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Ramesh Raghupathi on animal models of traumatic brain injury

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Ramesh Raghupathi is a professor in the Department of Neurobiology & Anatomy at Drexel University College of Medicine (PA, USA). We talked to Professor Raghupathi about his work in traumatic brain injury (TBI), investigating cell death and plasticity in a range of developed animal models of TBI.

Can you tell us a little about your career to date and how you came to the field of TBI?

I started working in TBI research straight after leaving graduate school in my postdoctoral fellowship with a research group that had already established a couple of different animal models of TBI. My background is more as a biochemist and as a molecular biologist and at the time the field of TBI was starting to look at cellular and molecular mechanisms underlying some of the neuronal changes that lead to cell death, particularly in moderate to severe TBI. These types of TBI were the primary focus of a lot of the TBI research back in the early 90’s, as the main goal was to develop an acute treatment for patients who had been involved in motor vehicle accidents, falls or assaults.

Over the years my research program has morphed into developing models for pediatric TBI such as nonaccidental, abusive head trauma, which has also been understudied from a research perspective. When I first entered this strain of research it was becoming clear that infants with TBI weren’t necessarily following the dogma that existed at that time which dictated that the developing brain is more likely to recover from an injury due to its greater level of plasticity. This is true for certain ages but not really for children <3 years old. Because of this, my lab started to develop models of pediatric TBI with the underlying idea that the developing brain won’t respond to a TBI in the same way as a mature brain. These models are needed if you want to come up with strategies that will focus on treating the developing brain. The ‘age factor’ therefore started to play a very significant role in the kind of research that we did.

The other change that happened is that we realized that while moderate to severe TBI is still a fairly large problem, a bigger problem, just in terms of numbers of people, is mild TBI (mTBI)– approximately 75–80% of all TBIs annually are classified as mild, with concussion being a part of this. This need for research into mTBI was also further highlighted by the fact that the military was facing significant problems with mTBI as a consequence of exposure to improvised explosive devices (IEDs). On top of this, mTBI was hard to diagnose compared to moderate and severe TBI and soldiers were covering up their problems because they wanted to stay on the battle front. In the 2000s the significance of the problem of mTBI in the military started to be recognized, at least in the USA, being linked to some extent with psychological problems experienced by returning soldiers.

Since then there’s been a lot of attention given to mTBI, particularly concussion, in part because of the issues related to the military, but also due to the links with contact sports. All of these things essentially began to highlight the fact that mTBI, both single and repetitive, was an issue that needed to be addressed at a basic research level.

This led me to develop more animal models, in this case for mTBI, which we have been doing for a few years now. My original thinking when I was working with moderate to severe TBI was that there was a linear response of the brain to injury severity, meaning that mTBI was just a milder version of what was happening in moderate and severe TBI, but then very quickly we started to get results which seemed to suggest quite the opposite to this. We saw that mTBI is essentially a disease in itself and that some of the changes that were happening in the mild injured brain were not necessarily visible in the moderately to severely injured brain. From a treatment standpoint and from a patient management standpoint this means mTBI could require very different strategies to those used for moderate or severe brain injury patients.

What are the pathological differences within the brains of patients with mild or severe brain injury?

The biggest difference is that in a severely injured brain there’s overt physical brain damage, much like you see in a stroke; cell death, necrosis, inflammation, lesions, skull fractures. Importantly too is the fact that it’s very unlikely that it is an isolated head injury. Usually there is other systemic damage. As all of the body’s systems interact with each other this impacts brain function in different ways, in addition to the fact that the brain is also injured. In contrast mild brain injuries are typically limited to just the brain.

Another difference is that in mild brain injury, particularly concussion, it’s really a diagnosis of exclusion – the CAT scans and MRIs are normal, there’s no skull fractures, there’s no bleeding, there’s no physical damage to the brain but the patient still complains of neurologic problems such as headaches, nausea, dizziness and cognitive problems. In this case there’s a diagnosis of concussion as opposed to moderate or severe injury. These symptoms suggest that there may be microstructural changes to the brain involving neuronal circuitry and neurochemistry that are not visible, even in some of the more sensitive MRI techniques.

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The opinions expressed in this interview are those of the interviewee and do not necessarily reflect those of Neurology Central or Future Science Group.

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