24 results on '"Caroline D. Rae"'
Search Results
2. Frequency drift in MR spectroscopy at 3T
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Steve C.N. Hui, Mark Mikkelsen, Helge J. Zöllner, Vishwadeep Ahluwalia, Sarael Alcauter, Laima Baltusis, Deborah A. Barany, Laura R. Barlow, Robert Becker, Jeffrey I. Berman, Adam Berrington, Pallab K. Bhattacharyya, Jakob Udby Blicher, Wolfgang Bogner, Mark S. Brown, Vince D. Calhoun, Ryan Castillo, Kim M. Cecil, Yeo Bi Choi, Winnie C.W. Chu, William T. Clarke, Alexander R. Craven, Koen Cuypers, Michael Dacko, Camilo de la Fuente-Sandoval, Patricia Desmond, Aleksandra Domagalik, Julien Dumont, Niall W. Duncan, Ulrike Dydak, Katherine Dyke, David A. Edmondson, Gabriele Ende, Lars Ersland, C. John Evans, Alan S.R. Fermin, Antonio Ferretti, Ariane Fillmer, Tao Gong, Ian Greenhouse, James T. Grist, Meng Gu, Ashley D. Harris, Katarzyna Hat, Stefanie Heba, Eva Heckova, John P. Hegarty, II, Kirstin-Friederike Heise, Shiori Honda, Aaron Jacobson, Jacobus F.A. Jansen, Christopher W. Jenkins, Stephen J. Johnston, Christoph Juchem, Alayar Kangarlu, Adam B. Kerr, Karl Landheer, Thomas Lange, Phil Lee, Swati Rane Levendovszky, Catherine Limperopoulos, Feng Liu, William Lloyd, David J. Lythgoe, Maro G. Machizawa, Erin L. MacMillan, Richard J. Maddock, Andrei V. Manzhurtsev, María L. Martinez-Gudino, Jack J. Miller, Heline Mirzakhanian, Marta Moreno-Ortega, Paul G. Mullins, Shinichiro Nakajima, Jamie Near, Ralph Noeske, Wibeke Nordhøy, Georg Oeltzschner, Raul Osorio-Duran, Maria C.G. Otaduy, Erick H. Pasaye, Ronald Peeters, Scott J. Peltier, Ulrich Pilatus, Nenad Polomac, Eric C. Porges, Subechhya Pradhan, James Joseph Prisciandaro, Nicolaas A Puts, Caroline D. Rae, Francisco Reyes-Madrigal, Timothy P.L. Roberts, Caroline E. Robertson, Jens T. Rosenberg, Diana-Georgiana Rotaru, Ruth L O'Gorman Tuura, Muhammad G. Saleh, Kristian Sandberg, Ryan Sangill, Keith Schembri, Anouk Schrantee, Natalia A. Semenova, Debra Singel, Rouslan Sitnikov, Jolinda Smith, Yulu Song, Craig Stark, Diederick Stoffers, Stephan P. Swinnen, Rongwen Tain, Costin Tanase, Sofie Tapper, Martin Tegenthoff, Thomas Thiel, Marc Thioux, Peter Truong, Pim van Dijk, Nolan Vella, Rishma Vidyasagar, Andrej Vovk, Guangbin Wang, Lars T. Westlye, Timothy K. Wilbur, William R. Willoughby, Martin Wilson, Hans-Jörg Wittsack, Adam J. Woods, Yen-Chien Wu, Junqian Xu, Maria Yanez Lopez, David K.W. Yeung, Qun Zhao, Xiaopeng Zhou, Gasper Zupan, and Richard A.E. Edden
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Magnetic resonance spectroscopy (MRS) ,Frequency drift ,3T ,Press ,Multi-vendor ,Multi-site ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Purpose: Heating of gradient coils and passive shim components is a common cause of instability in the B0 field, especially when gradient intensive sequences are used. The aim of the study was to set a benchmark for typical drift encountered during MR spectroscopy (MRS) to assess the need for real-time field-frequency locking on MRI scanners by comparing field drift data from a large number of sites. Method: A standardized protocol was developed for 80 participating sites using 99 3T MR scanners from 3 major vendors. Phantom water signals were acquired before and after an EPI sequence. The protocol consisted of: minimal preparatory imaging; a short pre-fMRI PRESS; a ten-minute fMRI acquisition; and a long post-fMRI PRESS acquisition. Both pre- and post-fMRI PRESS were non-water suppressed. Real-time frequency stabilization/adjustment was switched off when appropriate. Sixty scanners repeated the protocol for a second dataset. In addition, a three-hour post-fMRI MRS acquisition was performed at one site to observe change of gradient temperature and drift rate. Spectral analysis was performed using MATLAB. Frequency drift in pre-fMRI PRESS data were compared with the first 5:20 minutes and the full 30:00 minutes of data after fMRI. Median (interquartile range) drifts were measured and showed in violin plot. Paired t-tests were performed to compare frequency drift pre- and post-fMRI. A simulated in vivo spectrum was generated using FID-A to visualize the effect of the observed frequency drifts. The simulated spectrum was convolved with the frequency trace for the most extreme cases. Impacts of frequency drifts on NAA and GABA were also simulated as a function of linear drift. Data from the repeated protocol were compared with the corresponding first dataset using Pearson's and intraclass correlation coefficients (ICC). Results: Of the data collected from 99 scanners, 4 were excluded due to various reasons. Thus, data from 95 scanners were ultimately analyzed. For the first 5:20 min (64 transients), median (interquartile range) drift was 0.44 (1.29) Hz before fMRI and 0.83 (1.29) Hz after. This increased to 3.15 (4.02) Hz for the full 30 min (360 transients) run. Average drift rates were 0.29 Hz/min before fMRI and 0.43 Hz/min after. Paired t-tests indicated that drift increased after fMRI, as expected (p < 0.05). Simulated spectra convolved with the frequency drift showed that the intensity of the NAA singlet was reduced by up to 26%, 44 % and 18% for GE, Philips and Siemens scanners after fMRI, respectively. ICCs indicated good agreement between datasets acquired on separate days. The single site long acquisition showed drift rate was reduced to 0.03 Hz/min approximately three hours after fMRI. Discussion: This study analyzed frequency drift data from 95 3T MRI scanners. Median levels of drift were relatively low (5-min average under 1 Hz), but the most extreme cases suffered from higher levels of drift. The extent of drift varied across scanners which both linear and nonlinear drifts were observed.
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- 2021
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3. Impact of Inhibition of Glutamine and Alanine Transport on Cerebellar Glial and Neuronal Metabolism
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Abhijit Das, Gregory Gauthier-Coles, Stefan Bröer, and Caroline D. Rae
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glutamine ,alanine ,amino acid transporters ,Microbiology ,QR1-502 - Abstract
The cerebellum, or “little brain”, is often overlooked in studies of brain metabolism in favour of the cortex. Despite this, anomalies in cerebellar amino acid homeostasis in a range of disorders have been reported. Amino acid homeostasis is central to metabolism, providing recycling of carbon backbones and ammonia between cell types. Here, we examined the role of cerebellar amino acid transporters in the cycling of glutamine and alanine in guinea pig cerebellar slices by inhibiting amino acid transporters and examining the resultant metabolism of [1-13C]d-glucose and [1,2-13C]acetate by NMR spectroscopy and LCMS. While the lack of specific inhibitors of each transporter makes interpretation difficult, by viewing results from experiments with multiple inhibitors we can draw inferences about the major cell types and transporters involved. In cerebellum, glutamine and alanine transfer is dominated by system A, blockade of which has maximum effect on metabolism, with contributions from System N. Inhibition of neural system A isoform SNAT1 by MeAIB resulted in greatly decreased metabolite pools and reduced net fluxes but showed little effect on fluxes from [1,2-13C]acetate unlike inhibition of SNAT3 and other glutamine transporters by histidine where net fluxes from [1,2-13C]acetate are reduced by ~50%. We interpret the data as further evidence of not one but several glutamate/glutamine exchange pools. The impact of amino acid transport inhibition demonstrates that the cerebellum has tightly coupled cells and that glutamate/glutamine, as well as alanine cycling, play a major role in that part of the brain.
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- 2022
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4. Emerging Concepts in Vector Development for Glial Gene Therapy: Implications for Leukodystrophies
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Georg von Jonquieres, Caroline D. Rae, and Gary D. Housley
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leukodystrophies ,gene therapy ,glia ,adeno-associated virus ,hematopoietic stem cells ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Central Nervous System (CNS) homeostasis and function rely on intercellular synchronization of metabolic pathways. Developmental and neurochemical imbalances arising from mutations are frequently associated with devastating and often intractable neurological dysfunction. In the absence of pharmacological treatment options, but with knowledge of the genetic cause underlying the pathophysiology, gene therapy holds promise for disease control. Consideration of leukodystrophies provide a case in point; we review cell type – specific expression pattern of the disease – causing genes and reflect on genetic and cellular treatment approaches including ex vivo hematopoietic stem cell gene therapies and in vivo approaches using adeno-associated virus (AAV) vectors. We link recent advances in vectorology to glial targeting directed towards gene therapies for specific leukodystrophies and related developmental or neurometabolic disorders affecting the CNS white matter and frame strategies for therapy development in future.
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- 2021
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5. Reduced Glutamate in the Medial Prefrontal Cortex Is Associated With Emotional and Cognitive Dysregulation in People With Chronic Pain
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Brooke Naylor, Negin Hesam-Shariati, James H. McAuley, Simon Boag, Toby Newton-John, Caroline D. Rae, and Sylvia M. Gustin
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medial prefrontal cortex ,chronic pain ,spectroscopy ,glutamate ,N-acetylaspartate ,harm avoidance ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
A decrease in glutamate in the medial prefrontal cortex (mPFC) has been extensively found in animal models of chronic pain. Given that the mPFC is implicated in emotional appraisal, cognition and extinction of fear, could a potential decrease in glutamate be associated with increased pessimistic thinking, fear and worry symptoms commonly found in people with chronic pain? To clarify this question, 19 chronic pain subjects and 19 age- and gender-matched control subjects without pain underwent magnetic resonance spectroscopy. Both groups also completed the Temperament and Character, the Beck Depression and the State Anxiety Inventories to measure levels of harm avoidance, depression, and anxiety, respectively. People with chronic pain had significantly higher scores in harm avoidance, depression and anxiety compared to control subjects without pain. High levels of harm avoidance are characterized by excessive worry, pessimism, fear, doubt and fatigue. Individuals with chronic pain showed a significant decrease in mPFC glutamate levels compared to control subjects without pain. In people with chronic pain mPFC glutamate levels were significantly negatively correlated with harm avoidance scores. This means that the lower the concentration of glutamate in the mPFC, the greater the total scores of harm avoidance. High scores are associated with fearfulness, pessimism, and fatigue-proneness. We suggest that chronic pain, particularly the stress-induced release of glucocorticoids, induces changes in glutamate transmission in the mPFC, thereby influencing cognitive, and emotional processing. Thus, in people with chronic pain, regulation of fear, worry, negative thinking and fatigue is impaired.
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- 2019
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6. On the Reliability of Individual Brain Activity Networks.
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Ben Cassidy, F. DuBois Bowman, Caroline D. Rae, and Victor Solo
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- 2018
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7. Motor cortical excitability and pre‐supplementary motor area neurochemistry in healthy adults with substantia nigra hyperechogenicity
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Gabrielle Todd, Caroline D. Rae, Janet L. Taylor, Nigel C. Rogasch, Jane E. Butler, Michael Hayes, Robert A. Wilcox, Simon C. Gandevia, Karl Aoun, Adrian Esterman, Simon J. G. Lewis, Julie M. Hall, Elie Matar, Jana Godau, Daniela Berg, Christian Plewnia, Anna‐Katharina von Thaler, Clarence Chiang, Kay L. Double, Todd, Gabrielle, Rae, Caroline D, Taylor, Janet L, Rogasch, Nigel C, Butler, Jane E, Hayes, Michael, Wilcox, Robert A, Gandevia, Simon C, Aoun, Karl, Esterman, Adrian, Lewis, Simon JG, Hall, Julie M., Matar, Elie, Godau, Jana, Berg, Daniela, Plewnia, Christian, von Thaler, Anna Katharina, Chiang, Clarence, and Double, Kay L
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Cellular and Molecular Neuroscience ,substantia nigra ,motor cortex ,transcranial magnetic stimulation ,Cortical Excitability ,Motor Cortex ,Humans ,Parkinson Disease ,pre-supplementary motor area ,Aged - Abstract
Substantia nigra (SN) hyperechogenicity, viewed with transcranial ultrasound, is a risk marker for Parkinson's disease. We hypothesized that SN hyperechogenicity in healthy adults aged 50–70 years is associated with reduced short-interval intracortical inhibition in primary motor cortex, and that the reduced intracortical inhibition is associated with neurochemical markers of activity in the pre-supplementary motor area (pre-SMA). Short-interval intracortical inhibition and intracortical facilitation in primary motor cortex was assessed with paired-pulse transcranial magnetic stimulation in 23 healthy adults with normal (n = 14; 61 ± 7 yrs) or abnormally enlarged (hyperechogenic; n = 9; 60 ± 6 yrs) area of SN echogenicity. Thirteen of these participants (7 SN− and 6 SN+) also underwent brain magnetic resonance spectroscopy to investigate pre-SMA neurochemistry. There was no relationship between area of SN echogenicity and short-interval intracortical inhibition in the ipsilateral primary motor cortex. There was a significant positive relationship, however, between area of echogenicity in the right SN and the magnitude of intracortical facilitation in the right (ipsilateral) primary motor cortex (p = .005; multivariate regression), evidenced by the amplitude of the conditioned motor evoked potential (MEP) at the 10–12 ms interstimulus interval. This relationship was not present on the left side. Pre-SMA glutamate did not predict primary motor cortex inhibition or facilitation. The results suggest that SN hyperechogenicity in healthy older adults may be associated with changes in excitability of motor cortical circuitry. The results advance understanding of brain changes in healthy older adults at risk of Parkinson's disease. Refereed/Peer-reviewed
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- 2022
8. Network comparison with frequency domain persistent homology.
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Ben Cassidy, Caroline D. Rae, and Victor Solo
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- 2016
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9. Brain activity: Conditional dissimilarity and persistent homology.
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Ben Cassidy, Caroline D. Rae, and Victor Solo
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- 2015
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10. AMP‐activated protein kinase activators have compound and concentration‐specific effects on brain metabolism
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Lavanya B. Achanta, Donald S. Thomas, Gary D. Housley, and Caroline D. Rae
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Cellular and Molecular Neuroscience ,Biochemistry - Published
- 2023
11. Elevation of cell-associated HIV-1 transcripts in CSF CD4+ T cells, despite effective antiretroviral therapy, is linked to brain injury
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Kazuo Suzuki, John Zaunders, Thomas M. Gates, Angelique Levert, Shannen Butterly, Zhixin Liu, Takaomi Ishida, Sarah Palmer, Caroline D. Rae, Lauriane Jugé, Lucette A. Cysique, and Bruce J. Brew
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CD4-Positive T-Lymphocytes ,Multidisciplinary ,Brain Injuries ,HIV Seropositivity ,HIV-1 ,Leukocytes, Mononuclear ,Humans ,HIV Infections - Abstract
Antiretroviral therapy (ART) can attain prolonged undetectable HIV-1 in plasma and cerebrospinal fluid (CSF), but brain injury remains prevalent in people living with HIV-1 infection (PLHIV). We investigated cell-associated (CA)-HIV-1 RNA transcripts in cells in CSF and blood, using the highly sensitive Double-R assay, together with proton Magnetic Resonance Spectroscopy ( 1 H MRS) of major brain metabolites, in sixteen PLHIV. 14/16 CSF cell samples had quantifiable CA-HIV-1 RNA, at levels significantly higher than in their PBMCs (median 9,266 vs 185 copies /106 CD4+ T-cells; p+ CD49d + integrin β7-, CCR5 + CD4 + T-cells were highly enriched in CSF, compared with PBMC (p + T cells from blood, rather than trafficking monocytes. Future research should focus on inhibitors of this transcription to reduce local production of potentially neurotoxic and inflammatory viral products.
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- 2022
12. Brain Activity: Connectivity, Sparsity, and Mutual Information.
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Ben Cassidy, Caroline D. Rae, and Victor Solo
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- 2015
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13. Direct mapping of T2* signal changes induced by Transcranial Direct Current Stimulation.
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Ben Cassidy, Victor Solo, and Caroline D. Rae
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- 2013
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14. Time-to-Onset latency in fMRI: Fast detection of delayed activation.
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Victor Solo, Ben Cassidy, Christopher J. Long, and Caroline D. Rae
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- 2011
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15. A comprehensive guide to MEGA-PRESS for GABA measurement
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A.L. Peek, T.J. Rebbeck, A.M. Leaver, S.L. Foster, K.M. Refshauge, N.A. Puts, G. Oeltzschner, Ovidiu C. Andronesi, Peter B. Barker, Wolfgang Bogner, Kim M. Cecil, In-Young Choi, Dinesh K. Deelchand, Robin A. de Graaf, Ulrike Dydak, Richard AE. Edden, Uzay E. Emir, Ashley D. Harris, Alexander P. Lin, David J. Lythgoe, Mark Mikkelsen, Paul G. Mullins, Jamie Near, Gülin Öz, Caroline D. Rae, Melissa Terpstra, Stephen R. Williams, and Martin Wilson
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Biophysics ,Cell Biology ,Molecular Biology ,Biochemistry - Published
- 2023
16. Is Statistical Learning Affected by Sleep Apnoea?
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Joanne Arciuli, Andrew Vakulin, Angela D'Rozario, Hannah Openshaw, David J. Stevens, Doug McEvoy, Keith Wong, Caroline D. Rae, and Ron Grunstein
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- 2015
17. Identifying fMRI Model Violations With Lagrange Multiplier Tests.
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Ben Cassidy, Christopher J. Long, Caroline D. Rae, and Victor Solo
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- 2012
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18. Bootstrap quantification of cardiac pulsation artifact in DTI.
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SungWon Chung, Blandine Courcot, Michaël Sdika, Kristin Moffat, Caroline D. Rae, and Roland G. Henry
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- 2010
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19. Clinical predictors of working memory performance in obstructive sleep apnea patients before and during extended wakefulness
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David Stevens, Angela D’Rozario, Hannah Openshaw, Delwyn Bartlett, Caroline D Rae, Peter Catcheside, Keith Wong, R Doug McEvoy, Ronald R Grunstein, and Andrew Vakulin
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Adult ,Sleep Apnea, Obstructive ,Memory, Short-Term ,Polysomnography ,Physiology (medical) ,Humans ,Neurology (clinical) ,Middle Aged ,Wakefulness ,Sleep - Abstract
Study Objectives Extended wakefulness (EW) and obstructive sleep apnea (OSA) impair working memory (WM), but their combined effects are unclear. This study examined the impact of EW on WM function in OSA patients and identified clinical predictors of WM impairment. Methods Following polysomnography (PSG), 56 OSA patients (mean ± SD, age 49.5 ± 8.9, apnea hypopnea index 38.1 ± 25.0) completed WM 2-back performance tasks 10 times over 24 h of wakefulness to assess average accuracy and completion times measured after 6–12 h awake (baseline) compared to 18–24 h awake (EW). Hierarchical cluster analysis classified participants with poorer versus better WM performance at baseline and during EW. Clinical predictors of performance were examined via regression and receiver operator characteristic (ROC) analyses. Results WM performance decreased following EW and showed consistent correlations with age, Epworth Sleepiness Score (ESS), total sleep time, and hypoxemia (O2 nadir and mean O2 desaturation) at baseline and with EW (all p < .01). O2 nadir and age were significant independent predictors of performance at baseline (adjusted R2 = 0.30, p < .01), while O2 nadir and ESS were predictors of WM following EW (adjusted R2 = 0.38, p < .001). ROC analysis demonstrated high sensitivity and specificity of models to predict poorer versus better performing participants at baseline (83% and 69%) and during EW (84% and 74%). Conclusions O2 nadir, age, and sleepiness show prognostic value for predicting WM impairment in both rested and sleep-deprived OSA patients and may guide clinicians in identifying patients most at risk of impaired WM under both rested and heightened sleep pressure conditions. Clinical Trial Registration: This manuscript presents data collected as part of a larger trial—ANZCTR: Novel brain biomarkers of performance impairment in sleep apnea—https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=363830, No. ACTRN12613001171707.
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- 2021
20. Diffusion Tensor Imaging in Sport-Related Concussion: A Systematic Review Using an
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Briana, Lees, Nicola E, Earls, Susanne, Meares, Jennifer, Batchelor, Vincent, Oxenham, Caroline D, Rae, Lauriane, Jugé, and Lucette A, Cysique
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Diffusion Tensor Imaging ,Athletic Injuries ,Humans ,White Matter ,Brain Concussion - Abstract
Diffusion tensor imaging (DTI) of brain white matter (WM) may be useful for characterizing the nature and degree of brain injury after sport-related concussion (SRC) and assist in establishing objective diagnostic and prognostic biomarkers. This study aimed to conduct a systematic review using an
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- 2021
21. The cortical integration of tactile sensation in complex regional pain syndrome
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Caroline D, Rae, Prince of Wales Clinical School, Faculty of Medicine, UNSW, Mark, Schira, University of Wollongong, James, McAuley, Faculty of Medicine, UNSW, G Lorimer, Moseley, UniSA, Wang, Audrey, Prince of Wales Clinical School, Faculty of Medicine, UNSW, Caroline D, Rae, Prince of Wales Clinical School, Faculty of Medicine, UNSW, Mark, Schira, University of Wollongong, James, McAuley, Faculty of Medicine, UNSW, G Lorimer, Moseley, UniSA, and Wang, Audrey, Prince of Wales Clinical School, Faculty of Medicine, UNSW
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Much is still unknown about sensory and perceptual changes in the cortex associated with complex regional pain syndrome (CRPS). This PhD aimed to investigate cortical integration of tactile sensation of the hand specifically the fingers, and how this might be altered in CRPS. A match-paired cross-sectional design was used in a series of neuroimaging and psychophysical studies on patients with unilateral upper limb CRPS (n=21). Clinical characteristics were described and compared with age, gender and hand dominance matched controls (Chapter 2). Methodological improvements for fine-grained fingertip mapping in the primary somatosensory cortex were piloted (n=1) in two separate experiments (Chapter 3). Single fingertip stimulation versus bilateral simultaneous fingertip stimulation was compared using phase encoded functional magnetic resonance imaging (fMRI). Fine-grained fMRI maps of the fingertips in S1 in CRPS were described. Structural morphometry measures underlying the functional S1 fingertip maps including cortical thickness were analysed with step-wise mixed modelling with a priori hypothesised effects including hand dominance and medication. Patient characteristics including pain- related measures were correlated with morphometry measures (Chapter 4). A new finger illusion experiment was applied for the first time in patients with CRPS (Chapter 5). The pilot found that bilateral tactile stimulus was most suitable for use in CRPS and had superior time efficiency. Disordered S1 functional fingertip maps in CRPS with no distinct pattern were found using this stimulus, when compared to the orderly homogenous map pattern in healthy controls. These functional imaging observations were strengthened by the key finding that increased cortical thickness underlying these maps together with hand dominance predicted group (CRPS versus healthy controls) membership. An abnormal finger illusion response in CRPS compared to controls, also suggests a disruption to normal effici
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- 2017
22. Silent information regulator 1 modulator resveratrol increases brain lactate production and inhibits mitochondrial metabolism, whereas SRT1720 increases oxidative metabolism
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Benjamin D, Rowlands, Chew Ling, Lau, James G, Ryall, Donald S, Thomas, Matthias, Klugmann, Philip M, Beart, and Caroline D, Rae
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Male ,Carbon Isotopes ,Dose-Response Relationship, Drug ,Guinea Pigs ,Carbazoles ,Brain ,Heterocyclic Compounds, 4 or More Rings ,Magnetic Resonance Imaging ,Antioxidants ,Mitochondria ,Oxidative Stress ,Oxygen Consumption ,Sirtuin 1 ,Resveratrol ,Area Under Curve ,Astrocytes ,Stilbenes ,Animals ,Female ,Lactic Acid - Abstract
Silent information regulators (SIRTs) have been shown to deacetylate a range of metabolic enzymes, including those in glycolysis and the Krebs cycle, and thus alter their activity. SIRTs require NAD(+) for their activity, linking cellular energy status to enzyme activity. To examine the impact of SIRT1 modulation on oxidative metabolism, this study tests the effect of ligands that are either SIRT-activating compounds (resveratrol and SRT1720) or SIRT inhibitors (EX527) on the metabolism of (13)C-enriched substrates by guinea pig brain cortical tissue slices with (13)C and (1)H nuclear magnetic resonance spectroscopy. Resveratrol increased lactate labeling but decreased incorporation of (13)C into Krebs cycle intermediates, consistent with effects on AMPK and inhibition of the F0/F1-ATPase. By testing with resveratrol that was directly applied to astrocytes with a Seahorse analyzer, increased glycolytic shift and increased mitochondrial proton leak resulting from interactions of resveratrol with the mitochondrial electron transport chain were revealed. SRT1720, by contrast, stimulated incorporation of (13)C into Krebs cycle intermediates and reduced incorporation into lactate, although the inhibitor EX527 paradoxically also increased Krebs cycle (13)C incorporation. In summary, the various SIRT1 modulators show distinct acute effects on oxidative metabolism. The strong effects of resveratrol on the mitochondrial respiratory chain and on glycolysis suggest that caution should be used in attempts to increase bioavailability of this compound in the CNS.
- Published
- 2014
23. γ-Hydroxybutyrate and the GABAergic footprint: a metabolomic approach to unpicking the actions of GHB
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Fatima A, Nasrallah, Anthony D, Maher, Jane R, Hanrahan, Vladimir J, Balcar, and Caroline D, Rae
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Cerebral Cortex ,GABA Plasma Membrane Transport Proteins ,Principal Component Analysis ,Magnetic Resonance Spectroscopy ,Dose-Response Relationship, Drug ,Receptors, Drug ,Guinea Pigs ,In Vitro Techniques ,Ligands ,DNA Fingerprinting ,Pattern Recognition, Automated ,Receptors, GABA ,Receptors, GABA-B ,Data Interpretation, Statistical ,Pyruvic Acid ,Animals ,Metabolomics ,Sodium Oxybate ,gamma-Aminobutyric Acid - Abstract
Gamma-hydroxybutyrate is found both naturally in the brain and self-administered as a drug of abuse. It has been reported to act at endogenous γ-hydroxybutyrate (GHB) receptors and GABA(B) receptors [GABA(B)R], and may also be metabolized to GABA. Here, the metabolic fingerprints of a range of concentrations of GHB were measured in brain cortical tissue slices and compared with those of ligands active at GHB and GABA-R using principal components analysis (PCA) to identify sites of GHB activity. Low concentrations of GHB (1.0 μM) produced fingerprints similar to those of ligands active at GHB receptors and α4-containing GABA(A)R. A total of 10 μM GHB clustered proximate to mainstream GABAergic synapse ligands, such as 1.0 μM baclofen, a GABA(B)R agonist. Higher concentrations of GHB (30 μM) clustered with GABA(C)R agonists and the metabolic responses induced by blockade of the GABA transporter-1 (GAT1). The metabolic responses induced by 60 and 100 μM GHB were mimicked by simultaneous blockade of GAT1 and GAT3, addition of low concentrations of GABA(C)R antagonists, or increasing cytoplasmic GABA concentrations by incubation with the GABA transaminase inhibitor vigabatrin. These data suggest that at concentrations30 μM, GHB may be active via metabolism to GABA, which is then acting upon an unidentified GABAergic master switch receptor (possibly a high-affinity extrasynaptic receptor), or GHB may itself be acting directly on an extrasynaptic GABA-R, capable of turning off large numbers of cells. These results offer an explanation for the steep dose-response curve of GHB seen in vivo, and suggest potential target receptors for further investigation.
- Published
- 2010
24. 030 Brain aging and cardiovascular risk factors in chronic HIV: A longitudinal MRI study
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Caroline D Rae, Bruce J Brew, David Jakabek, and Lucette A Cysique
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Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Published
- 2021
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