**Transcript of Cyberseminar**

**Mild TBI Diagnosis and Management Strategies**

**Neuroimaging in the Assessment of Traumatic Brain Injury (TBI), Mild TBI, and PTSD**

**Presenter:  David H. Salat, PhD**

**May 28, 2014**

*This is an unedited transcript of this session. As such, it may contain omissions or errors due to sound quality or misinterpretation. For clarification or verification of any points in the transcript, please refer to the audio version posted at www.hsrd.research.va.gov/cyberseminars/catalog-archive.cfm or contact David.Salat@va.gov*

*Moderator:*It looks like we are at the top of the hour. I would like to introduce our speaker for today speaking for us, we have – sorry, Dr. David Salat. He is a Health Science Specialist at VA Boston Healthcare System for Translational Research Center for TBI and Stress Disorders; also, an Assistant Professor in Radiology at Harvard Medical School, and an Assistant Neuroscientist at Massachusetts General Hospital. We are very grateful to have David joining us today. I will turn it over to you now.

*Dr. Salat:*Okay, thank you. I want to thank everyone for the opportunity to talk to you today a little bit about neuroimaging and the assessment of traumatic brain injury, mild traumatic brain injury, and post traumatic stress disorder. As it was just mentioned, I am an investigator in the Neuroimaging Research for Veterans Center here at VA Boston as well as in the Translational Research Center for TBI and Stress Disorder. 

The field of imaging in traumatic brain injury is extremely broad. There is a very dense literature. I just want to stress here that I really prepared a conceptual overview of this topic, including sort of the overall scope of the problem. I picked some selected examples of how neuroimaging can be applied in the study of TBI and PTSD. These are – this is a very limited or a very selected set of examples. It is no way meant to be comprehensive or even a consensus of findings in the field. 

I also want to note that a variety of groups have different ways of defining the various concepts that we are going to be trying to apply imaging to here. I am not going to necessarily go into much detail about differences and ways that people define these things. But basically again, just try to explain how imaging can be used to understand these conditions. 

I will be focusing mostly on traumatic brain injury. I will mention a little bit about PTSD at the end of the presentation. I will be pulling information across a range of diverse fields including civilian as well as military TBI. Again, just in an effort to try to really understand how you can apply these sorts of techniques to the study of traumatic brain injury. 

I would like to start out by going with this poll question here just to ask and really get an idea of who is out there. Who is listening to this right now. Basically, starting with your primary roles at the VA. You can just answer that there.

*Moderator:*Thank you. It looks like the answers are streaming in. your options are student training our fellow, clinician, researcher, manager or policymaker, or other. If you do select other at the end of the presentation during the feedback survey, you will have a more extensive list to specify your roles. We do appreciate you answering this poll. It looks like the answers have stopped streaming in.

*Dr. Salat:*Okay. 

*Moderator:*Let me take that down.

*Dr. Salat:*Okay, there you go. Okay. It looks like mostly we are looking at students, trainings, and fellows, and some researchers. Okay, there we go – and some clinicians. Okay. Now, how do we make...?  

*Moderator:*We have ...[crosstalk].

*Dr. Salat:*I guess that – and then the second question is for those of you who have done research or what best describes people's research experience?  You can just go ahead and answer that question. 

*Moderator:*Thank you, and do be not shy, folks. These are anonymous answers. We are just trying to get a feel for the experience that’s out in the field.

*Dr. Salat:*It looks like most people have collaborated or have conducted research themselves. Okay?

*Moderator:*David, I was not sure if you wanted to go to the slide with the highlighted green. 

*Dr. Salat:*Yeah.

*Dr. Salat:*Yeah, sorry. I just wanted to let people know that my role and my particular experience is as a researcher here at VA Boston. I want to – I think that is important to mention that I am not a clinician. Anything that I mention here is not really based from clinical training. It is really based from most of what I talk about is going to be from a research perspective. 

Finally, I just want to go with poll question three, which is if you have done imaging research, what experience do you have in imaging?  There are a variety of different techniques that I have listed here on the poll questions. 

Okay. It looks like a variety of functional imaging and some EEG, and some MRI. Okay. My experience just so you know is basically as mostly instructional imaging and diffusion imaging, and functional imaging. I do a little bit of other types of MR imaging as well as a little bit of positron emissions and tomography in my research. 

I would like to just start off by talking about the scope of the problem. I think people in this field are fairly familiar with the problem of traumatic brain injury. I would like to note that much of the existing epidemiology on traumatic brain injury has actually been very well detailed in times that are basically prior to recent U.S. military conflict. The numbers that I present from various studies maybe are likely an underestimate. 

As I had mentioned, this is not necessarily limited to, for example, military TBI, but it also may include civilian and TBI as well. But just if you take a few numbers that are out there in the literature, we can see that there is an annual incidence of approximately 1.5 million traumatic brain injuries in the U.S. Eighty percent of them being considered mild and 20 percent being moderate to severe. Somewhere around 50,000 people per year may die of these traumatic brain injuries, 230,000 may be hospitalized. Then, somewhere around 80,000 to 90,000 may experience long-term disability. 

Of course, this is – it poses a large economic burden to society. Given this tremendous burden, it is unfortunate that we  are still fairly limited in our knowledge about the effects of traumatic brain injury on the brain and how traumatic brain injury contributes to cognitive, behavioral, and psychiatric conditions. In fact, even a definition of traumatic brain injury can differ across a variety of studies. Typically it is your –  a diagnosis of traumatic brain injury is based on information about the syndrome at the time of the event. The conditions surrounding the event such as what occurred?  

The phenomenon, including loss of consciousness, or retrograde and post-traumatic amnesia, and disorientation, and confusion. It will also be based on some neurological signs basically focal signs, and potentially seizure, or intercranial lesion on what is referred to as conventional imaging. I will be talking a little bit about differentiating conventional imaging from research imaging. Because they really provide – they are really used in very different ways. 

For example, a contusion, a hematoma, a hemorrhage, or edema that might be apparent on certain types of conventional imaging as well as common or standardized scales such as the Glasgow Coma Scale, which assesses motor, verbal, and eye responses. It has different scores for basically what we considered a severe, or moderate, and mild traumatic brain injury. 

When trying to think about how we might use imaging to study traumatic brain injury, it is important to think about what is actually known of what the brain...  What the brain injury is in traumatic brain injury. Various people have documented this in sort of a longstanding literature. For example, some important points are that the anterior cortex is vulnerable to damage. That there is some axonal injury that is due to sort of these linear and rotational forces that are associated with the trauma. But that there is also a fairly and less known secondary set of effects that may include biochemical, cellular, and metabolic, cascades that may continue well past sort of the acute period of the injury.

With regard to those types of damage, a little bit more specifically, there are a variety of types of tissue pathology that can occur as a result of trauma; which include a contusion. Where the blood vessels are damaged by the trauma. The blood may invade neural tissue and would lead to necrosis. A laceration where there are –  some membranes are torn at the site of injury. Herniation where there is a, basically a mass effect of brain and tissue; which can increase the intracranial pressure and produce potentially...  

Well, all of these conditions can produce a life  threatening conditions. But particularly herniation could be problematic. Just axonal injury or just what is referred to as diffuse axonal injury where there is damage to fibers within the cerebral white matter. Swelling which is a result of edema or accumulation of intracellular or extracurricular fluid. As well as with severe injury, intraventricular hemorrhage; which is basically bleeding into the ventricular system. 

When talking about traumatic brain injuries, it is they are often graded on the scale of mild, to moderate, to severe. Mild traumatic brain injury is a topic of great importance given the fact that this is a condition that is basically to some degree and potentially diagnosed based on the lack of findings on conventional neuroimaging. It is a little bit more challenging to understand given that there is not – there is often not obvious findings on standard sort of conventional medical neuroimaging. 

Now, I will just – I just want to talk a little bit about mild traumatic brain injury in relation to concussion. A concussion is a term that people are fairly familiar with. But the specific definition of concussion is a complex pathophysiological process affecting the brain and induced by traumatic biomechanical forces. However, the term concussion is often used anonymously with mild traumatic brain injury. You will see those two words used synonymously in the literature, and very often. Typically what is referred to as the head injury with a temporary loss of brain function. That loss of brain function may refer to a loss a change in consciousness such as post-traumatic amnesia or some findings based on the Glasgow Coma Scale. It is really graded depending on the loss of consciousness at the time whether or not there was a loss of consciousness present or absent. The duration of changes in mental status post even. 

The symptoms of mild traumatic brain injury or concussion typically result in hours to weeks. It can be a very short scale to sub-short scale events. But a primary feature again is sort of that in terms of determining a mild traumatic brain injury, it is a lack of growth structural changes on conventional imaging; which is often used as a diagnostic criteria for mild traumatic brain injury. There is an additional category of mild traumatic brain injury that is called complicated. Where there are some findings potentially on – abnormal findings on imagings that are included in the diagnosis. 

The field of understanding mild traumatic brain injury has been very important given the strong – given the recent prevalences of this condition and associated disability particularly with military conflict. Also, given the fact that there is a known cumulative effect in multiple concussions that may have particularly long-term consequences that are not currently well understood. In addition, the repetitive exposure to a concussion in early life may have an influence in later life on potentially secondary consequences, including the increased risk for the development of neurodegenerative disease as well as dementia in late life. 

One of the difficulties in understanding  traumatic brain injury is that this is a fairly heterogenous. It can be a fairly heterogenous condition as compared to other sort of more well characterized and progressive degenerative conditions. TBI, a traumatic brain injury may be heterogenous based on the type of exposure and the force. The specifics of the force. The direction of the exposure. The time since the exposure and time course of the injury. 

Then adding to this heterogeneity is the distinction between what may be military or combat associated traumatic brain injury versus civilian traumatic brain injury. In addition to sort of blunt traumatic brain injury, there is a highly prevalent condition of combat associated blast exposure. I am just pulling out some numbers from a study by Okie and colleagues basically suggesting that 59 percent of patients who were admitted to Walter Reed or who have been exposed to a blast, and evaluated for brain injury. Fifty-nine percent of them obtained the TBI diagnosis with 56 percent of them being in the moderate to severe range; and 44 percent of them being in the mild range. Again, this is prevalent condition amongst Veterans that has been exposed to blast as part of conflicts. 

The mechanisms of blast injury may be different or are somewhat different from the source of mechanisms that we associate with, for example, civilian damage, say due to a car accident or that sort of traumatic brain injury. This is from a review by Taber and colleagues in 2006 who describe basically the mechanism that can occur as a result of blast exposure, including a direct result of the blast wave-induced changes in the atmospheric pressure, or the barotrauma; which they refer to as the primary blast injury. 

But also, a secondary damage due to objects put in motion by the blast that may result in blunt trauma; as well as people being forcibly put in motion by the blast – which is referred to as the tertiary blast injury. These sorts of injuries, all three of these can result in potential shear and stress waves to the brain and resulting in damage to the brain tissue. On the right, you basically – you can see sort of  a time course of events of experience with a blast type traumatic brain injury where sort of initially over, there is an increase in peak dynamic pressure that basically decreases as the blast wave passes with the pressure oscillation. Then, result in a second positive phase after a brief period of vacuum. It is thought that these sorts of dramatic changes in pressure are able to damage tissue in addition to the primary force – the forces of sort of blunt trauma.

In that same review, Taber and colleagues noted some of the sort of most common types of influence of these sorts of blast trauma or non-penetrating injuries. As you can see here, in this colored image basically demonstrating in the pink regions what they – what the...  Basically the diffuse axonal injury, typically which occurs sort of at the borders of the gray matter and the white matter; typically in anterior regions of the brain. The blue regions here in the front and back, refer to areas that are most common for a contusion particularly in the anterior frontal and temporal regions. Finally, subdural hemorrhage, which is most common in sort of the frontal and parietal convexities as you can see here in the purple. 

Typically, the source of damage that have been – that I just demonstrated on the prior slide is what is being assessed for with clinical imaging?  Clinical imaging, particularly computed tomography of the head is the study of choice to evaluate traumatic brain injury. Really what one is doing with CT imaging in the acute phase is basically evaluating the damage that has occurred as well as the need for a potential surgical intervention. Computed tomography can be performed with patients with deterioration for assessment of the progression of damage or injury across time. 

CT can also be used in the classification of injury based on pathophysiological mechanisms for targeted interventions. This is a figure that was presented by Saatman and colleagues looking at various types of damage that may occur as a result of traumatic brain injury as measured by computer – by CT. CT is typically performed clinically within the first 24 hours after injury. It is a form of x-ray imaging. In the CT images you would see certain types of damage such as edema, and infarction, and it is dark. Calcification, hemorrhage, bone trauma; it might show up as bright. 

The benefits of CT imaging is that it is widely available. It is very cost effective. It has very short imaging times. It can be performed with various life support hardware such as.... including implants and shrapnel, which could be a problem for other types of procedures like magnetic resonance imaging. It is considered the most appropriate for determining immediate or acute medical needs. Some of the limitations of CT are the reduced resolution. There is a limited amount of contrast or information that you can get from a CT scan. There is some degree of ionizing radiation considered moderate to high. 

There is basically a lack of imaging findings typically as I had mentioned before of CT; which is used to classify...  the mild traumatic brain injury cases. Also, people have noted that CT findings may not be correlated with outcome. However, as presented here, really if there is an effort to classify the type of injury by CT, there may be better correlations between the degree of damage and the outcome. Here are six different patients that had traumatic brain injuries. 

You can see that they have listed as an epidural hematoma on the top left. Basically a contusion and parenchymal hematoma in the center here. Diffuse axonal injury, and you can see this little blip on the top right here. subarachnoid hemorrhage and intraventricular hemorrhage on the bottom middle, sorry – I missed the subdural hematoma; the subarachnoid hemorrhage and intraventricular hemorrhage; and diffuse brain swelling on the bottom right here. 

By using a CT to better classify the specifics of the damage, it is possible that CT can be better used to correlate with secondary outcome. MRI is often also used clinically to identify sort of the acute damage of mild – of traumatic brain injury. That includes the use of T2 and FLAIR-imaging for measuring edema. It may be used to measure the degree of hemorrhage as well as microhemorrhage or small lesions using gradient echo MRI procedures. 

What I have been referring to so far is really how MRI is used – I am sorry. How imaging is used clinically for the assessment of traumatic brain injury. However, there is a whole field of research imaging which has been applied to the study of traumatic brain injury and mild traumatic brain injury. It really offers a whole different set of information than what is examined typically clinically. Basically when I distinguish clinical imaging from research imaging, I really am distinguishing the basic use of imaging for being used in clinical judgment and medical decisions versus the use of imaging to try to uncover novel information about the conditions under study; which is the research domain. 

There are a range of imaging procedures that are available. That are not typically used in the clinical setting, but may provide information for future information for diagnosing conditions, and tracking injury progression. Potentially tracking the efficacy of novel and therapeutic interventions in the case of say a clinical trial; as well as better understanding the mechanisms of injury. The different – the reason why we have such a diverse range of imaging – of research imaging procedures is because they differ in a variety of strengths and limitations; in particular we tend to focus on their spacial and temporal resolution. 

That is how detailed of an image they can create in resolution as well as for example, how detailed an image they can create in time. For example, when you are measuring things like brain activity or brain function. They also may differ in their contrast mechanisms. By contrast mechanisms I mean what you could measure based on that imaging procedure. Whereas, for example, MRI is basically – is based on contrast due to protons and water. 

Another procedure like positron emission tomography or PET can obtain contrast with and based on various aspects of protein and neurochemistry. Research imaging procedures can target various aspects of brain tissue structure, function, physiology, and chemistry. There are a number of ways, a very active field of sort of research into how you make collect  – acquire data on these different imaging technologies. Process the data and analyze the data, which provides different strengths and weaknesses for uncovering aspects of brain pathology.

The procedures you will see are typically used in what is referred to as group space comparisons. Where you take a group of individuals with a condition such as traumatic brain injury and compare them to another group of individuals such as a control population or individuals that have not been exposed to brain trauma. Typically, imaging is also used to look at how a particular type of brain and neural measure may be associated with neuropsychological findings or a clinical scale to try to uncover what types of changes may most substantially contribute to symptoms in a given condition. 

The imaging, the research imaging is really particularly – it has a particular application to the study of mild traumatic brain injury whereas I had mentioned before, sort of what I – what we referred to as conventional imaging or standard clinical imaging on CT findings may be limited. The question is can these research procedures uncover the changes in the brain that may be correlated with any sort of given clinical syndrome. There has been a significant effort. This is a very large field with a lot of work that has been done. Yet, there is definitely some. 

There is definitely work that needs to be done with regard to trying to better place the findings to date into a consistent framework. I am going to, as I had mentioned before, just show some procedures and trends as opposed to detailed information about the work to date. Just to again, give an example of how you might apply these sorts of procedures to the study of traumatic brain injury. 

 I had mentioned before, there are a variety, almost an infinite set of procedures that we can use to study the brain using research imaging. Broadly, they are broken down into structural procedures and functional procedures. But this is really a, not a perfect classification. When we talk about the structural imaging, we may be talking about more of a metric procedure. These are procedures where we are measuring the amount of tissue. For example, the volume or the thickness; or it is just basically the total amount of tissue of different brain structures. 

We may also look at abnormal tissue or measure sort of lesion or damaged tissue using procedures like T2 and FLAIR-MRI. We may be looking at some microstructural properties of brain tissues. These are procedures like diffusion tensor imaging and magnetization transfer imaging. What I mean by microstructural is that within the sort of unit of resolution, a voxel will typically in imaging either one millimeter or two millimeter tubes – some information about sort of the microstructural or the properties of the tissue within that voxel. We can also look at things like with PET imaging and positron emissions tomography, and receptor densities, and metabolic activity. We can use procedures like susceptibility weighted imaging to measure small hemorrhages in the brain. 

With regard to functional imaging, we are typically talking about the measurement of brain activity. A very common procedure for measuring brain activity is referred to as functional magnetic resonance imaging. Other procedures include electroencephalography, magneto-encephalography. Differences, for example, in those procedures is that functional magnetic resonance imaging has very good spacial resolution. You can get very clear pictures at say resolution of one to two millimeter tubes using modern technology. But at the same time, the time – the time course of that activity is very limited in that it is, you can only collect information on the order of seconds as opposed to information that you can get in milliseconds such as this sort of neural activity that you get from electroencephalography. 

A limitation of procedure like electroencephalography is that it has very limited spatial resolution. You cannot necessarily, determining where the source of the information is in electroencephalography is less resolved than, for example, what we get from magnetic – from the functional magnetic resonance imaging. With PET imaging, we can measure properties such as glucose, and metabolism, and oxygen utilization. There are also procedures like magnetic resonance spectroscopy where we can measure certain neurochemical and metabolic processes, as well as arterial spin labeling perfusion, which is an MRI procedure that allows us to measure cerebral blood flow. They are just pointing that out to demonstrate that there are a variety of different procedures that can be applied to the study of traumatic brain injury. That is just a subset of them. 

I am going to also mention that there is a very recent, and fairly comprehensive review that I would suggest people look at by Eierud and colleagues that was published in 2014. I am going to – by the way, there will be references presented at the end of the slide. All of these references will be available at the end of the slide. I am going to point out a few slides from this, a few of the findings from this study in the rest of the talk. But I think  it is... They did a really good job of sort of summarizing the literature on imaging and mild traumatic brain injuries to date. It is probably something that is good to look at. 

As you can see here on the left, they are basically highlighting the number of publications going from 1990 to 2010. You can see really this very strong uptake – uptick in publications of mild traumatic brain injury. Particularly around 2007, where you see this sort of big jump in the study of the field. With regard to imaging, they have basically plotted the publications based on imaging modality. You can see that there are basically, of a range of these imaging procedures have been applied to the study of traumatic brain injury. With certain procedures such as functional imaging, EEG, and MEG being applied to a great degree as well as in  tensor imaging. 

Diffusion tensor imaging has gotten a lot of attention in the field of mild traumatic brain injury. I will just give a little bit of background on this procedure. It is a magnetic resonance diffusion weighted. Or tensor imaging is a type of magnetic resonance imaging. It is one type of procedure that can be performed with magnetic resonance imaging. It is basically a procedure that quantifies the degree and the directionality of water diffusion in the brain. The reason why that is important is because water diffusion is basically influenced by tissue structure. For example, it is influenced. Its ability to diffuse is influenced by macro molecules, membranes. It tends to follow fiber structures in the brain. 

When you can model the diffusion data that you acquire from diffusion imaging to provide information about micros – what is referred, typically referred to as microstructural properties of the tissue. Diffusion tensor imaging is an extension of what is more standard diffusion weighted imaging; which provides information that can be used to model sort of anatomy and directionality of a structure like large fiber bundles. There are different ways of modeling the diffusion data that provide different types of what I am referring to here as contrast that is linked to different aspects of tissue property. 

Just very simply, two types of contrast that people look at are the axial versus the radial diffusivity with diffusion imaging. The axial referring to diffusion along its primary direction. How much diffusion is occurring along its primary direction?  For example, along the fibers versus how much diffusion is occurring in the perpendicular directions or across the fiber structure?  Those two types of information seem to be related to different types of pathologic processes, for example, in animal models. 

Differentiating the type of diffusion, it may be useful for differentiating pathologic processes in the brain. Diffusion is – imaging is in vivo and noninvasive. It be performed with MRI, which is a noninvasive procedure. It is thought to be potentially sensitive to diffuse axonal injury. I would refer you to this review here for more information. 

 Here is an example of the type of information that comes from diffusion imaging. On the left is something referred to as in the red, yellow; it is what is referred to as a fractional and anisotropy image. This describes the dominance of water diffusion for a particular direction. If you look where the bright yellow areas are. Those are areas where there are highly organized fiber structures such as the corpus callosum and the corticospinal tract. Areas where you see lower intensity of color are areas where the fiber structure is not as well organized. For example, where these fibers intersect the corticospinal tract and the corpus callosum. 

This is just the normal facet of anatomy. What you can do is take these images and compare, for example, at any given location what an individual looks like who is a control participant versus a patient; which might tell you something about changes in the tissue structure of the patient. As I had mentioned before, we get a variety of different types of maps from the diffusion data that can be used in these types of analysis that may provide different contrasts, types of contrast. 

On the right is what is referred to as a tensormap. These are the maps that give us information about the directionality of what diffusion in the brain. You could see here, for example. You see that the water diffuses along the corticospinal tract and the superior inferior direction in blue here. In red, we see that the water diffuses sort of in the medial to lateral direction. These tensormaps can tell us something about the specific fibers that might be effective in a given condition such as traumatic brain injury. 

I am just going to quickly present this study by Lipton and colleagues that basically use diffusion imaging to look at changes in 20 patients that were diagnosed with mild traumatic brain injury to be interesting. An interesting point about this study is that they were and looked at individuals within two weeks of injury. They had mild traumatic brain injuries due to motor vehicle accidents or falls. There was any injury on conventional imaging was an exclusion factor. 

They used a whole brain analysis approach to examine the diffusion data, which basically puts all of the individual subjects into a common brain space. Then performs statistics at each location in the brain. What they noted was that there were clusters of lower tissue integrity in this frontal white matter where they had lower anisotropy and higher diffusivity, two measures from the diffusion data in the patients compared to the individuals without TBI. That these changes in the diffusion parameters were also correlated with their executive functions.

In contrast, for example, this study by Levin and colleagues. It is a very different study. I just want to point out the challenges to this kind of work; which is that they looked at 37 Veterans and service members. The post injury interval was much longer than the prior study, which is typical for these kinds of studies and service members. They used the standard region of interest and other procedures for doing their analysis. 

What they found was that there were not. They did not see big group differences in the blasts and mild traumatic brain injury group compared to their controlled. Although, they did see correlations of the diffusion variables with symptom measures. I am sorry, with cognitive measures, and neuropsychological measures. They concluded that the correlations of TBI variables and diffusion variables with symptom measures were nonsignificant and inconsistent. 

Again, it is just a...  These are two very different studies that use diffusion imaging to study traumatic brain injury and come to different results, of course, that would be expected. But it just shows you sort of the range of different types of studies that have contributed to the literature to try to understand traumatic brain injury. I will just note that in the ... the review that I had mentioned. They performed the metanalysis of diffusion findings and really localized that there are some hotspots basically where abnormalities might be most expected. In particular, they noted an anterior to posterior potential gradient where potentially a most likely effect will be found in sort of the frontal white matter. 

But also, that there is a complicated diffusion time course such that the anisotropy may be increased in the acute phases and decreased in the chronic phases as has been noted in prior work. Animal models demonstrate that there is definitely a time course to the diffusion changes whereas the changes in diffusion signal may occur hours, to weeks, or longer after injury. It is something to keep in mind when performing diffusion studies. Sort of the time since injury can be an important factor. 

I will very briefly mention functional magnetic resonance imaging and functional imaging and magnetic resonance imaging is a procedure used to measure brain activity. The contrast is based on a blood flow response. It is not measuring neural activity directly. It is measuring a secondary response of the activity to blood flow. The signal can be measured in response to a cognitive or a behavioral stimulus. What is referred to as the hemodynamic response. Or, it can be used to measure net worth in the resting state. On the right here, you just see an example of a functional map that was produced from a task where somebody was just tapping their finger in the scanner, and, of course, activating where we would expect and showing that blood flow response in motor cortex.

Here is a study by Matthews and colleagues demonstrating functional imaging used to study individuals that were exposed to blasts, and mild traumatic brain injuries. But basically differed in their symptoms of depression. They had these individuals undergo an emotional face matching task using functional magnetic resonance imaging where they were presented images of a variety of faces, including fearful faces. They were interested to see whether or not individuals with depression shows differential activation to fearful faces. 

What they found was that the individuals with depression had greater amygdala activity during fearful, the fear matching trials; and lower activity and emotional control structures such as the dorsolateral prefrontal cortex. You can see an example of their results here on the top right showing that increased amygdala activity in response in particular to the fearful faces compared to other faces as well as the control stimuli. 

They also noted that there...  They also performed diffusion tensor imaging and noted that lower diffusion measures in the superior longitudinal fasciculus were found in the depressed group. Those changes where those measures of – their diffusion measures were associated with depression symptoms. Again, showing here that certain co-morbid conditions such as depression may have an important influence in the study of TBI. It needs to be considered in these personal studies. 

I will just leave this for you guys to look at, the direct reference. But basically, the metanalysis also demonstrated findings that seemed to be somewhat consistent for functional imaging with certain regions consistently more active in individuals with mild traumatic brain injury, particularly anterior regions and other regions tending to be and showing lower activity in the mouth in mTBI individuals including the more posterior regions. You should note that doing a metanalysis of these sorts of findings is very challenging given that there are a variety of different paradigms that people use for their functional imaging. 

Positron emissions tomography is another type of imaging. This is  a non-MRI procedure. This is a nuclear medicine technique; which is based in the detection of gamma rays that are emitted by a radionuclide. That is typically what is referred to as a PET ligands, which is a biologically active molecule. That is basically injected into the body. It can be used to measure a variety of different physiological, and... and chemical properties, including receptor concentrations and metabolic activity, blood flow, inflammation. It is a very - it is a nice aspect of PET is that it is very diverse in the types of contrast that you can get from it. However, it is lower in its spacial resolution than a procedure like structural magnetic resonance.

This is just an example of the application of PET imaging to the study of mild traumatic brain injury. This is a study that Peskind and colleagues where they compared 12 Iraq war Veterans with one or more blast exposure and a diagnosis of mild traumatic brain injury and persistent post concussion syndrome to 12 cognitively normal community volunteers using fludeoxyglucose test. This is a measure of brain metabolism. 

They also did a detailed neuropsychological and clinical assessment. What they found was that the individuals of mild traumatic brain injury had a decreased metabolic rate of glucose in the cerebellum, vermin, and pons in the medial temporal lobe as you can see here in sort of the bright colored on this image here to the right.

Our center here in Boston is referred to as TRACTS, the Translational Research Center for Traumatic Brain Injury and Stress Disorders. This is a rehabilitation, research, and development center of excellence under the direction of Gina McGlinchey, at Boston VA with the goal of understanding the complex changes that occur in the brain and thinking that result from traumatic brain injury and post traumatic stress disorder. Currently enrolling Veterans from Operation Enduring Freedom and Operation Iraqi Freedom. 

What I will...  I am going to show you an example from our study basically looking at morphometry. This is, for example, a measurement of cortical thickness. In brief, you can see how we make these computerized models of the brain here on the left. You can see on this image, we basically create these surfaces that differentiate the gray matter from the white matter, and the gray matter from the cerebral spinal fluid; which allows us to basically measure the thickness of the cortex as a measure of the integrity of the neural tissue. 

These procedures are meant to match what has been done, for example, in postmortem tissue or neuropathologically to measure degenerative changes although with imaging. We do not. We do not have an interpretation necessarily other than that. That we can measure changes in the actual structure. We cannot say necessarily what those changes in structure  new fields. 

This is a study by Lindemer and colleagues that basically looked at the association between cortical thickness and stress – PTSD symptoms measured by the Clinician-Administered PTSD Scale or CAPS. What was done here was basically an examination of CAPS scores and cortical thickness. You can see on the top right, regions where there was an association between cortical thickness and CAPS scores. 

What was important was that there was a strong association between thickness and current symptoms. However, that association was even stronger when a lifetime measure of PTSD was considered, or a lifetime CAPS score, which was referred to as a cumulative lifetime burden. Basically demonstrating that when we consider an individual, that the current symptoms might not tell the full story about what is going on neurally. 

Additionally, we found that there was an additional influence of a mild traumatic brain injury such that if an individual had experienced a mild traumatic brain injury that the associations in certain regions between symptoms, CAPS score, and cortical thickness was stronger. I just presented that. Again, an example of the complexity of doing these kinds of studies. As I have been mentioning, the study of traumatic brain injury is difficult because this is a potentially heterogeneous condition. 

I will just point out here a study by Davenport and colleagues, which is – it has been performed in other studies as well; basically demonstrating the need for considering each individual as opposed to grouping people into sort of these group based analysis. What they did was they basically created an abnormality score for each individual, which did not basic – did not make the assumption that everybody was spatially similar in the changes in their brain tissue. What you can see here is that individuals with multiple blasts had greater abnormalities than individuals that were exposed to a single blast versus individuals with no exposure to a blast. 

What is important about this is that they did not find significant results when they only – when they used standard measures of sort of group based comparisons. Again, demonstrating that this is a heterogenous condition that really needs to be considered, and really be potentially, it may require individualized measures to understand what types of damage may contribute to an individual's particular symptoms. I will just... These are sort of the caveats that I have gone – that I have mentioned throughout the talk. 

But since we are running out of time, I will just quickly mention that there are a number of caveats for these studies, including the study participants, the type of exposure, and how the TBI was diagnosed. The times since the injury, and the mechanism of injury. Any binding in any particular of group of individuals may not be generalizable for the overall population of individuals with traumatic brain injury. There are also a number of caveats to the imaging. They are both technical and biological reasons that the imaging measures can be confounded or difficult to interpret. Given that the large of number of tests that are performed with imaging, there is very much a possibility of statistical error in studies. Small participant samples can be difficult and lead to spurious results given the number of factors that one has to consider in these sorts of studies. 

I will mention that the meta-analysis was a very important effort or categorizing the various types of imaging that has been done in these studies. Sort of the findings were any sort of consensus to date. I will note that the authors also mentioned that this is – that was challenging. That basically the studies are and still require more work to determine things like the functional MRI results as well as sort of these time course results that we may see with diffusion imaging. 

I would like to end optimistically and say that there is a lot that's been said and that has been gained from the application of neuroimaging to date. These procedures provide a window into brain pathology. The procedures facilitate the measurement of a variety of aspects of brain structure, function, and physiology. We do have the potential to uncover mechanisms of traumatic brain injury associated, cognitive, behavioral, and psychiatric conditions particularly conditions related to mild traumatic brain injury that may not show obvious imaging findings on conventional imaging. That development and imaging goes  on every day. Advances in novel acquisition and analysis procedures as well as the participant and characterization on an image integration is really going to be necessary. It is really going to propel the field I the years to come. 

I would like to just acknowledge the VA, TRACTS, the Neuroimaging Research Center here, and my close colleagues, Drs. Keane, McGlinchey, and Milberg. Encourage you, if you have any questions to go ahead and e-mail me. As I have mentioned, there are references all over the studies that I talked about here in the slides. I know I went through everything very quickly. But hopefully you can go back and kind of look at anything that is of interest. Hopefully it gives at least an overview of some of the procedures that are used in this kind of work.

*Moderator:*Thank you very much. We actually do have some time to take questions right now. I know that a lot of our attendees joined us after the top of the hour. To submit your questions or comments, please use that Q&A box that is located in the upper right-hand corner of your screen. Just simply type it into the lower box and press the speech bubble. We will be able to get to those. 

While we wait for any questions to come in, I just want to take a moment and let you all know that we do have an entire series dedicated to TBI. We do also have a couple of upcoming sessions. The first one that is going to be coming up is. Sorry, let me pull up my date book real quick. Alright, the first one we have coming up next is on, next month on the 24th at 2:00 p.m. That is going to be presented by Dawn Schiehser. That is on Diagnosis, Mechanism, and Management of Fatigue in Mild Traumatic Brain Injury. You can go to our online registration catalog and sign up for that. 

I am still waiting for any questions. Please feel free to take this opportunity. While we wait for those to come in, I am also going to put up our feedback form. Please do share your opinions with us as it is your opinions that help guide which sessions we have presented for us. Here we go. I do have the Q&A box. It is right there in the center of the screen, if any of you come in, as I mentioned earlier when we asked you what your role is. 

We do have the more extensive list now located in the upper right-hand corner of your screen. Just let me move the Q&A box a little more. Feel free to specify there. It looks like we are getting a lot of feedback, which is great. No questions have come in yet. David, while we are getting the feedback, do you have any concluding comments you would like give?

*Dr. Salat:*I guess, I – again, I went through that quickly. I know that there was a lot of information in there. I would encourage people to look at the references. I do think there are some very good reviews out there in the literature that I think would be very beneficial to people if they have not. If they are not familiar with this field. Because there is a lot of... There is a good deal of good work that has been done. Trying to – really, we are at a point where we need to figure out how we put it together. How these studies are going to be done going forward. Taking the information that we have already acquired, which is again a good deal of it. Understand how we are going to be able to do these studies going forward. It may have very important implications for how one designs their own studies in the future, including for example, how they are going to characterize their participants for the time since injuries, et cetera. All of these various factors that may be related to whether or not we can actually see our results in an individual with mild traumatic brain injury.

*Moderator:*Thank you. We do have some comments that have come in, several appreciative attendees are saying excellent presentation. Thank you so much. One person is wondering if this presentation will be accessible later. The answer is yes. We have recorded it. You will receive a followup e-mail two days from now that has a link leading directly to that recording. You can feel free to pass it along to anybody. Those, all of our sessions are stored in our online archive catalog; which is available 24/7. 

Yes. You will receive a followup e-mail and also, the handouts will be available. We do have a question. There seems to be a current push to find biomarkers including imaging to differentiate TBI from PTSD. Considering the heterogeneity of both conditions individually, and greater heterogeneity when combined, is differentiation a meaningful goal for the individual clinical case and for forensic uses?

*Dr. Salat:*I think that is an excellent question. It is probably going to be a better question for a clinician. That basically is going to be using – is going to be, and would be using that information in practice. What I can say is that from an imaging perspective and from neurobiological perspective, I think it is important to try to differentiate these conditions. Now, one – just keep in mind, we are either...  When we are talking about differentiating, we are talking about – we are talking about one condition, which is an exposure and another condition which is a syndrome or a  result of some type of exposure. In terms of the way that I might think about this with imaging is that each of those factors may be influencing the brain in different ways. In trying to understand them, we want to know how they may be differentially influencing the brain. The difficulty, of course, is that it is... 

First of all, they are highly co-morbid conditions meaning that it is really difficult to get certain samples; for example, that have had a traumatic brain injury that do not have some form of PTSD. When you do, it is complicated with regard to the fact that how basically our procedures for detailing the fine details of the symptoms of each on individually. I think that by – and this is, I guess a personal opinion. But I think that by getting as much information as we can. Of course, in as large a sample as we can, we will be able to pull apart sort of something that might be related to specifically to physical trauma versus something that might be related to psychological trauma. They might have their individual targets for a therapeutic intervention.

*Moderator:*Thank you for that response. Well, that is the final pending question. We have reached the top of the hour. At this time I would like thank you very much for presenting for us. We do appreciate you lending your expertise to the field and for also making yourself available for any followup e-mail questions. 

I also want to thank our attendees for joining us. Once again, please look for future and separate sessions that you may be interested in. I will be leaving this feedback survey up for a good while. Feel free to take your time responding to it. Once again, thank you so much, David, we really appreciate it. 

*Dr. Salat:*Thank you. Thanks for giving me the time.

*Moderator:*Any time, have a wonderful day, everybody.

*Dr. Salat:*Bye-bye.

[END OF TAPE] 

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