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Development of Diffusion Tensor Imaging (DTI) Phantoms to Enhance the Diagnosis of Moderate Traumatic Brain Injury (TBI)


OBJECTIVE: Traumatic Brain Injury (TBI) is one of the hallmark injuries of the current conflicts in Iraq and Afghanistan. The primary source of these injuries is exposure to blast from Improvised Explosive Devices (IEDs). TBIs have a wide spectrum of sequelae associated with them. While severe TBIs are rapidly identifiable (many are skull penetrating), mild and moderate TBIs are much more difficult to detect and diagnose. Indeed, much of military medical research is devoted towards understanding these subtle injuries. Mild and moderate and TBIs are suspected in Post Traumatic Stress Disorder, seizures and even in Alzheimer"s disease and Parkinsonism. Diffusion Tensor Imaging is a subset of Magnetic Resonance Imaging (MRI) technology, which many Radiologists, Medical Physicists and Clinicians hypothesize could be a key tool towards unraveling the pathological nature of mild and moderate TBIs. One of the major challenges precluding this technique from wider acceptance as a tool for TBI detection and diagnosis is the lack of data acquisition and instrumentation standards between manufacturers and researchers. Standards or tools that could be used to calibrate measurements between operators and instrumentation would greatly increase our knowledge of TBIs. It would enable more direct comparisons between datasets acquired at differing medical institutions. It would also help to standardize long-term instrument performance at a given institution. This would reduce the amount of noise within single datasets and empower their standalone statistical significance. This topic seeks Research, Development, Test and Evaluation funds to develop MRI phantoms for DTI in order to provide a means of calibrating MRI scanner performance across multiple research facilities. This would greatly enable the meaningful analysis and sharing of complex TBI patient datasets. As a result, it would great help move the field towards imaging biomarkers for these injuries. DESCRIPTION: The human brain is perhaps the most complex information management and processing system ever created. It is also arguably one of the most fragile. Despite centuries of study, our understanding of how the structure of the brain is altered in response to the pathologies of disease and injury is still in its infancy. Traumatic Brain Injury (TBI) research is a high priority for today"s military since these injuries are often seen currently seen in theater. Many of these are the result of exposure to Improvised Explosive Devices (IEDs). High performance medical imaging techniques have enabled our understanding of diseases and pathologies such as stroke, multiple sclerosis and Parkinsonism (1-3). Techniques such as Computed Tomography (CT) and MRI also have been used to understand severe TBIs (4); however it has become clear that these conventional anatomical imaging methods in their current forms offer little towards understanding the full nature of mild and moderate TBIs. One novel technique currently under evaluation for its potential to evaluate mild and moderate TBIs is Diffusion Tensor Imaging (DTI), a subset of MRI. In DTI, the alterations in the microenvironments in brain, such as in neuronal fibers can be detected by changes in the diffusion properties of water. While Levin et al. (6) present evidence that DTI could be of limited use for mild and moderate TBIs, several other reports show that DTI offers the potential to identify imaging biomarkers of these injuries (7-8). A recently hosted DTI workshop identified some of the major bottlenecks towards improving the sensitivity and specificity of DTI (9). Improving the sensitivity and specificity was identified as a key component towards addressing the efficacy of this technique to identify injuries associated with mild and moderate TBIs. One strategy towards boosting the sensitivity and specificity of this technique is to acquire DTI-specific phantoms, which would be used to standardized instrumentation and acquisition parameters. This standardization is envisioned not only to be used across institutions; but as an internal standard across large patient cohorts acquired at a single site. The latter point is very important since dataset homogeneity is required to enhance any potential signal associated with very subtle differences in brain anatomy that may be attributable to mild or moderate TBI. MR scanner performance is well known to require occasional calibration. Secondly, standardization across multiple instruments and facilities will allow for sharing of datasets. This, in turn, would greatly increase the statistical power of these measurements. This topic therefore seeks the development of DTI phantoms for performance standardization of MR scanners. The ability to calibrate the performance of MR scanners to specifically perform DTI undoubtedly will reduce systematic errors associated with the acquisition of DTI datasets. PHASE I: The intent of this effort is to develop DTI phantoms that will mimic axonal integrity and water/dye diffusion through axons. Preliminary validation is expected at the end of Phase I. A validation plan should be presented as part of the proposal. The primary emphasis of the validation should pertain to the data acquisition chain in DTI rather than post processing. PHASE II: The selected proposal will outline a plan by which the prototype will be fully validated on a minimum of two different MRI scanners made by different manufacturers. The scanners used must be clinical scanners with data acquisition packages that are cleared for routine use by the FDA or local IRB. It is expected that as part of the validation process, the initial prototype will be refined. The validation plan should include a robust discussion of how improvements in data acquisition will be quantified. The end product of this development cycle is expected to generate a reproducible, complete phantom for DTI image acquisition standardization. The finished phantom prototype will be tested for a series of three reproductions of the prototype phantom. The selected proposal will outline a plan by which quality assurance for this low-scale initial production can be accomplished. It is expected that this plan will be similar to the original validation for the early prototype and will use multiple scanners of different manufacturer makes. PHASE III DUAL USE APPLICATIONS: In addition to improving our knowledge of combat-induced imaging biomarkers for mild and moderate TBI, other diseases such as Multiple Sclerosis and Parkinsonism would also benefit from the use of these phantoms. Standardizing the performance of MRI scanners for DTI could reveal subtle imaging-related clues regarding the onset of these diseases at their earliest stages. Phase III of this solicitation would therefore consider how these devices could advance our knowledge of imaging biomarkers for these diseases in a clinical setting. Other neuropathological diseases would be considered as well. The ultimate goal for this phase will be to validate a DTI imaging protocol for any proposed neurological or neuropathological insult that the offeror wishes to study outside of mild and moderate TBI. REFERENCES: (1) Ramli N, Rahmat K, Azmi K, Chong HT; The past, present and future of imaging in multiple sclerosis; J Clin Neurosci. 2010 Apr;17(4):422-7. Epub 2010 Feb 18. (2) Seppi K, Poewe W; Brain magnetic resonance imaging techniques in the diagnosis of parkinsonian syndromes. Neuroimaging Clin N Am. 2010 Feb;20(1):29-55. (3) Wardlaw JM; Neuroimaging in acute ischaemic stroke: insights into unanswered questions of pathophysiology; J Intern Med. 2010 Feb;267(2):172-90. (4) Jagoda AS, Bazarian JJ, Bruns JJ Jr, Cantrill SV, Gean AD, Howard PK, Ghajar J, Riggio S, Wright DW, Wears RL, Bakshy A, Burgess P, Wald MM, Whitson RR; Clinical policy: neuroimaging and decisionmaking in adult mild traumatic brain injury in the acute setting. J Emerg Nurs. 2009 Apr;35(2):e5-40. (5) Belanger HG, Vanderploeg RD, Curtiss G, Warden DL; Recent neuroimaging techniques in mild traumatic brain injury. J Neuropsychiatry Clin Neurosci. 2007 Winter;19(1):5-20. (6) Levin HS, Wilde E, Troyanskaya M, Petersen NJ, Scheibel R, Newsome M, Radaideh M, Wu T, Yallampalli R, Chu Z, Li X; Diffusion tensor imaging of mild to moderate blast-related traumatic brain injury and its sequelae. J Neurotrauma. 2010 Apr;27(4):683-94. (7) Hartikainen KM, Waljas M, Isoviita T, Dastidar P, Liimatainen S, Solbakk AK, Ogawa KH, Soimakallio S, Ylinen A, Ohman J; Persistent symptoms in mild to moderate traumatic brain injury associated with executive dysfunction. J Clin Exp Neuropsychol. 2010 Mar 1:1-8. (8) Kumar R, Gupta RK, Husain M, Chaudhry C, Srivastava A, Saksena S, Rathore RK; Comparative evaluation of corpus callosum DTI metrics in acute mild and moderate traumatic brain injury: its correlation with neuropsychometric tests. Brain Inj. 2009 Jul;23(7):675-85. (9) Diffusion MRI for TBI Roadmap Development Workshop. June 2-3, 2010, Omni Hotel, Chicago.
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