Theodore P Trouard

Interests

Teaching

Medical Imaging, Introduction to Engineering Design

Research

Magnetic Resonance Imaging (MRI), neuroimaging, focused ultrasound for drug delivery, Alzheimer's Disease, Parkinson's Disease, Niemann-Pick Type C Disease

Courses

Scholarly Contributions

Journals/Publications

• Lopez, F. V., O'Shea, A., Huo, Z., DeKosky, S. T., Trouard, T. P., Alexander, G. E., Woods, A. J., & Bowers, D. (2024). Frontal-temporal regional differences in brain energy metabolism and mitochondrial function using P MRS in older adults. GeroScience.
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  Aging is a major risk for cognitive decline and transition to dementia. One well-known age-related change involves decreased brain efficiency and energy production, mediated in part by changes in mitochondrial function. Damaged or dysfunctional mitochondria have been implicated in the pathogenesis of age-related neurodegenerative conditions like Alzheimer's disease (AD). The aim of the current study was to investigate mitochondrial function over frontal and temporal regions in a sample of 70 cognitively normal older adults with subjective memory complaints and a first-degree family history of AD. We hypothesized cerebral mitochondrial function and energy metabolism would be greater in temporal as compared to frontal regions based on the high energy consumption in the temporal lobes (i.e., hippocampus). To test this hypothesis, we used phosphorous (P) magnetic resonance spectroscopy (MRS) which is a non-invasive and powerful method for investigating in vivo mitochondrial function via high energy phosphates and phospholipid metabolism ratios. We used a single voxel method (left temporal and bilateral prefrontal) to achieve optimal sensitivity. Results of separate repeated measures analyses of variance showed P MRS ratios of static energy, energy reserve, energy consumption, energy demand, and phospholipid membrane metabolism were greater in the left temporal than bilateral prefrontal voxels. Our findings that all P MRS ratios were greater in temporal than bifrontal regions support our hypothesis. Future studies are needed to determine whether findings are related to cognition in older adults.
• Succar, B., Chou, Y. H., Hsu, C. H., Rapcsak, S., Trouard, T., & Zhou, W. (2024). Carotid Revascularization is Associated with Improved Mood in Patients with Advanced Carotid Disease. Annals of surgery.
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  To investigate the impact of carotid interventions on patients' mental condition in patients with carotid stenosis.
• Nolin, S. A., Cowart, H., Merritt, S., McInerney, K., Bharadwaj, P. K., Franchetti, M. K., Raichlen, D. A., Jessup, C. J., Hishaw, G. A., Van Etten, E. J., Trouard, T. P., Geldmacher, D. S., Wadley, V. G., Porges, E. S., Woods, A. J., Cohen, R. A., Levin, B. E., Rundek, T., Alexander, G. E., & Visscher, K. M. (2023). Validity of the NIH toolbox cognitive battery in a healthy oldest-old 85+ sample. Journal of the International Neuropsychological Society : JINS, 29(6), 605-614.
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  To evaluate the construct validity of the NIH Toolbox Cognitive Battery (NIH TB-CB) in the healthy oldest-old (85+ years old).
• Song, H., Bharadwaj, P. K., Raichlen, D. A., Habeck, C. G., Huentelman, M. J., Hishaw, G. A., Trouard, T. P., & Alexander, G. E. (2023). Association of homocysteine-related subcortical brain atrophy with white matter lesion volume and cognition in healthy aging. Neurobiology of aging, 121, 129-138.
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  Homocysteine (Hcy) is a vascular risk factor associated with cognitive impairment and cerebrovascular disease but has also been implicated in Alzheimer's disease (AD). Using multivariate Scaled Subprofile Model (SSM) analysis, we sought to identify a network pattern in structural neuroimaging reflecting the regionally distributed association of plasma Hcy with subcortical gray matter (SGM) volumes and its relation to other health risk factors and cognition in 160 healthy older adults, ages 50-89. We identified an SSM Hcy-SGM pattern that was characterized by bilateral hippocampal and nucleus accumbens volume reductions with relative volume increases in bilateral caudate, pallidum, and putamen. Greater Hcy-SGM pattern expression was associated with greater white matter hyperintensity (WMH) volume, older age, and male sex, but not with other vascular and AD-related risk factors. Mediation analyses revealed that age predicted WMH volume, which predicted Hcy-SGM pattern expression, which, in turn, predicted cognitive processing speed performance. These findings suggest that the multivariate SSM Hcy-SGM pattern may be indicative of cognitive aging, reflecting a potential link between vascular health and cognitive dysfunction in healthy older adults.
• Succar, B., Chou, Y. H., Hsu, C. H., Rapcsak, S., Trouard, T., & Zhou, W. (2023). Cognitive effects of carotid revascularization in octogenarians. Surgery, 174(4), 1078-1082.
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  Cognitive impairment is the epitome of cerebrovascular diseases, causing a significant economic burden on our health care system. Growing evidence has indicated the benefits of carotid interventions in patients with severe carotid atherosclerosis. However, the neurocognitive outcome of carotid revascularization in octogenarians is not clearly understood. We aim to evaluate postintervention cognitive changes in seniors older than 80 years.
• Molugu, T. R., Thurmond, R. L., Alam, T. M., Trouard, T. P., & Brown, M. F. (2022). Phospholipid headgroups govern area per lipid and emergent elastic properties of bilayers. Biophysical journal, 121(21), 4205-4220.
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  Phospholipid bilayers are liquid-crystalline materials whose intermolecular interactions at mesoscopic length scales have key roles in the emergence of membrane physical properties. Here we investigated the combined effects of phospholipid polar headgroups and acyl chains on biophysical functions of membranes with solid-state H NMR spectroscopy. We compared the structural and dynamic properties of phosphatidylethanolamine and phosphatidylcholine with perdeuterated acyl chains in the solid-ordered (s) and liquid-disordered (l) phases. Our analysis of spectral lineshapes of 1,2-diperdeuteriopalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE-d) and 1,2-diperdeuteriopalmitoyl-sn-glycero-3-phosphocholine (DPPC-d) in the s (gel) phase indicated an all-trans rotating chain structure for both lipids. Greater segmental order parameters (S) were observed in the l (liquid-crystalline) phase for DPPE-d than for DPPC-d membranes, while their mixtures had intermediate values irrespective of the deuterated lipid type. Our results suggest the S profiles of the acyl chains are governed by methylation of the headgroups and are averaged over the entire system. Variations in the acyl chain molecular dynamics were further investigated by spin-lattice (R) and quadrupolar-order relaxation (R) measurements. The two acyl-perdeuterated lipids showed distinct differences in relaxation behavior as a function of the order parameter. The R rates had a square-law dependence on S, implying collective mesoscopic dynamics, with a higher bending rigidity for DPPE-d than for DPPC-d lipids. Remodeling of lipid average and dynamic properties by methylation of the headgroups thus provides a mechanism to control the actions of peptides and proteins in biomembranes.
• Zhou, W., Succar, B., Murphy, D. P., Ashouri, Y., Chou, Y. H., Hsu, C. H., Rapcsak, S., & Trouard, T. (2022). Carotid Intervention Improves Cognitive Function in Patients With Severe Atherosclerotic Carotid Disease. Annals of surgery, 276(3), 539-544.
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  Carotid revascularization procedures are effective in stroke prevention in appropriately selected patients. We sought to understand the effects of the carotid intervention on cognitive function in a well-defined cohort of prospectively recruited patients.
• Chen, Z., Chen, L., Shirakawa, M., Liu, W., Ortega, D., Chen, J., Balu, N., Trouard, T., Hatsukami, T. S., Zhou, W., & Yuan, C. (2021). Corrigendum to "Intracranial vascular feature changes in time of flight MR angiography in patients undergoing carotid revascularization surgery" [Magn. Reson. Imaging, 75, Jan 2021, 45-50]. Magnetic resonance imaging.
• Chen, Z., Chen, L., Shirakawa, M., Liu, W., Ortega, D., Chen, J., Balu, N., Trouard, T., Hatsukami, T. S., Zhou, W., & Yuan, C. (2021). Intracranial vascular feature changes in time of flight MR angiography in patients undergoing carotid revascularization surgery. Magnetic resonance imaging, 75, 45-50.
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  To characterize the intracranial vascular features extracted from time of flight (TOF) images and their changes from baseline to follow-up in patients undergoing carotid revascularization, using arterial spin labeling (ASL) cerebral blood flow (CBF) measurement as a reference.
• Van Etten, E. J., Bharadwaj, P. K., Hishaw, G. A., Huentelman, M. J., Trouard, T. P., Grilli, M. D., & Alexander, G. E. (2021). Influence of regional white matter hyperintensity volume and apolipoprotein E ε4 status on hippocampal volume in healthy older adults. Hippocampus, 31(5), 469-480.
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  While total white matter hyperintensity (WMH) volume on magnetic resonance imaging (MRI) has been associated with hippocampal atrophy, less is known about how the regional distribution of WMH volume may differentially affect the hippocampus in healthy aging. Additionally, apolipoprotein E (APOE) ε4 carriers may be at an increased risk for greater WMH volumes and hippocampal atrophy in aging. The present study sought to investigate whether regional WMH volume mediates the relationship between age and hippocampal volume and if this association is moderated by APOE ε4 status in a group of 190 cognitively healthy adults (APOE ε4 status [carrier/non-carrier] = 59/131), ages 50-89. Analyses revealed that temporal lobe WMH volume significantly mediated the relationship between age and average bilateral hippocampal volume, and this effect was moderated by APOE ε4 status (-0.020 (SE = 0.009), 95% CI, [-0.039, -0.003]). APOE ε4 carriers, but not non-carriers, showed negative indirect effects of age on hippocampal volume through temporal lobe WMH volume (APOE ε4 carriers: -0.016 (SE = 0.007), 95% CI, [-0.030, -0.003]; APOE ε4 non-carriers: .005 (SE = 0.006), 95% CI, [-0.006, 0.017]). These findings remained significant after additionally adjusting for sex, years of education, hypertension status and duration, cholesterol status, diabetes status, Body Mass Index, history of smoking, and the Wechsler Adult Intelligence Scale-IV Full Scale IQ. There were no significant moderated mediation effects for frontal, parietal, and occipital lobe WMH volumes, with or without covariates. Our findings indicate that in cognitively healthy older adults, elevated WMH volume regionally localized to the temporal lobes in APOE ε4 carriers is associated with reduced hippocampal volume, suggesting greater vulnerability to brain aging and the risk for Alzheimer's disease.
• Alexander, G. E., Lin, L., Yoshimaru, E. S., Bharadwaj, P. K., Bergfield, K. L., Hoang, L. T., Chawla, M. K., Chen, K., Moeller, J. R., Barnes, C. A., & Trouard, T. P. (2020). Age-Related Regional Network Covariance of Magnetic Resonance Imaging Gray Matter in the Rat. Frontiers in aging neuroscience, 12, 267.
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  Healthy human aging has been associated with brain atrophy in prefrontal and selective temporal regions, but reductions in other brain areas have been observed. We previously found regional covariance patterns of gray matter with magnetic resonance imaging (MRI) in healthy humans and rhesus macaques, using multivariate network Scaled Subprofile Model (SSM) analysis and voxel-based morphometry (VBM), supporting aging effects including in prefrontal and temporal cortices. This approach has yet to be applied to neuroimaging in rodent models of aging. We investigated 7.0T MRI gray matter covariance in 10 young and 10 aged adult male Fischer 344 rats to identify, using SSM VBM, the age-related regional network gray matter covariance pattern in the rodent. SSM VBM identified a regional pattern that distinguished young from aged rats, characterized by reductions in prefrontal, temporal association/perirhinal, and cerebellar areas with relative increases in somatosensory, thalamic, midbrain, and hippocampal regions. Greater expression of the age-related MRI gray matter pattern was associated with poorer spatial learning in the age groups combined. Aging in the rat is characterized by a regional network pattern of gray matter reductions corresponding to aging effects previously observed in humans and non-human primates. SSM MRI network analyses can advance translational aging neuroscience research, extending from human to small animal models, with potential for evaluating mechanisms and interventions for cognitive aging.
• Barnes, C. A., Umapathy, L., Trouard, T. P., Pena, N. M., Gray, D. T., Engle, J. R., Burke, S. N., & Barnes, C. A. (2020). Auditory Processing Deficits Are Selectively Associated with Medial Temporal Lobe Mnemonic Function and White Matter Integrity in Aging Macaques.. Cerebral cortex (New York, N.Y. : 1991), 30(5), 2789-2803. doi:10.1093/cercor/bhz275
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  Deficits in auditory function and cognition are hallmarks of normative aging. Recent evidence suggests that hearing-impaired individuals have greater risks of developing cognitive impairment and dementia compared to people with intact auditory function, although the neurobiological bases underlying these associations are poorly understood. Here, a colony of aging macaques completed a battery of behavioral tests designed to probe frontal and temporal lobe-dependent cognition. Auditory brainstem responses (ABRs) and visual evoked potentials were measured to assess auditory and visual system function. Structural and diffusion magnetic resonance imaging were then performed to evaluate the microstructural condition of multiple white matter tracts associated with cognition. Animals showing higher cognitive function had significantly better auditory processing capacities, and these associations were selectively observed with tasks that primarily depend on temporal lobe brain structures. Tractography analyses revealed that the fractional anisotropy (FA) of the fimbria-fornix and hippocampal commissure were associated with temporal lobe-dependent visual discrimination performance and auditory sensory function. Conversely, FA of frontal cortex-associated white matter was not associated with auditory processing. Visual sensory function was not associated with frontal or temporal lobe FA, nor with behavior. This study demonstrates significant and selective relationships between ABRs, white matter connectivity, and higher-order cognitive ability.
• Franchetti, M. K., Bharadwaj, P. K., Nguyen, L. A., Van Etten, E. J., Klimentidis, Y. C., Hishaw, G. A., Trouard, T. P., Raichlen, D. A., & Alexander, G. E. (2020). Interaction of Age and Self-reported Physical Sports Activity on White Matter Hyperintensity Volume in Healthy Older Adults. Frontiers in aging neuroscience, 12, 576025.
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  Cerebral white matter (WM) lesion load, as measured by white matter hyperintensity (WMH) volume with magnetic resonance imaging (MRI), has been associated with increasing age and cardiovascular risk factors, like hypertension. Physical sports activity (PSA) may play an important role in maintaining WM in the context of healthy aging. In 196 healthy older adults, we investigated whether participants reporting high levels of PSA ( = 36) had reduced total and regional WMH volumes compared to those reporting low levels of PSA ( = 160). Age group [young-old (YO) = 50-69 years; old-old (OO) = 70-89 years], PSA group, and age by PSA group interaction effects were tested, with sex, hypertension, and body mass index (BMI) as covariates. We found significant main effects for age group and age by PSA group interactions for total, frontal, temporal, and parietal WMH volumes. There were no main effects of PSA group on WMH volumes. The OO group with low PSA had greater total, frontal, temporal, and parietal WMH volumes than the YO with low PSA and OO with high PSA groups. WMH volumes for the YO and OO groups with high PSA were comparable. These findings indicate an age group difference in those with low PSA, with greater WMH volumes in older adults, which was not observed in those with high PSA. The results suggest that engaging in high levels of PSA may be an important lifestyle factor that can help to diminish WMH lesion load in old age, potentially reducing the impact of brain aging.
• Gray, D. T., De La Peña, N. M., Umapathy, L., Burke, S. N., Engle, J. R., Trouard, T. P., & Barnes, C. A. (2020). Auditory and Visual System White Matter Is Differentially Impacted by Normative Aging in Macaques. The Journal of neuroscience : the official journal of the Society for Neuroscience, 40(46), 8913-8923.
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  Deficits in auditory and visual processing are commonly encountered by older individuals. In addition to the relatively well described age-associated pathologies that reduce sensory processing at the level of the cochlea and eye, multiple changes occur along the ascending auditory and visual pathways that further reduce sensory function in each domain. One fundamental question that remains to be directly addressed is whether the structure and function of the central auditory and visual systems follow similar trajectories across the lifespan or sustain the impacts of brain aging independently. The present study used diffusion magnetic resonance imaging and electrophysiological assessments of auditory and visual system function in adult and aged macaques to better understand how age-related changes in white matter connectivity at multiple levels of each sensory system might impact auditory and visual function. In particular, the fractional anisotropy (FA) of auditory and visual system thalamocortical and interhemispheric corticocortical connections was estimated using probabilistic tractography analyses. Sensory processing and sensory system FA were both reduced in older animals compared with younger adults. Corticocortical FA was significantly reduced only in white matter of the auditory system of aged monkeys, while thalamocortical FA was lower only in visual system white matter of the same animals. Importantly, these structural alterations were significantly associated with sensory function within each domain. Together, these results indicate that age-associated deficits in auditory and visual processing emerge in part from microstructural alterations to specific sensory white matter tracts, and not from general differences in white matter condition across the aging brain. Age-associated deficits in sensory processing arise from structural and functional alterations to both peripheral sensory organs and central brain regions. It remains unclear whether different sensory systems undergo similar or distinct trajectories in function across the lifespan. To provide novel insights into this question, this study combines electrophysiological assessments of auditory and visual function with diffusion MRI in aged macaques. The results suggest that age-related sensory processing deficits in part result from factors that impact the condition of specific white matter tracts, and not from general decreases in connectivity between sensory brain regions. Such anatomic specificity argues for a framework aimed at understanding vulnerabilities with relatively local influence and brain region specificity.
• Kraemer, C., Nisson, P., Wheeler, G., Guzmán Pérez-Carrillo, G. J., Bernstein, A., Hsu, C. H., Bock, D., Trouard, T., & Zhou, W. (2020). Patient risk factors associated with embolic stroke volumes after revascularization. Journal of vascular surgery, 72(6), 2061-2068.
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  Previous research has shown that subclinical, microembolic infarcts result in long-term cognitive changes. Whereas both carotid endarterectomy (CEA) and carotid artery stenting (CAS) have potential for microembolic events, CAS has been shown to have a larger volume of infarct. We have previously shown that large-volume infarction is associated with long-term memory deterioration. The purpose of this study was to identify independent risk factors that trend toward higher embolic volumes in both procedures.
• Lorza, A. M., Ravi, H., Philip, R. C., Galons, J. P., Trouard, T. P., Parra, N. A., Von Hoff, D. D., Read, W. L., Tibes, R., Korn, R. L., & Raghunand, N. (2020). Dose-response assessment by quantitative MRI in a phase 1 clinical study of the anti-cancer vascular disrupting agent crolibulin. Scientific reports, 10(1), 14449.
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  The vascular disrupting agent crolibulin binds to the colchicine binding site and produces anti-vascular and apoptotic effects. In a multisite phase 1 clinical study of crolibulin (NCT00423410), we measured treatment-induced changes in tumor perfusion and water diffusivity (ADC) using dynamic contrast-enhanced MRI (DCE-MRI) and diffusion-weighted MRI (DW-MRI), and computed correlates of crolibulin pharmacokinetics. 11 subjects with advanced solid tumors were imaged by MRI at baseline and 2-3 days post-crolibulin (13-24 mg/m). ADC maps were computed from DW-MRI. Pre-contrast T maps were computed, co-registered with the DCE-MRI series, and maps of area-under-the-gadolinium-concentration-curve-at-90 s (AUC) and the Extended Tofts Model parameters k, v, and v were calculated. There was a strong correlation between higher plasma drug [Formula: see text] and a linear combination of (1) reduction in tumor fraction with [Formula: see text] mM s, and, (2) increase in tumor fraction with [Formula: see text]. A higher plasma drug AUC was correlated with a linear combination of (1) increase in tumor fraction with [Formula: see text], and, (2) increase in tumor fraction with [Formula: see text]. These findings are suggestive of cell swelling and decreased tumor perfusion 2-3 days post-treatment with crolibulin. The multivariable linear regression models reported here can inform crolibulin dosing in future clinical studies of crolibulin combined with cytotoxic or immune-oncology agents.
• Sabat, J., Bock, D., Hsu, C. H., Tan, T. W., Weinkauf, C., Trouard, T., Perez-Carrillo, G. G., & Zhou, W. (2020). Risk factors associated with microembolization after carotid intervention. Journal of vascular surgery, 71(5), 1572-1578.
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  Microembolization after carotid artery stenting (CAS) and carotid endarterectomy (CEA) has been documented and may confer risk for neurocognitive impairment. Patients undergoing stenting are known to be at higher risk for microembolization. In this prospective cohort study, we compare the microembolization rates for patients undergoing CAS and CEA and perioperative characteristics that may be associated with microembolization.
• Shang, Y., Mishra, A., Wang, T., Wang, Y., Desai, M., Chen, S., Mao, Z., Do, L., Bernstein, A. S., Trouard, T. P., & Brinton, R. D. (2020). Evidence in support of chromosomal sex influencing plasma based metabolome vs APOE genotype influencing brain metabolome profile in humanized APOE male and female mice. PloS one, 15(1), e0225392.
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  Late onset Alzheimer's disease (LOAD) is a progressive neurodegenerative disease with four well-established risk factors: age, APOE4 genotype, female chromosomal sex, and maternal history of AD. Each risk factor impacts multiple systems, making LOAD a complex systems biology challenge. To investigate interactions between LOAD risk factors, we performed multiple scale analyses, including metabolomics, transcriptomics, brain magnetic resonance imaging (MRI), and beta-amyloid assessment, in 16 months old male and female mice with humanized human APOE3 (hAPOE3) or APOE4 (hAPOE4) genes. Metabolomic analyses indicated a sex difference in plasma profile whereas APOE genotype determined brain metabolic profile. Consistent with the brain metabolome, gene and pathway-based RNA-Seq analyses of the hippocampus indicated increased expression of fatty acid/lipid metabolism related genes and pathways in both hAPOE4 males and females. Further, female transcription of fatty acid and amino acids pathways were significantly different from males. MRI based imaging analyses indicated that in multiple white matter tracts, hAPOE4 males and females exhibited lower fractional anisotropy than their hAPOE3 counterparts, suggesting a lower level of white matter integrity in hAPOE4 mice. Consistent with the brain metabolomic and transcriptomic profile of hAPOE4 carriers, beta-amyloid generation was detectable in 16-month-old male and female brains. These data provide therapeutic targets based on chromosomal sex and APOE genotype. Collectively, these data provide a framework for developing precision medicine interventions during the prodromal phase of LOAD, when the potential to reverse, prevent and delay LOAD progression is greatest.
• Valdez, M. A., Fernandez, E., Matsunaga, T., Erickson, R. P., & Trouard, T. P. (2020). Distribution and Diffusion of Macromolecule Delivery to the Brain via Focused Ultrasound using Magnetic Resonance and Multispectral Fluorescence Imaging. Ultrasound in medicine & biology, 46(1), 122-136.
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  Focused ultrasound (FUS), in combination with microbubble contrast agents, can be used to transiently open the blood-brain barrier (BBB) to allow intravascular agents to cross into the brain. Often, FUS is carried out in conjunction with magnetic resonance imaging (MRI) to evaluate BBB opening to gadolinium-based MRI contrast agents. Although MRI allows direct visualization of the distribution of gadolinium-based contrast agents in the brain parenchyma, it does not allow measurements of the distribution of other molecules crossing the BBB. Therapeutic molecules (e.g., monoclonal antibodies) are much different in size than MRI contrast agents and have been found to have different distributions in the brain after FUS-mediated BBB opening. In the work described here, we combined in vivo MRI and ex vivo multispectral fluorescence imaging to compare the distributions of MRI contrast and dextran molecules of different molecular weights (3, 70 and 500 kDa) after FUS-mediated BBB opening through a range of ultrasound pressures (0.18-0.46 MPa) in laboratory mice. The volume of brain exposed was calculated from the MRI and fluorescence images and was significantly dependent on both molecular weight and ultrasound pressure. Diffusion coefficients of the different-molecular-weight dextran molecules in the brain parenchyma were also calculated from the fluorescence images and were negatively correlated with the molecular weight of the dextran molecules. The results of this work build on a body of knowledge that is critically important for the FUS technique to be used in clinical delivery of therapeutics to the brain.
• Van Etten, E. J., Bharadwaj, P. K., Nguyen, L. A., Hishaw, G. A., Trouard, T. P., & Alexander, G. E. (2020). Right hippocampal volume mediation of subjective memory complaints differs by hypertension status in healthy aging. Neurobiology of aging, 94, 271-280.
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  Subjective memory complaints (SMCs) may be an important early indicator of cognitive aging and preclinical Alzheimer's disease risk. This study investigated whether age-related differences in right or left hippocampal volume underlie SMCs, if these relationships differ by hypertension status, and how they are related to objective memory performance in a group of 190 healthy older adults, 50-89 years of age. Analyses revealed a significant mediation of the relationship between age and mild SMCs by right hippocampal volume that was moderated by hypertension status. This moderated mediation effect was not observed with left hippocampal volume. Additionally, a moderated serial mediation model showed that age predicted right hippocampal volume, which predicted SMCs, and in turn predicted objective memory performance on several measures of verbal selective reminding in individuals with hypertension, but not in non-hypertensives. Together, these findings suggest that even mild SMCs, in the context of hypertension, provide an early indicator of cognitive aging, reflecting a potential link among vascular risk, SMCs, and the preclinical risk for Alzheimer's disease.
• Zhou, W., Nisson, P. L., Chou, Y. H., Zhou, W., Wheeler, G., Trouard, T. P., Nisson, P., Hsu, C. H., Guzman, G., Chou, Y., & Black, J. (2020). Size and Location of Subclinical Microinfarcts Affect Their Cognitive Effects. Journal of Vascular Surgery, 72(1), e19. doi:10.1016/j.jvs.2020.04.043
• Bernstein, A. S., Chen, N. K., & Trouard, T. P. (2019). Bootstrap analysis of diffusion tensor and mean apparent propagator parameters derived from multiband diffusion MRI. Magnetic resonance in medicine, 82(5), 1796-1803.
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  To directly compare diffusion metrics derived from multiband (MB) imaging sequences to those derived using a single-band acquisition.
• Gray, D. T., Umapathy, L., De La Peña, N. M., Burke, S. N., Engle, J. R., Trouard, T. P., & Barnes, C. A. (2019). Auditory Processing Deficits Are Selectively Associated with Medial Temporal Lobe Mnemonic Function and White Matter Integrity in Aging Macaques. Cerebral cortex (New York, N.Y. : 1991).
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  Deficits in auditory function and cognition are hallmarks of normative aging. Recent evidence suggests that hearing-impaired individuals have greater risks of developing cognitive impairment and dementia compared to people with intact auditory function, although the neurobiological bases underlying these associations are poorly understood. Here, a colony of aging macaques completed a battery of behavioral tests designed to probe frontal and temporal lobe-dependent cognition. Auditory brainstem responses (ABRs) and visual evoked potentials were measured to assess auditory and visual system function. Structural and diffusion magnetic resonance imaging were then performed to evaluate the microstructural condition of multiple white matter tracts associated with cognition. Animals showing higher cognitive function had significantly better auditory processing capacities, and these associations were selectively observed with tasks that primarily depend on temporal lobe brain structures. Tractography analyses revealed that the fractional anisotropy (FA) of the fimbria-fornix and hippocampal commissure were associated with temporal lobe-dependent visual discrimination performance and auditory sensory function. Conversely, FA of frontal cortex-associated white matter was not associated with auditory processing. Visual sensory function was not associated with frontal or temporal lobe FA, nor with behavior. This study demonstrates significant and selective relationships between ABRs, white matter connectivity, and higher-order cognitive ability.
• Kraemer, C., Nisson, P., Wheeler, G., Guzman, G., Bernstein, A., Hsu, C., Bock, D., Trouard, T., & Zhou, W. (2019). Patient Risk Factors Associated With Embolic Stroke Volumes After Revascularization. JOURNAL OF VASCULAR SURGERY, 70(3), E94-E94.
• Willeman, M. N., Chawla, M. K., Zempare, M. A., Biwer, L. A., Hoang, L. T., Uprety, A. R., Fitzhugh, M. C., De Both, M., Coleman, P. D., Trouard, T. P., Alexander, G. E., Mitchell, K. D., Barnes, C. A., Hale, T. M., & Huentelman, M. (2019). Gradual hypertension induction in middle-aged Cyp1a1-Ren2 transgenic rats produces significant impairments in spatial learning. Physiological reports, 7(6), e14010.
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  Hypertension is a major health concern in the developed world, and its prevalence increases with advancing age. The impact of hypertension on the function of the renal and cardiovascular systems is well studied; however, its influence on the brain regions important for cognition has garnered less attention. We utilized the Cyp1a1-Ren2 xenobiotic-inducible transgenic rat model to mimic both the age of onset and rate of induction of hypertension observed in humans. Male, 15-month-old transgenic rats were fed 0.15% indole-3-carbinol (I3C) chow to slowly induce renin-dependent hypertension over a 6-week period. Systolic blood pressure significantly increased, eventually reaching 200 mmHg by the end of the study period. In contrast, transgenic rats fed a control diet without I3C did not show significant changes in blood pressure (145 mmHg at the end of study). Hypertension was associated with cardiac, aortic, and renal hypertrophy as well as increased collagen deposition in the left ventricle and kidney of the I3C-treated rats. Additionally, rats with hypertension showed reduced savings from prior spatial memory training when tested on the hippocampus-dependent Morris swim task. Motor and sensory functions were found to be unaffected by induction of hypertension. Taken together, these data indicate a profound effect of hypertension not only on the cardiovascular-renal axis but also on brain systems critically important for learning and memory. Future use of this model and approach may empower a more accurate investigation of the influence of aging on the systems responsible for cardiovascular, renal, and neurological health.
• Chen, N. K., Chang, H. C., Bilgin, A., Bernstein, A., & Trouard, T. P. (2018). A diffusion-matched principal component analysis (DM-PCA) based two-channel denoising procedure for high-resolution diffusion-weighted MRI. PloS one, 13(4), e0195952.
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  Over the past several years, significant efforts have been made to improve the spatial resolution of diffusion-weighted imaging (DWI), aiming at better detecting subtle lesions and more reliably resolving white-matter fiber tracts. A major concern with high-resolution DWI is the limited signal-to-noise ratio (SNR), which may significantly offset the advantages of high spatial resolution. Although the SNR of DWI data can be improved by denoising in post-processing, existing denoising procedures may potentially reduce the anatomic resolvability of high-resolution imaging data. Additionally, non-Gaussian noise induced signal bias in low-SNR DWI data may not always be corrected with existing denoising approaches. Here we report an improved denoising procedure, termed diffusion-matched principal component analysis (DM-PCA), which comprises 1) identifying a group of (not necessarily neighboring) voxels that demonstrate very similar magnitude signal variation patterns along the diffusion dimension, 2) correcting low-frequency phase variations in complex-valued DWI data, 3) performing PCA along the diffusion dimension for real- and imaginary-components (in two separate channels) of phase-corrected DWI voxels with matched diffusion properties, 4) suppressing the noisy PCA components in real- and imaginary-components, separately, of phase-corrected DWI data, and 5) combining real- and imaginary-components of denoised DWI data. Our data show that the new two-channel (i.e., for real- and imaginary-components) DM-PCA denoising procedure performs reliably without noticeably compromising anatomic resolvability. Non-Gaussian noise induced signal bias could also be reduced with the new denoising method. The DM-PCA based denoising procedure should prove highly valuable for high-resolution DWI studies in research and clinical uses.
• Chen, N. K., Chou, Y. H., Sundman, M., Hickey, P., Kasoff, W. S., Bernstein, A., Trouard, T. P., Lin, T., Rapcsak, S. Z., Sherman, S. J., & Weingarten, C. P. (2018). Alteration of Diffusion-Tensor Magnetic Resonance Imaging Measures in Brain Regions Involved in Early Stages of Parkinson's Disease. Brain connectivity, 8(6), 343-349.
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  Many nonmotor symptoms (e.g., hyposmia) appear years before the cardinal motor features of Parkinson's disease (PD). It is thus desirable to be able to use noninvasive brain imaging methods, such as magnetic resonance imaging (MRI), to detect brain abnormalities in early PD stages. Among the MRI modalities, diffusion-tensor imaging (DTI) is suitable for detecting changes in brain tissue structure due to neurological diseases. The main purpose of this study was to investigate whether DTI signals measured from brain regions involved in early stages of PD differ from those of healthy controls. To answer this question, we analyzed whole-brain DTI data of 30 early-stage PD patients and 30 controls using improved region of interest-based analysis methods. Results showed that (i) the fractional anisotropy (FA) values in the olfactory tract (connected with the olfactory bulb: one of the first structures affected by PD) are lower in PD patients than healthy controls; (ii) FA values are higher in PD patients than healthy controls in the following brain regions: corticospinal tract, cingulum (near hippocampus), and superior longitudinal fasciculus (temporal part). Experimental results suggest that the tissue property, measured by FA, in olfactory regions is structurally modulated by PD with a mechanism that is different from other brain regions.
• Gray, D. T., Umapathy, L., Burke, S. N., Trouard, T. P., & Barnes, C. A. (2018). Tract-Specific White Matter Correlates of Age-Related Reward Devaluation Deficits in Macaque Monkeys. Journal of neuroimaging in psychiatry & neurology, 3(2), 13-26.
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  Cognitive aging is known to alter reward-guided behaviors that require interactions between the orbitofrontal cortex (OFC) and amygdala. In macaques, OFC, but not amygdala volumes decline with age and correlate with performance on a reward devaluation (RD) task. The present study used diffusion magnetic resonance imaging (dMRI) methods to investigate whether the condition of the white matter associated with amygdala-OFC connectivity changes with age and relates to reward devaluation.
• Mendez, O. A., Potter, C. J., Valdez, M., Bello, T., Trouard, T. P., & Koshy, A. A. (2018). Semi-automated quantification and neuroanatomical mapping of heterogeneous cell populations. Journal of neuroscience methods, 305, 98-104.
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  Our group studies the interactions between cells of the brain and the neurotropic parasite Toxoplasma gondii. Using an in vivo system that allows us to permanently mark and identify brain cells injected with Toxoplasma protein, we have identified that Toxoplasma-injected neurons (TINs) are heterogeneously distributed throughout the brain. Unfortunately, standard methods to quantify and map heterogeneous cell populations onto a reference brain atlas are time consuming and prone to user bias.
• Watson, J. R., Martirosyan, N., Lemole, G. M., Trouard, T. P., & Romanowski, M. (2018). Intraoperative brain tumor resection with indocyanine green using augmented microscopy. Journal of biomedical optics, 23(9), 1-4.
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  Treatment outcomes for brain cancer have seen dismal improvements over the last two decades as evident in available statistical data. Efforts to address this challenge include development of near-infrared contrast agents for improvements in diagnostic and therapeutic modalities. This creates a need for imaging technologies that can support the intraoperative use of such agents. Here, we report implementation of a recently introduced augmented microscope in combination with indocyanine green (ICG), a near-infrared contrast agent, for surgical image guidance of a glioma resection in a rat model. Luc-C6 cells were implanted in rats in the left-frontal lobe and grown for 22 days. Surgical resection was performed by a neurosurgeon using the augmented microscope with ICG contrast. ICG accumulated in the tumor tissue due to enhanced permeation and retention from the compromised blood-brain barrier. Videos and images were acquired to evaluate image quality and resection margins. The augmented microscope highlighted tumor tissue regions via visualization of ICG fluorescence and was capable of guiding the rat glioma resection.
• Yin, F., Yin, F., Trouard, T. P., Shang, Y., Mishra, A., Mao, Z., Do, L., & Brinton, R. D. (2018). P2-204: SEX DIFFERENCES IN METABOLIC AND INFLAMMATORY AGING OF THE BRAIN IN HUMANIZED APOE-ε4 KNOCK-IN RATS. Alzheimers & Dementia, 14(7S_Part_14). doi:10.1016/j.jalz.2018.06.892
• Totenhagen, J. W., Bernstein, A., Yoshimaru, E. S., Erickson, R. P., & Trouard, T. P. (2017). Quantitative magnetic resonance imaging of brain atrophy in a mouse model of Niemann-Pick type C disease. PloS one, 12(5), e0178179.
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  In vivo magnetic resonance imaging (MRI) was used to investigate regional and global brain atrophy in the neurodegenerative Niemann Pick Type C1 (NPC1) disease mouse model. Imaging experiments were conducted with the most commonly studied mouse model of NPC1 disease at early and late disease states. High-resolution in vivo images were acquired at early and late stages of the disease and analyzed with atlas-based registration to obtain measurements of twenty brain region volumes. A two-way ANOVA analysis indicated eighteen of these regions were different due to genotype and thirteen showed a significant interaction with age and genotype. The ability to measure in vivo neurodegeneration evidenced by brain atrophy adds to the ability to monitor disease progression and treatment response in the mouse model.
• Berman, B. P., Pandey, A., Li, Z., Jeffries, L., Trouard, T. P., Oliva, I., Cortopassi, F., Martin, D. R., Altbach, M. I., & Bilgin, A. (2016). Volumetric MRI of the lungs during forced expiration. Magnetic resonance in medicine, 75(6), 2295-302.
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  Lung function is typically characterized by spirometer measurements, which do not offer spatially specific information. Imaging during exhalation provides spatial information but is challenging due to large movement over a short time. The purpose of this work is to provide a solution to lung imaging during forced expiration using accelerated magnetic resonance imaging. The method uses radial golden angle stack-of-stars gradient echo acquisition and compressed sensing reconstruction.
• Raichlen, D. A., Bharadwaj, P. K., Fitzhugh, M. C., Haws, K. A., Torre, G. A., Trouard, T. P., & Alexander, G. E. (2016). Differences in Resting State Functional Connectivity between Young Adult Endurance Athletes and Healthy Controls. Frontiers in human neuroscience, 10, 610.
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  Expertise and training in fine motor skills has been associated with changes in brain structure, function, and connectivity. Fewer studies have explored the neural effects of athletic activities that do not seem to rely on precise fine motor control (e.g., distance running). Here, we compared resting-state functional connectivity in a sample of adult male collegiate distance runners (n = 11; age = 21.3 ± 2.5) and a group of healthy age-matched non-athlete male controls (n = 11; age = 20.6 ± 1.1), to test the hypothesis that expertise in sustained aerobic motor behaviors affects resting state functional connectivity in young adults. Although generally considered an automated repetitive task, locomotion, especially at an elite level, likely engages multiple cognitive actions including planning, inhibition, monitoring, attentional switching and multi-tasking, and motor control. Here, we examined connectivity in three resting-state networks that link such executive functions with motor control: the default mode network (DMN), the frontoparietal network (FPN), and the motor network (MN). We found two key patterns of significant between-group differences in connectivity that are consistent with the hypothesized cognitive demands of elite endurance running. First, enhanced connectivity between the FPN and brain regions often associated with aspects of working memory and other executive functions (frontal cortex), suggest endurance running may stress executive cognitive functions in ways that increase connectivity in associated networks. Second, we found significant anti-correlations between the DMN and regions associated with motor control (paracentral area), somatosensory functions (post-central region), and visual association abilities (occipital cortex). DMN deactivation with task-positive regions has been shown to be generally beneficial for cognitive performance, suggesting anti-correlated regions observed here are engaged during running. For all between-group differences, there were significant associations between connectivity, self-reported physical activity, and estimates of maximum aerobic capacity, suggesting a dose-response relationship between engagement in endurance running and connectivity strength. Together these results suggest that differences in experience with endurance running are associated with differences in functional brain connectivity. High intensity aerobic activity that requires sustained, repetitive locomotor and navigational skills may stress cognitive domains in ways that lead to altered brain connectivity, which in turn has implications for understanding the beneficial role of exercise for brain and cognitive function over the lifespan.
• Raichlen, D. A., Bharadwaj, P., Fitzhugh, M., Haws, K., Torre, G., Trouard, T. P., & Alexander, G. E. (2016). Differences in resting state functional connectivity between young adult endurance athletes and healthy controls. Frontiers in Human Neuroscience, 10, 610.
• Umashankar, A., Corenblum, M. J., Ray, S., Valdez, M., Yoshimaru, E. S., Trouard, T. P., & Madhavan, L. (2016). Effects of the iron oxide nanoparticle Molday ION Rhodamine B on the viability and regenerative function of neural stem cells: relevance to clinical translation. International journal of nanomedicine, 11, 1731-48.
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  An essential component of developing successful neural stem cell (NSC)-based therapies involves the establishment of methodologies to noninvasively monitor grafted NSCs within brain tissues in real time. In this context, ex vivo labeling with ultrasmall superparamagnetic iron oxide (USPIO) particles has been shown to enable efficient tracking of transplanted NSCs via magnetic resonance imaging (MRI). However, whether and how USPIO labeling affects the intrinsic biology of NSCs is not thoroughly understood, and remains an active area of investigation. Here, we perform a comprehensive examination of rat NSC survival and regenerative function upon labeling with the USPIO, Molday ION Rhodamine B (MIRB), which allows for dual magnetic resonance and optical imaging. After optimization of labeling efficiency, two specific doses of MIRB (20 and 50 μg/mL) were chosen and were followed for the rest of the study. We observed that both MIRB doses supported the robust detection of NSCs, over an extended period of time in vitro and in vivo after transplantation into the striata of host rats, using MRI and post hoc fluorescence imaging. Both in culture and after neural transplantation, the higher 50 μg/mL MIRB dose significantly reduced the survival, proliferation, and differentiation rate of the NSCs. Interestingly, although the lower 20 μg/mL MIRB labeling did not produce overtly negative effects, it increased the proliferation and glial differentiation of the NSCs. Additionally, application of this dose also changed the morphological characteristics of neurons and glia produced after NSC differentiation. Importantly, the transplantation of NSCs labeled with either of the two MIRB doses upregulated the immune response in recipient animals. In particular, in animals receiving the 50 μg/mL MIRB-labeled NSCs, this immune response consisted of an increased number of CD68(+)-activated microglia, which appeared to have phagocytosed MIRB particles and cells contributing to an exaggerated MRI signal dropout in the animals. Overall, these results indicate that although USPIO particles, such as MIRB, may have advantageous labeling and magnetic resonance-sensitive features for NSC tracking, a further examination of their effects might be necessary before they can be used in clinical scenarios of cell-based transplantation.
• Nael, K., Trouard, T. P., Lafleur, S. R., Krupinski, E. A., Salamon, N., & Kidwell, C. S. (2015). White matter ischemic changes in hyperacute ischemic stroke: voxel-based analysis using diffusion tensor imaging and MR perfusion. Stroke, 46(2), 413-8.
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  The purpose of this study was to evaluate changes in fractional anisotropy (FA), as measured by diffusion tensor imaging, of white matter (WM) infarction and hypoperfusion in patients with acute ischemic stroke using a quantitative voxel-based analysis.
• Stephen, R. M., Jha, A. K., Roe, D. J., Trouard, T. P., Galons, J., Kupinski, M. A., Frey, G., Cui, H., Squire, S., Pagel, M. D., Rodriguez, J. J., Gillies, R. J., & Stopeck, A. T. (2015). Diffusion MRI with Semi-Automated Segmentation Can Serve as a Restricted Predictive Biomarker of the Therapeutic Response of Liver Metastasis. Magnetic Resonance Imaging, 33(10), 1267-73.
• Burke, S. N., Thome, A., Plange, K., Engle, J. R., Trouard, T. P., Gothard, K. M., & Barnes, C. A. (2014). Orbitofrontal cortex volume in area 11/13 predicts reward devaluation, but not reversal learning performance, in young and aged monkeys. The Journal of neuroscience : the official journal of the Society for Neuroscience, 34(30), 9905-16.
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  The orbitofrontal cortex (OFC) and amygdala are both necessary for decisions based on expected outcomes. Although behavioral and imaging data suggest that these brain regions are affected by advanced age, the extent to which aging alters appetitive processes coordinated by the OFC and the amygdala is unknown. In the current experiment, young and aged bonnet macaques were trained on OFC- and amygdala-dependent tasks that test the degree to which response selection is guided by reward value and can be adapted when expected outcomes change. To assess whether the structural integrity of these regions varies with levels of performance on reward devaluation and object reversal tasks, volumes of areas 11/13 and 14 of the OFC, central/medial (CM), and basolateral (BL) nuclei of the amygdala were determined from high-resolution anatomical MRIs. With age, there were significant reductions in OFC, but not CM and BL, volume. Moreover, the aged monkeys showed impairments in the ability to associate an object with a higher value reward, and to reverse a previously learned association. Interestingly, greater OFC volume of area 11/13, but not 14, was significantly correlated with an animal's ability to anticipate the reward outcome associated with an object, and smaller BL volume was predictive of an animal's tendency to choose a higher value reward, but volume of neither region correlated with reversal learning. Together, these data indicate that OFC volume has an impact on monkeys' ability to guide choice behavior based on reward value but does not impact ability to reverse a previously learned association.
• Yoshimaru, E., Totenhagen, J., Alexander, G. E., & Trouard, T. P. (2014). Design, manufacture, and analysis of customized phantoms for enhanced quality control in small animal MRI systems. Magnetic Resonance in Medicine, 71(2), 880-884.
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  Abstract: Purpose Magnetic resonance imaging (MRI) is widely used in human brain research to evaluate the effects of healthy aging and development, as well as neurological disorders. Although standardized methods for quality assurance of human MRI instruments have been established, such approaches have typically not been translated to small animal imaging. We present a method for the generation and analysis of customized phantoms for small animal MRI systems that allows rapid and accurate system stability monitoring. Methods Computer-aided design software was used to produce a customized phantom using a rapid prototyping printer. Automated registration algorithms were used on three-dimensional images of the phantom to allow system stability to be easily monitored over time. Results The design of the custom phantom allowed reliable placement relative to the imaging coil. Automated registration showed superior ability to detect gradient changes reflected in the images than with manual measurements. Registering images acquired over time allowed monitoring of gradient drifts of less than one percent. Conclusion A low cost, MRI compatible phantom was successfully designed using computer-aided design software and a three-dimensional printer. Registering phantom images acquired over time allows monitoring of gradient stability of the MRI system. © 2013 Wiley Periodicals, Inc.
• Totenhagen, J. W., Yoshimaru, E. S., Erickson, R. P., & Trouard, T. P. (2013). ¹H magnetic resonance spectroscopy of neurodegeneration in a mouse model of Niemann-Pick type C1 disease. Journal of Magnetic Resonance Imaging, 37(5), 1195-1201.
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  PMID: 23165972;PMCID: PMC3652275;Abstract: Purpose: To evaluate brain metabolite levels as in vivo indicators of disease progression in a widely studied mouse model of Niemann-Pick type C1 (NPC1) disease with quantitative 1H magnetic resonance spectroscopy (MRS). Materials and Methods: Single voxel MRS experiments were carried out in vivo in a mouse model of NPC1 disease and in control mice in two brain regions (central and posterior) at two timepoints (presymptomatic and endstage) to examine changes in metabolite levels in NPC1 disease. Concentrations of nine metabolites were quantified by fitting a simulated basis set of metabolite signals to the acquired spectra. Results: The only differences found in brain metabolite levels between NPC1 disease model and control mice were increased myo-inositol and decreased taurine in the posterior region of the brain at the endstage of the disease. Metabolite changes reported in past clinical MRS studies of NPC disease were not found in the current study of the mouse model. Conclusions: The 1H spectra obtained from NPC1 mice and control mice were very similar, even at endstages of the disease. Although differences in two metabolites associated with neurodegenerative diseases were found and could inform future studies of the disease model, it appears that MRS in this mouse model of NPC1 disease does not have the sensitivity desired for a biomarker. © 2012 Wiley Periodicals, Inc.
• Borbon, I., Totenhagen, J., Fiorenza, M. T., Canterini, S., Wangjing, K. e., Trouard, T., & Erickson, R. P. (2012). Niemann-pick c1 mice, a model of "juvenile alzheimer's disease", with normal gene expression in neurons and fibrillary astrocytes show long term survival and delayed neurodegeneration. Journal of Alzheimer's Disease, 30(4), 875-887.
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  PMID: 22495346;Abstract: Niemann-Pick C1 (NPC) disease, also known as "juvenile Alzheimer's disease", is a disease in which alterations in intracellular cholesterol trafficking occur. The contribution of various CNS cell types to the neurodegeneration has been of much interest. We have previously shown that expression of the normal gene only in fibrillary astrocytes could extend survival of Npc1-/- mice over 3-fold (Zhang et al., 2008 [13]). We have now studied expression only in neurons or in both neurons and fibrillary astrocytes. Neuron-only expression resulted in survivals of over a year (>5-fold) but motor symptoms started at about 6 months. As reflected in weight gain, this especially affected females who weighed less than wild-type starting at about 10 weeks while male differences in weight are delayed. Expression in both cell types led to a nearly normal phenotype with motor symptoms developing at about ten months and increased survival times. Purkinje cell loss was slowed, but severe, in both NSE-and NSE-GFAP-Npc1, transgenic Npc1-/- mice. MRI studies showed that myelination of the long tracts was significantly improved in NSE-Npc1 transgenics, perhaps less than in GFAP-Npc1 transgenics, and not differently than in the double transgenics. Memory was improved in both single and double transgenics. Somatic disease had not been ameliorated and lungs were massively infiltrated with foamy macrophages at 10 months. Our results suggest that neuron-only expression does not completely prevent neurodegeneration and that the addition of astrocyte expression decreases the rate/degree of decline. © 2012 - IOS Press and the authors.
• Maue, R. A., Burgess, R. W., Wang, B., Wooley, C. M., Seburn, K. L., Vanier, M. T., Rogers, M. A., Chang, C. C., Chang, T., Harris, B. T., Graber, D. J., Penatti, C. A., Porter, D. M., Szwergold, B. S., Henderson, L. P., Totenhagen, J. W., Trouard, T. P., Borbon, I. A., & Erickson, R. P. (2012). A novel mouse model of Niemann-Pick type C disease carrying a D1005G-Npc1 mutation comparable to commonly observed human mutations. Human Molecular Genetics, 21(4), 730-750.
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  PMID: 22048958;PMCID: PMC3263988;Abstract: We have identified a point mutation in Npc1 that creates a novel mouse model (Npc1 nmf164) of Niemann-Pick type C1 (NPC) disease: a single nucleotide change (A to G at cDNA bp 3163) that results in an aspartate to glycine change at position 1005 (D1005G). This change is in the cysteine-rich luminal loop of the NPC1 protein and is highly similar to commonly occurring human mutations. Genetic and molecular biological analyses, including sequencing the Npc1 spm allele and identifying a truncating mutation, confirm that the mutation in Npc1 nmf164 mice is distinct from those in other existing mouse models of NPC disease (Npc1 nih, Npc1 spm). Analyses of lifespan, body and spleen weight, gait and other motor activities, as well as acoustic startle responses all reveal a more slowly developing phenotype in Npc1 nmf164 mutant mice than in mice with the null mutations (Npc1 nih, Npc1 spm). Although Npc1 mRNA levels appear relatively normal, Npc1 nmf164 brain and liver display dramatic reductions in Npc1 protein, as well as abnormal cholesterol metabolism and altered glycolipid expression. Furthermore, histological analyses of liver, spleen, hippocampus, cortex and cerebellum reveal abnormal cholesterol accumulation, glial activation and Purkinje cell loss at a slower rate than in the Npc1 nih mouse model. Magnetic resonance imaging studies also reveal significantly less demyelination/dysmyelination than in the null alleles. Thus, although prior mouse models may correspond to the severe infantile onset forms of NPC disease, Npc1 nmf164 mice offer many advantages as a model for the late-onset, more slowly progressing forms of NPC disease that comprise the large majority of human cases. © The Author 2011. Published by Oxford University Press. All rights reserved.
• Russell, G., Harkins, K. D., Secomb, T. W., Galons, J., & Trouard, T. P. (2012). A finite difference method with periodic boundary conditions for simulations of diffusion-weighted magnetic resonance experiments in tissue. Physics in Medicine and Biology, 57(4), N35-N46.
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  PMID: 22297418;Abstract: A new finite difference (FD) method for calculating the time evolution of complex transverse magnetization in diffusion-weighted magnetic resonance imaging and spectroscopy experiments is described that incorporates periodic boundary conditions. The new FD method relaxes restrictions on the allowable time step size employed in modeling which can significantly reduce computation time for simulations of large physical extent and allow for more complex, physiologically relevant, geometries to be simulated. © 2012 Institute of Physics and Engineering in Medicine.
• Totenhagen, J. W., Lope-Piedrafita, S., Borbon, I. A., Yoshimaru, E. S., Erickson, R. P., & Trouard, T. P. (2012). In vivo assessment of neurodegeneration in niemann-pick type C mice by quantitative T2 mapping and diffusion tensor imaging. Journal of Magnetic Resonance Imaging, 35(3), 528-536.
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  PMID: 22045516;PMCID: PMC3652272;Abstract: Purpose: To quantitatively and noninvasively assess neurological disease progression in a mouse model of Niemann-Pick type C (NPC) disease by measuring white matter status with magnetic resonance imaging (MRI) techniques of T2 mapping and diffusion tensor imaging (DTI). Materials and Methods: Quantitative T2 and DTI experiments were performed in vivo in NPC disease model and control mice at three timepoints to quantify differences and changes in white matter with measurements of T2 relaxation and DTI parameters. Histological staining for myelin content was also performed at two timepoints to compare with the MRI findings. Results: The results of the T2 and DTI measurements show significant differences in white matter areas of the brain in the NPC disease model compared to control mice at several timepoints, and were seen to change over time in both groups. Conclusion: The findings of this study suggest that quantitative MRI measurements may be suitable in vivo biomarkers of disease status for future studies of NPC disease models. The changes in white matter measurements between timepoints in both control and NPC disease groups suggest that white matter structures continue to change and develop over time in the NPC model and can be tracked with MRI techniques. Copyright © 2011 Wiley Periodicals, Inc.
• Harkins, K. D., Galons, J., Divijak, J. L., & Trouard, T. P. (2011). Changes in intracellular water diffusion and energetic metabolism in response to ischemia in perfused C6 rat glioma cells. Magnetic Resonance in Medicine, 66(3), 859-867.
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  PMID: 21446036;PMCID: PMC3621130;Abstract: This work reports results of experiments in hollow-fiber bioreactor C6 glioma cell cultures where the apparent diffusion coefficient (ADC) of intracellular water (iADC) was measured at diffusion times between 0.83 and 40 ms. The experiments were carried out before and after the onset of permanent ischemia. The changes in iADC following ischemia were dependent on the diffusion time employed in the experiment. An ischemia-induced decrease in the iADC was measured at short diffusion times, while at long diffusion times the iADC increased. Decreases in the iADC measured at short diffusion times are interpreted to be a result of a decrease in the intrinsic diffusivity of intracellular water due to energy failure. Increases in iADC measured at long diffusion times, are interpreted to result from cell swelling. Copyright © 2011 Wiley-Liss, Inc.
• Jelinek, D., Millward, V., Birdi, A., Trouard, T. P., Heidenreich, R. A., & Garver, W. S. (2011). NPC1 haploinsufficiency promotes weight gain and metabolic features associated with insulin resistance. Human Molecular Genetics, 20(2), 312-321.
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  PMID: 21036943;PMCID: PMC3005903;Abstract: A recent population-based genome-wide association study has revealed that the Niemann-Pick C1 (NPC1) gene is associated with early-onset and morbid adult obesity. Concurrently, our candidate gene-based mouse growth study performed using the BALB/cJ NPC1 mouse model (Npc1) with decreased Npc1 gene dosage independently supported these results by suggesting an Npc1 gene-diet interaction in relation to early-onset weight gain. To further investigate the Npc1 gene in relation to weight gain and metabolic features associated with insulin resistance, we interbred BALB/cJ Npc1 +/- mice with wild-type C57BL/6J mice, the latter mouse strain commonly used to study aspects of diet-induced obesity and insulin resistance. This breeding produced a hybrid (BALB/cJ-C57BL/6J) Npc1 +/- mouse model with increased susceptibility to weight gain and insulin resistance. The results from our study indicated that these Npc1 +/- mice were susceptible to increased weight gain characterized by increased whole body and abdominal adiposity, adipocyte hypertrophy and hepatic steatosis in the absence of hyperphagia. Moreover, these Npc1 +/- mice developed abnormal metabolic features characterized by impaired fasting glucose, glucose intolerance, hyperinsulinemia, hyperleptinemia and dyslipidemia marked by an increased concentration of cholesterol and triacylglycerol associated with low-density lipoprotein and high-density lipoprotein. The overall results are consistent with a unique Npc1 gene-diet interaction that promotes both weight gain and metabolic features associated with insulin resistance. Therefore, the NPC1 gene now represents a previously unrecognized gene involved in maintaining energy and metabolic homeostasis that will contribute to our understanding concerning the current global epidemic of obesity and type 2 diabetes mellitus. © The Author 2010. Published by Oxford University Press. All rights reserved.
• Lingling, P. u., Trouard, T. P., Ryan, L., Huang, C., Altbach, M. I., & Bilgin, A. (2011). Model-based compressive diffusion tensor imaging. Proceedings - International Symposium on Biomedical Imaging, 254-257.
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  Abstract: Diffusion tensor imaging (DTI) is a Magnetic Resonance Imaging (MRI) technique that can reveal in vivo tissue microstructure by measuring diffusion of water in tissue. DTI has become an important tool in many clinical applications, such as assessment of white matter maturation, locating white matter lesions, and providing anatomical connectivity information. However, DTI usually requires long examination times due to the repetitive nature of the acquisition and is very sensitive to motion. These drawbacks have become the largest obstacles to full utilization of DTI. In this work, we propose to overcome these obstacles by using a model-based compressive imaging approach. Our approach consist of models to efficiently represent diffusion-encoded images and the corresponding recovery schemes based on compressive sensing (CS) principles. Our results indicate that the proposed model-based approach can allow reliable recovery of DTI signal from undersampled measurements and outperforms conventional CS recovery. © 2011 IEEE.
• Walther, K., Bendlin, B. B., Glisky, E. L., Trouard, T. P., Lisse, J. R., Posever, J. O., & Ryan, L. (2011). Anti-inflammatory drugs reduce age-related decreases in brain volume in cognitively normal older adults. Neurobiology of Aging, 32(3), 497-505.
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  PMID: 19386384;Abstract: Previous studies have indicated a decreased risk for developing Alzheimer's disease in anti-inflammatory (AI) drug users. Yet few studies have determined whether AI drug use provides a protective effect against normal age-related changes in the brains of older adults. Regional volume changes in gray and white matter were assessed cross-sectionally using optimized voxel-based morphometry in 36 females taking AI drugs as arthritis or pain medication and 36 age- and education-matched female controls. Although mean gray and white matter volume differences between AI drug users and the non-AI group were small, AI drug use interacted with age, such that the non-AI group showed significantly greater age-related volume changes in regions of both gray and white matter compared to the AI drug users. These regions included the superior and medial frontal gyri, middle and inferior temporal gyri, fusiform and parahippocampal gyri, and occipital gray matter as well as temporal, parietal, and midbrain white matter. The results are consistent with the notion that AI drugs provide protection against age-related changes in brain volume. It is possible that inflammation plays a role in volume decreases associated with normal aging, and that suppressing the inflammatory response moderates this decrease. © 2009 Elsevier Inc.
• Harkins, K. D., Galons, J., Secomb, T. W., & Trouard, T. P. (2009). Assessment of the effects of cellular tissue properties on ADC measurements by numerical simulation of water diffusion. Magnetic Resonance in Medicine, 62(6), 1414-1422.
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  PMID: 19785014;PMCID: PMC2855231;Abstract: The apparent diffusion coefficient (ADC), as measured by diffusion-weighted MRI, has proven useful in the diagnosis and evaluation of ischemic stroke. The ADC of tissue water is reduced by 30-50% following ischemia and provides excellent contrast between normal and affected tissue. Despite its clinical utility, there is no consensus on the biophysical mechanism underlying the reduction in ADC. In this work, a numerical simulation of water diffusion is used to predict the effects of cellular tissue properties on experimentally measured ADC. The model indicates that the biophysical mechanisms responsible for changes in ADC postischemia depend upon the time over which diffusion is measured. At short diffusion times, the ADC is dependent upon the intrinsic intracellular diffusivity, while at longer, clinically relevant diffusion times, the ADC is highly dependent upon the cell volume fraction. The model also predicts that at clinically relevant diffusion times, the 30-50% drop in ADC after ischemia can be accounted for by cell swelling alone when intracellular T2 is allowed to be shorter than extra-cellular T2. © 2009 Wiley-Liss, Inc.
• Bilgin, A., Kim, Y., Lalgudi, H. G., Trouard, T. P., & Altbach, M. I. (2008). Parallel magnetic resonance imaging using compressed sensing. Proceedings of SPIE - The International Society for Optical Engineering, 7073.
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  Abstract: Although magnetic resonance imaging (MRI) is routinely used in clinical practice, long acquisition times limit its practical utility in many applications. To increase the data acquisition speed of MRI, parallel MRI (pMRI) techniques have recently been proposed. These techniques utilize multi-channel receiver arrays and are based on simultaneous acquisition of data from multiple receiver coils. Recently, a novel framework called Compressed Sensing (CS) was introduced. Since this new framework illustrates how signals can be reconstructed from much fewer samples than suggested by the Nyquist theory, it has the potential to significantly accelerate data acquisition in MRI. This paper illustrates that CS and pMRI techniques can be combined and such joint processing yields results that are superior to those obtained from independent utilization of each technique.
• Lope-Piedrafita, S., Garcia-Martin, M. L., Galons, J., Gillies, R. J., & Trouard, T. P. (2008). Longitudinal diffusion tensor imaging in a rat brain glioma model. NMR in Biomedicine, 21(8), 799-808.
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  PMID: 18470959;PMCID: PMC2857329;Abstract: In order to investigate the properties of water motion within and around brain tumors as a function of tumor growth, longitudinal diffusion tensor imaging (DTI) was carried out in a rat brain glioma (C6) model. As tumors grew in size, significant anisotropy of water diffusion was seen both within and around the tumor. The tissue water surrounding the tumor exhibited high planar anisotropy, as opposed to the linear anisotropy normally seen in white matter, indicating that cells were experiencing stress in a direction normal to the tumor border. When tumors were sufficiently large, significant anisotropy was also seen within the tumor because of longer-range organization of cancer cells within the tumor borders. These findings have important implications for diffusion-weighted MRI experiments examining tumor growth and response to therapy. Copyright © 2008 John Wiley & Sons, Ltd.
• Lope-Piedrafita, S., Totenhagen, J. W., Hicks, C. M., Erickson, R. P., Trouard, T. P., & Trouard, T. P. (2008). MRI detects therapeutic effects in weanling Niemann-Pick type C mice. Journal of Neuroscience Research, 86(12), 2802-2807.
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  PMID: 18512758;Abstract: To noninvasively evaluate the early effects of Niemann-Pick type C (NPC) disease, diffusion tensor imaging (DTI) was carried out in the brains of very young (23-day-old) mice. The diffusion of water in white matter tracts of Npc1-/- mice at this young age was already abnormal, exhibiting decreased anisotropy, as quantified by fractional anisotropy (FA), compared with their wild-type littermates, the controls. Postmortem histological staining revealed myelin de.ciencies in Npc1-/- mice, consistent with the reduction in FA measured vivo. Beneficial effects of treatment with allopregnanolone and/ or 2 hydroxypropyl-beta-cyclodextrin was also detectable at this age by FA, which correlated with increased myelination as seen by histology. This is the earliest detection of a therapeutic effect in Npc1-/- mice. © 2008 Wiley-Liss, Inc.
• Trouard, T. P., Harkins, K. D., Divijak, J. L., Gillies, R. J., & Galons, J. (2008). Ischemia-induced changes of intracellular water diffusion in rat glioma cell cultures. Magnetic Resonance in Medicine, 60(2), 258-264.
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  PMID: 18666112;Abstract: Diffusion-weighted MRI is commonly used in the diagnosis and evaluation of ischemic stroke because of the rapid decrease observed in the apparent diffusion coefficient (ADC) of tissue water following ischemia. Although this observation has been clinically useful for many years, the biophysical mechanisms underlying the reduction of tissue ADC are still unknown. To help elucidate these mechanisms, we have employed a novel three-dimensional (3D) hollow-fiber bioreactor (HFBR) perfused cell culture system that enables cells to be grown to high density and studied via MRI and MRS. By infusing contrast media into the HFBR, signals from intracellular water and extracellular water are spectroscopically resolved and can be investigated individually. Diffusion measurements carried out on C6 glioma HFBR cell cultures indicate that ischemia-induced cellular swelling results in an increase in the ADC of intracellular water from 0.35 μm2/ms to approximately 0.5 μm2/ms (diffusion time = 25 ms). © 2008 Wiley-Liss, Inc.
• Bendlin, B. B., Trouard, T. P., & Ryan, L. (2007). Caffeine attenuates practice effects in word stem completion as measured by fMRI BOLD signal. Human Brain Mapping, 28(7), 654-662.
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  PMID: 17094121;Abstract: Caffeine ingestion results in increased brain cell metabolism (Nehlig et al. [1992] Brain Res Brain Res Rev 17:139-170) and decreased cerebral blood flow (Field et al. [2003] Radiology 227:129-135; Mulderink et al. [2002] Neuroimage 15:37-44). The current study investigated the effect of caffeine in a word stem completion task using only novel word stems (no repeated stimuli). Resting perfusion was measured with arterial spin labeled perfusion MRI, along with blood oxygenation level-dependent (BOLD) signal before and after ingestion of regular coffee, decaffeinated coffee, and water. Based on previous research (Laurienti et al. [2002] Neuroimage 17:751-757; Mulderink et al. [2002] Neuroimage 15:37-44), we hypothesized that caffeine would result in increased BOLD signal intensity and extent of BOLD activation. As expected, caffeine resulted in a significant decrease in cerebral perfusion. However, both the control and caffeine groups showed an increase in BOLD signal amplitude across two sets of novel word stems. Additionally, the control group showed a 50% reduction in the extent of BOLD activation, while the caffeine group showed no change in activation extent. Neither group showed changes in BOLD baseline signal over time, which had been suggested to mediate caffeine-related BOLD signal changes. The results suggest that caffeine may attenuate general task practice effects that have been described in recent functional MRI studies of word stem completion (Buckner et al. [2000] Brain 123:620-640). © 2006 Wiley-Liss, Inc.
• Cramer, S. C., Parrish, T. B., Levy, R. M., Stebbins, G. T., Ruland, S. D., Lowry, D. W., Trouard, T. P., Squire, S. W., Weinand, M. E., Savage, C. R., Wilkinson, S. B., Juranek, J., Leu, S., & Himes, D. M. (2007). Predicting functional gains in a stroke trial. Stroke, 38(7), 2108-2114.
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  PMID: 17540966;Abstract: BACKGROUND AND PURPOSE - A number of therapies in development for patients with central nervous system injury aim to reduce disability by improving function of surviving brain elements rather than by salvaging tissue. The current study tested the hypothesis that, after adjusting for a number of clinical assessments, a measure of brain function at baseline would improve prediction of behavioral gains after treatment. METHODS - Twenty-four patients with chronic stroke underwent baseline clinical and functional MRI assessments, received 6 weeks of rehabilitation therapy with or without investigational motor cortex stimulation, and then had repeat assessments. Thirteen baseline clinical/radiological measures were evaluated for ability to predict subsequent trial-related gains. RESULTS - Across all patients, bivariate analyses found that greater trial-related functional gains were predicted by (1) smaller infarct volume, (2) greater baseline clinical status, and (3) lower degree of activation in stroke-affected motor cortex on baseline functional MRI. When these 3 variables were further assessed using multivariate linear regression modeling, only lower motor cortex activation and greater clinical status at baseline remained significant predictors. Note that lower baseline motor cortex activation was also associated with larger increases in motor cortex activation after treatment. CONCLUSIONS - Lower motor cortex activity at baseline predicted greater behavioral gains after therapy, even after controlling for a number of clinical assessments. The boosts in cortical activity that paralleled behavioral gains suggest that in some patients, low baseline cortical activity represents underuse of surviving cortical resources. A measure of brain function might be important for optimal clinical decision-making in the context of a restorative intervention. © 2007 American Heart Association, Inc.
• Raghunand, N., Jagadish, B., Trouard, T. P., Galons, J., Gillies, R. J., & Mash, E. A. (2006). Redox-sensitive contrast agents for MRI based on reversible binding of thiols to serum albumin. Magnetic Resonance in Medicine, 55(6), 1272-1280.
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  PMID: 16700014;PMCID: PMC1808246;Abstract: DOTA-based complexes of gadolinium (Gd) bearing a thiol moiety on a propyl or hexyl arm were synthesized. It was hypothesized that these complexes would form reversible covalent linkages with human serum albumin (HSA), which contains a reactive thiol at cysteine-34. The binding constant of the hexyl complex to HSA was measured to be 64 mM-1 and decreased to 17, 6.1, and 3.6 mM-1 in the presence of 0.5, 1, and 2 mM homocysteine, respectively. The binding constant of the propyl complex to HSA was significantly lower (5.0 mM-1) and decreased to 2.0, 1.5, and 0.87 mM-1 in the presence of 0.5, 1, and 2 mM homocysteine, respectively. The longitudinal water-proton relativities of the hexyl and propyl complexes at 37°C and 4.7 T were 2.3 and 2.9 mM-1 s-1, respectively, in saline. The relaxivities of the HSA-bound forms of the hexyl and propyl complexes were calculated to be 5.3 and 4.5 mM-1 s-1, respectively. The in vivo pharmacokinetics of both thiol complexes were altered by a chase of homocysteine but not saline, while the washout of GdDTPA was unaffected by either chase. Such redox-sensitive reversible binding of Gd complexes to plasma albumin can be exploited for imaging tissue redox and the blood-pool by MRI. © 2006 Wiley-Liss, Inc.
• Ahmad, I., Lope-Piedrafita, S., Xiaoning, B. i., Hicks, C., Yao, Y., Clara, Y. u., Chaitkin, E., Howison, C. M., Weberg, L., Trouard, T. P., & Erickson, R. P. (2005). Allopregnanolone treatment, both as a single injection or repetitively, delays demyelination and enhances survival of Niemann-Pick C mice. Journal of Neuroscience Research, 82(6), 811-821.
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  PMID: 16273542;Abstract: Niemann-Pick C disease (NPC) is an irreversible neurodegenerative disorder without current treatment. It is thought to result from deficient intracellular cholesterol and/or ganglioside trafficking. We have investigated the effects of allopregnanolone treatments on survival, weight loss, motor function, magnetic resonance imaging (MRI), and neuropathology in the mouse model of NPC (Npc1 -/- mice). We confirmed previous results showing that a single injection of 250 μg of allopregnanolone on postnatal day 7 significantly extended the life span of Npc1-/- mice. This caused a marked difference in the weight curves of the treated mice but no statistical difference in the Rota-Rod performance. T2-weighted MRI and diffusion tensor imaging (DTI) of treated mice showed values of signal intensity and fractional anisotropy closer to those of wild-type mice than those of untreated Npc1 -/- mice. Neuropathology showed that day-7 treatment markedly suppressed astrocyte reaction and significantly reduced microglial activation. Furthermore, the steroid treatment also increased myelination in brains of Npc1-/- mice. Similar effects of allopregnanolone treatment were observed in Npc1-/-, mdr1a-/- double-mutant mice, which have a deficient blood-brain barrier, resulting in increased steroid uptake. The effects on survival and weight loss of a single injection on day 7 followed by injections every 2 weeks were also evaluated in Npc1-/- mice, and the beneficial effects were found to be greater than with the single injection at day 7. We conclude that allopregnanolone treatment significantly ameliorates several symptoms of NPC in Npc1-/- mice, presumably by effects on myelination or neuronal connectivity. © 2005 Wiley-Liss, Inc.
• Altbach, M. I., Bilgin, A., Zhiqiang, L. i., Clarkson, E. W., Trouard, T. P., & Gmitro, A. F. (2005). Processing of radial fast spin-echo data for obtaining T₂ estimates from a single k-space data set. Magnetic Resonance in Medicine, 54(3), 549-559.
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  PMID: 16086321;Abstract: Radially acquired fast spin-echo data can be processed to obtain T 2-weighted images and a T2 map from a single k-space data set. The general approach is to use data at a specific TE (or narrow TE range) In the center of k-space and data at other TE values in the outer part of k-space. With this method high-resolution T2-weighted images and T2 maps are obtained in a time efficient manner. The mixing of TE data, however, introduces errors in the T2-weighted images and T2 maps that affect the accuracy of the T2 estimates. In this work, various k-space data processing methods for reconstructing T2-weighted images and T2 maps from a single radial fast spin-echo k-space data set are analyzed in terms of the accuracy of T2 estimates. The analysis is focused on the effect of image artifacts, object dependency, and noise on the T2 estimates. Results are presented in computer-generated phantoms and in vivo. © 2005 Wiley-Liss, Inc.
• Galons, J., Lope-Piedrafita, S., Divijak, J. L., Corum, C., Gillies, R. J., & Trouard, T. P. (2005). Uncovering of intracellular water in cultured cells. Magnetic Resonance in Medicine, 54(1), 79-86.
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  PMID: 15968680;Abstract: The complexity of biologic tissues, with multiple compartments each with its own diffusion and relaxation properties, requires complex formalisms to model water signal in most magnetic resonance imaging or magnetic resonance spectroscopy experiments. In this article, we describe a magnetic susceptibility-induced shift in the resonance frequency of extracellular water by the introduction of a gadolinium contrast agent to medium perfusing a hollow fiber bioreactor. The frequency shift of the extracellular water (+185 Hz at 9.4 T) uncovers the intracellular water and allows direct measurement of motional and relaxation properties of the intracellular space. The proposed method provides a unique tool for understanding the mechanisms underlining diffusion and relaxation in the intracellular space. © 2005 Wiley-Liss, Inc.
• Gmitro, A. F., Kono, M., Theilmann, R. J., Altbach, M. I., Zhiqiang, L. i., & Trouard, T. P. (2005). Radial GRASE: Implementation and applications. Magnetic Resonance in Medicine, 53(6), 1363-1371.
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  PMID: 15906298;Abstract: RAD-GRASE is an MRI sequence that combines radial (RAD) k-space scanning with the gradient and spin-echo (GRASE) technique. RAD-GRASE has the advantages of all radial data acquisition methods in that it can reduce motion sensitivity and correct motion-induced data errors, which can be exploited to achieve high-resolution diffusion-weighted imaging (DWI). One can obtain different types of image contrast, including DWI, T1, T2, and T 2*, in RAD-GRASE by controlling the magnetization preparation and sequence timing. Moreover, because there is oversampling of the low spatial frequencies inherent to radial sequences, partial data reconstruction can be used to achieve multiple forms of image contrast from a single acquired data set, and to generate parametric image maps of equilibrium magnetization, T 2, and T2. The RAD-GRASE technique can also be used to achieve fat-suppressed and/or separated fat and water images by choosing the appropriate timing parameters. © 2005 Wiley-Liss, Inc.
• Lalgudi, H. G., Bilgin, A., Marcellin, M. W., Tabesh, A., Nadar, M. S., & Trouard, T. P. (2005). Four-dimensional compression of fMRI using JPEG2000. Progress in Biomedical Optics and Imaging - Proceedings of SPIE, 5747(II), 1028-1037.
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  Abstract: Many medical imaging techniques available today generate 4D data sets, One such technique is functional magnetic resonance imaging (fMRI) which aims to determine regions of the brain that are activated due to various cognitive and/or motor functions or sensory stimuli. These data sets often require substantial resources for storage and transmission and hence call for efficient compression algorithms. fMRI data can be seen as a time-series of 3D images of the brain. Many different strategies can be employed for compressing such data. One possibility is to treat each 2D slice independently. Alternatively, it is also possible to compress each 3D image independently. Such methods do not fully exploit the redundancy present in 4D data. In this work, methods using 4D wavelet transforms are proposed. They are compared to different 2D and 3D methods. The proposed schemes are based on JPEG2000, which is included in the DICOM standard as a transfer syntax. Methodologies to test the effects of lossy compression on the end result of fMRI analysis are introduced and used to compare different compression algorithms.
• Sarlls, J. E., Newbould, R. D., Altbach, M. I., Gmitro, A. F., Seeger, J., & Trouard, T. P. (2005). Isotropic diffusion weighting in radial fast spin-echo magnetic resonance imaging. Magnetic Resonance in Medicine, 53(6), 1347-1354.
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  PMID: 15906289;Abstract: Radial fast spin-echo (radial-FSE) methods enable multishot diffusion-weighted MRI (DWMRI) to be carried out without significant artifacts due to motion and/or susceptibility and can be used to generate DWMRI images with high spatial resolution. In this work, a novel method that allows isotropic diffusion weighting to be obtained in a single radial k-space data set is presented. This is accomplished by altering the direction of diffusion weighting gradients between groups of TR periods, which yield sets of radial lines that possess diffusion weighting sensitive to motion in different directions. By altering the diffusion weighting directions and controlling the view ordering appropriately within the sequence, an effectively isotropic diffusion-weighted image can be obtained within one radial-FSE scan. The order in which radial lines are acquired can also be controlled to yield data sets without significant artifacts due to motion, T2 decay, and/or diffusion anisotropy. © 2005 Wiley-Liss, Inc.
• Trouard, T. P., Heidenreich, R. A., Seeger, J. F., & Erickson, R. P. (2005). Diffusion tensor imaging in Niemann-Pick Type C disease. Pediatric Neurology, 33(5), 325-330.
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  PMID: 16243219;Abstract: Niemann-Pick Type C disease is a homozygous recessive disorder resulting in errant intracellular cholesterol metabolism and the accumulation of intracellular unesterified cholesterol and sphingolipids. Although no current effective treatment exists for Niemann-Pick Type C disease, a number of therapies are under development in animal models. As therapies are brought into clinical trials, it will be extremely helpful to have a reliable means to track the progression of the disease and to monitor its response to therapy. In this effort, diffusion tensor imaging has been applied to investigate the white matter in a Niemann-Pick Type C patient, and the results compared to those from age-matched control subjects. Diffusion tensor imaging enables quantitative measurement of water diffusion in white matter, which is sensitive to the architecture and integrity of the tissue. Compared with control subjects, significant reductions in fractional anisotropy values were observed in regions of white matter, most prominently in the corpus callosum. The results from this case study suggest that diffusion tensor imaging may allow progression of the disease to be quantitatively measured and may be able to play a role as a surrogate marker in clinical trials. © 2005 by Elsevier Inc. All rights reserved.
• Bascuñan-Castillo, E. C., Erickson, R. P., Howison, C. M., Hunter, R. J., Heidenreich, R. H., Hicks, C., Trouard, T. P., & Gillies, R. J. (2004). Tamoxifen and vitamin E treatments delay symptoms in the mouse model of Niemann-Pick C. Journal of Applied Genetics, 45(4), 461-467.
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  PMID: 15523158;Abstract: Niemann-Pick C disease (NPC) is an irreversible neurodegenerative disorder without current treatment. It is the result of deficient intracellular cholesterol movement. We investigated the effects of tamoxifen and vitamin E (D-alpha tocopherol) treatment on patterns of weight loss and motor function in the mouse model of Niemann-Pick C disease (Npc1-/- mice). Tamoxifen has multiple metabolic effects, including reducing oxidative damage, while vitamin E primarily has this property. Npc1-/- mice were identified and treatment was initiated at an approximate age of 21 days. Tamoxifen suspended in peanut oil was administered via intraperitoneal injection (weekly, at a dose calculated to deliver 0.023 μg/g/day). Vitamin E (25 IU) was administered orally via gavage once a week. Weight loss and Rota-Rod performance were analyzed by using Kaplan-Meyer survival curves. Tamoxifen treatment by itself significantly delayed weight loss (an endpoint of neurodegeneration) in male and female mice compared to untreated controls. Motor function was evaluated by performance on a Rota-Rod. Tamoxifen maintained Rota-Rod performance for about an extra week. Vitamin E treatment significantly delayed weight loss in females only. Rota-Rod performance was maintained slightly longer in mice treated with vitamin E. Simultaneous use of both treatments did not delay weight loss longer than tamoxifen-only treatment but had a greater effect than either treatment alone on Rota-Rod performance and demonstrated a significant positive effect on the early "learning curve" portion of the Rota-Rod evaluations. We found significant but relatively small improvements in rate of disease progression by treating Npc1-/- mice with tamoxifen and/or vitamin E. Some sex differences in response and an early improvement in Rota-Rod performance suggest areas for further study.
• Theilmann, R. J., Borders, R., Trouard, T. P., Xia, G., Outwater, E., Ranger-Moore, J., Gillies, R. J., & Stopeck, A. (2004). Changes in water mobility measured by diffusion MRI predict response of metastatic breast cancer to chemotherapy. Neoplasia, 6(6), 831-837.
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  PMID: 15720810;PMCID: PMC1531687;Abstract: A goal of oncology is the individualization of patient care to optimize therapeutic responses and minimize toxicities. Achieving this will require noninvasive, quantifiable, and early markers of tumor response. Preclinical data from xenografted tumors using a variety of antitumor therapies have shown that magnetic resonance imaging (MRI)-measured mobility of tissue water (apparent diffusion coefficient of water, or ADCW) is a biomarker presaging cell death in the tumor. This communication tests the hypothesis that changes in water mobility will quantitatively presage tumor responses in patients with metastatic liver lesions from breast cancer. A total of 13 patients with metastatic breast cancer and 60 measurable liver lesions were monitored by diffusion MRI after initiation of new courses of chemotherapy. MR images were obtained prior to, and at 4, 11, and 39 days following the initiation of therapy for determination of volumes and ADCW values. The data indicate that diffusion MRI can predict response by 4 or 11 days after commencement of therapy, depending on the analytic method. The highest concordance was observed in tumor lesions that were less than 8 cm3 in volume at presentation. These results suggest that diffusion MRI can be useful to predict the response of liver metastases to effective chemotherapy.
• Theilmann, R. J., Gmitro, A. F., Altbach, M. I., & Trouard, T. P. (2004). View-Ordering in Radial Fast Spin-Echo Imaging. Magnetic Resonance in Medicine, 51(4), 768-774.
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  PMID: 15065250;Abstract: Radial MRI sequences are frequently used to obtain images with reduced sensitivity to motion. To decrease imaging time, multiple spin-echo acquisitions can be incorporated into radial sequences. In this case, different radial lines of Fourier data have different TE times and the resulting images can contain streaking artifacts due to T2 decay. The streaking is not only dependent on the T2 of the object and the timing of the data acquisition, but also on the order in which radial lines are collected (view order). The view ordering can easily be controlled to minimize artifacts due to T2 decay as well as motion. Four view-ordering techniques are presented and evaluated for the radial FSE sequence. © 2004 Wiley-Liss, Inc.
• Beeson, P. M., Rapcsak, S. Z., Plante, E., Chargualaf, J., Chung, A., Johnson, S. C., & Trouard, T. P. (2003). The neural substrates of writing: A functional magnetic resonance imaging study. Aphasiology, 17(6-7), 647-665.
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  Abstract: Background: Hypotheses regarding the neural substrates of writing have been derived from the study of individuals with acquired agraphia. Functional neuroimaging offers another methodology to test these hypotheses in neurologically intact individuals. Aims: This study was designed to identify possible neural substrates for the linguistic and motor components of writing in normal English-speaking individuals. Methods & procedures: Functional magnetic resonance imaging was used with 12 adults to examine activation associated with generative writing of words from semantic categories contrasted with writing letters of the alphabet and drawing circles. In addition, the generative writing condition was contrasted with a subvocal generative naming condition. Outcomes & results: Semantically guided retrieval of orthographic word forms for the generative writing condition revealed activation in the left inferior and dorsolateral prefrontal cortex, as well as the left posterior inferior temporal lobe (BA 37). However, no activation was detected in the left angular gyrus (BA 39). The motor components of writing were associated with activation in left fronto-parietal cortex including the region of the intraparietal sulcus, superior parietal lobule, dorsolateral and medial premotor cortex, and sensorimotor areas for the hand. Conclusions: These observations suggest an important role of the left posterior inferior temporal cortex in lexical-orthographic processing and fail to support the long-held notion that the dominant angular gyrus is the storage site for orthographic representations of familiar words. Our findings also demonstrate the involvement of left superior parietal and frontal premotor regions in translating orthographic information into appropriate hand movements.
• Guo, J., Erickson, R., Trouard, T., Galons, J., & Gillies, R. (2003). Magnetization transfer contrast imaging in Niemann pick type C mouse liver. Journal of Magnetic Resonance Imaging, 18(3), 321-327.
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  PMID: 12938127;Abstract: Purpose: To investigate livers of mice afflicted with Niemann Pick type C (NP-C) disease using magnetization transfer contrast (MTC) imaging and to test the hypothesis that the MT ratio reproducibly changes during disease progression. Background: NP-C is a heritable defect of lipid metabolism that results in the accumulation of unesterified cholesterol and gangliosides in virtually all cells. Symptoms predominate in brain and liver, which have high endogenous rates of lipid turnover. It is fatal to children, usually early in the second decade of life. Previous work has shown that the efficiency of magnetization transfer (MT) can be affected by cholesterol and collagen in tissues. The MT ratio (MTR) was calculated and compared during growth and therapy of diseased and control mice. Results: Significant differences in the MTR were observed between livers of diseased and control mice. These ratios were consistent with collagen deposition associated with fibrosis, and not the accumulation of unesterified cholesterol in this organ. Conclusion: These results indicate that MTC imaging may have clinical potential for monitoring progression and therapy in NP-C disease. © 2003 Wiley-Liss, Inc.
• Mahendra, N., Plante, E., Magloire, J., Milman, L., & Trouard, T. P. (2003). fMRI variability and the localization of languages in the bilingual brain. NeuroReport, 14(9), 1225-1228.
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  PMID: 12824764;Abstract: The cerebral localization of multiple languages is a topic of active research. This study presents a method for assessing whether partial overlap of active voxels reflects differential language localization, or simply the variability known to occur with multiple runs of the same task in fMRI studies. Two groups of bilingual subjects (early and later learners of L2) performed word fluency and sentence generation tasks in both languages. The degree of separation for regions of activation did not exceed that associated with run-to-run variability for either task or either group. Early bilinguals, however, showed greater total numbers of active voxels than Late bilinguals for both tasks. This effect occurred despite a lack of a behavioral performance differences by the two groups. © 2003 Lippincott Williams & Wilkins.
• Weerd, P. D., Reinke, K., Ryan, L., McIsaac, T., Perschler, P., Schnyer, D., Trouard, T., & Gmitro, A. (2003). Cortical mechanisms for acquisition and performance of bimanual motor sequences. NeuroImage, 19(4), 1405-1416.
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  PMID: 12948698;Abstract: We used functional magnetic resonance imaging to investigate the cortical mechanisms contributing to the acquisition and performance of a complex, bimanual motor sequence. To that aim, five subjects were trained on a difficult, asymmetrical finger opposition task. Their performance rate almost doubled in the course of training and approached the performance rate in an untrained, symmetrical finger opposition task. Before training, performance of the asymmetrical sequence was associated with activity in M1, premotor cortex, supplementary motor cortex, and parietal cortex. After training, performance of the asymmetrical sequence was associated mainly with activity in M1, and little activity outside M1 remained. The latter pattern of cortical activation resembled that observed during the execution of symmetrical sequences, which was unaffected by practice with the asymmetrical sequence. The activation pattern obtained with the symmetrical bimanual sequence was indistinguishable from the combined activation measured in contralateral hemispheres during unimanual control sequences. The data indicate that cortical regions previously implicated in the acquisition of difficult unimanual motor sequences also contribute to the acquisition of asymmetrical bimanual sequences. We found no evidence for an expansion of activity in M1 after acquisition of the asymmetrical sequence (while this has been reported after acquisition of unimanual sequences). In the context of existing literature, the data suggest that the acquisition of unimanual and bimanual motor sequences may rely on similar cortical mechanisms, but that the formation of long-term, procedural memories for the two types of sequences might at least in part depend on different mechanisms. © 2003 Elsevier Science (USA). All rights reserved.
• Altbach, M. I., Outwater, E. K., Trouard, T. P., Krupinski, E. A., Theilmann, R. J., Stopeck, A. T., Kono, M., & Gmitro, A. F. (2002). Radial fast spin-echo method for T2-weighted imaging and T2 mapping of the liver. Journal of Magnetic Resonance Imaging, 16(2), 179-189.
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  PMID: 12203766;Abstract: Purpose: To evaluate a multishot radial fast-spin echo (RAD-FSE) method developed to improve the quality of abdominal T2-weighted imaging as well as the characterization of focal liver lesions. Materials and Methods: The RAD-FSE sequence used in this work consisted of a preparatory period followed by a short echo train (ETL = 16). A novel radial k-space trajectory was used to minimize streaking artifacts due to T2 variations and motion. Small diffusion gradients (b = 1.2 mm/s2) were used to improve flow suppression. The quality of images obtained with RAD-FSE was compared to multishot 2DFT fast spin-echo (2DFT-FSE) and half-Fourier acquisition single-shot turbo-spin-echo (HASTE) images using data from 16 patients. A postprocessing algorithm was used to generate multiple high-resolution images (at different effective TE values) as well as a T2 map from a single RAD-FSE data set. The T2 maps were used to differentiate malignant from benign lesions for a set of 33 lesions ranging from 0.8-194 cm3. Results: RAD-FSE produces high-resolution images of the liver in a breath-hold without the motion artifacts of 2DFT-FSE methods, and without the blurriness and loss of small lesion detectability of HASTE. The inclusion of diffusion weighting in RAD-FSE decreases the signal from blood in hepatic vessels, which improves lesion visualization. The T2 values obtained by postprocessing a single RAD-FSE data set can differentiate malignant from benign lesions. The mean T2 values obtained for malignancies, hemangiomas, and cysts are 108 ± 30 msec, 240 ± 14 msec, and 572 ± 334 msec, respectively. Conclusion: These results indicate that RAD-FSE produces abdominal images of higher quality than 2DFT-FSE and HASTE. In addition, lesions can be characterized using T2 maps generated from a single RAD-FSE data set. © 2002 Wiley-Liss, Inc.
• Fridriksson, J., Holland, A. L., Coull, B. M., Plante, E., Trouard, T. P., & Beeson, P. (2002). Aphasia severity: Association with cerebral perfusion and diffusion. Aphasiology, 16(9), 859-871.
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  Abstract: Background: Previous studies of the relationship between perfusion, diffusion, and stroke suggest that the extent of cerebral hypoperfusion may be a better indicator of neurological status than lesion size in the early phases of recovery. It is not clear how these factors are related to aphasia severity. Aims: The purpose of this study was to investigate the relationship between cerebral perfusion, diffusion, and aphasia severity in stroke. Methods & procedure: Nine participants were examined within 24 hours of stroke onset and six were re-examined at 1 month post stroke. The examination included administration of an aphasia test, a face recognition task, and a neuroimaging session including T2-, perfusion-, and diffusion-weighted MRI. Outcomes & results: Participants with a variety of aphasia types and severity were included in the study. Visual inspection suggested larger perfusion abnormality than the actual lesion in eight of nine subjects at day 1. The correlation between aphasia severity and hypoperfusion was significant at day 1 and at 1 month post stroke. However, this was not the case for the relationship between aphasia severity and lesion size where the correlation was not statistically significant at day 1 or at 1 month post stroke. Conclusions: These results suggest that cerebral hypoperfusion is a more accurate indicator of aphasia severity in early stroke than lesion volume.
• Jennings, D., Hatton, B. N., Guo, J., Galons, J., Trouard, T. P., Raghunand, N., Marshall, J., & Gillies, R. J. (2002). Early response of prostate carcinoma xenografts to docetaxel chemotherapy monitored with diffusion MRI. Neoplasia, 4(3), 255-262.
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  PMID: 11988845;PMCID: PMC1531699;Abstract: For many anticancer therapies, it would be desirable to accurately monitor and quantify tumor response early in the treatment regimen. This would allow oncologists to continue effective therapies or discontinue ineffective therapies early in the course of treatment, and hence, reduce morbidity. This is especially true for second-line therapies, which have reduced response rates and increased toxicities. Previous works by others and ourselves have shown that water mobility, measured by diffusion-weighted magnetic resonance imaging (DW-MRI), increases early in tumors destined to respond to therapies. In the current communication, we further characterize the utility of DW-MRI to predict response of prostate cancer xenografts to docetaxel in SCID mice in a preclinical setting. The current data illustrate that tumor volumes and secreted prostate-specific antigen both respond strongly to docetaxel in a dose-responsive manner, and the apparent diffusion coefficient of water (ADCw) increases significantly by 2 days even at the lowest doses (10 mg/kg). The ADCw data were parsed by histogram analyses. Our results indicate that DW-MRI can be used for early detection of prostate carcinoma xenograft response to docetaxel chemotherapy.
• Schnyer, D. M., Ryan, L., Trouard, T., & Forster, K. (2002). Masked word repetition results in increased fMRI signal: A framework for understanding signal changes in priming. NeuroReport, 13(3), 281-284.
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  PMID: 11930123;Abstract: Evidence from multiple paradigms has converged on the finding that stimulus repetition most often results in decreases in neural activity. The mechanisms of these decreases, however, are not yet well understood. The current study attempted to determine, through the use of masked word repetition priming, whether decreases in activity levels occur in response to pre- or post-prime identification processes. fMRI was performed while participants engaged in a lexical decision task where words were primed with a briefly presented and masked word. Masked word priming resulted in increased fMRI signal in regions of cortex associated with the perceptual identification of the target words. This finding provides evidence suggesting that the impact of repetition priming on the fMRI signal may depend upon whether or not the prime is identified. © 2002 Lippincott Williams & Wilkins.
• Altbach, M. I., Trouard, T. P., Van, R., Theilmann, R. J., Clarkson, E., Barrett, H. H., & Gmitro, A. F. (2001). Chemical-shift imaging utilizing the positional shifts along the readout gradient direction. IEEE Transactions on Medical Imaging, 20(11), 1156-1166.
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  PMID: 11700741;Abstract: In this work, we describe a method that uses the linear phase acquired during the readout period due to chemical shift to generate individual magnetic resonance (MR) images of chemically shifted species. The method utilizes sets of Fourier (or κ-space) data acquired with different directions of the readout gradient and a postprocessing algorithm to generate chemical shift images. The methodology is developed for both Cartesian data acquisition and for radial data acquisition. The method is presented here for two chemically shifted species but it can be extended to more species. In this work, we present the theory, show the results in phantoms and in human images, and discuss the artifacts and signal-to-noise ratio of the images obtained with the technique.
• Brennick, M. J., Trouard, T. P., Gmitro, A. F., & Fregosi, R. F. (2001). MRI study of pharyngeal airway changes during stimulation of the hypoglossal nerve branches in rats. Journal of Applied Physiology, 90(4), 1373-1384.
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  PMID: 11247937;Abstract: The medial branch (Med) of the hypoglossal nerve innervates the tongue protrudor muscles, whereas the lateral branch (Lat) innervates tongue retractor muscles. Our previous finding that pharyngeal airflow increased during either selective Med stimulation or whole hypoglossal nerve (WHL) stimulation (coactivation of protrudor and retractor muscles) led us to examine how WHL, Med, or Lat stimulation affected tongue movements and nasopharyngeal (NP) and oropharyngeal (OP) airway volume. Electrical stimulation of either WHL, Med, or Lat nerves was performed in anesthetized, tracheotomized rats while magnetic resonance images of the NP and OP were acquired (slice thickness 0.5 mm, in-plane resolution 0.25 mm). NP and OP volume was greater during WHL and Med stimulation vs. no stimulation (P < 0.05). Ventral tongue depression (measured in the midsagittal images) and OP volume were greater during Med stimulation than during WHL stimulation (P < 0.05). Lat stimulation did not alter NP volume (P = 0.39). Our finding that either WHL or Med stimulation dilates the NP and OP airways sheds new light on the control of pharyngeal airway caliber by extrinsic tongue muscles and may lead to new treatments for patients with obstructive sleep apnea.
• McCabe, K., Houser, D., Ryan, L., Smith, V., & Trouard, T. (2001). A functional imaging study of cooperation in two-person reciprocal exchange. Proceedings of the National Academy of Sciences of the United States of America, 98(20), 11832-11835.
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  PMID: 11562505;PMCID: PMC58817;Abstract: Cooperation between individuals requires the ability to infer each other's mental states to form shared expectations over mutual gains and make cooperative choices that realize these gains. From evidence that the ability for mental state attribution involves the use of prefrontal cortex, we hypothesize that this area is involved in integrating theory-of-mind processing with cooperative actions. We report data from a functional MRI experiment designed to test this hypothesis. Subjects in a scanner played standard two-person "trust and reciprocity" games with both human and computer counterparts for cash rewards. Behavioral data shows that seven subjects consistently attempted cooperation with their human counterpart. Within this group prefrontal regions are more active when subjects are playing a human than when they are playing a computer following a fixed (and known) probabilistic strategy. Within the group of five noncooperators, there are no significant differences in prefrontal activation between computer and human conditions.
• Ryan, L., Ryan, L., Nadel, L., Nadel, L., Keil, K., Keil, K., Putnam, K., Putnam, K., Schnyer, D., Schnyer, D., Trouard, T., Trouard, T., Moscovitch, M., & Moscovitch, M. (2001). Hippocampal complex and retrieval of recent and very remote autobiographical memories: Evidence from functional magnetic resonance imaging in neurologically intact people. Hippocampus, 11(6), 707-714.
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  PMID: 11811665;Abstract: It has been argued that the role of the hippocampus in memory is time-limited: during a period of memory consolidation, other brain regions such as the neocortex are said to acquire the ability to support memory retention and retrieval on their own. An alternative view is that retention and retrieval of memory for autobiographical episodes depend on the hippocampal complex, regardless of the age of the memory. We examined the participation of the hippocampal complex in a functional magnetic resonance imaging (fMRI) study in which participants were asked to recollect autobiographical events that occurred either within the last 4 years or more than 20 years ago. We found equivalent levels of hippocampal activation in both conditions in all participants (N = 10). In addition, activation in neocortical regions did not differ as a function of the age of the memory, even though most of the recent memories recalled were less than 2 years old and the remote memories more than 35 years old. The results support the notion that the hippocampal complex participates in retention and recovery of even very old autobiographical memories, and place boundary conditions on theories of memory consolidation. © 2001 Wiley-Liss, Inc.
• Reinke, K. S., Ryan, L., Fuglevand, A., Johnson, J., Trouard, T., Schnyer, D., & Weerd, P. D. (2000). Activation of motor areas during bimanual finger tapping: An FMRI study. NeuroImage, 11(5 PART II), S813.
• Schnyer, D., Ryan, L., & Trouard, T. (2000). An event-related fMRI examination of format specific word priming. NeuroImage, 11(5 PART II), S428.
• Trouard, T. P. (1999). Influence of cholesterol on dynamics of dimyristoylphosphatidylcholine bilayers as studied by deuterium NMR relaxation. Journal of Chemical Physics, 110(17), 8802-8818.
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  Abstract: Investigation of the deuterium (2H) nuclear magnetic resonance (NMR) relaxation rates of lipid bilayers containing cholesterol can yield new insights regarding its role in membrane function and dynamics. Spin-lattice (R1Z) and quadrupolar order (R1Q) 2H NMR relaxation rates were measured at 46.1 and 76.8 MHz for macroscopically oriented bilayers of 1,2-diperdeuterio-myristoyl-sn-glycero-3-priosphocholine (DMPC-d54) containing cholesterol (1/1 molar ratio) in the liquid-ordered phase at 40 °C. The data for various segmental positions along the DMPC-d54 acyl chain were simultaneously fitted to a composite membrane deformation model, including fast segmental motions which preaverage the coupling tensor along the lipid acyl chain, slow molecular reorientations, and small-amplitude collective fluctuations. In contrast to pure DMPC-d54 in the liquid-crystalline (Lα) phase, for the DMPC-d54:cholesterol (1/1) system a linear square-law functional dependence of the relaxation rates on the order parameter (quadrupolar splitting) does not appear evident. Moreover, for acyl segments closer to the top of the chain, the angular anisotropy of the 2H R1Z and R1Q relaxation rates is more pronounced than toward the chain terminus. The residual (preaveraged) coupling tensor has its greatest effective asymmetry parameter near the polar groups, decreasing for the groups closest to the end of the chain. The results suggest that axial rotations of the phospholipid molecules occur at a somewhat higher rate than in pure bilayers, as a consequence of the higher ordering and reduction of chain entanglement. On the other hand, the rigid cholesterol molecule appears to undergo somewhat slower axial rotation, possibly due to its noncylindrical shape. Collective motions are found to be less predominant in the case of DMPC-d54:cholesterol than for pure DMPC-d54, which may indicate an increased dynamical rigidity of lipid bilayers containing cholesterol versus pure lipid systems. © 1999 American Institute of Physics.
• Trouard, T. P., Theilmann, R. J., Altbach, M. I., & Gmitro, A. F. (1999). High-resolution diffusion imaging with DIFRAD-FSE (diffusion-weighted radial acquisition of data with fast spin-echo) MRI. Magnetic Resonance in Medicine, 42(1), 11-18.
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  PMID: 10398944;Abstract: A novel MRI method, DIFRAD-FSE (diffusion-weighted radial acquisition of data with fast spin-echo), is demonstrated that enables rapid, high- resolution multi-shot diffusion-weighted MRI without significant artifacts due to motion. Following a diffusion-weighting spin-echo preparation period, multiple radial lines of Fourier data are acquired using spin-echo refocusing. Images can be reconstructed from the radial data set using a magnitude-only filtered back-projection reconstruction algorithm that removes phase errors due to motion. Results from human brain imaging demonstrate the ability of DIFRAD-FSE to acquire multiple radial lines of Fourier data each TR period without significant artifacts due to relaxation and to produce high-resolution diffusion-weighted MR images without significant artifacts from motion.
• Unger, E. C., Shen, D., Guanli, W. u., Stewart, L., Matsunaga, T. O., & Trouard, T. P. (1999). Gadolinium-containing copolymeric chelates - A new potential MR contrast agent. Magnetic Resonance Materials in Physics, Biology and Medicine, 8(3), 154-162.
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  PMID: 10504042;Abstract: Rationale and objectives: To develop and partially characterize a new class of potential blood pool magnetic resonance (MR) contrast agents. Methods: Various copolymeric chelates of gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) were prepared with differing molecular weights of polyethylene glycol (PEG) or polypropylene glycol (PPG) as linkers between the monomeric chelate units. Gadolinium content of the polymeric chelates was determined by atomic absorption spectra. Relaxivity of the polymeric chelates was measured at 1.5 Tesla and compared with Gadolinium-DTPA. MR angiography (MRA) was performed in rabbits comparing Gd-DTPA with Gd-copolymers. Results: The gadolinium content of the copolymeric chelates ranged from 2.95 to 22.2% on weight basis. The molecular weight of the PEG linkers in the copolymers ranged from about 150 to about 3400. The r1 (1/T1, mM-1 s-1) for Gd-DTPA = 4.1. The r1 values for the different Gd-containing polymers ranged from 3.8 to 5.8, with the lowest r1 for the polymer prepared with the lowest- molecular-weight complex. The higher-molecular-weight complexes resulted in moderately higher relaxivity. MRA with Gd-copolymers, in rabbits, showed markedly greater vascular enhancement relative to an equivalent dose of Gd- DTPA. Vascular enhancement was much more sustained with the copolymeric agent and confined to vascular space; i.e. no appreciable background tissue enhancement - a reflection of distribution into extravascular fluid space - was observed. Conclusions: Relative to Gd-DTPA monomers, PEG-containing Gd- DTPA polymeric complexes provided moderate increases in relaxivity but markedly greater efficacy during in vivo MRA. In vitro relaxivity studies of Gd-copolymers showed only an approximately 50% increase in r1 relaxivity compared with Gd-DTPA. The PEG-containing complex's lack of rigidity may have diminished the effect of spin diffusion on relaxation, thereby accounting for this modest increase. The greater efficacy of Gd-copolymers during in vivo MRA may reflect compartmentalization within the vascular space and possibly enhanced relaxation of the macromolecular copolymers in the blood. Gd- copolymers are promising agents that merit additional study.
• Nevzorov, A. A., Trouard, T. P., & Brown, M. F. (1998). Lipid bilayer dynamics from simultaneous analysis of orientation and frequency dependence of deuterium spin-lattice and quadrupolar order relaxation. Physical Review E - Statistical Physics, Plasmas, Fluids, and Related Interdisciplinary Topics, 58(2 SUPPL. B), 2259-2281.
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  Abstract: Simultaneous analysis of the deuterium (2H) NMR spin relaxation rates of lipid bilayers as a function of both frequency and sample orientation may be decisive in evaluating different models for the dynamics of membranes. Angular dependent 2H spin-lattice (R1Z) and quadrupolar order (R1Q) 2H relaxation rates have been measured at 46.1 and 76.8 MHz for macroscopically oriented bilayers of 1,2-diperdeuteriomyristoylsn-glycero-3-phosphocholine (DMPC-d54), with perdeuterated acyl chains, in the liquid-crystalline (Lα) state. The data have been simultaneously fitted to various dynamical models, together with frequency dependent 2H R1Z data for vesicles of specifically 2H-labeled DMPC. The same mechanism for the nuclear spin relaxation in lipids has been assumed for both oriented bilayers and vesicles, except for the presence of orientational averaging and a possible contribution from vesicle tumbling in the latter case. A noncollective model describing individual molecular reorientations in the presence of a potential of mean torque is able to adequately account for the orientation dependence; however, the quality of the fits to the frequency dispersion is less satisfactory. By contrast, a three-dimensional director fluctuation model accounts for the frequency dispersion for DMPC vesicles, but does not fit the orientation dependence of the R1Z and R1Q relaxation data. Higher-order director fluctuations have also been included, which do not significantly improve the quality of the fits to the collective model. Therefore, a composite membrane model is proposed including both noncollective molecular motions and director fluctuations. The model adequately describes both the frequency and orientation dependent data along the entire acyl chain simultaneously, which suggests that both dynamical processes can be detected by analyzing the 2H NMR relaxation rates in the MHz range. Quantitative information about the bilayer dynamics including lipid reorientation rates, degree of molecular ordering, relative contributions from collective and noncollective motions, and director-frame spectral densities of motion has been obtained. The results suggest the bilayer dynamics in the MHz regime reflect molecular reorientations that are superimposed onto nematiclike deformations of the membrane interior in the liquid crystalline state.
• Srisiri, W., Benedicto, A., O'Brien, D. F., Trouard, T. P., Orädd, G., Persson, S., & Lindblom, G. (1998). Stabilization of a bicontinuous cubic phase from polymerizable monoacylglycerol and diacylglycerol. Langmuir, 14(7), 1921-1926.
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  Abstract: Technological applications of lipids may be possible through stabilization of various liquid-crystalline phases. One important approach to stabilized self-assembling materials utilizes polymerization of liquid-crystalline phases composed of reactive lipids. Polymerization of lipids has been utilized to modify the chemical and physical properties of lamellar assemblies (e.g., lipid monolayers, multilayers, and bilayer vesicles). In addition, polymerization of the lipid region of three-dimensional nonlamellar lipid-phase structures has recently been reported, including the reversed bicontinuous cubic (QII) phase, belonging to the space group Pn3m and the reversed hexagonal (HII) phase. Here we show that an easily prepared polymerizable monoacylglycerol combined in a 9/1 molar ratio with the corresponding polymerizable 1,2-diacylglycerol forms nonlamellar phases upon hydration at room temperature. Phase investigation using cross-polarized light, 2H NMR spectroscopy, and X-ray diffraction showed that the lipid mixture formed a well-defined cubic phase from at least 5 to 45 °C. The X-ray diffraction pattern corresponded to a cubic phase with Ia3d symmetry and a unit cell size of 131 Å at 25 °C. Polymerization to high conversion of this cubic phase was accomplished via the thermal decomposition of H2O2. The resultant polymers dissolved in organic solvent, indicating they were not cross-linked. The visual clear character, cross-polarized light test, and X-ray diffraction showed that isotropic architecture was maintained up to at least 70 °C after sample polymerization. The diffusion coefficient of water (23 °C) within the polymerized cubic phase, determined by pulsed field gradient NMR spectroscopy, was 1.2 ± 0.2 × 10-10m2/s, a value consistent with retention of the cubic phase during and after the polymerization. The biocompatible and mesoporous nature of the polymerized cubic phase suggests it could be used as the host for incorporation of synthetic or biological molecules in a manner that has already proven especially useful in microporous solids.
• Nevzorov, A. A., Trouard, T. P., & Brown, M. F. (1997). Correlation functions for lipid membrane dynamics obtained from NMR spectroscopy. Physical Review E - Statistical Physics, Plasmas, Fluids, and Related Interdisciplinary Topics, 55(3 SUPPL. B), 3276-3282.
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  Abstract: Nuclear magnetic resonance (NMR) studies of the spin relaxation of lipid membranes provide a powerful tool for investigating the dynamics of these important biological structural elements. Here spectral densities of motion for various dynamical models have been fitted to 2H spin-lattice relaxation rates (R1Z) measured for vesicles for 1,2-dimyristoyl-sn-glycero-3-phosphocholine, in the liquid-crystalline state, over a broad frequency range (2.50-95.3 MHz; total of 15 magnetic-field strengths). Moreover, the corresponding 13C R1Z values predicted from the models have been compared to experiment from 15.0 to 151 MHz, thereby enabling unification of the NMR relaxation data for bilayer lipids. A molecular diffusion model or alternatively a three-dimensional collective fluctuation model describes best the 2H and 13C R1Z data. To emphasize the universality of this approach, the models have also been fitted to 13C R1Z data for vesicles of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (15.0-151 MHz; eight magnetic field strengths), and the 2H R1Z values for the corresponding multilamellar dispersions theoretically predicted. Correlation functions have been calculated for the lipid reorientations from the analysis of NMR relaxation data. The results suggest that slower motions are predominant in the low to mid megahertz range due to noncollective molecular motions or thermal collective excitations, whereas the bilayer interior corresponds to liquid hydrocarbon. The reorientational correlation functions derived from NMR spectroscopy are compared to recent molecular-dynamics simulations of bilayer lipids in the fluid phase.
• Trouard, T. P., Altbach, M. I., Hunter, G. C., Eskelson, C. D., & Gmitro, A. F. (1997). MRI and NMR spectroscopy of the lipids of atherosclerotic plaque in rabbits and humans. Magnetic Resonance in Medicine, 38(1), 19-26.
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  PMID: 9211375;Abstract: The early stages of atherosclerosis are characterized by the deposition of cholesteryl esters and triglycerides into the arterial wall. In the excised human atherosclerotic plaque these lipids are in a liquid-like state at body temperature and observable via MRI and NMR spectroscopy. To assess the ability of MRI to quantitatively image the lipids of atherosclerotic plaque in vivo, we have investigated eight New Zealand White rabbits fed atherogenic diets (2 weight (wt)% cholesterol, 1 wt% cholesterol + 6 wt% peanut oil, and 1 wt% cholesterol + 6 wt% corn oil). Postmortem examination indicated that all rabbits developed atherosclerosis in the aorta. Except for one animal, magnetic resonance angiography showed no noticeable obstruction in the aorta. MRI was carried out in an attempt to image atherosclerotic plaque lipids directly, but no signal was detected in vivo. However, a plaque lipid signal was observed from excised tissue using a small diameter RF coil. 1H NMR spectroscopy of the atherosclerotic plaque from excised aortas indicated that the major fraction of plaque lipids in rabbits is not in a liquid state at physiological temperature and are only marginally MRI- visible compared to human plaque lipid. The differences in the MRI characteristics of rabbit and human plaque are due to differences in the fatty acid profile of the cholesteryl esters, chiefly a decrease of linoleic acid in rabbit lesions.
• Galons, J., Trouard, T., Gmitro, A. F., & Lien, Y. H. (1996). Hemodialysis increases apparent diffusion coefficient of brain water in nephrectomized rats measured by isotropic diffusion-weighted magnetic resonance imaging. Journal of Clinical Investigation, 98(3), 750-755.
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  PMID: 8698867;PMCID: PMC507485;Abstract: The nature of brain edema in dialysis disequilibrium syndrome (DDS) was investigated by diffusion-weighted magnetic resonance imaging ((DWI). DWI was performed on normal or bilaterally nephrectomized rats before, and immediately after, hemodialysis. Hemodialysis was performed with a custom- made dialyzer (surface area 150 cm2) against a bicarbonate-buffered bath for 90 min with or without 70 mM urea. Hemodialysis with non-urea bath decreased plasma urea by 21 mM, and plasma osmolality by 22 mos-mol/kg H2O, and increased brain water content by 8.0% (all P < 0.05), while hemodialysis with urea bath did no affect plasma urea, osmolality, or brain water content. Three sets of axial DWI images of the brain were obtained at different gradient weighing factors with an in-plane resolution of 0.39 mm2. The apparent diffusion coefficient (D(app)) of the brain water was not affected by bilateral nephrectomy, or by hemodialysis in normal rats. In nephrectomized rats, brain D(app) was significantly increased after dialysis with non-urea bath (1.15 ± 0.08 vs. 0.89 ± 0.07 x 10-9m2/sec, P < 0.01). No significant changes of brain water D(app) could be observed after dialysis with urea bath. The increased D(app) associated with DDS indicates that brain extracellular water increases and/or intracellular water decreases after hemodialysis. Our results strongly suggest that the brain edema induced by hemodialysis in uremic rats is due to interstitial edema rather than cytotoxic edema. Furthermore, our results support a primary role for the 'reverse urea effect' in the pathogenesis of brain edema in DDS. DWI may be a useful diagnostic tool for DDS in patients with end-stage renal disease.
• Morein, S., Trouard, T. P., Hauksson, J. B., Rilfors, L., Arvidson, G., & Lindblom, G. (1996). Two-dimensional ¹H-NMR of transmembrane peptides from Escherichia coli phosphatidylglycerophosphate synthase in micelles. European Journal of Biochemistry, 241(2), 489-497.
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  PMID: 8917447;Abstract: Two 28-residue peptides, PTLLTLFRVILIPFFVLVFYKKKGKKKG [Pgs-(6-25)-peptidyl-KKKGKKKG; Pgs peptide A] and VEYAGIALFFVAAVLTLWSMLQYLSAAR [Pgs-(149-176)-peptide, Pgs peptide E], were synthesized and studied by CD and two-dimensional 1H-NMR spectroscopy. The first 20 amino acid residues of Pgs peptide A are identical to one predicted transmembrane segment (Pro6-Tyr25) of the integral membrane protein phosphatidylglycerophosphate synthase (Pgs) of Escherichia coli. Pgs peptide E is identical to another predicted transmembrane segment (Val149-Arg176), which is located in the C-terminal end of this lipid synthase. Pgs peptides A and E were dissolved in methanol or trifluoroethanol or were incorporated into solvent-free micelles of fully deuterated SDS. In all these systems, CD spectra of both peptides indicated an α-helical secondary structure. However, peptides that were solubilized in micelles exhibited the highest content of a-helix as judged from comparison of the CD spectra. Thermodynamically stable isotropic solutions at high peptide concentrations (1-3 mM) could only be obtained with the peptide incorporated in micelles; in organic solvents, significant peptide aggregation occurred. Relatively sharp peaks were obtained with 1H-NMR spectroscopy of the peptides in SDS micelles, which indicates rapid tumbling of the peptides in the micellar environment. Translational-diffusion coefficients of the micelles with and without peptide, determined by pulsed-field-gradient NMR, showed that the micellar size was unaffected by the solubilized peptide. The radius of the hydrated micelles was estimated to be about 2.7 nm (i.e. the mass of the aggregate is almost 30 kDa). Two-dimensional NMR spectroscopy of both peptides solubilized in the micelles indicated an a-helical conformation. This observation is strengthened by an investigation of the hydrogen exchange of the peptide amide protons, where significantly less exchange of the amide protons was observed in the middle of the peptides compared with the ends.
• Trouard, T. P., Sabharwal, Y., Altbach, M. I., & Gmitro, A. F. (1996). Analysis and comparison of motion-correction techniques in Diffusion-Weighted Imaging. Journal of Magnetic Resonance Imaging, 6(6), 925-935.
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  PMID: 8956139;Abstract: Motion continues to be a significant problem in MRI, producing image artifacts that can severely degrade image quality. In diffusion-weighted imaging (DWI), the problem is amplified by the presence of large gradient fields used to produce the diffusion weighting. Three correction methods applicable for correction of specific classes of motion are described and compared. The first is based on a generalized projection onto convex sets (GPOCS) postprocessing algorithm. The second technique uses the collection of navigator echoes to track phase errors. The third technique is based on a radial-scan data acquisition combined with a modified projection-reconstruction algorithm. Although each technique corrects well for translations, the radial-scan method proves to be more robust when more complex motions are present. A detailed description of the causes of MR data errors caused by rigid body motion is included as an appendix. © ISMRM, 1996.
• Killian, J., Trouard, T. P., Greathouse, D. V., Chupin, V., & Lindblom, G. (1994). A general method for the preparation of mixed micelles of hydrophobic peptides and sodium dodecyl sulphate. FEBS Letters, 348(2), 161-165.
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  PMID: 8034033;Abstract: A new method is reported for the incorporation of hydrophobic peptides into sodium dodecyl sulphate (SDS) micelles. First, a homogeneous solution of peptide and detergent is obtained by adding the peptide in trifluoroethanol to an equal volume of an aqueous solution of SDS. Upon subsequent addition of excess water, mixed peptide-SDS micelles are formed. Next, all solvent is removed by lyophilization and an appropriate amount of water is added to the dry powder. For various hydrophobic peptides this was shown to yield clear and stable solutions that are highly concentrated and suitable for characterization by spectroscopic techniques. © 1994.
• Trouard, T. P., Alam, T. M., & Brown, M. F. (1994). Angular dependence of deuterium spin-lattice relaxation rates of macroscopically oriented dilauroylphosphatidylcholine in the liquid-crystalline state. The Journal of Chemical Physics, 101(6), 5229-5261.
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  Abstract: Deuterium (2H) NMR relaxation plays a major role in the study of lipid reorientational dynamics, with the angular dependence of the relaxation rates providing a novel and critical test of proposed motional models. Spin-lattice relaxation rates (R1Z) were measured for macroscopically oriented bilayers of 1,2-diperdeuteriolauroyl-sn-glycero-3-phosphocholine (DLPC-d46) in the liquid-crystalline (Lα) phase. The results for different positions along the chain (index i) were dependent on the angle θ between the macroscopic bilayer normal and the static external magnetic field, and allowed the anisotropy of R1Z(i) to be determined for nine resolved quadrupolar resonances. Angular-dependent relaxation data were evaluated using simple models of anisotropic rotational diffusion within an odd or even potential of mean torque as a framework for describing (i) segmental reorientations of the chains, or alternatively (ii) noncollective molecular motions within the bilayer. Moreover, (iii) a simple quasi-hydrodynamic formulation involving collective fluctuations of a local director axis was considered (continuum model). For segmental motions the static electric field gradient (EFG) tensor due to the electronic structure of the C-2H bond is averaged by local reorientations of the acyl chains, e.g., due to trans-gauche rotational isomerizations and/or torsional oscillations. The second and third formulations assume the static EFG tensor is preaveraged by local motions, yielding a residual EFG tensor which is further modulated by order fluctuations due to relatively slow motions of larger amplitude; separation of time scales is implicit. The latter treatments differ in that the molecular model allows for variation in both the principal values and principal axes of the residual EFG tensor, and includes the possibility of a nonzero effective asymmetry parameter ηeff. By contrast, the collective model considers an axially symmetric residual EFG tensor (ηeff=0), in which the relatively slow motions are described in terms of continuum fluctuations of a local director axis within the small-angle approximation. Each of the three models can account for the observed angular anisotropy of the R1Z(i) relaxation rates along the chains to a greater or lesser degree of success, depending on the number of adjustable parameters. The collective formulation has the fewest parameters and may be an oversimplification for description of the relaxation anisotropy. In addition, for each bilayer orientation, profiles of the relaxation rates R 1Z(i) and order parameters |SCD(i)| as a function of acyl position exhibited a square-law functional dependence within experimental error. This observation points to an influence on the relaxation arising from relatively slow fluctuations in the order gradient set up along the chains by faster internal motions, viz. order fluctuations due to noncollective molecular motions or collective excitations of the bilayer. Finally, the rather small contribution from local internal motions suggests that the microviscosity of the bilayer interior corresponds to essentially liquid hydrocarbon. These new results illustrate the utility of R1Z(i) angular anisotropies of phospholipids having perdeuterated acyl chains in experimental and theoretical investigations of molecular dynamics in liquid-crystalline bilayers. The implications of the findings in relation to previous biophysical studies of membranes are discussed. © 1994 American Institute of Physics.
• Trouard, T. P., Mannock, D. A., Lindblom, G., Rilfors, L., Akiyama, M., & McElhaney, R. N. (1994). Thermotropic phase properties of 1,2-di-O-tetradecyl-3-O-(3-O-methyl-β- D-glucopyranosyl)-sn-glycerol. Biophysical Journal, 67(3), 1090-1100.
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  PMID: 7811919;PMCID: PMC1225461;Abstract: The hydration properties and the phase structure of 1,2-di-O-tetradecyl- 3-O-(3-O-methyl-β-D-glucopyranosyl)-sn-glycerol (3-O-Me-β-D-GlcDAlG) in water have been studied via differential scanning calorimetry, 1H-NMR and 2H-NMR spectroscopy, and x-ray diffraction. Results indicate that this lipid forms a crystalline (L(c)) phase up to temperatures of 60-70°C, where a transition through a metastable reversed hexagonal (H(II)) phase to a reversed micellar solution (L2) phase occurs. Experiments were carried out at water concentrations in a range from 0 to 35 wt %, which indicate that all phases are poorly hydrated, taking up
• Barry, J. A., Trouard, T. P., Salmon, A., & Brown, M. F. (1992). Erratum: Low-temperature ²H NMR spectroscopy of phospholipid bilayers containing docosahexaenoyl (22:6ω3) chains (Biochemistry (August 27, 1991) 30 (8386-8394)). Biochemistry, 31(7), 2187-.
• Trouard, T. P., Alam, T. M., Zajicek, J., & Brown, M. F. (1992). Angular anisotropy of ²H NMR spectral densities in phospholipid bilayers containing cholesterol. Chemical Physics Letters, 189(1), 67-75.
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  Abstract: Spin-lattice (R1Z) and quadrupolar order (R1Q) relaxation rates were measured for bilayers of macroscopically oriented 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC-d54) containing cholesterol (1:1 molar ratio), using inversion recovery and broadband Jeener-Broekaert pulse sequences, respectively. Anisotropic deuterium (2H) NMR spin relaxation data were obtained for the first time along the entire flexible acyl chains of the phospholipid molecules in the liquid-crystalline state. Individual spectral densities J1(ω0) and J2(2ω0) were calculated from these relaxation rates, and a strong dependence on the angle θ between the macroscopic bilayer normal and the static magnetic field was observed. The spectral densities exhibited opposite angular anisotropies, which were explained in terms of a simple rotational diffusion model for the molecular dynamics of membrane lipid constituents. © 1992.
• Jansson, M., Thurmond, R. L., Trouard, T. P., & Brown, M. F. (1990). Magnetic alignment and orientational order of dipalmitoylphosphatidylcholine bilayers containing palmitoyllsyophosphatidylcholine. Chemistry and Physics of Lipids, 54(3-4), 157-170.
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  PMID: 2225236;Abstract: Mixed bilayers of 1-palmitoyl-sn-glycero-3-phosphocholine (palmitoyllysophosphatidylcholine; PaLPC) and 1,2-dipalmitoyl-sn- glycero-3-phosphocholine (dipalmitoyl phosphatidylcholine; DPPC) have been investigated by 2H-NMR and 31P-NMR spectroscopy. Binary phospholipid mixtures were studied in which the acyl chains of one or the other component were perdeuterated. At temperatures below the main order-disorder phase transition, the mixed PaLPC/DPPC bilayers appear to coexist with PaLPC micelles. The micelles disappear at temperatures above the phase transition, where mixed bilayers in the liquid-crystalline state are formed. The orientational order of the alkyl chains of the PaLPC component is essentially identical to that of the DPPC component in the mixed bilayers, both in the low temperature and liquid-crystalline phase. However, the presence of PaLPC perturbs the segmental ordering of DPPC as compared to the pure system. The order is increased in the low-temperature phase, where effective diffusion of the chains about their long axes occurs, but is decreased in the liquid-crystalline phase compared to pure DPPC bilayers. The mixed liquid-crystalline bilayers orient preferentially with their director axes perpendicular to the magnetic field. This alignment is easily observed in 31P- and 2H-NMR spectra, where the intensity of the perpendicular edges of the lineshapes is pronounced. One possible explanation of the magnetic alignment involves alteration of the curvature free energy of the DPPC bilayer due to incorporation of PaLPC in the mixed membranes. © 1990.
• Scher, R. L., Ropka, M. E., Neal, D. A., Berr, S., Trouard, T., Deutsch, B., Cantrell, R. W., & Levine, P. A. (1990). NMR spectroscopy evaluation of plasma 'oncolipids' in head and neck cancer. Otolaryngology - Head and Neck Surgery, 102(1), 34-40.
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  PMID: 2106116;Abstract: The use of water-suppressed proton nuclear magnetic resonance spectroscopy of plasma as a serologic test for the detection of malignancy was first described in 1986. That report prompted the present study, which was undertaken to evaluate the efficacy of this test in differentiating patients who have head and neck malignancy from normal controls. Forty-six patients who had a biopsy-proven malignancy of the head and neck and 32 healthy individuals provided plasma for which the nuclear magnetic resonance spectrum was plotted, blind to patient diagnosis or group. The average line-width of methyl and methylene resonance was calculated. Significant differences (p
• Wiedmann, T. S., Trouard, T., Shekar, S. C., Polikandritou, M., & Rahman, Y. (1990). Interaction of cyclosporin A with dipalmitoylphosphatidylcholine. BBA - Biomembranes, 1023(1), 12-18.
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  PMID: 2317490;Abstract: Cyclosporin A, a hydrophobic cyclic peptide, is a potent immunosuppressant. In an attempt to determine the localization of cyclosporin A in phospholipid membranes, the effect of cyclosporin A on dipalmitoylphosphatidylcholine (DPPC) has been investigated using deuterium nuclear magnetic resonance (2H-NMR) spectroscopy and differential scanning calorimetry (DSC). Cyclosporin A was dispersed within acyl chain per-deuterated DPPC at a concentration of 6 mole percent, hydrated with buffer, and the spectra obtained over a range of temperatures were compared with that of pure DPPC. The changes caused by cyclosporin A were assessed by the first moment (M1) and order parameters calculated from the spectra. The presence of cyclosporin A decreases the magnitude of M1 at temperatures below the gel to liquid-crystalline state, cyclosporin A causes an increase in the order parameters along the acyl chains which suggests that cyclosporin A is located along the acyl chains of the phospholipid. For DSC, cyclosporin A was dispersed in non-deuterated DPPC at different peptide to phospholipid mole ratios. The endothermic peaks associated with the gel to liquid-cystalline phase transition and pretransition were recorded and compared with similar mole ratios of cholesterol to lipid. At 30 mole percent cyclosporin A, small decreases in the main transition temperature and associated enthalpy were observed, whereas at 30 mole percent cholesterol, the main transition is barely distinguishable from the baseline. The pretransition was not observed with the addition of 11 mole percent of either cyclosporin A or cholesterol. The results of the thermal analysis indicate that although cyclosporin A and cholesterol appear to be both located along the acyl chains of the phospholipids, they have dramatically different interactions with the membrane lipids. © 1990.

Proceedings Publications

• Bilgin, A., Do, L., Martin, P. A., Lockhart, E., Bernstein, A. S., Ugonna, C., Dieckhaus, L., Comrie, C., Hutchinson, E. B., Chen, N., Alexander, G. E., Barnes, C. A., & Trouard, T. P. (2021). Accelerating Diffusion Tensor Imaging of the Rat Brain using Deep Learning. In Annual Meeting of the International Society for Magnetic Resonance in Medicine.
• Lindley, M., Bernstein, A. S., McKinnon, A., Ugonna, C., Bruck, D., Johnson, K., Altbach, M. I., Ryan, T. L., Guzman Perez-Carrillo, G., Chen, N., Chou, Y., Trouard, T. P., & Weinkauf, C. C. (2019, Spring). Functional and Microstructural Changes in the Brain After Carotid Endarterectomy. In International Society for Magnetic Resonance in Medicine.
• Terrazas, A., Pyon, W., Zempare, M., Young, K., Dalmendray, A., Do, L., David, B., Bohne, K., Caey, N., Chawla, M., Trouard, T. P., Worley, P., & Barnes, C. (2019, Fall). Effects of NPTX2 knockout on behavior, brain volume by MRI and CA1 hippocampal single unit properties. In Society for Neuroscience.
• Zempare, M., Carey, N., Dalmendray, A., Young, K., Bohne, K., Do, L., Trouard, T. P., Mitchell, K., Chawla, M., Huentelman, M., & Barnes, C. (2019, Fall). Effects of induced hypertension in middle aged CYP1A1-REN2 transgenic rats. In Society for Neuroscience.
• Bernstein, A., Chen, N., & Trouard, T. P. (2018, June). A Bootstrap Analysis of Diffusion MRI Parameters Derived from Simultaneous Multislice Diffusion MRI. In Joint International Society for Magnetic Resonance in Medicine & The European Society for Magnetic Resonance in Medicine and Biology (ISMRM-ESMRMB) Annual Meeting.
• Chen, N., Trouard, T. P., Bernstein, A., Chang, H. C., Bilgin, A., Bilgin, A., Chang, H. C., Bernstein, A., Trouard, T. P., & Chen, N. (2018, June). A diffusion-matched principal component analysis (DM-PCA) based denoising procedure for high-resolution diffusion-weighted MRI. In Joint International Society for Magnetic Resonance in Medicine & The European Society for Magnetic Resonance in Medicine and Biology (ISMRM-ESMRMB) Annual Meeting.
• Lindley, M., Bernstein, A., Ugonna, C., Bruck, D., Johnson, K., Altbach, M. I., Ryan, L., Chen, N., Chou, Y., Guzman Perez-Carrillo, G., Trouard, T. P., & Weinkauf, C. C. (2018, June). Impact of Carotid Endarterectomy on Functional Connectivity. In Joint International Society for Magnetic Resonance in Medicine & The European Society for Magnetic Resonance in Medicine and Biology (ISMRM-ESMRMB) Annual Meeting, 5562.

Presentations

• Do, L., Bernstein, A., Bharadwaj, P. K., Alexander, G. E., Barnes, C. A., & Trouard, T. P. (2017, November). Advanced Techniques for Characterizing Rodent Brains with Diffusion MRI. Neuroscience 2017. Washington, DC: Society for Neuroscience.
• Do, L., Bernstein, A., Xiao, J., Barnes, C. A., Alexander, G. E., & Trouard, T. P. (2017, October). Advanced Techniques for Characterizing Rodent Brains with Diffusion MRI. Biomedical Engineering Society Meeting. Phoenix AZ: BMES.

Poster Presentations

• Bernstein, A., Pokorney, A., Hu, H., Miller, J., Duncan, B. R., & Trouard, T. P. (2017, April). Constrained Spherical Deconvolution Has the Potential to Better Characterize Neuronal Structure in Cerebral Palsy Before and After Therapy.. International Society for Magnetic Resonance in Medicine. Honolulu HI.
• Do, L., Bernstein, A., Alexander, G. E., Barnes, C. A., & Trouard, T. P. (2017, November). Advanced Techniques for Characterizing Rodent Brains with Diffusion MRI.. Society for Neuroscience. Washington DC: SFN.
• Do, L., Do, L., Bharadwaj, P., Bharadwaj, P., Bernstein, A., Bernstein, A., Xiao, J., Xiao, J., Alexander, G. E., Alexander, G. E., Barnes, C. A., Barnes, C. A., Trouard, T. P., & Trouard, T. P. (2017, May). Bias Correction Method Improves Automatic Brain Extraction in Rodent MR Imaging. Arizona Alzheimer's Consortium Scientific MeetingArizona Alzheimer's Consortium.
• Wheeler, G., Do, L., Zhou, W., & Trouard, T. P. (2017, November). Semi-automated Analysis of Microembolic Lesions in Brain Diffusion Weighted MRI. University of Arizona College of Medicine Junior Investigators Forum. Tucson: University of Arizona College of MEdicine.
• Wheeler, G., Do, L., Zhou, W., & Trouard, T. P. (2017, October). Semi-automated Analysis of Microembolic Lesions in Brain Diffusion Weighted MRI. Biomedical Engineering Society Annual Meeting. Phoenix AZ.