itself was the driver of outcome, independent of injury mechanism or combat exposure intensity. We noted that headache, severity, and PTSD symptoms were worse in blast exposed controls than in non-blast exposed controls. And there's ongoing research in the CNRM and other places around the world focused on the effects of sub-concussive blast exposures. As I showed you in that slide, the people who had blast exposure which did not meet criteria for TBI would be considered sub-concussive blast exposures. And that's a real hot topic in research right now. And the bottom line, which I bolded here, is that depression severity was the strongest correlate of overall clinical outcomes, irrespective of mechanism of injury and when accounting for other factors, at least the ones we could measure. Okay. Next chapter is the work that we did in Afghanistan. And in this work, we used acute predictors of six to 12-month outcomes. One of the things I had neglected to mention was that the studies in longitudinal were involved quite a bit of delay. And the average was 14 days between injury and time to arrival in longitudinal, but it could have stretched out to 30 days or even longer. When we were in Afghanistan, we did work at two major concussion care centers in Afghanistan. We were able to enroll and evaluate military service members with these injuries acutely, zero to seven days after injury. And so that was a really valuable opportunity. So this study involved 38 service members with concussive TBI and 34 controls. And the goal was to determine if acute clinical measures could be used to predict six to 12-month outcomes. So what we found was that the acute assessments had heightened post-concussive, post-traumatic stress, depressive symptoms, and worse cognitive performance in those with blast TBI. And at six to 12 months, 63% of those with blast TBI had moderate overall disability compared with 20% of controls. The predictors of later global adverse outcomes included the TBI diagnosis, older age, and more severe post-traumatic stress symptoms. Even at that early time, the severity of post-traumatic stress symptoms was reflective of overall outcome. So these are some of the data that was in this paper that was published by Christine McDonald et al. in Brain in 2015. The concussive symptoms, no surprise, were high after people had concussion. Balance was impaired, but not statistically significantly, although a hallmark of concussion and balance impairments were not particularly strong drivers. PTSD symptoms were dramatically worse in the TBI patients compared with controls, as were the depressive symptoms. We don't usually think of these things as occurring acutely after traumatic brain injury, but our findings were contrary to that, that PTSD symptoms and depressive symptoms were very profound immediately after concussion and acute period. These were our outcomes. The outcomes were substantially better in the control group. Again, the controls were people who were evaluated for other reasons at these military treatment facilities in Afghanistan. Substantially better, close to 80% of the controls had made a good recovery six to 12 months later, whereas in the 30 to 40% range had made a good recovery at later times in the TBI group. These were our neurobehavioral outcomes. Now, this is at six to 12 months later. The neurobehavioral rating scale was higher in many domains, worse in many domains after TBI. There were more neuropsychological test abnormalities after TBI than the controls. Again, similar to the previous studies, there was a bit of a mismatch in this study in the sense that the controls, there were more officers in the controls and more enlisted service members in the TBI group. But when we looked at enlisted subjects only, we still found the same result. So, a good example of where reviewers in the paper actually point out an important area that makes the study stronger. This is our depression and PTSD severity notes. And similar to the previous study, the TBI patients had higher levels of depression, higher levels of post-traumatic stress. And the post-traumatic stress was in, especially in the Caps B category of re-experiencing and in hyper-arousal, the effect on avoidance and numbing was less profound. Still there, but not as severe. And when we made another multivariate model to try to predict the Glasgow outcome scale outcome 6 to 12 months later, we found that a model that included the post-traumatic stress scale, TBI versus control, and age had an area under the curve of 0.84 for predicting outcome after the blast-related injury versus control in these military service numbers. So, it was possible to use early findings to have a moderately good degree of prediction 6 to 12 months later. Again, focusing on the role of PTSD and depression. The model was similar when we used depression severity, acute depression severity. So, again, the finding is that the high proportion of individuals who had blast TBI had a moderate overall disability 6 to 12 months later, and that the acute predictors of later global adverse events included TBI diagnosis, older age, and more severe post-traumatic stress symptoms. You may be wondering about post-traumatic stress and depression. All throughout all these studies, post-traumatic stress and depressive symptoms were highly correlated with each other, with R's of about 0.8. So, in the modeling, they were highly redundant with each other. So, usually, one of those outcomes superseded the other one, but the models were almost as good with the other one. So, if this model used post-traumatic stress, it could have used depression and been almost as good. Importantly, 90 plus percent of these service members who were enrolled in the studies in Afghanistan returned to duty. They were not evacuated from theater, and yet, 6 to 12 months later, they still had poor outcomes in 63 percent of the time. So, it was an important finding that just removing these service members from theater was not the cause of their adverse outcomes. It was the TBI, the post-traumatic stress, and the depression. Pause and move to the next chapter. So, at right around the time that we were performing these studies, there was a major change in policy from the Department of Defense. This was the Directive Type Memorandum, a policy guidance for management of concussion-slash-mild traumatic brain injury in the deployed setting. So, we looked at 6 to 12-month outcomes across multiple cohorts. We've done multiple studies. I've only shown you the results from a few of them here, but we did multiple studies from 2008 through 2013, coincidentally, before and after the Directive Type Memorandum. So, we have an opportunity to explore the effects of this natural experiment of the Directive Type Memorandum, which really standardized concussion evaluation and care in theater. What we found is that across the cohorts, there were high levels of disability in the moderate disability category in all of our TBI subjects compared with controls. The disability all throughout the study was mostly due to a combination of work and non-work disability. Very few had only work disability, and only a moderate number had only non-work disability. This is a much higher rate of disability than in other TBI, concussive TBI circumstances. So, if you looked at, for example, if you looked at sports concussion or other mild car accidents or things like that, other things that cause, quote, mild, unquote, or concussive TBI, usually the rates of disability 6 to 12 months later are in the 10 to 20, maybe 25 percent range. Here, we're in the 60s to 90s. It's much, much higher. So, and same thing, we had continued high rates of neuropsychological tests abnormalities across multiple cohorts. So, here's the interesting result that looked at the sort of evaluated the relationship with the Directive Type Memorandum that occurred in 2010. Overall, there was a trend towards less severe depression and less severe post-traumatic stress as a function of time. It looks like we were getting better at managing post-traumatic stress and depression severity, as you can see, from before the Directive Type Memorandum versus after the Directive Type Memorandum for depression, before the Directive Type Memorandum versus after the Directive Type Memorandum for post-traumatic stress severity. So, that's encouraging. It looked like some progress was being made. However, not nearly enough. These depressive severities are still quite high. These post-traumatic stress severities are still quite high and higher than any of the control groups. So, some progress, but not nearly enough. When we did another one of these multivariate models, with the whole group, we found, again, a moderately good ability to predict overall outcomes measured by the Glasgow Outcome Score using variables of TBI versus control. TBI is associated with worst outcome. Enrollment site associated with worst outcome. Medical evacuation was associated with worst outcome. No surprise. More severely injured people tend to be evacuated than less severely injured people. And again, depression and post-traumatic stress severity being highly related to the overall outcome. So, again, a very consistent picture over multiple studies. So, the summary of this section was that global disability was more common in those with TBI, those evacuated from theater, and those with more severe depression and PTSD. Disability was not significantly related to neuropsychological performance, to age, education, self-reported sleep deprivation, injury mechanism, or date of enrollment in this multivariate model. One of the things I had not talked about very much is imaging. A lot of the work that we were doing in Iraq and Afghanistan and at Longfield had to do with advanced imaging studies, things like diffusion tensor imaging. We found a lot of abnormalities. We published a lot of papers on those. But importantly, the imaging findings did not predict disability or specific outcomes. So, this really, although this was an interesting group of studies, it was really actually negative as far as what our primary hypotheses were, which were trying to involve imaging predictors of disability and outcomes. So, I'll pause here and show you just a little bit of work, additional work from my colleague, Christine McDonald, about the acute set of predictors of five-year outcomes. Christine, Dr. McDonald and her team in 2017 showed that there was still severe post-traumatic stress and depression five years after blast TBI. There was evolution, not resolution of these severe outcomes. She found that the PCLM scores involving the post-traumatic stress increased 54% between the acute period and the five-year period, compared to 30% increase in controls. And that, again, PCLM was the most informative measure of predicting long-term functional outcome, as we had shown previously with the prediction of one-year functional outcome. She also, again, in another study published in 2019, showed increased PTSD severity five years after in the Kikasa BLAST TBI group compared with combat-deployed controls. And insomnia severity was also elevated, anxiety was elevated, but things like alcohol misuse were not elevated. So again, she was able to show a slightly lower but still strong prediction of outcome based on zero to seven-day characteristics, predicting the five-year outcome measures. The prediction was, again, based on some of the same abnormalities that you have seen in the previous findings. So five-year outcomes are still pretty substantially adverse in this patient population. So again, the summary is that these patients fared poorly at five years compared with controls. The self-reported PTSD symptom severity within seven days is almost as good as a multivariate model by itself in predicting five-year outcomes. And these are all service members who had prospectively diagnosed TBI. One of the weaknesses of other studies in the field is that oftentimes the diagnosis of TBI is made retrospectively at the time that evaluations are being performed. And so there's the bias, potentially, of, well, I'm not doing well, therefore I must have had a bad TBI. These were all prospectively diagnosed and evaluated, followed longitudinally over time. And again, nearly all of them returned to duty within 28 days. So it's not the removal from duty itself that is responsible for these outcomes. So the logic here is that screening based on early PTSD and also depressive symptoms would be a logical approach for future interventions designed to improve outcomes after blast-related TBI. If we ever enter into another serious conflict where we are having high rates of concussive TBI from blasts in theater, this would be a very logical intervention. And hopefully we'll be able to retain these lessons learned. So the overall summary of the first part of my talk is that blast-related concussive TBI in U.S. military personnel is associated with advanced MRI abnormalities, which I didn't show today, and adverse clinical outcomes. And there's evolution, but not resolution, of brain injury pathology and clinical symptoms over time. Both the acute phase and early phase clinical measures can inform long-term clinical outcome up to five years. Oh, and by the way, Dr. McDonald is working on assessing the 10-year outcomes for many of these service members right now. We hope we'll hear about that soon. And these findings have implications for early intervention strategies, especially focused on mood dysregulation like depression, post-traumatic stress. We find the way we interpret this results is that wartime TBI itself, independent of the mechanism of injury like blast or blast-blast impact or impact alone, appears to be the driver of clinical outcome. And there's really clearly further work is required to distinguish if there is the distinction between blast and impact TBI. Again, we could not distinguish them based on the clinical findings that we reported here. So, we will, new methods will be required to directly assess the precise relationships between the structural brain injury and specific neurological sequelae. The imaging methods we used involving the fusion-tense imaging were not sufficient to do so. There are a lot of advanced MRI methods and other biomarkers that could be potentially useful in this domain, but that remains to be done. Ongoing work in our laboratory involves developing molecular contrast MRI methods that might reveal new pathologies with greater sensitivity and specificity. So there's a lot of work to be done in this domain. I do want to leave this one note that was from McDonald's JAMA Neurology 2017 of interest. In a one-in-five-year study of year study evaluations, 18 of the combat-deployed controls and 40 patients with concussive blast TBI endorsed seeking assistance from a licensed mental health care professional, defined as a psychologist, psychiatrist, therapist, social worker, or other licensed credentialed mental health care professional. Only nine of the controls and nine with their blast TBI patients reported that the mental health programs helped. Currently we have a lot of work to do with regard to treating these adverse outcomes from wartime TBI. So we'll pause there for a second, and now we'll make a transition to the second part of the talk, which involves treatment of depression and PTSD in the context of TBI. So the current standards of care are primarily include evidence-based psychotherapy. We think it's most likely to be similarly effective in TBI versus non-TBI populations. But one of the major challenges has been the availability of appropriate therapists and the commitment of patients to receive full courses of therapy. Many of our service members live in areas where high-quality evidence-based psychotherapy is not readily available. Many of our service members will attend part of a set of evidence-based psychotherapy sessions but not complete the evidence-based psychotherapy approach. In the domain of pharmacotherapy, there's really relatively little evidence-based practice. For example, randomized controlled trials of sertraline have not shown efficacy in the context of TBI. In fact, they've shown that they have not been effective for relieving depressive symptoms in the context of TBI. There is some indication from a small trial that methylphenidate or ritalin may be effective at reducing PTSD symptoms in the context of TBI. So it is very possible there's not been nearly enough evidence-based practice in this domain, but it's possible that pharmacotherapy in the context of TBI may be different than in the context of other sources or etiologies for depression. And that brings us to the topic of transcranial magnetic stimulation. Though transcranial magnetic stimulation is approved by FDA for treatment of refractory depression, traditionally TBI was considered a contraindication to transcranial magnetic stimulation due to seizure risk. However, we've recently appreciated that seizure risk is not significantly different from general population after a concussion or mild TBI, which is in fact 85% of military TBI and 100% of patients in our studies all had concussion slash mild TBI. I put mild in quotes because there's nothing mild about this. As you can see, the outcomes are actually quite significantly adverse. Nonetheless, the seizure risk appears to correlate with hemorrhagic lesions in the brain and especially contusions to the temporal lobe and penetrating injury. None of our patients had contusions in the temporal lobe. None of our patients had significant hemorrhage. None of them had penetrating TBI in these studies. So their risk of seizures is no different from the general population. So we reasoned that it would be potentially feasible to perform transcranial magnetic stimulation in military service members and other concussive patients, TBI patients. Many of you are very familiar with transcranial magnetic stimulation or the rest. This is an overview. The idea is that a wire coil is used to generate a pulsed magnetic field, which through the laws of induction will produce highly rapidly changing electric fields in the underlying neural tissue at depth of two or three centimeters below the surface of the brain and directly stimulate action potentials in the neurons of the underlying region of cortex. So this is how it looks in one of our subjects at Washington University. This is the coil. There's a stereotactic navigation system. He's seated in a chair for positioning. This is actually one of my patients from my transcranial injury clinic at Washington University. And this is the genius who thought of this idea, Sean Siddiqui. Currently he was a resident at Washington University working with me. He's now at the Israel Deaconess University at Harvard Medical School. In a paper that we studied, that we published in 2019 in the Journal of Neuropsychiatry and Clinical Neuroscience, Dr. Siddiqui and his colleagues found that resting state functional magnetic resonance imaging could be used to map networks in the brain in individual subjects. So there's been a lot of work on using fMRI to look at connectivity. And what we mean by connectivity is the correlation of fluctuations in the bold signal over time. Two areas where there are bold signal fluctuations are correlated or said to be functionally connected. And using these functional connectivity, you can map out networks. Networks are regions that have a high degree of functional connectivity with each other. The most famous is called the default mode network, which is shown in red here. These are the parts of the brain that are fluctuating coherently with each other at rest when we're not doing anything in particular in the default state. And what Sean was able to show is that you can map out the default mode network in individual subjects and the location in the brain of the default mode network is very different from person to person. And what you notice is that the red areas in these four rows, these three rows rather, are very different from each other. You can see the red areas, there's a lot of heterogeneity from person to person. And this comes into play because transcranial magnetic stimulation is usually given in a quote one size fits all fashion. Everybody gets stimulated in the same spot. Sean reasoned, Dr. Siddiqui reasoned, that we would be missing the most important places in a substantial fraction of people if we stimulated the same spot in everyone. So what Dr. Siddiqui decided to do was to map each individual subject and find hotspots, which were like areas that have a high likelihood of membership in what's called the dorsal attention system and a low likelihood of membership in the default mode network. So why those two networks, the dorsal attention system and the default mode network? Well, because the default mode network is highly correlated and often includes the subgenual anterior cingulate. Subgenual anterior cingulate is the part of the brain that's probably, I would say, most highly associated with depressive symptoms. The groundbreaking work of Helen Maberg and many others around the world have shown that overactivity of the subgenual anterior cingulate is highly associated with depressive symptoms and turning down the activity of the subgenual anterior cingulate is associated with improvement in depressive symptoms. So the tricky bit is that we can't stimulate or get at the subgenual anterior cingulate directly with transcranial magnetic stimulator. That requires an invasive procedure like deep brain stimulation, which we were not doing. But instead of going after it directly, we can go after it indirectly using a teeter-totter mechanism. What do I mean by that? Well, the dorsal attention network is anti-correlated with the default mode network. They're like flip-flop. If the dorsal attention network is on, the default mode network is off. If the dorsal attention network is off, the default mode network is on. So by strengthening the dorsal attention network, we reasoned we could weaken the default node network, including the subgenual anterior cingulate. So long-winded explanation for we tried to find the part of the dorsal attention network that was the most anti-correlated, the most flip-flopped with the default mode network. And here's an example of it right here in this highlighted circle. This is our hotspot, and this is the part we stimulate. So what did we see? Well, first of all, when we mapped these regions in a variety of different traumatic brain injury patients, we found that their functional anatomy, just as we suspected, is very different across the brain. So if we had stimulated all in one place, so for example, with the green, where we stimulate everybody in the same area, like this is what you would get if you went to get conventional transcranial magnetic stimulation, as approved by the FDA, you'd get stimulation always in the same place. You'd be pretty close to a good target, like shown by the red here, in some of the patients, but you'd be pretty far away from the best target in a good number of the other subjects. So that's an example of why we think the individual subject targeting is important. So one of the things we had to show, though, before we actually got into the treatment, is that we could actually do this reliably, because the MRI scans are noisy, and sometimes the patient doesn't hold still in the scanner, and how well could we really do this reliably? Well, what we showed, to make a long story short, is that we could map the targets reliably in two different scans. We put the person in the scanner, mapped the target, take them out, bring them back the next day, put them back in again, do the mapping again, blinded to what we got the first time. We found that our test-to-retest reliability usually got us within four or five millimeters of the target, and that's really good, because the inter-individual variability was between seven and 10 millimeters. So we felt that we had a fairly good reliability of the target. Not perfect, but not bad either. So when we did this study, we randomized several—oh, sorry, this isn't the randomized study yet. This is one individual participant, a patient of mine, who was one of our first patients that we studied. His pretreatment moderate score was quite high in the mid-30s, and post-treatment was substantially better, and a six-week follow-up was substantially better. This individual benefited dramatically from the transcranial myocardial stimulation, even though he had had no effects of multiple pharmacotherapy opportunities and had chances to do evidence-based psychotherapy, but had not really been compliant with that. He had no serious adverse effects, and his quality of life improved quite dramatically across many domains, including anger, anxiety, depression, behavioral discontrol, executive function. His NIH toolbox scores did not consistently change. We didn't get substantially better or substantially worse. These changes were not consistent, nor did his temperament and character index. He did not have a major change, with the exception of persistence. His self-reported persistence was extremely low prior to the transcranial magnetic stimulation and up into the normal range afterwards. So it also affected the network connectivity. So it actually did change the connectivity of the brain. The medial temporal lobe to default mode network was very far outside of normal range prior to transcranial magnetic stimulation, and pushed it into the normal range after TMS. His subgenual anterior cingulate to default mode network was a little outside the normal range before, and solidly in the normal range afterwards. And same thing for medial orbital frontal to anterior cingulate. Now, this is one that we didn't understand exactly, and we still don't exactly understand. His dorsal attention system to default mode network was very far outside the range before his treatment, and got even more outside the range after his treatment, which was associated with benefit. So it is an oversimplification to just say that we were pushing the brain back into a normal state. That is what we were hypothesizing, that we were pushing the brain back into a normal connectivity. But that is an oversimplification of our result. That does not exactly explain all these results. And so, as I think you'll see, we're very encouraged about these results so far, and you'll see them in the next part as well. But we don't understand them completely, as often happens. So after the encouraging initial case, we performed a very small randomized control trial in which we assessed 32 patients for eligibility, randomized 15, nine of them got active treatment, six got sham, one of the shams withdrew, and we were left with nine and five at the end. This was published in Journal of Neurotrauma in 2019. The demographics, they were similar age, 40s to 50s. These were mostly civilians in my clinic at Washington University, but some also had concomitant post-traumatic stress disorder, as our military service members have. They had had depression for quite a number of years, five to eight years on average. They were quite chronic in the eight years, but a long range of duration after their injuries. And they had an average of about five unsuccessful antidepressant or augmentation or cognitive behavioral therapy trials. So they were quite refractory. And this is the bottom line result. At baseline, the people in the active range, in the active group, had high moderate scores. Mid-treatment after 10 sessions, they were a little bit better. And post-treatment after 20 sessions, they were substantially better in a large fraction of them. Now, many people who were in the markedly severe depressive range got down into the moderate-to-marked, many who were, and some even into the mild-to-moderate range. Some who were in the moderate-to-marked range got into the mild and even into the remission area. There missed one moderate in this individual, but only got partial data. And even somebody who was mild-to-moderate severity at baseline got into the remission range. Now, transcranial magnetic stimulation is a lot of work. It's 20 sessions, sitting in a chair, you have to come in for an hour every day, and you work with somebody who really cares about you. The person who's doing the stimulation was generally very nice people, and you're doing all these evaluations, it gets you out of the house, et cetera. So no surprise, there was an effect of sham as well. This is a very powerful placebo effect. And even the sham participants did improve somewhat, but not nearly as much as the ones in the active group. So this was a very encouraging result in this small randomized controlled trial. We looked across the different domains of depression, and the biggest effect was in the domain of lassitude, where the lassitude was almost alleviated completely. It's a 75% to 100% reduction in the lassitude, whereas about 25% change in the controls. All the subcategories of depressive symptoms improved, but this is the one that was the most traumatic and highly statistically significant. You remember, one of the things I mentioned was the apathy personality change in that one individual that I showed you earlier. So it's possible that some aspects of depressive symptomatology are more affected by transcranial magnetic stimulation in the context of traumatic brain injury than others. A lot more work will be needed to determine that in more detail, but it generates an interesting set of hypotheses. We had some secondary outcomes. We looked at the NIH emotional toolbox battery. The effects were not very exciting. Cognitive effects, again, were not very consistent. There was not a global overall effect of cognitive function. It's actually not a bad thing. We were not expecting there to be. We were just hoping that by manipulating the brain circuitry and connectivity that we wouldn't make cognitive function worse, and we did not. There was no evidence of cognitive worsening. Everybody got a little better on the NIH toolbox scores, probably due to practice effects. Headache is one of the symptoms, also one of the side effects of transcranial magnetic stimulation. There was actually not a worsening of headaches overall in the group. In fact, if anything, the headaches got slightly better in the active group compared with the shams. The shams, their headaches didn't really change. In the active group, they actually got a little bit better over time. Now, there were some patients who had headache during the transcranial magnetic stimulation as a whole, but their global headache rating for the HIT-6 asks them how they've been doing over the entire month. It was overall a little bit better, not significantly significant, but definitely not worse as a secondary outcome. So, you know, again, our hypotheses were that changes in the brain network connectivity were the drivers of the improvements. And so to test that, we looked to see whether there were connectivity differences in the brain that would predict the clinical outcome. And in fact, we found that the correlates of improvement were, for example, the strength of the connectivity of the right stimulation site to the default mode network shown here, and the strength of the connectivity of the right stimulation site to the subjunctal anterior cingulate cortex. These go together, of course, because subjunctal anterior cingulate is highly correlated with the default mode network, as I mentioned. The left side was not as strong. We don't know exactly what that means, whether that means the stimulation on the right side is more important than the stimulation of the left side, or just that the correlations are not as strong in this group. Obviously, further work is going to be required to sort this out. Okay, so that was encouraging. But what about transcranial magnetic stimulation for a military service? This is a major priority for our research group, the CNRM, and we are in the process of designing a large multicenter randomized controlled trial that will assess this. We did a small two-site transcranial magnetic stimulation trial that enrolled 10 subjects, and then was closed out because of COVID. These are our, this is our team, Charlene Simon, Lindsay Oberman, Diana Nora, and Alex Kuzman. We are now, have an even larger team of the folks you see here. Circella Sanaceros, Charlene Simon again, Lindsay Oberman, Diana Nora, Alex Kuzman, Sean Siddiqui, Sung Pham, Tad Haight, Yu Chu, and Holly Listonby. We are going to involve six sites around military treatment facilities around the country. We hope to start, well, this may be a little optimistic, but we hope to start enrolling in 2021 and finish enrolling in 2025-26 using an adaptive trial for the treatment of depression associated with concussion using repetitive transcranial magnetic stimulation. This is an ambitious study, and I think will be a definitive one to determine whether we can make a major difference in the depressive symptoms using transcranial magnetic stimulation in military service members with traumatic brain injury. So, again, I thought I'll end with the credits. The first part of the talk involving the studies in Iraq and Afghanistan in L'Anse aux was led by Christine McDonald, and the second part involving the transcranial magnetic stimulation work was led by Dr. Sean Siddiqui. I'll thank you all for your attention and looking forward to taking questions offline or by email or in person when we finally get to see each other again in person or at any other time in the future. Thanks very much.

depression

post-traumatic stress disorder

traumatic brain injury

military service members

resting-state functional magnetic resonance imaging

transcranial magnetic stimulation

clinical outcomes

blast-related TBI

non-blast-related TBI