30 results on '"Rae CD"'
Search Results
2. Corrigendum: Reduced Glutamate in the Medial Prefrontal Cortex Is Associated With Emotional and Cognitive Dysregulation in People With Chronic Pain.
- Author
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Naylor, B, Hesam-Shariati, N, McAuley, JH, Boag, S, Newton-John, T, Rae, CD, Gustin, SM, Naylor, B, Hesam-Shariati, N, McAuley, JH, Boag, S, Newton-John, T, Rae, CD, and Gustin, SM
- Abstract
[This corrects the article DOI: 10.3389/fneur.2019.01110.].
- Published
- 2022
3. Corrigendum: Reduced Glutamate in the Medial Prefrontal Cortex Is Associated With Emotional and Cognitive Dysregulation in People With Chronic Pain.
- Author
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Naylor, B, Hesam-Shariati, N, McAuley, JH, Boag, S, Newton-John, T, Rae, CD, Gustin, SM, Naylor, B, Hesam-Shariati, N, McAuley, JH, Boag, S, Newton-John, T, Rae, CD, and Gustin, SM
- Abstract
[This corrects the article DOI: 10.3389/fneur.2019.01110.].
- Published
- 2022
4. Emerging Concepts in Vector Development for Glial Gene Therapy: Implications for Leukodystrophies
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von Jonquieres, G, Rae, CD, Housley, GD, von Jonquieres, G, Rae, CD, and Housley, GD
- 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
5. Frequency drift in MR spectroscopy at 3T
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Hui, SCN, Mikkelsen, M, Zollner, HJ, Ahluwalia, V, Alcauter, S, Baltusis, L, Barany, DA, Barlow, LR, Becker, R, Berman, J, Berrington, A, Bhattacharyya, PK, Blicher, JU, Bogner, W, Brown, MS, Calhoun, VD, Castillo, R, Cecil, KM, Choi, YB, Chu, WCW, Clarke, WT, Craven, AR, Cuypers, K, Dacko, M, de la Fuente-Sandoval, C, Desmond, P, Domagalik, A, Dumont, J, Duncan, NW, Dydak, U, Dyke, K, Edmondson, DA, Ende, G, Ersland, L, Evans, CJ, Fermin, ASR, Ferretti, A, Fillmer, A, Gong, T, Greenhouse, I, Grist, JT, Gu, M, Harris, AD, Hatz, K, Heba, S, Heckova, E, Hegarty, JP, Heise, K-F, Honda, S, Jacobson, A, Jansen, JFA, Jenkins, CW, Johnston, SJ, Juchem, C, Kangarlu, A, Kerr, AB, Landheer, K, Lange, T, Lee, P, Levendovszky, SR, Limperopoulos, C, Liu, F, Lloyd, W, Lythgoe, DJ, Machizawa, MG, MacMillan, EL, Maddock, RJ, Manzhurtsev, A, Martinez-Gudino, ML, Miller, JJ, Mirzakhanian, H, Moreno-Ortega, M, Mullins, PG, Nakajima, S, Near, J, Noeske, R, Nordhoy, W, Oeltzschner, G, Osorio-Duran, R, Otaduy, MCG, Pasaye, EH, Peeters, R, Peltier, SJ, Pilatus, U, Polomac, N, Porges, EC, Pradhan, S, Prisciandaro, JJ, Puts, NA, Rae, CD, Reyes-Madrigal, F, Roberts, TPL, Robertson, CE, Rosenberg, JT, Rotaru, D-G, Tuura, RLO, Saleh, MG, Sandberg, K, Sangill, R, Schembri, K, Schrantee, A, Semenova, NA, Singel, D, Sitnikov, R, Smith, J, Song, Y, Stark, C, Stoffers, D, Swinnen, SP, Tain, R, Tanase, C, Tapper, S, Tegenthoff, M, Thiel, T, Thioux, M, Truong, P, van Dijk, P, Vella, N, Vidyasagar, R, Vovk, A, Wang, G, Westlye, LT, Wilbur, TK, Willoughby, WR, Wilson, M, Wittsack, H-J, Woods, AJ, Wu, Y-C, Xu, J, Lopez, MY, Yeung, DKW, Zhao, Q, Zhou, X, Zupan, G, Edden, RAE, Hui, SCN, Mikkelsen, M, Zollner, HJ, Ahluwalia, V, Alcauter, S, Baltusis, L, Barany, DA, Barlow, LR, Becker, R, Berman, J, Berrington, A, Bhattacharyya, PK, Blicher, JU, Bogner, W, Brown, MS, Calhoun, VD, Castillo, R, Cecil, KM, Choi, YB, Chu, WCW, Clarke, WT, Craven, AR, Cuypers, K, Dacko, M, de la Fuente-Sandoval, C, Desmond, P, Domagalik, A, Dumont, J, Duncan, NW, Dydak, U, Dyke, K, Edmondson, DA, Ende, G, Ersland, L, Evans, CJ, Fermin, ASR, Ferretti, A, Fillmer, A, Gong, T, Greenhouse, I, Grist, JT, Gu, M, Harris, AD, Hatz, K, Heba, S, Heckova, E, Hegarty, JP, Heise, K-F, Honda, S, Jacobson, A, Jansen, JFA, Jenkins, CW, Johnston, SJ, Juchem, C, Kangarlu, A, Kerr, AB, Landheer, K, Lange, T, Lee, P, Levendovszky, SR, Limperopoulos, C, Liu, F, Lloyd, W, Lythgoe, DJ, Machizawa, MG, MacMillan, EL, Maddock, RJ, Manzhurtsev, A, Martinez-Gudino, ML, Miller, JJ, Mirzakhanian, H, Moreno-Ortega, M, Mullins, PG, Nakajima, S, Near, J, Noeske, R, Nordhoy, W, Oeltzschner, G, Osorio-Duran, R, Otaduy, MCG, Pasaye, EH, Peeters, R, Peltier, SJ, Pilatus, U, Polomac, N, Porges, EC, Pradhan, S, Prisciandaro, JJ, Puts, NA, Rae, CD, Reyes-Madrigal, F, Roberts, TPL, Robertson, CE, Rosenberg, JT, Rotaru, D-G, Tuura, RLO, Saleh, MG, Sandberg, K, Sangill, R, Schembri, K, Schrantee, A, Semenova, NA, Singel, D, Sitnikov, R, Smith, J, Song, Y, Stark, C, Stoffers, D, Swinnen, SP, Tain, R, Tanase, C, Tapper, S, Tegenthoff, M, Thiel, T, Thioux, M, Truong, P, van Dijk, P, Vella, N, Vidyasagar, R, Vovk, A, Wang, G, Westlye, LT, Wilbur, TK, Willoughby, WR, Wilson, M, Wittsack, H-J, Woods, AJ, Wu, Y-C, Xu, J, Lopez, MY, Yeung, DKW, Zhao, Q, Zhou, X, Zupan, G, and Edden, RAE
- 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 f
- Published
- 2021
6. Brain amyloid in virally suppressed HIV-associated neurocognitive disorder
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Howdle, GC, Quidé, Y, Kassem, MS, Johnson, K, Rae, CD, Brew, BJ, Cysique, LA, Howdle, GC, Quidé, Y, Kassem, MS, Johnson, K, Rae, CD, Brew, BJ, and Cysique, LA
- Abstract
OBJECTIVE: To determine whether virally suppressed HIV neuropathogenesis, a chronic neuroinflammatory state, promotes abnormal brain amyloid deposition. METHODS: A total of 10 men with virally suppressed HIV-associated neurocognitive disorder (HAND), aged 46-68 years, underwent 11C-labeled Pittsburgh compound B PET. Data from the Australian Imaging, Biomarkers and Lifestyle (AIBL), including 39 cognitively normal individuals (aged 60-74 years), 7 individuals with mild cognitive impairment (MCI) (aged 64-71 years), and 11 individuals with Alzheimer disease (AD) (aged 55-74 years), were used as reference. Apart from more women, the AIBL cohort was demographically comparable with the HIV sample. Also, the AIBL PET data did not differ by sex. Cerebellum standardized uptake value ratio amyloid values within 22 regions of interest were estimated. In the HIV sample, apolipoprotein E (APOE) was available in 80%, CSF biomarkers in 60%, and 8-10 years of long-term health outcomes in 100%. RESULTS: HAND and the AIBL group with no cognitive deficits had similar amyloid deposition, which was lower than that in both the MCI and AD groups. At the individual level, one HAND case showed high amyloid deposition consistent with AD. This case also had a CSF-AD-like profile and an E4/E4 for APOE. Clinically, this case declined over 18 years with mild HAND symptoms first, followed by progressive memory decline 8-9 years after the study PET, then progression to severe dementia within 2-3 years, and lived a further 6 years. Another HAND case showed increased amyloid deposition restricted to the hippocampi. Two other HAND cases showed abnormally decreased amyloid in subcortical areas. CONCLUSIONS: Relative to cognitively normal older controls, brain amyloid burden does not differ in virally suppressed HAND at the group level. However, individual analyses show that abnormally high and low amyloid burden occur.
- Published
- 2020
7. L-Aspartate, L-Ornithine and L-Ornithine-L-Aspartate (LOLA) and Their Impact on Brain Energy Metabolism
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Das, A, Fröhlich, D, Achanta, LB, Rowlands, BD, Housley, GD, Klugmann, M, Rae, CD, Das, A, Fröhlich, D, Achanta, LB, Rowlands, BD, Housley, GD, Klugmann, M, and Rae, CD
- Abstract
L-Ornithine-L-aspartate (LOLA), a crystalline salt, is used primarily in the management of hepatic encephalopathy. The degree to which it might penetrate the brain, and the effects it might have on metabolism in brain are poorly understood. Here, to investigate the effects of LOLA on brain energy metabolism we incubated brain cortical tissue slices from guinea pig (Cavea porcellus) with the constituent amino acids of LOLA, L-ornithine or L-aspartate, as well as LOLA, in the presence of [1-13C]D-glucose and [1,2-13C]acetate; these labelled substrates are useful indicators of brain metabolic activity. L-Ornithine produced significant “sedative” effects on brain slice metabolism, most likely via conversion of ornithine to GABA via the ornithine aminotransferase pathway, while L-aspartate showed concentration-dependent excitatory effects. The metabolic effects of LOLA reflected a mix of these two different processes and were concentration-dependent. We also investigated the effect of an intraperitoneal bolus injection of L-ornithine, L-aspartate or LOLA on levels of metabolites in kidney, liver and brain cortex and brain stem in mice (C57Bl6J) 1 h later. No significant changes in metabolite levels were seen following the bolus injection of L-aspartate, most likely due to rapid metabolism of aspartate before reaching the target tissue. Brain cortex glutamate was decreased by L-ornithine but no other brain effects were observed with any other compound. Kidney levels of aspartate were increased after injection of L-ornithine and LOLA which may be due to interference by ornithine with the kidney urea cycle. It is likely that without optimising chronic intravenous infusion, LOLA has minimal impact on healthy brain energy metabolism due to systemic clearance and the blood - brain barrier.
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- 2020
8. L-Aspartate, L-Ornithine and L-Ornithine-L-Aspartate (LOLA) and Their Impact on Brain Energy Metabolism
- Author
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Das, A, Fröhlich, D, Achanta, LB, Rowlands, BD, Housley, GD, Klugmann, M, Rae, CD, Das, A, Fröhlich, D, Achanta, LB, Rowlands, BD, Housley, GD, Klugmann, M, and Rae, CD
- Abstract
L-Ornithine-L-aspartate (LOLA), a crystalline salt, is used primarily in the management of hepatic encephalopathy. The degree to which it might penetrate the brain, and the effects it might have on metabolism in brain are poorly understood. Here, to investigate the effects of LOLA on brain energy metabolism we incubated brain cortical tissue slices from guinea pig (Cavea porcellus) with the constituent amino acids of LOLA, L-ornithine or L-aspartate, as well as LOLA, in the presence of [1-13C]D-glucose and [1,2-13C]acetate; these labelled substrates are useful indicators of brain metabolic activity. L-Ornithine produced significant “sedative” effects on brain slice metabolism, most likely via conversion of ornithine to GABA via the ornithine aminotransferase pathway, while L-aspartate showed concentration-dependent excitatory effects. The metabolic effects of LOLA reflected a mix of these two different processes and were concentration-dependent. We also investigated the effect of an intraperitoneal bolus injection of L-ornithine, L-aspartate or LOLA on levels of metabolites in kidney, liver and brain cortex and brain stem in mice (C57Bl6J) 1 h later. No significant changes in metabolite levels were seen following the bolus injection of L-aspartate, most likely due to rapid metabolism of aspartate before reaching the target tissue. Brain cortex glutamate was decreased by L-ornithine but no other brain effects were observed with any other compound. Kidney levels of aspartate were increased after injection of L-ornithine and LOLA which may be due to interference by ornithine with the kidney urea cycle. It is likely that without optimising chronic intravenous infusion, LOLA has minimal impact on healthy brain energy metabolism due to systemic clearance and the blood - brain barrier.
- Published
- 2020
9. CRPS is not associated with altered sensorimotor cortex GABA or glutamate
- Author
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Lee, B, Henderson, LA, Rae, CD, Di Pietro, F, Lee, B, Henderson, LA, Rae, CD, and Di Pietro, F
- Abstract
Complex regional pain syndrome (CRPS) is a debilitating chronic pain disorder typically in the upper or lower limbs. While CRPS usually develops from a peripheral event, it is likely maintained by CNS changes. Indeed, CRPS is reported to be associated with sensorimotor cortex changes, or functional “reorganization,” as well as deficits such as poor tactile acuity. While the mechanisms underpinning cortical reorganization in CRPS are unknown, some have hypothesized that it involves disinhibition (i.e., a reduction in GABA activity). In this study, we addressed this hypothesis by using edited magnetic resonance spectroscopy to determine sensorimotor GABA and glutamate concentrations in 16 humans with CRPS and 30 matched control subjects and the relationship of these concentrations with tactile acuity. We found that individuals with upper limb CRPS displayed reduced tactile acuity in the painful hand, compared with the nonpainful hand and pain-free control subjects. Despite this acuity deficit, CRPS was not associated with altered GABA or glutamate concentrations within the sensorimotor cortex on either the side that represents the affected or unaffected hand. Furthermore, there was no significant relationship between sensorimotor GABA or glutamate concentrations and tactile acuity in CRPS subjects or control subjects. Although our sample was small, these data suggest that CRPS is not associated with altered total sensorimotor GABA or glutamate concentrations. While these results are at odds with the sensorimotor cortex disinhibition hypothesis, it is possible that GABAergic mechanisms other than total GABA concentration may contribute to such disinhibition.
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- 2020
10. Fine-Grained mapping of cortical somatotopies in chronic complex regional pain syndrome
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Mancini, F, Wang, AP, Schira, MM, Isherwood, ZJ, McAuley, JH, Iannetti, GD, Sereno, MI, Moseley, GL, Rae, CD, Mancini, F, Wang, AP, Schira, MM, Isherwood, ZJ, McAuley, JH, Iannetti, GD, Sereno, MI, Moseley, GL, and Rae, CD
- Abstract
It has long been thought that severe chronic pain conditions, such as complex regional pain syndrome (CRPS), are not only associated with, but even maintained by a reorganization of the somatotopic representation of the affected limb in primary somatosensory cortex (S1). This notion has driven treatments that aim to restore S1 representations in CRPS patients, such as sensory discrimination training and mirror therapy. However, this notion is based on both indirect and incomplete evidence obtained with imaging methods with low spatial resolution. Here, we used fMRI to characterize the S1 representation of the affected and unaffected hand in humans (of either sex) with unilateral CRPS. The cortical area, location, and geometry of the S1 representation of the CRPS hand were largely comparable with those of both the unaffected hand and healthy controls. We found no differential relation between affected versus unaffected hand map measures and clinical measures (pain severity, upper limb disability, disease duration). Thus, if any map reorganization occurs, it does not appear to be directly related to pain and disease severity. These findings compel us to reconsider the cortical mechanisms underlying CRPS and the rationale for interventions that aim to "restore" somatotopic representations to treat pain.
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- 2019
11. Understanding autism spectrum disorder and social functioning in children with neurofibromatosis type 1: Protocol for a cross-sectional multimodal study
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Haebich, KM, Pride, NA, Walsh, KS, Chisholm, A, Rouel, M, Maier, A, Anderson, V, Barton, B, Silk, T, Korgaonkar, M, Seal, M, Lami, F, Lorenzo, J, Williams, K, Dabscheck, G, Rae, CD, Kean, M, North, KN, Payne, JM, Haebich, KM, Pride, NA, Walsh, KS, Chisholm, A, Rouel, M, Maier, A, Anderson, V, Barton, B, Silk, T, Korgaonkar, M, Seal, M, Lami, F, Lorenzo, J, Williams, K, Dabscheck, G, Rae, CD, Kean, M, North, KN, and Payne, JM
- Abstract
Introduction Children with the single-gene disorder neurofibromatosis type 1 (NF1) appear to be at an increased risk for autism spectrum disorder (ASD) and exhibit a unique social-cognitive phenotype compared with children with idiopathic ASD. A complete framework is required to better understand autism in NF1, from neurobiological levels through to behavioural and functional outcomes. The primary aims of this study are to establish the frequency of ASD in children with NF1, examine the social cognitive phenotype, investigate the neuropsychological processes contributing to ASD symptoms and poor social functioning in children with NF1, and to investigate novel structural and functional neurobiological markers of ASD and social dysfunction in NF1. The secondary aim of this study is to compare the neuropsychological and neurobiological features of ASD in children with NF1 to a matched group of patients with idiopathic ASD. Methods and analysis This is an international, multisite, prospective, cross-sectional cohort study of children with NF1, idiopathic ASD and typically developing (TD) controls. Participants will be 200 children with NF1 (3-15 years of age), 70 TD participants (3-15 years) and 35 children with idiopathic ASD (7-15 years). Idiopathic ASD and NF1 cases will be matched on age, sex and intelligence. All participants will complete cognitive testing and parents will rate their child's behaviour on standardised questionnaires. Neuroimaging will be completed by a subset of participants aged 7 years and older. Children with NF1 that screen at risk for ASD on the parent-rated Social Responsiveness Scale 2nd Edition will be invited back to complete the Autism Diagnostic Observation Scale 2nd Edition and Autism Diagnostic Interview-Revised to determine whether they fulfil ASD diagnostic criteria. Ethics and dissemination This study has hospital ethics approval and the results will be disseminated through peer-reviewed publications and international conferences.
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- 2019
12. Understanding autism spectrum disorder and social functioning in children with neurofibromatosis type 1: protocol for a cross-sectional multimodal study
- Author
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Haebich, KM, Pride, NA, Walsh, KS, Chisholm, A, Rouel, M, Maier, A, Anderson, V, Barton, B, Silk, T, Korgaonkar, M, Seal, M, Lami, F, Lorenzo, J, Williams, K, Dabscheck, G, Rae, CD, Kean, M, North, KN, Payne, JM, Haebich, KM, Pride, NA, Walsh, KS, Chisholm, A, Rouel, M, Maier, A, Anderson, V, Barton, B, Silk, T, Korgaonkar, M, Seal, M, Lami, F, Lorenzo, J, Williams, K, Dabscheck, G, Rae, CD, Kean, M, North, KN, and Payne, JM
- Abstract
INTRODUCTION: Children with the single-gene disorder neurofibromatosis type 1 (NF1) appear to be at an increased risk for autism spectrum disorder (ASD) and exhibit a unique social-cognitive phenotype compared with children with idiopathic ASD. A complete framework is required to better understand autism in NF1, from neurobiological levels through to behavioural and functional outcomes. The primary aims of this study are to establish the frequency of ASD in children with NF1, examine the social cognitive phenotype, investigate the neuropsychological processes contributing to ASD symptoms and poor social functioning in children with NF1, and to investigate novel structural and functional neurobiological markers of ASD and social dysfunction in NF1. The secondary aim of this study is to compare the neuropsychological and neurobiological features of ASD in children with NF1 to a matched group of patients with idiopathic ASD. METHODS AND ANALYSIS: This is an international, multisite, prospective, cross-sectional cohort study of children with NF1, idiopathic ASD and typically developing (TD) controls. Participants will be 200 children with NF1 (3-15 years of age), 70 TD participants (3-15 years) and 35 children with idiopathic ASD (7-15 years). Idiopathic ASD and NF1 cases will be matched on age, sex and intelligence. All participants will complete cognitive testing and parents will rate their child's behaviour on standardised questionnaires. Neuroimaging will be completed by a subset of participants aged 7 years and older. Children with NF1 that screen at risk for ASD on the parent-rated Social Responsiveness Scale 2nd Edition will be invited back to complete the Autism Diagnostic Observation Scale 2nd Edition and Autism Diagnostic Interview-Revised to determine whether they fulfil ASD diagnostic criteria. ETHICS AND DISSEMINATION: This study has hospital ethics approval and the results will be disseminated through peer-reviewed publications and international conference
- Published
- 2019
13. Reduced Glutamate in the Medial Prefrontal Cortex Is Associated With Emotional and Cognitive Dysregulation in People With Chronic Pain
- Author
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Naylor, B, Hesam-Shariati, N, McAuley, JH, Boag, S, Newton-John, T, Rae, CD, Gustin, SM, Naylor, B, Hesam-Shariati, N, McAuley, JH, Boag, S, Newton-John, T, Rae, CD, and Gustin, SM
- Abstract
© Copyright © 2019 Naylor, Hesam-Shariati, McAuley, Boag, Newton-John, Rae and Gustin. 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.
- Published
- 2019
14. Reduced Glutamate in the Medial Prefrontal Cortex Is Associated With Emotional and Cognitive Dysregulation in People With Chronic Pain
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Naylor, B, Hesam-Shariati, N, McAuley, JH, Boag, S, Newton-John, T, Rae, CD, Gustin, SM, Naylor, B, Hesam-Shariati, N, McAuley, JH, Boag, S, Newton-John, T, Rae, CD, and Gustin, SM
- Abstract
© Copyright © 2019 Naylor, Hesam-Shariati, McAuley, Boag, Newton-John, Rae and Gustin. 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.
- Published
- 2019
15. Brain bioenergetics during resting wakefulness are related to neurobehavioral deficits in severe obstructive sleep apnea: A 31 P magnetic resonance spectroscopy study
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D'Rozario, AL, Bartlett, DJ, Wong, KKH, Sach, T, Yang, Q, Grunstein, RR, Rae, CD, D'Rozario, AL, Bartlett, DJ, Wong, KKH, Sach, T, Yang, Q, Grunstein, RR, and Rae, CD
- Abstract
Study Objectives: Obstructive sleep apnea (OSA) is a well-established cause of impaired daytime functioning. However, there is a complex interindividual variability in neurobehavioral performance in OSA patients. We previously reported compromised brain bioenergetics during apneic sleep in severe OSA. In this study, we investigate whether brain bioenergetics during resting wakefulness are related to neurobehavioral performance. Methods: Patients attended the sleep laboratory in the evening and were kept awake over-night. Repeated testing on the 10-minute psychomotor vigilance task (PVT, at 9 pm, 11 pm, 1 am, 3 am, 5 am) and 30-minute AusEd driving simulator task (9 pm and 5 am) was performed. Brain bioenergetics (inorganic phosphate/adenosine triphosphate ratio, Pi/ATP) were measured in the temporal lobe during resting wakefulness at 7 am in a 1.5T MRI scanner using phosphorus magnetic resonance spectroscopy (31P MRS). Results: Fifteen males with severe OSA (age 47.7 ± 10.4 years, body mass index [BMI] 34 ± 6.6 kg/m2, apnea hypopnea index [AHI] 79.7 ± 21.8/ hour) were investigated. A higher Pi/ATP ratio in the brain (lower phosphorylation potential) was correlated with worse PVT and driving simulator performance across the testing period (PVT lapses: r = 0.632, r2 = 0.399, p = 0.012; and AusEd braking reaction time: r = 0.609, p = 0.016). In contrast, the conventional AHI measure of disease severity was not significantly correlated with performance (PVT lapses: r = -0.084, p = 0.8; and AusEd braking reaction time: r = -0.326, p = 0.2). Conclusions: Lower phosphorylation potential was associated with worse performance. Compromised brain bioenergetics may in part underlie the neurobehavioral deficits in untreated OSA. We speculate that better brain bioenergetics may explain why some OSA patients are relatively asymptomatic compared with others.
- Published
- 2018
16. The relationship between thalamic GABA content and resting cortical rhythm in neuropathic pain
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Di Pietro, F, Macey, PM, Rae, CD, Alshelh, Z, Macefield, VG, Vickers, ER, Henderson, LA, Di Pietro, F, Macey, PM, Rae, CD, Alshelh, Z, Macefield, VG, Vickers, ER, and Henderson, LA
- Abstract
Recurrent thalamocortical connections are integral to the generation of brain rhythms and it is thought that the inhibitory action of the thalamic reticular nucleus is critical in setting these rhythms. Our work and others' has suggested that chronic pain that develops following nerve injury, that is, neuropathic pain, results from altered thalamocortical rhythm, although whether this dysrhythmia is associated with thalamic inhibitory function remains unknown. In this investigation, we used electroencephalography and magnetic resonance spectroscopy to investigate cortical power and thalamic GABAergic concentration in 20 patients with neuropathic pain and 20 pain-free controls. First, we found thalamocortical dysrhythmia in chronic orofacial neuropathic pain; patients displayed greater power than controls over the 4–25 Hz frequency range, most marked in the theta and low alpha bands. Furthermore, sensorimotor cortex displayed a strong positive correlation between cortical power and pain intensity. Interestingly, we found no difference in thalamic GABA concentration between pain subjects and control subjects. However, we demonstrated significant linear relationships between thalamic GABA concentration and enhanced cortical power in pain subjects but not controls. Whilst the difference in relationship between thalamic GABA concentration and resting brain rhythm between chronic pain and control subjects does not prove a cause and effect link, it is consistent with a role for thalamic inhibitory neurotransmitter release, possibly from the thalamic reticular nucleus, in altered brain rhythms in individuals with chronic neuropathic pain.
- Published
- 2018
17. Uncoupling N-acetylaspartate from brain pathology: implications for Canavan disease gene therapy
- Author
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von Jonquieres, G, Spencer, ZHT, Rowlands, BD, Klugmann, CB, Bongers, A, Harasta, AE, Parley, KE, Cederholm, J, Teahan, O, Pickford, R, Delerue, F, Ittner, LM, Fröhlich, D, McLean, CA, Don, AS, Schneider, M, Housley, GD, Rae, CD, Klugmann, M, von Jonquieres, G, Spencer, ZHT, Rowlands, BD, Klugmann, CB, Bongers, A, Harasta, AE, Parley, KE, Cederholm, J, Teahan, O, Pickford, R, Delerue, F, Ittner, LM, Fröhlich, D, McLean, CA, Don, AS, Schneider, M, Housley, GD, Rae, CD, and Klugmann, M
- Abstract
N-Acetylaspartate (NAA) is the second most abundant organic metabolite in the brain, but its physiological significance remains enigmatic. Toxic NAA accumulation appears to be the key factor for neurological decline in Canavan disease—a fatal neurometabolic disorder caused by deficiency in the NAA-degrading enzyme aspartoacylase. To date clinical outcome of gene replacement therapy for this spongiform leukodystrophy has not met expectations. To identify the target tissue and cells for maximum anticipated treatment benefit, we employed comprehensive phenotyping of novel mouse models to assess cell type-specific consequences of NAA depletion or elevation. We show that NAA-deficiency causes neurological deficits affecting unconscious defensive reactions aimed at protecting the body from external threat. This finding suggests, while NAA reduction is pivotal to treat Canavan disease, abrogating NAA synthesis should be avoided. At the other end of the spectrum, while predicting pathological severity in Canavan disease mice, increased brain NAA levels are not neurotoxic per se. In fact, in transgenic mice overexpressing the NAA synthesising enzyme Nat8l in neurons, supra-physiological NAA levels were uncoupled from neurological deficits. In contrast, elimination of aspartoacylase expression exclusively in oligodendrocytes elicited Canavan disease like pathology. Although conditional aspartoacylase deletion in oligodendrocytes abolished expression in the entire CNS, the remaining aspartoacylase in peripheral organs was sufficient to lower NAA levels, delay disease onset and ameliorate histopathology. However, comparable endpoints of the conditional and complete aspartoacylase knockout indicate that optimal Canavan disease gene replacement therapies should restore aspartoacylase expression in oligodendrocytes. On the basis of these findings we executed an ASPA gene replacement therapy targeting oligodendrocytes in Canavan disease mice resulting in reversal of pre-existing CN
- Published
- 2018
18. Uncoupling N-acetylaspartate from brain pathology: implications for Canavan disease gene therapy
- Author
-
von Jonquieres, G, Spencer, ZHT, Rowlands, BD, Klugmann, CB, Bongers, A, Harasta, AE, Parley, KE, Cederholm, J, Teahan, O, Pickford, R, Delerue, F, Ittner, LM, Frohlich, D, McLean, CA, Don, AS, Schneider, M, Housley, GD, Rae, CD, Klugmann, M, von Jonquieres, G, Spencer, ZHT, Rowlands, BD, Klugmann, CB, Bongers, A, Harasta, AE, Parley, KE, Cederholm, J, Teahan, O, Pickford, R, Delerue, F, Ittner, LM, Frohlich, D, McLean, CA, Don, AS, Schneider, M, Housley, GD, Rae, CD, and Klugmann, M
- Abstract
N-Acetylaspartate (NAA) is the second most abundant organic metabolite in the brain, but its physiological significance remains enigmatic. Toxic NAA accumulation appears to be the key factor for neurological decline in Canavan disease-a fatal neurometabolic disorder caused by deficiency in the NAA-degrading enzyme aspartoacylase. To date clinical outcome of gene replacement therapy for this spongiform leukodystrophy has not met expectations. To identify the target tissue and cells for maximum anticipated treatment benefit, we employed comprehensive phenotyping of novel mouse models to assess cell type-specific consequences of NAA depletion or elevation. We show that NAA-deficiency causes neurological deficits affecting unconscious defensive reactions aimed at protecting the body from external threat. This finding suggests, while NAA reduction is pivotal to treat Canavan disease, abrogating NAA synthesis should be avoided. At the other end of the spectrum, while predicting pathological severity in Canavan disease mice, increased brain NAA levels are not neurotoxic per se. In fact, in transgenic mice overexpressing the NAA synthesising enzyme Nat8l in neurons, supra-physiological NAA levels were uncoupled from neurological deficits. In contrast, elimination of aspartoacylase expression exclusively in oligodendrocytes elicited Canavan disease like pathology. Although conditional aspartoacylase deletion in oligodendrocytes abolished expression in the entire CNS, the remaining aspartoacylase in peripheral organs was sufficient to lower NAA levels, delay disease onset and ameliorate histopathology. However, comparable endpoints of the conditional and complete aspartoacylase knockout indicate that optimal Canavan disease gene replacement therapies should restore aspartoacylase expression in oligodendrocytes. On the basis of these findings we executed an ASPA gene replacement therapy targeting oligodendrocytes in Canavan disease mice resulting in reversal of pre-existing CN
- Published
- 2018
19. An objective short sleep insomnia disorder subtype is associated with reduced brain metabolite concentrations in vivo: A preliminary magnetic resonance spectroscopy assessment
- Author
-
Miller, CB, Rae, CD, Green, MA, Yee, BJ, Gordon, CJ, D'Rozario, AL, Kyle, SD, Espie, CA, Grunstein, RR, Bartlett, DJ, Miller, CB, Rae, CD, Green, MA, Yee, BJ, Gordon, CJ, D'Rozario, AL, Kyle, SD, Espie, CA, Grunstein, RR, and Bartlett, DJ
- Abstract
Objectives: To evaluate brain metabolites in objective insomnia subtypes defined from polysomnography (PSG): Insomnia with short sleep duration (I-SSD) and insomnia with normal sleep duration (I-NSD), relative to good sleeping controls (GSCs). Methods: PSG empirically grouped insomnia patients into I-SSD (n = 12: Mean [SD] total sleep time [TST] = 294.7 minutes [30.5]) or I-NSD (n = 19: TST = 394.4 minutes [34.9]). 1H magnetic resonance spectroscopy (MRS) acquired in the left occipital cortex (LOCC), left prefrontal cortex, and anterior cingulate cortex was used to determine levels of creatine, aspartate, glutamate, and glutamine (referenced to water). Glutathione, glycerophosphocholine, lactate, myoinositol, and N-acetylaspartate measurements were also obtained. Sixteen GSCs were included for comparison. Multivariate analysis of variance was used to evaluate differences in creatine, aspartate, glutamate, and glutamine. Results: Aspartate and glutamine concentrations were reduced in the LOCC in I-SSD compared with I-NSD (both p < .05, d = .80-.99). Creatine displayed a nonsignificant mean reduction in I-SSD compared with I-NSD (p = .05, d = .58). Glutamine was reduced in I-SSD compared with controls (p < .05, d = .93). There were no differences in metabolites between all (I-SSD and I-NSD) insomnia patients and controls. In patients with insomnia, LOCC glutamine concentrations were found to be positively correlated with TST (r = .43, p < .05) and negatively correlated with wake-time after sleep onset (r = -.40, p < .05). Conclusions: Results indicate that I-SSD is associated with reduced brain metabolites in the LOCC compared with I-NSD and control concentrations of aspartate, glutamine, and creatine.
- Published
- 2017
20. Glutathione in the human brain: Review of its roles and measurement by magnetic resonance spectroscopy
- Author
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Rae, CD, Williams, SR, Rae, CD, and Williams, SR
- Abstract
We review the transport, synthesis and catabolism of glutathione in the brain as well as its compartmentation and biochemistry in different brain cells. The major reactions involving glutathione are reviewed and the factors limiting its availability in brain cells are discussed. We also describe and critique current methods for measuring glutathione in the human brain using magnetic resonance spectroscopy, and review the literature on glutathione measurements in healthy brains and in neurological, psychiatric, neurodegenerative and neurodevelopmental conditions In summary: Healthy human brain glutathione concentration is ∼1–2 mM, but it varies by brain region, with evidence of gender differences and age effects; in neurological disease glutathione appears reduced in multiple sclerosis, motor neurone disease and epilepsy, while being increased in meningiomas; in psychiatric disease the picture is complex and confounded by methodological differences, regional effects, length of disease and drug-treatment. Both increases and decreases in glutathione have been reported in depression and schizophrenia. In Alzheimer's disease and mild cognitive impairment there is evidence for a decrease in glutathione compared to age-matched healthy controls. Improved methods to measure glutathione in vivo will provide better precision in glutathione determination and help resolve the complex biochemistry of this molecule in health and disease.
- Published
- 2017
21. Toluene inhalation in adolescent rats reduces flexible behaviour in adulthood and alters glutamatergic and GABAergic signalling
- Author
-
Furlong, TM, Duncan, JR, Corbit, LH, Rae, CD, Rowlands, BD, Maher, AD, Nasrallah, FA, Milligan, CJ, Petrou, S, Lawrence, AJ, Balleine, BW, Furlong, TM, Duncan, JR, Corbit, LH, Rae, CD, Rowlands, BD, Maher, AD, Nasrallah, FA, Milligan, CJ, Petrou, S, Lawrence, AJ, and Balleine, BW
- Abstract
Toluene is a commonly abused inhalant that is easily accessible to adolescents. Despite the increasing incidence of use, our understanding of its long-term impact remains limited. Here, we used a range of techniques to examine the acute and chronic effects of toluene exposure on glutameteric and GABAergic function, and on indices of psychological function in adult rats after adolescent exposure. Metabolomics conducted on cortical tissue established that acute exposure to toluene produces alterations in cellular metabolism indicative of a glutamatergic and GABAergic profile. Similarly, in vitro electrophysiology in Xenopus oocytes found that acute toluene exposure reduced NMDA receptor signalling. Finally, in an adolescent rodent model of chronic intermittent exposure to toluene (10 000 ppm), we found that, while toluene exposure did not affect initial learning, it induced a deficit in updating that learning when response-outcome relationships were reversed or degraded in an instrumental conditioning paradigm. There were also group differences when more effort was required to obtain the reward; toluene-exposed animals were less sensitive to progressive ratio schedules and to delayed discounting. These behavioural deficits were accompanied by changes in subunit expression of both NMDA and GABA receptors in adulthood, up to 10 weeks after the final exposure to toluene in the hippocampus, prefrontal cortex and ventromedial striatum; regions with recognized roles in behavioural flexibility and decision-making. Collectively, our data suggest that exposure to toluene is sufficient to induce adaptive changes in glutamatergic and GABAergic systems and in adaptive behaviour that may underlie the deficits observed following adolescent inhalant abuse, including susceptibility to further drug-use.
- Published
- 2016
22. Alterations of GABA and glutamate-glutamine levels in premenstrual dysphoric disorder: A 3T proton magnetic resonance spectroscopy study
- Author
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Liu, B, Wang, G, Gao, D, Gao, F, Zhao, B, Qiao, M, Yang, H, Yu, Y, Ren, F, Yang, P, Chen, W, Rae, CD, Liu, B, Wang, G, Gao, D, Gao, F, Zhao, B, Qiao, M, Yang, H, Yu, Y, Ren, F, Yang, P, Chen, W, and Rae, CD
- Abstract
Increasing evidence has suggested that the GABAergic neurotransmitter system is involved in the pathogenesis of premenstrual dysphoric disorder (PMDD). We used proton magnetic resonance spectroscopy (1H MRS) to investigate whether PMDD is associated with alterations in brain GABA levels. Levels of glutamate-glutamine (Glx) were also explored. Participants comprised 22 women with PMDD and 22 age-matched healthy controls who underwent 3T 1H MRS during the late luteal phase of the menstrual cycle. GABA+ and Glx levels were quantified in the anterior cingulate cortex/medial prefrontal cortex (ACC/mPFC) and the left basal ganglia (ltBG). Water-scaled GABA+ concentrations and GABA+/tCr ratios were significantly lower in both the ACC/mPFC and ltBG regions of PMDD women than in healthy controls. Glx/tCr ratios were significantly higher in the ACC/mPFC region of PMDD women than healthy controls. Our preliminary findings provide the first report of abnormal levels of GABA+ and Glx in mood-related brain regions of women with PMDD, indicating that dysregulation of the amino acid neurotransmitter system may be an important neurobiological mechanism in the pathogenesis of PMDD.
- Published
- 2015
23. Ethanol, not detectably metabolized in brain, significantly reduces brain metabolism, probably via action at specific GABA(A) receptors and has measureable metabolic effects at very low concentrations
- Author
-
Rae, CD, Davidson, JE, Maher, AD, Rowlands, BD, Kashem, MA, Nasrallah, FA, Rallapalli, SK, Cook, JM, Balcar, VJ, Rae, CD, Davidson, JE, Maher, AD, Rowlands, BD, Kashem, MA, Nasrallah, FA, Rallapalli, SK, Cook, JM, and Balcar, VJ
- Abstract
Ethanol is a known neuromodulatory agent with reported actions at a range of neurotransmitter receptors. Here, we measured the effect of alcohol on metabolism of [3-13C]pyruvate in the adult Guinea pig brain cortical tissue slice and compared the outcomes to those from a library of ligands active in the GABAergic system as well as studying the metabolic fate of [1,2- 13C]ethanol. Analyses of metabolic profile clusters suggest that the significant reductions in metabolism induced by ethanol (10, 30 and 60 mM) are via action at neurotransmitter receptors, particularly α4β3δ receptors, whereas very low concentrations of ethanol may produce metabolic responses owing to release of GABA via GABA transporter 1 (GAT1) and the subsequent interaction of this GABA with local α5- or α1-containing GABA(A)R. There was no measureable metabolism of [1,2-13C]ethanol with no significant incorporation of 13C from [1,2- 13C]ethanol into any measured metabolite above natural abundance, although there were measurable effects on total metabolite sizes similar to those seen with unlabelled ethanol. © 2013 International Society for Neurochemistry.
- Published
- 2014
24. A guide to the metabolic pathways and function of metabolites observed in human brain 1H magnetic resonance spectra
- Author
-
Rae, CD and Rae, CD
- Abstract
The current knowledge of the normal biochemistry of compounds that give rise to resonances in human brain proton magnetic resonance spectra measureable at readily available field strengths (i.e. ≤3 T) is reviewed. Molecules covered include myo- and scyllo-inositol, glycerophospho- and phospho-choline and choline, creatine and phosphocreatine, N-acetylaspartate, N-acetylaspartylglutamate, glutamate, glutamine, γ-aminobutyrate, glucose, glutathione and lactate. The factors which influence changes in the levels of these compounds are discussed. As most proton resonances in the brain at low field are derived from a combination of moieties whose biochemistry is complex and interrelated, an understanding of the mechanisms underlying why these species change is crucial to meaningful interpretation of human brain spectra. © 2013 Springer Science+Business Media New York.
- Published
- 2014
25. Alterations of GABA and glutamate-glutamine levels in premenstrual dysphoric disorder: A 3T proton magnetic resonance spectroscopy study
- Author
-
Liu, B, Wang, G, Gao, D, Gao, F, Zhao, B, Qiao, M, Yang, H, Yu, Y, Ren, F, Yang, P, Chen, W, Rae, CD, Liu, B, Wang, G, Gao, D, Gao, F, Zhao, B, Qiao, M, Yang, H, Yu, Y, Ren, F, Yang, P, Chen, W, and Rae, CD
- Abstract
Increasing evidence has suggested that the GABAergic neurotransmitter system is involved in the pathogenesis of premenstrual dysphoric disorder (PMDD). We used proton magnetic resonance spectroscopy (1H MRS) to investigate whether PMDD is associated with alterations in brain GABA levels. Levels of glutamate-glutamine (Glx) were also explored. Participants comprised 22 women with PMDD and 22 age-matched healthy controls who underwent 3T 1H MRS during the late luteal phase of the menstrual cycle. GABA+ and Glx levels were quantified in the anterior cingulate cortex/medial prefrontal cortex (ACC/mPFC) and the left basal ganglia (ltBG). Water-scaled GABA+ concentrations and GABA+/tCr ratios were significantly lower in both the ACC/mPFC and ltBG regions of PMDD women than in healthy controls. Glx/tCr ratios were significantly higher in the ACC/mPFC region of PMDD women than healthy controls. Our preliminary findings provide the first report of abnormal levels of GABA+ and Glx in mood-related brain regions of women with PMDD, indicating that dysregulation of the amino acid neurotransmitter system may be an important neurobiological mechanism in the pathogenesis of PMDD.
- Published
- 2014
26. Thalamic activity and biochemical changes in individuals with neuropathic pain following spinal cord injury
- Author
-
Wrigley, PJ, Gusin, SM, Youssef, AM, McIndoe, L, Wilcox, SL, Rae, CD, Edden, R, Siddal, PJ, Henderson, LA, Wrigley, PJ, Gusin, SM, Youssef, AM, McIndoe, L, Wilcox, SL, Rae, CD, Edden, R, Siddal, PJ, and Henderson, LA
- Abstract
There is increasing evidence relating thalamic changes to the generation and/or maintenance of neuropathic pain. We have recently reported that neuropathic orofacial pain is associated with altered thalamic anatomy, biochemistry, and activity, which may result in disturbed thalamocortical oscillatory circuits. Despite this evidence, it is possible that these thalamic changes are not responsible for the presence of pain per se, but result as a consequence of the injury. To clarify this subject, we compared brain activity and biochemistry in 12 people with below-level neuropathic pain after complete thoracic spinal cord injury with 11 people with similar injuries and no neuropathic pain and 21 age- and gender-matched healthy control subjects. Quantitative arterial spinal labelling was used to measure thalamic activity, and magnetic resonance spectroscopy was used to determine changes in neuronal variability quantifying N-acetylaspartate and alterations in inhibitory function quantifying gamma amino butyric acid. This study revealed that the presence of neuropathic pain is associated with significant changes in thalamic biochemistry and neuronal activity. More specifically, the presence of neuropathic pain after spinal cord injury is associated with significant reductions in thalamic N-acetylaspartate, gamma amino butyric acid content, and blood flow in the region of the thalamic reticular nucleus. Spinal cord injury on its own did not account for these changes. These findings support the hypothesis that neuropathic pain is associated with altered thalamic structure and function, which may disturb central processing and play a key role in the experience of neuropathic pain.
- Published
- 2014
27. Thalamic activity and biochemical changes in individuals with neuropathic pain following spinal cord injury
- Author
-
Wrigley, PJ, Gusin, SM, Youssef, AM, McIndoe, L, Wilcox, SL, Rae, CD, Edden, R, Siddal, PJ, Henderson, LA, Wrigley, PJ, Gusin, SM, Youssef, AM, McIndoe, L, Wilcox, SL, Rae, CD, Edden, R, Siddal, PJ, and Henderson, LA
- Abstract
There is increasing evidence relating thalamic changes to the generation and/or maintenance of neuropathic pain. We have recently reported that neuropathic orofacial pain is associated with altered thalamic anatomy, biochemistry, and activity, which may result in disturbed thalamocortical oscillatory circuits. Despite this evidence, it is possible that these thalamic changes are not responsible for the presence of pain per se, but result as a consequence of the injury. To clarify this subject, we compared brain activity and biochemistry in 12 people with below-level neuropathic pain after complete thoracic spinal cord injury with 11 people with similar injuries and no neuropathic pain and 21 age- and gender-matched healthy control subjects. Quantitative arterial spinal labelling was used to measure thalamic activity, and magnetic resonance spectroscopy was used to determine changes in neuronal variability quantifying N-acetylaspartate and alterations in inhibitory function quantifying gamma amino butyric acid. This study revealed that the presence of neuropathic pain is associated with significant changes in thalamic biochemistry and neuronal activity. More specifically, the presence of neuropathic pain after spinal cord injury is associated with significant reductions in thalamic N-acetylaspartate, gamma amino butyric acid content, and blood flow in the region of the thalamic reticular nucleus. Spinal cord injury on its own did not account for these changes. These findings support the hypothesis that neuropathic pain is associated with altered thalamic structure and function, which may disturb central processing and play a key role in the experience of neuropathic pain.
- Published
- 2014
28. HIV, Vascular and Aging Injuries in the Brain of Clinically Stable HIV-Infected Adults: A 1H MRS Study
- Author
-
Cysique, LA, Moffat, K, Moore, DM, Lane, TA, Davies, NWS, Carr, AD, Brew, BJ, Rae, CD, Cysique, LA, Moffat, K, Moore, DM, Lane, TA, Davies, NWS, Carr, AD, Brew, BJ, and Rae, CD
- Abstract
BACKGROUND:Cardiovascular disease (CVD) and premature aging have been hypothesized as new risk factors for HIV associated neurocognitive disorders (HAND) in adults with virally-suppressed HIV infection. Moreover, their significance and relation to more classical HAND biomarkers remain unclear.METHODS:92 HIV- infected (HIV+) adults stable on combined antiretroviral therapy (cART) and 30 age-comparable HIV-negative (HIV-) subjects underwent (1)H Magnetic Resonance Spectroscopy (MRS) of the frontal white matter (targeting HIV, normal aging or CVD-related neurochemical injury), caudate nucleus (targeting HIV neurochemical injury), and posterior cingulate cortex (targeting normal/pathological aging, CVD-related neurochemical changes). All also underwent standard neuropsychological (NP) testing. CVD risk scores were calculated. HIV disease biomarkers were collected and cerebrospinal fluid (CSF) neuroinflammation biomarkers were obtained in 38 HIV+ individuals.RESULTS:Relative to HIV- individuals, HIV+ individuals presented mild MRS alterations: in the frontal white matter: lower N-Acetyl-Aspartate (NAA) (p
- Published
- 2013
29. Combining MR elastography and diffusion tensor imaging for the assessment of anisotropic mechanical properties: A phantom study
- Author
-
Qin, E, Sinkus, R, Geng, G, Cheng, SK, Green, M, Rae, CD, Bilston, LE, Qin, E, Sinkus, R, Geng, G, Cheng, SK, Green, M, Rae, CD, and Bilston, LE
- Published
- 2013
30. Statistical integration of 1H NMR and MRS data from difefrent biofluids and tissues enhances recovery of biological information from individuals with HIV-1 infection
- Author
-
Maher, A, Cysique, LA, Brew, BJ, Rae, CD, Maher, A, Cysique, LA, Brew, BJ, and Rae, CD
- Abstract
Nuclear magnetic resonance (NMR) spectroscopy is widely used in metabonomics studies, but optimal recovery of latent biological information requires increasingly sophisticated statistical methods to identify quantitative relationships within these often highly complex data sets. Statistical heterospectroscopy (SHY) extracts latent relationships between NMR and mass spectrometry (MS) data from the same samples. Here we extend this concept to identify novel metabolic correlations between different biofluids and tissues from the same individuals. We acquired NMR data from blood plasma and cerebrospinal fluid (CSF) (N = 19) from HIV-1-infected individuals, who are known to be susceptible to neuropsychological dysfunction. We compared two computational approaches to SHY, namely the Pearson’s product moment correlation and the Spearman’s rank correlation. High correlations were observed for glutamine, valine, and polyethylene glycol, a drug delivery vehicle. Orthogonal projections to latent structures (OPLS) identified metabolites in blood plasma spectra that predicted the amounts of key CSF metabolites such as lactate, glutamine, and myo-inositol. Finally, brain metabolic data from magnetic resonance spectroscopy (MRS) measurements in vivo were integrated with CSF data to identify an association between 3-hydroxyvalerate and frontal white matter N-acetyl aspartate levels. The results underscore the utility of tools such as SHY and OPLS for coanalysis of high dimensional data sets to recover biological information unobtainable when such data are analyzed in isolation.
- Published
- 2011
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