Caroline Rae

Impact of Inhibition of Glutamine and Alanine Transport on Cerebellar Glial and Neuronal Metabolism

Publisher: MDPI AG

Date: 27-08-2022

DOI: 10.3390/BIOM12091189

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.

Metabolic Effects of Blocking Lactate Transport in Brain Cortical Tissue Slices Using an Inhibitor Specific to MCT1 and MCT2

Publisher: Springer Science and Business Media LLC

Date: 29-04-2009

DOI: 10.1007/S11064-009-9973-0

Abstract: A novel inhibitor of lactate transport, AR-C122982, was used to study the effect of inhibiting the monocarboxylate transporters MCT1 and MCT2 on cortical brain slice metabolism. We studied metabolism of L-[3-13C]lactate, and D-[1-13C]glucose under a range of conditions. Experiments using L-[3-13C]lactate showed that the inhibitor AR-C122982 altered exchange of lactate. Under depolarizing conditions, net flux of label from D-[1-13C]glucose was barely altered by 10 or 100 nM AR-C122982. In the presence of AMPA or glutamate there were increases in net flux of label and metabolic pool sizes. These data suggest lactate may supply compartments in the brain not usually directly accessed by glucose. In general, it would appear that movement of lactate between cell types is not essential for metabolic activity, with the heavy metabolic workloads imposed being unaffected by inhibition of MCT1 and MCT2. Further experiments investigating the mechanism of operation of AR-C122982 are necessary to corroborate this finding.

Thalamic activity and biochemical changes in individuals with neuropathic pain after spinal cord injury

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 05-2014

DOI: 10.1016/J.PAIN.2014.02.008

Compartmentation of metabolism probed by [2- ]alanine: improved NMR sensitivity using a CryoProbe detects evidence of a glial metabolon

Publisher: Elsevier BV

Date: 2003

DOI: 10.1016/S0197-0186(02)00064-5

Abstract: The labelling of metabolites with the NMR active nucleus 13C allows not only metabolite enrichments to be monitored, but also the relative fluxes through competing pathways to be delineated. [2-13C, 15N]alanine was used as a metabolic probe to investigate compartmentation in superfused cerebral slices. Perchloric acid extracts of the tissue were investigated using 13C NMR spectroscopy. The spectra were obtained using a CryoProbe optimised for 13C detection (dual CryoProbe [13C, 1H]) in which the receiver and transmitter coils are cooled to approximately 20K to reduce contributions to noise in the signal obtained. Compared with conventional inverse geometry probe, the signal-to-noise ratio (S/N) was increased by approximately 17-fold using this device. A large proportion of alanine was initially metabolised over the first 20 min by glial cells, as indicated by the relative importance of the glial, only enzyme pyruvate carboxylase to the labelling pattern of glutamate, with the ratio of pyruvate carboxylase to pyruvate dehydrogenase derived glutamate being 0.25, and exported [2-13C, 15N]aspartate. Using the increased sensitivity of the CryoProbe, [2-13C, 15N]aspartate was also detected in the extracts of cerebral tissue. This metabolite could only have been derived via the pyruvate carboxylase pathway, and given the large export of the metabolite into the superfusion buffer suggests the occurrence of a "metabolon" arrangement of enzymes within glial cells.

Bootstrap quantification of cardiac pulsation artifact in DTI

Publisher: Elsevier BV

Date: 2010

DOI: 10.1016/J.NEUROIMAGE.2009.06.067

Abstract: While several studies have shown the benefit of cardiac gating in diffusion MRI with single-shot EPI acquisition, cardiac gating is still not commonly used. This is probably because it requires additional time and many investigators may not be convinced that cardiac gating is worth the extra effort. Here, we tested a clinically feasible protocol with a minimal increase in scan time, and quantified the effect of cardiac gating under partial or full Fourier acquisition. Eight volunteers were scanned on a 3 T scanner with a SENSE 8-channel head coil. Diffusion-weighted, single-shot spin-echo EPI images were acquired along 32 gradient directions, with or without cardiac gating and with partial or full Fourier acquisition. Vectorcardiography (VCG) was used to trigger acquisition at a minimum delay (30 ms). The uncertainties of DTI derived parameters were estimated using residual bootstrap. With partial Fourier, cardiac gating reduced the uncertainties, and better efficiency in reducing DTI parameter variability was also achieved even allowing for the increase in total scan time. For full Fourier acquisition, minimum time gating slightly decreased the uncertainties but the efficiency was worse. A minimum trigger delay might not be the optimal scheme to avoid the majority of systole but it allows clinically acceptable scan times. We have demonstrated that cardiac gating, especially of partial Fourier acquisitions, can reduce the uncertainties of DTI derived parameters in a time-efficient manner.

Sleep spindle activity correlates with implicit statistical learning consolidation in untreated obstructive sleep apnea patients

Publisher: Elsevier BV

Date: 10-2021

DOI: 10.1016/J.SLEEP.2021.01.035

HIV, Vascular and Aging Injuries in the Brain of Clinically Stable HIV-Infected Adults: A 1H MRS Study

Publisher: Public Library of Science (PLoS)

Date: 19-04-2013

DOI: 10.1371/JOURNAL.PONE.0061738

Glutamate Metabolism is Impaired in Transgenic Mice with Tau Hyperphosphorylation

Publisher: SAGE Publications

Date: 23-01-2013

DOI: 10.1038/JCBFM.2012.212

Abstract: In neurodegenerative diseases including Alzheimer's disease and frontotemporal dementia, the protein tau is hyperphosphorylated and eventually aggregates to develop neurofibrillary tangles. Here, the consequences of tau hyperphosphorylation on both neuronal and astrocytic metabolism and amino-acid neurotransmitter homeostasis were assessed in transgenic mice expressing the pathogenic mutation P301L in the human tau gene (pR5 mice) compared with nontransgenic littermate controls. Mice were injected with the neuronal and astrocytic substrate [1- 13 C]glucose and the astrocytic substrate [1,2- 13 C]acetate. Hippoc us and cerebral cortex extracts were analyzed using 1 H and 13 C nuclear magnetic resonance spectroscopy, gas chromatography–mass spectrometry and high-performance liquid chromatography. The glutamate level was reduced in the hippoc us of pR5 mice, accompanied by reduced incorporation of 13 C label derived from [1- 13 C]glucose in glutamate. In the cerebral cortex, glucose utilization as well as turnover of glutamate, glutamine, and GABA, were increased. This was accompanied by a relative increase in production of glutamate via the pyruvate carboxylation pathway in cortex. Overall, we revealed that astrocytes as well as glutamatergic and GABAergic neurons in the cortex of pR5 mice were in a hypermetabolic state, whereas in the hippoc us, where expression levels of mutant human tau are the highest, glutamate homeostasis was impaired.

Comparison of the 1H and 31P NMR Spectra of Erythrocytes and Plasma from some Australian Native Animals: Bandicoot, Echidna, Koala, Little Penguin, Tammar Wallaby, Tasmanian Devil, Tree Kangaroo and W

Publisher: Springer Science and Business Media LLC

Date: 1993

DOI: 10.1007/BF00368109

Mind Meld: Collaborative Approaches to Understanding How We All Think

Publisher: Springer Science and Business Media LLC

Date: 16-10-2008

DOI: 10.1007/S11682-008-9036-1

Creatine supplementation affects glucose homeostasis but not insulin secretion in humans

Publisher: S. Karger AG

Date: 2003

DOI: 10.1159/000068908

Abstract: i Aims: /i In this study, it was investigated whether the glucose homeostasis is affected by dietary creatine supplementation. For this purpose, the plasma glucose concentration and the plasma insulin response to an oral glucose load were measured in creatine-supplemented vegetarians. i Methods: /i The subjects were supplemented with either 5 g of creatine monohydrate (creatine-treated group, CREAT) or 5 g of maltodextrin (control group, CON) per day for 42 days. On days 0 and 43, blood s les were collected before as well as 10, 20, and 30 min following an oral glucose load and analyzed for plasma creatine, insulin, and glucose levels. i Results: /i Creatine supplementation resulted in an increase in plasma creatine (CREAT 92.7 ± 14.6 µ i M /i vs. CON 31.2 ± 3.2 µ i M /i p = 0.001). There was a trend (p = 0.07) towards elevated fasting plasma glucose levels following creatine supplementation, while the plasma glucose response to the glucose load was enhanced (CREAT 168.2 ± 5.3 m i M /i · min vs. CON 129.6 ± 14.7 m i M /i ·min p = 0.05). There was no difference observed in the plasma insulin response to the glucose load between the groups. i Conclusion: /i This study shows that creatine supplementation may result in abnormalities in glucose homeostasis in the absence of changes in insulin secretion.

Uncoupling N-acetylaspartate from brain pathology: implications for Canavan disease gene therapy

Publisher: Springer Science and Business Media LLC

Date: 07-11-2017

DOI: 10.1007/S00401-017-1784-9

Metabolites from cerebrospinal fluid in aneurysmal subarachnoid haemorrhage correlate with vasospasm and clinical outcome: a pattern-recognition1H NMR study

Publisher: Wiley

Date: 2005

DOI: 10.1002/NBM.918

Abstract: Following subarachnoid haemorrhage the most significant complication is sustained cerebral vascular contraction (vasospasm), which may result in terminal brain damage from cerebral infarction. Despite this, the biochemical cause of vasospasm remains poorly understood. In this study, the global high-concentration metabolite composition of CSF has been correlated with patient outcome after subarachnoid haemorrhage using multivariate statistics and 1H NMR spectroscopy. In total, 16 patients with aneurysmal subarachnoid haemorrhage (aSAH) were compared with 16 control patients who required a procedure where CSF was obtained but did not have aSAH. Multivariate statistics readily distinguished the aSAH group from the heterogeneous control group, even when only those controls with blood contamination in the CSF were used. Using principal components analysis and orthogonal signal correction, vasospasm was correlated to the concentrations of lactate, glucose and glutamine. These pattern recognition models of the NMR data also predicted Glasgow Coma Score (54% within +/- 1 of the actual score on a scale of 1-15 for the whole patient group), Hunt and Hess SAH severity score (88% within +/- 1 of the actual score on a scale of 1-5 for the aSAH group) and cognitive outcome scores (78% within +/- 3 of the actual score on a 100% scale for the whole patient group). Thus, the approach allowed the prediction of outcome as well as confirming the presence of aSAH.

1H NMR spectroscopic survey of plasma and erythrocytes from selected marsupials and domestic animals of Australia

Publisher: Elsevier BV

Date: 1991

DOI: 10.1016/0305-0491(91)90340-J

Abstract: 1. 1H NMR spectra were acquired from whole plasma, intact erythrocytes, and ultrafiltrates of erythrocytes from nine native and eight introduced (domestic) Australian animals single-pulse, spin-echo and 2-dimensional spectra were obtained. The aim was to detect and at least semi-quantify metabolites in the s les and compare the profiles amongst the species. 2. The Australian natives that were studied were all marsupials: greater brown bandicoot bettong eastern grey kangaroo red kangaroo koala possum red necked pademelon Tammar wallaby and wombat. The introduced mammals that were studied were: cat cattle dog goat horse pig rabbit and sheep. 3. Because of the range of habitats and diets amongst the animals, it was postulated that the concentrations of the common metabolites in the blood would show marked differences and that there would also be some metabolites that were peculiar to a given animal. There were several major differences in the spectra: in the spectra of plasma, the glycoprotein and lipoprotein resonances showed the largest inter-species variation, whereas the most dramatic finding from the spectra of erythrocytes was a very high concentration of lysine in the cells from the Tammar wallaby.

Rottlerin Inhibits (Na+, K+)-ATPase Activity in Brain Tissue and Alters d-Aspartate Dependent Redistribution of Glutamate Transporter GLAST in Cultured Astrocytes

Publisher: Springer Science and Business Media LLC

Date: 03-06-2009

DOI: 10.1007/S11064-009-9996-6

Abstract: The naturally occurring toxin rottlerin has been used by other laboratories as a specific inhibitor of protein kinase C-delta (PKC-delta) to obtain evidence that the activity-dependent distribution of glutamate transporter GLAST is regulated by PKC-delta mediated phosphorylation. Using immunofluorescence labelling for GLAST and deconvolution microscopy we have observed that D-aspartate-induced redistribution of GLAST towards the plasma membranes of cultured astrocytes was abolished by rottlerin. In brain tissue in vitro, rottlerin reduced apparent activity of (Na+, K+)-dependent ATPase (Na+, K+-ATPase) and increased oxygen consumption in accordance with its known activity as an uncoupler of oxidative phosphorylation ("metabolic poison"). Rottlerin also inhibited Na+, K+-ATPase in cultured astrocytes. As the glutamate transport critically depends on energy metabolism and on the activity of Na+, K+-ATPase in particular, we suggest that the metabolic toxicity of rottlerin and/or the decreased activity of the Na+, K+-ATPase could explain both the glutamate transport inhibition and altered GLAST distribution caused by rottlerin even without any involvement of PKC-delta-catalysed phosphorylation in the process.

Lactate-induced inhibition of glucose catabolism in guinea pig cortical brain slices

Publisher: Elsevier BV

Date: 11-1999

DOI: 10.1016/S0197-0186(99)00085-6

Abstract: Extracellular lactate concentration rises following ischaemic stroke in both the infarcted area and in the surrounding ischaemic penumbra. We investigated the effect of lactate accumulation on glucose metabolism in cortical slices from guinea pigs initially by varying superfusion medium to tissue volumes. Stable intracellular K+ concentrations indicated that a decrease in media/ tissue volume did not impair viability of the tissue, but 13C NMR demonstrated that lactate accumulation in the superfusion medium reduced glucose oxidation with inhibition of glial metabolism via pyruvate carboxylase. The concentration of lactate which had accumulated when significant inhibition was observed was approximately 0.85 mM. In independent experiments we found that superfusion of brain slices with lactate at this concentration (even using a 'high-volume' of superfusion fluid) decreased oxygen consumption by 40 +/- 3%. K(-)-induced depolarisation partially reversed this effect. These results suggest that even low extracellular lactate concentrations may depress metabolic rates in inactive and poorly perfused brain tissue in vivo through inhibition of glial metabolism of glucose.

Activity‐dependent γ‐aminobutyric acid release controls brain cortical tissue slice metabolism

Publisher: Wiley

Date: 26-05-2011

DOI: 10.1002/JNR.22649

Abstract: Vigabatrin (γ-vinyl-GABA) is an irreversible inhibitor of the enzyme γ-aminobutyric acid (GABA) transaminase. It has been shown to increase levels of GABA in brain and result in increased release of GABA from nonsynaptic sources following activation. Here, we use a guinea pig cortical tissue slice model to identify the metabolic sequelae of vigabatrin when incubated with tissue slices alone or when the tissue slices were activated by ligands with targeted activating mechanisms. We show that incubation of slices with AMPA, the group II metabotropic glutamate antagonist EGLU [(2S)-α-ethylglutamic acid], or the GABA(B) R antagonist CGP 52432 in the presence of vigabatrin produces very similar metabolic profiles, consistent with the large-scale turning off of metabolic activity. This effect is blocked by the GABA(Arho) antagonist TPMPA [(1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid]. Taken together, these results suggest that GABA, released following activation, acts on extrasynaptic receptors consistent with GABA(Arho) and that these receptors act as a kind of "master switch" that is capable of turning off a range of differently induced activities.

Atrophic brain signatures of mild forms of neurocognitive impairment in virally suppressed HIV infection

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 02-01-2019

DOI: 10.1097/QAD.0000000000002042

Increased permeability of the malaria-infected erythrocyte to organic cations

Publisher: Elsevier BV

Date: 2000

DOI: 10.1016/S0005-2736(99)00187-X

Abstract: The human malaria parasite, Plasmodium falciparum, induces in the plasma membrane of its host red blood cell new permeation pathways (NPP) that allow the influx of a variety of low molecular weight solutes. In this study we have demonstrated that the NPP confer upon the parasitised erythrocyte a substantial permeability to a range of monovalent organic (quaternary ammonium) cations, the largest having an estimated minimum cross-sectional diameter of 11-12 A. The rate of permeation of these cations showed a marked dependence on the nature of the anion present, increasing with the lyotropicity of the anion. There was no clear relationship between the permeation rate and either the size or the hydrophobicity of these solutes. However, the data were consistent with the rate of permeation being influenced by a combination of these two factors, with the pathways showing a marked preference for the relatively small and hydrophobic phenyltrimethylammonium ion over larger or less hydrophobic solutes. Large quaternary ammonium cations inhibited flux via the NPP, as did long-chain n-alkanols. For both classes of compound the inhibitory potency increased with the size and hydrophobicity of the solute. This study extends the range of solutes known to permeate the NPP of malaria-infected erythrocytes as well as providing some insight into the factors governing the rate of permeation.

Understanding autism spectrum disorder and social functioning in children with neurofibromatosis type 1: protocol for a cross-sectional multimodal study

Publisher: BMJ

Date: 09-2019

DOI: 10.1136/BMJOPEN-2019-030601

Abstract: 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. 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. This study has hospital ethics approval and the results will be disseminated through peer-reviewed publications and international conferences.

A Guide to the Metabolic Pathways and Function of Metabolites Observed in Human Brain 1H Magnetic Resonance Spectra

Publisher: Springer Science and Business Media LLC

Date: 21-11-2013

DOI: 10.1007/S11064-013-1199-5

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.

β-Hydroxybutyrate Boosts Mitochondrial and Neuronal Metabolism but is not Preferred Over Glucose Under Activated Conditions

Publisher: Springer Science and Business Media LLC

Date: 18-03-2017

DOI: 10.1007/S11064-017-2228-6

Abstract: The ketone body, β-hydroxybutyrate (βOHB), is metabolised by the brain alongside the mandatory brain fuel glucose. To examine the extent and circumstances by which βOHB can supplement glucose metabolism, we studied guinea pig cortical brain slices using increasing concentrations of [U-

Corrigendum: Reduced Glutamate in the Medial Prefrontal Cortex Is Associated With Emotional and Cognitive Dysregulation in People With Chronic Pain

Publisher: Frontiers Media SA

Date: 16-03-2022

DOI: 10.3389/FNEUR.2022.872851

Brain amyloid in virally suppressed HIV-associated neurocognitive disorder

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 11-05-2020

DOI: 10.1212/NXI.0000000000000739

Abstract: To determine whether virally suppressed HIV neuropathogenesis, a chronic neuroinflammatory state, promotes abnormal brain amyloid deposition. A total of 10 men with virally suppressed HIV-associated neurocognitive disorder (HAND), aged 46–68 years, underwent 11 C-labeled Pittsburgh compound B PET. Data from the Australian Imaging, Biomarkers and Lifestyle (AIBL), including 39 cognitively normal in iduals (aged 60–74 years), 7 in iduals with mild cognitive impairment (MCI) (aged 64–71 years), and 11 in iduals 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 s le. 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 s le, apolipoprotein E (APOE) was available in 80%, CSF biomarkers in 60%, and 8–10 years of long-term health outcomes in 100%. 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 in idual 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 hippoc i. Two other HAND cases showed abnormally decreased amyloid in subcortical areas. Relative to cognitively normal older controls, brain amyloid burden does not differ in virally suppressed HAND at the group level. However, in idual analyses show that abnormally high and low amyloid burden occur.

AMP‐activated protein kinase activators have compound and concentration‐specific effects on brain metabolism

Publisher: Wiley

Date: 06-04-2023

DOI: 10.1111/JNC.15815

Abstract: AMP‐activated protein kinase (AMPK) is a key sensor of energy balance playing important roles in the balancing of anabolic and catabolic activities. The high energy demands of the brain and its limited capacity to store energy indicate that AMPK may play a significant role in brain metabolism. Here, we activated AMPK in guinea pig cortical tissue slices, both directly with A769662 and PF 06409577 and indirectly with AICAR and metformin. We studied the resultant metabolism of [1‐ 13 C]glucose and [1,2‐ 13 C]acetate using NMR spectroscopy. We found distinct activator concentration‐dependent effects on metabolism, which ranged from decreased metabolic pool sizes at EC 50 activator concentrations with no expected stimulation in glycolytic flux to increased aerobic glycolysis and decreased pyruvate metabolism with certain activators. Further, activation with direct versus indirect activators produced distinct metabolic outcomes at both low (EC 50 ) and higher (EC 50 × 10) concentrations. Specific direct activation of β1‐containing AMPK isoforms with PF 06409577 resulted in increased Krebs cycle activity, restoring pyruvate metabolism while A769662 increased lactate and alanine production, as well as labelling of citrate and glutamine. These results reveal a complex metabolic response to AMPK activators in brain beyond increased aerobic glycolysis and indicate that further research is warranted into their concentration‐ and mechanism‐dependent impact. image

A metabonomic study of inhibition of GABA uptake in the cerebral cortex

Publisher: Springer Science and Business Media LLC

Date: 28-08-2009

DOI: 10.1007/S11306-009-0176-0

Brain biochemistry in Duchenne muscular dystrophy: A 1H magnetic resonance and neuropsychological study

Publisher: Elsevier BV

Date: 10-1998

DOI: 10.1016/S0022-510X(98)00190-7

Abstract: Duchenne muscular dystrophy (DMD) is a progressive muscle disorder associated with an intellectual deficit which is non-progressive. We obtained localised 1H magnetic resonance spectra from the left frontal lobe and left cerebellum of 15 boys with DMD (mean age 106 months+/-32) and 15 similarly aged control boys (mean age 115 months+/-31) all boys underwent a battery of neuropsychological tests. We found a significant (P 0.80) revealed a significant difference in ability on the MAT (P<0.05). DMD boys whose Cho/NA ratio is more than two standard deviations higher than controls perform significantly better on the MAT than DMD boys whose Cho/NA ratio is within the normal range. This finding suggests that the observed elevation in Cho/NA and Cho/creatine is not associated with intellectual deficit (as s led by the MAT), and may represent a compensatory mechanism. The possible interpretations of these metabolic changes are discussed.

Acetate metabolism does not reflect astrocytic activity, contributes directly to GABA synthesis, and is increased by silent information regulator 1 activation

Publisher: Wiley

Date: 23-01-2017

DOI: 10.1111/JNC.13916

Abstract: [

The energetic cost of a night on the town.

Publisher: Oxford University Press (OUP)

Date: 12-2014

DOI: 10.5665/SLEEP.4230

Silent information regulator 1 modulator resveratrol increases brain lactate production and inhibits mitochondrial metabolism, whereas SRT1720 increases oxidative metabolism

Publisher: Wiley

Date: 09-02-2015

DOI: 10.1002/JNR.23570

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.

An objective short sleep insomnia disorder subtype is associated with reduced brain metabolite concentrations in vivo: A preliminary magnetic resonance spectroscopy assessment

Publisher: Oxford University Press (OUP)

Date: 25-08-2017

DOI: 10.1093/SLEEP/ZSX148

Abstract: 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). 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. 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). 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. Insomnia MRS imaging sleep study: Australia New Zealand Clinical Trials Registry (ANZCTR): www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12612000050853. 12612000050853.

Brain bioenergetics during resting wakefulness are related to neurobehavioral deficits in severe obstructive sleep apnea: a 31P magnetic resonance spectroscopy study

Publisher: Oxford University Press (OUP)

Date: 06-2018

DOI: 10.1093/SLEEP/ZSY117

Abstract: Obstructive sleep apnea (OSA) is a well-established cause of impaired daytime functioning. However, there is a complex inter-in idual 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. 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). 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). 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.

Diffusion Tensor Imaging in Sport-Related Concussion: A Systematic Review Using an a priori Quality Rating System

Publisher: Mary Ann Liebert Inc

Date: 15-11-2021

DOI: 10.1089/NEU.2021.0154

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

On the Reliability of Individual Brain Activity Networks

Publisher: Institute of Electrical and Electronics Engineers (IEEE)

Date: 02-2018

DOI: 10.1109/TMI.2017.2774364

Metabolism, Compartmentation, Transport and Production of Acetate in the Cortical Brain Tissue Slice

Publisher: Springer Science and Business Media LLC

Date: 08-2012

DOI: 10.1007/S11064-012-0847-5

Abstract: Acetate is a two carbon intermediate in metabolism. It is an accepted marker of astrocytic metabolism, and a substrate for production of metabolites such as glutamine, glutamate and GABA. However, anomalies exist in the current explanations of compartmentation and metabolism of acetate. Here, we investigated these anomalies by examining transport, production and metabolism of acetate. Acetate is a good substrate for the neuronal monocarboxylate transporter MCT2 (K(M) = 2.58 ± 0.8) and the glial MCT1 but a poor substrate for the glial MCT4. Acetate is accumulated by brain cortical tissue slices to concentrations in excess of those in the media, suggesting active transport, possibly via the sodium dependent SMCT. [2-(13)C]Acetate is produced from [3-(13)C]pyruvate, [3-(13)C]lactate and [1-(13)C]glucose with the rate of production related to acetyl-CoA levels, which is likely generated in a ubiquitous cytosolic compartment via acetyl-CoA hydrolase. Citrate breakdown occurs in response to demand for acetyl-CoA units this citrate is not derived from acetate carbon but its fate is influenced by acetate levels. Finally, use of acetate is altered by levels of nicotinamide or NAD(+). This suggests that metabolism of acetate is controlled rigorously at the enzyme level, via changes in the acetylation status of acetyl-CoA synthetase and is not regulated by restriction of uptake.

Fine-grained mapping of cortical somatotopies in chronic Complex Regional Pain Syndrome

Publisher: Cold Spring Harbor Laboratory

Date: 08-09-2018

DOI: 10.1101/409094

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 reorganisation of the somatotopic representation of the affected limb in primary somatosensory cortex (S1). This notion has driven treatments that aim to restore S1 representations, 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 functional MRI to characterize the S1 representation of the affected and unaffected hand in patients with unilateral CRPS. At the group level, the cortical area, location, and geometry of the S1 representation of the CRPS hand were largely comparable to those of the healthy hand and controls. However, the area of the map of the affected hand was modulated by disease duration (the smaller the map, the more chronic the CRPS), but not by pain intensity, pain sensitivity and severity of the physical disability. Thus, if any map reorganization occurs, it does not appear to be directly related to our pain measures. 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. This study shows that the spatial map of the fingers in S1 is largely preserved in chronic CRPS. Shrinkage of the area of the affected hand map can occur in the most chronic stages of disease. Map shrinkage is related to CRPS duration rather than diagnosis, and is unrelated to how much pain patients experience or to the severity of the physical disability. These findings challenge the rationale for using sensory interventions to treat pain by restoring somatotopic representations in CRPS patients.

Do maternal opioids reduce neonatal regional brain volumes? A pilot study

Publisher: Springer Science and Business Media LLC

Date: 19-06-2014

DOI: 10.1038/JP.2014.111

Abstract: A substantial number of children exposed to gestational opioids have neurodevelopmental, behavioral and cognitive problems. Opioids are not neuroteratogens but whether they affect the developing brain in more subtle ways (for ex le, volume loss) is unclear. We aimed to determine the feasibility of using magnetic resonance imaging (MRI) to assess volumetric changes in healthy opioid-exposed infants. Observational pilot cohort study conducted in two maternity hospitals in New South Wales, Australia. Maternal history and neonatal urine and meconium screens were obtained to confirm drug exposure. Volumetric analysis of MRI scans was performed with the ITK-snap program. Scans for 16 infants (mean (s.d.) gestational age: 40.9 (1.5) weeks, birth weight: 3022.5 (476.6) g, head circumference (HC): 33.7 (1.5 cm)) were analyzed. Six (37.5%) infants had HC <25th percentile. Fourteen mothers used methadone, four used buprenorphine and 11 used more than one opioid (including heroin, seven). All scans were structurally normal whole brain volumes (357.4 (63.8)) and basal ganglia (14.5 (3.5)) ml were significantly smaller than population means (425.4 (4.8), 17.1 (4.4) ml, respectively) but lateral ventricular volumes (3.5 (1.8) ml) were larger than population values (2.1(1.5)) ml. Our pilot study suggests that brain volumes of opioid-exposed babies may be smaller than population means and that specific regions, for ex le, basal ganglia, that are involved in neurotransmission, may be particularly affected. Larger studies including correlation with neurodevelopmental outcomes are warranted to substantiate this finding.

Skeletal muscle abnormalities and exercise capacity in adults with a Fontan circulation

Publisher: BMJ

Date: 11-07-2013

DOI: 10.1136/HEARTJNL-2013-304249

Abstract: The peripheral muscle pump is key in promoting cardiac filling during exercise, especially in subjects who lack a subpulmonary ventricle (the Fontan circulation). A muscle-wasting syndrome exists in acquired heart failure but has not been assessed in Fontan subjects. We sought to investigate whether adults with the Fontan circulation exhibit reduced skeletal muscle mass and/or metabolic abnormalities. Sixteen New York Heart Association Class I/II Fontan adults (30±2 years) underwent cardiopulmonary exercise testing and lean mass quantification with dual x-ray absorptiometry (DXA) eight had calf muscle (31)P magnetic resonance spectroscopy as did eight healthy age-matched and sex-matched controls. DXA results were compared with Australian reference data. Single tertiary referral centre. Peak VO2 was 1.9±0.1 L/min (66±3% of predicted values). Skeletal muscle mass assessed by relative appendicular lean mass index was significantly reduced compared with age-matched and sex-matched reference values (Z-score -1.46±0.22, p<0.0001). Low skeletal muscle mass correlated with poorer VO2 max (r=0.67, p=0.004). Overall, skeletal muscle mass T-score (derived from comparison with young normal reference mean) was -1.47±0.21 4/16 Fontan subjects had sarcopenic range muscle wasting (T-score <-2.0) and 9/16 had less marked, but clinically significant wasting (T-score <-1.0 but ≥-2.0). Muscle aerobic capacity, measured by the rate constant (k) of postexercise phosphocreatine resynthesis, was significantly impaired in Fontan adults versus controls (1.48±0.13 vs 2.40±0.33 min(-1), p=0.02). Fontan adults have reduced skeletal muscle mass and intrinsic muscle metabolic abnormalities.

Pyruvate Carboxylation in Different Model Systems Studied by 13C MRS

Publisher: Springer Science and Business Media LLC

Date: 15-09-2010

DOI: 10.1007/S11064-010-0257-5

Inhibitors of glutamate transport modulate distinct patterns in brain metabolism

Publisher: Wiley

Date: 03-11-2006

DOI: 10.1002/JNR.21108

Abstract: High affinity uptake of glutamate plays a major role in the termination of excitatory neurotransmission. Identification of the ramifications of transporter function is essential to understand the diseases in which defective excitatory amino acid transporters (EAAT) have been implicated. In this work we incubated Guinea pig cortical tissue slices with [3-(13)C]pyruvate and major currently available glutamate uptake inhibitors and studied the resultant metabolic sequelae by (13)C and (1)H NMR spectroscopy using a multivariate statistical approach. Perturbation of glutamate uptake produced significant effects on metabolic flux through the Krebs cycle, and on glutamate/glutamine cycling rates, with this effect accounting for 76% of the variation in the total data set. The effects of all inhibitors were separable from each other along three major principal components. The competitive inhibitor L-CCG III ((2S,1'S,2'R)-2-carboxycyclopropyl)glycine) differed most from the other inhibitors, showing negative weightings on both the first and second principal components, whereas the EAAT2-specific inhibitor dihydrokainate (DHK) showed metabolic patterns similar to that of anti-endo-3,4-methanopyrolidine dicarboxylate but separate from those of DL-threo-beta-benzyloxyaspartate (TBOA) and L-trans-pyrrolidine-2,4-dicarboxylate (L-tPDC). This indicates that different inhibition mechanisms or different colocalisation of the separate transporter subtypes with glutamate receptors can produce significantly different metabolic and functional outcomes for the brain.

Glutathione in the human brain: Review of its roles and measurement by magnetic resonance spectroscopy

Publisher: Elsevier BV

Date: 07-2017

DOI: 10.1016/J.AB.2016.12.022

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.

Actions of Alcohol in Brain: Genetics, Metabolomics, GABA Receptors, Proteomics and Glutamate Transporter GLAST/EAAT1

Publisher: Bentham Science Publishers Ltd.

Date: 31-12-2020

DOI: 10.2174/1874467213666200424155244

Abstract: We present an overview of genetic, metabolomic, proteomic and neurochemical studies done mainly in our laboratories that could improve prediction, mechanistic understanding and possibly extend to diagnostics and treatment of alcoholism and alcohol addiction. Specific polymorphisms in genes encoding for interleukins 2 and 6, catechol-O-methyl transferase (COMT), monaminooxidase B (MAO B) and several other enzymes were identified as associated with altered risks of alcoholism in humans. A polymorphism in the gene for BDNF has been linked to the risk of developing deficiences in colour vision sometimes observed in alcoholics. Metabolomic studies of acute ethanol effects on guinea pig brain cortex in vitro, lead to the identification of specific subtypes of GABA(A) receptors involved in the actions of alcohol at various doses. Acute alcohol affected energy metabolism, oxidation and the production of actaldehyde and acetate this could have specific consequences not only for the brain energy production/utilization but could influence the cytotoxicity of alcohol and impact the epigenetics (histone acetylation). It is unlikely that brain metabolism of ethanol occurs to any significant degree the reduction in glucose metabolism following alcohol consumption is due to ethanol effects on receptors, such as α4β3δ GABA(A) receptors. Metabolomics using post-mortem human brain indicated that the catecholaminergic signalling may be preferentially affected by chronic excessive drinking. Changes in the levels of glutathione were consistent with the presence of severe oxidative stress. Proteomics of the post-mortem alcoholic brains identified a large number of proteins, the expression of which was altered by chronic alcohol, with those associated with brain energy metabolism among the most numerous. Neurochemical studies found the increased expression of glutamate transporter GLAST/EAAT1 in brain as one of the largest changes caused by alcoholism. Given that GLAST/EAAT1 is one of the most abundant proteins in the nervous tissue and is intimately associated with the function of the excitatory (glutamatergic) synapses, this may be among the most important effects of chronic alcohol on brain function. It has so far been observed mainly in the prefrontal cortex. We show several experiments suggesting that acute alcohol can translocate GLAST/EAAT1 in astrocytes towards the plasma membrane (and this effect is inhibited by the GABA(B) agonist baclofen) but neither the mechanism nor the specificity (to alcohol) of this phenomenon have been established. Furthermore, as GLAST/EAAT1 is also expressed in testes and sperm (and could also be affected there by chronic alcohol), the levels of GLAST/EAAT1 in sperm could be used as a diagnostic tool in testing the severity of alcoholism in human males. We conclude that the reviewed studies present a unique set of data which could help to predict the risk of developing alcohol dependence (genetics), to improve the understanding of the intoxicating actions of alcohol (metabolomics), to aid in assessing the extent of damage to brain cells caused by chronic excessive drinking (metabolomics and proteomics) and to point to molecular targets that could be used in the treatment and diagnosis of alcoholism and alcohol addiction.

Reduced glutamate in the medial prefrontal cortex is associated with emotional and cognitive dysregulation in people with chronic pain

Publisher: Frontiers Media SA

Date: 03-12-2019

DOI: 10.3389/FNEUR.2019.01110

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. In iduals 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.

Metabolomics of Neurotransmitters and Related Metabolites in Post-Mortem Tissue from the Dorsal and Ventral Striatum of Alcoholic Human Brain

Publisher: Springer Science and Business Media LLC

Date: 22-01-2016

DOI: 10.1007/S11064-016-1830-3

Abstract: We report on changes in neurotransmitter metabolome and protein expression in the striatum of humans exposed to heavy long-term consumption of alcohol. Extracts from post mortem striatal tissue (dorsal striatum DS comprising caudate nucleus CN and putamen P and ventral striatum VS constituted by nucleus accumbens NAc) were analysed by high performance liquid chromatography coupled with tandem mass spectrometry. Proteomics was studied in CN by two-dimensional gel electrophoresis followed by mass-spectrometry. Proteomics identified 25 unique molecules expressed differently by the alcohol-affected tissue. Two were dopamine-related proteins and one a GABA-synthesizing enzyme GAD65. Two proteins that are related to apoptosis and/or neuronal loss (BiD and amyloid-β A4 precursor protein-binding family B member 3) were increased. There were no differences in the levels of dopamine (DA), 3,4-dihydrophenylacetic acid (DOPAC), serotonin (5HT), homovanillic acid (HVA), 5-hydroxyindoleacetic acid (HIAA), histamine, L-glutamate (Glu), γ-aminobutyric acid (GABA), tyrosine (Tyr) and tryptophan (Tryp) between the DS (CN and P) and VS (NAc) in control brains. Choline (Ch) and acetylcholine (Ach) were higher and norepinephrine (NE) lower, in the VS. Alcoholic striata had lower levels of neurotransmitters except for Glu (30 % higher in the alcoholic ventral striatum). Ratios of DOPAC/DA and HIAA/5HT were higher in alcoholic striatum indicating an increase in the DA and 5HT turnover. Glutathione was significantly reduced in all three regions of alcohol-affected striatum. We conclude that neurotransmitter systems in both the DS (CN and P) and the VS (NAc) were significantly influenced by long-term heavy alcohol intake associated with alcoholism.

Statistical Total Correlation Spectroscopy Scaling for Enhancement of Metabolic Information Recovery in Biological NMR Spectra

Publisher: American Chemical Society (ACS)

Date: 27-12-2011

DOI: 10.1021/AC202720F

Abstract: The high level of complexity in nuclear magnetic resonance (NMR) metabolic spectroscopic data sets has fueled the development of experimental and mathematical techniques that enhance latent biomarker recovery and improve model interpretability. We previously showed that statistical total correlation spectroscopy (STOCSY) can be used to edit NMR spectra to remove drug metabolite signatures that obscure metabolic variation of diagnostic interest. Here, we extend this "STOCSY editing" concept to a generalized scaling procedure for NMR data that enhances recovery of latent biochemical information and improves biological classification and interpretation. We call this new procedure STOCSY-scaling (STOCSY(S)). STOCSY(S) exploits the fixed proportionality in a set of NMR spectra between resonances from the same molecule to suppress or enhance features correlated with a resonance of interest. We demonstrate this new approach using two exemplar data sets: (a) a streptozotocin rat model (n = 30) of type 1 diabetes and (b) a human epidemiological study utilizing plasma NMR spectra of patients with metabolic syndrome (n = 67). In both cases significant biomarker discovery improvement was observed by using STOCSY(S): the approach successfully suppressed interfering NMR signals from glucose and lactate that otherwise dominate the variation in the streptozotocin study, which then allowed recovery of biomarkers such as glycine, which were otherwise obscured. In the metabolic syndrome study, we used STOCSY(S) to enhance variation from the high-density lipoprotein cholesterol peak, improving the prediction of in iduals with metabolic syndrome from controls in orthogonal projections to latent structures discriminant analysis models and facilitating the biological interpretation of the results. Thus, STOCSY(S) is a versatile technique that is applicable in any situation in which variation, either biological or otherwise, dominates a data set at the expense of more interesting or important features. This approach is generally appropriate for many types of NMR-based complex mixture analyses and hence for wider applications in bioanalytical science.

Brain metabolic markers reflect susceptibility status in cytokine gene knockout mice with murine cerebral malaria

Publisher: Elsevier BV

Date: 11-2006

DOI: 10.1016/J.IJPARA.2006.07.004

Abstract: Treatment of cerebral malaria, a complication of the world's most significant parasitic disease, remains problematic due to lack of understanding of its pathogenesis. Metabolic changes, along with cytokine expression alterations and blood cell sequestration in the brain, have previously been reported during severe disease in human infection and mouse models leading to the "cytopathic hypoxia" and "sequestration" theories of pathogenesis. Here, to determine the robustness of the metabolic changes and their relationship to disease development, we investigated changes in cerebral metabolic markers in a mouse model of cerebral malaria (CM) in wildtype (C57BL/6) and cytokine knockout (TNF(-/-), IFNgamma(-/-) and LTalpha(-/-)) mice using multinuclear magnetic resonance spectroscopy. Mice susceptible to CM (wildtype, TNF(-/-)) showed decreased cerebral glucose use, decreased Krebs cycle metabolism and decreased high-energy phosphates. Conversely, mice resistant to CM (IFNgamma(-/-), LTalpha(-/-)) showed little sign of these effects, despite identical levels of parasitemia. Previously reported changes in lactate were shown to be strain dependent. Elevated glutamine and decreased phosphorylation potential emerged as robust metabolic markers of susceptibility, further implicating the trytophan/NAD(+) pathway in disease development. Thus these metabolic changes are firmly linked both to the immune system response to malaria and to the occurrence of pathogenic changes in experimental CM.

Hand function is impaired in healthy older adults at risk of Parkinson’s disease

Publisher: Springer Science and Business Media LLC

Date: 03-05-2014

DOI: 10.1007/S00702-014-1218-Y

Abstract: Abnormal substantia nigra morphology in healthy in iduals, viewed with transcranial ultrasound, is a significant risk factor for Parkinson's disease. However, little is known about the functional consequences of this abnormality (termed 'hyperechogenicity') on movement. The aim of the current study was to investigate hand function in healthy older adults with (SN+) and without (SN-) substantia nigra hyperechogenicity during object manipulation. We hypothesised that SN+ subjects would exhibit increased grip force and a slower rate of force application compared to SN- subjects. Twenty-six healthy older adults (8 SN+ aged 58 ± 8 years, 18 SN- aged 57 ± 6 years) were asked to grip and lift a light-weight object with the dominant hand. Horizontal grip force, vertical lift force, acceleration, and first dorsal interosseus EMG were recorded during three trials. During the first trial, SN+ subjects exhibited a longer period between grip onset and lift onset (i.e. preload duration 0.27 ± 0.25 s) than SN- subjects (0.13 ± 0.08 s P = 0.046). They also exerted a greater downward force prior to lift off (-0.54 ± 0.42 N vs. -0.21 ± 0.12 N P = 0.005) and used a greater grip force to lift the object (19.5 ± 7.0 N vs. 14.0 ± 4.3 N P = 0.022) than SN- subjects. No between group differences were observed in subsequent trials. SN+ subjects exhibit impaired planning for manipulation of new objects. SN+ in iduals over-estimate the grip force required, despite a longer contact period prior to lifting the object. The pattern of impairment observed in SN+ subjects shares similarities with de novo Parkinson's disease patients.

Repeatability of brain phase-based magnetic resonance electric properties tomography methods and effect of compressed SENSE and RF shimming

Publisher: Springer Science and Business Media LLC

Date: 30-03-2023

DOI: 10.1007/S13246-023-01248-1

Abstract: Magnetic resonance electrical properties tomography (MREPT) is an emerging imaging modality to noninvasively measure tissue conductivity and permittivity. Implementation of MREPT in the clinic requires repeatable measurements at a short scan time and an appropriate protocol. The aim of this study was to investigate the repeatability of conductivity measurements using phase-based MREPT and the effects of compressed SENSE (CS), and RF shimming on the precision of conductivity measurements. Conductivity measurements using turbo spin echo (TSE) and three-dimensional balanced fast field echo (bFFE) with CS factors were repeatable. Conductivity measurement using bFFE phase showed smaller mean and variance that those measured by TSE. The conductivity measurements using bFFE showed minimal deviation with CS factors up to 8, with deviation increasing at CS factors 8. Subcortical structures produced less consistent measurements than cortical parcellations at higher CS factors. RF shimming using full slice coverage 2D dual refocusing echo acquisition mode (DREAM) and full coverage 3D dual TR approaches further improved measurement precision. BFFE is a more optimal sequence than TSE for phase-based MREPT in brain. Depending on the area of the brain being measured, the scan can be safely accelerated with compressed SENSE without sacrifice of precision, offering the potential to employ MREPT in clinical research and applications. RF shimming with better field mapping further improves precision of the conductivity measures.

Binge drinking in young people: protocol for a systematic review of neuropsychological, neurophysiological and neuroimaging studies

Publisher: BMJ

Date: 07-2018

DOI: 10.1136/BMJOPEN-2018-023629

Abstract: Binge drinking is the most common pattern of alcohol use among young people in Western countries. Adolescence and young adulthood is a vulnerable developmental period and binge drinking during this time has a higher potential for neurotoxicity and interference with ongoing neural and cognitive development. The purpose of this systematic review will be to assess and integrate evidence of the impact of binge drinking on cognition, brain structure and function in youth aged 10–24 years. Cross-sectional studies will synthesise the aberrations associated with binge drinking, while longitudinal studies will distinguish the cognitive and neural antecedents from the cognitive and neural effects that are a consequence of binge drinking. A total of five peer-reviewed databases (PubMed, EMBASE, Medline, PsychINFO, ProQuest) will be systematically searched and the search period will include all studies published prior to 1 April 2018. The search terms will be a combination of MeSH keywords that are based on previous relevant reviews. Study selection will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and study quality will be assessed using The Grades of Recommendation, Assessment, Development and Evaluation approach. All studies will be screened against eligibility criteria designed to synthesise studies that examined a young binge drinking s le and used neuropsychological, neurophysiological or neuroimaging assessment techniques. Studies will be excluded if participants were significantly involved in other substances or if they had been clinically diagnosed with an alcohol use disorder, or any psychiatric, neurological or pharmacological condition. If available data permits, a meta-analysis will be conducted. Formal ethics approval is not required as primary data will not be collected. The results will be disseminated through a peer-reviewed publication, conference presentations and social media. International Prospective Register for Systematic Reviews (PROSPERO) number: CRD42018086856.

White matter measures are near normal in controlled HIV infection except in those with cognitive impairment and longer HIV duration

Publisher: Springer Science and Business Media LLC

Date: 21-03-2017

DOI: 10.1007/S13365-017-0524-1

Abstract: The objective of the current study was to quantify the degree of white matter (WM) abnormalities in chronic and virally suppressed HIV-infected (HIV+) persons while carefully taking into account demographic and disease factors. Diffusion tensor imaging (DTI) was conducted in 40 HIV- and 82 HIV+ men with comparable demographics and life style factors. The HIV+ s le was clinically stable with successful viral control. Diffusion was measured across 32 non-colinear directions with a b-value of 1000 s/mm

Imaging correlates of the blood–brain barrier disruption in HIV-associated neurocognitive disorder and therapeutic implications

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 10-2019

DOI: 10.1097/QAD.0000000000002300

Identifying fMRI Model Violations With Lagrange Multiplier Tests

Publisher: Institute of Electrical and Electronics Engineers (IEEE)

Date: 07-2201

DOI: 10.1109/TMI.2012.2195327

Validity and reliability of measurements of aponeurosis dimensions from magnetic resonance images

Publisher: Wiley

Date: 04-03-2019

DOI: 10.1111/SMS.13407

Abstract: Muscle performance is closely related to the structure and function of tendons and aponeuroses, the sheet-like, intramuscular parts of tendons. The architecture of aponeuroses has been difficult to study with magnetic resonance imaging (MRI) because these thin, collagen-rich connective tissues have very short transverse relaxation (T2) times and therefore provide a weak signal with conventional MRI sequences. Here, we validated measurements of aponeurosis dimensions from two MRI sequences commonly used in muscle-tendon research (mDixon and T1-weighted images), and an ultrashort echo time (UTE) sequence designed for imaging tissues with short T2 times. MRI-based measurements of aponeurosis width, length, and area of 20 sheep leg muscles were compared to direct measurements made with three-dimensional (3D) quantitative microdissection. The errors in measurement of aponeurosis width relative to the mean width were 1.8% for UTE, 3.7% for T1, and 18.8% for mDixon. For aponeurosis length, the errors were 7.6% for UTE, 1.9% for T1, and 21.0% for mDixon. Measurements from T1 and UTE scans were unbiased, but mDixon scans systematically underestimated widths, lengths, and areas of the aponeuroses. Using the same methods, we then found high inter-rater reliability (intraclass correlation coefficients >0.92 for all measures) of measurements of the dimensions of the central aponeurosis of the human tibialis anterior muscle from T1-weighted scans. We conclude that valid and reliable measurements of aponeurosis dimensions can be obtained from UTE and from T1-weighted scans. When the goal is to study the macroscopic architecture of aponeuroses, UTE does not hold an advantage over T1-weighted imaging.

A Metabolomic Approach to Ionotropic Glutamate Receptor Subtype Function: A Nuclear Magnetic Resonance in vitro Investigation

Publisher: SAGE Publications

Date: 14-12-2005

DOI: 10.1038/SJ.JCBFM.9600257

Abstract: A range of behaviours are elucidated via ionotropic glutamate receptors (iGluR). In this work, we examined the acute activation of iGluRs by a range of receptor ligands and effectors to see whether distinguishable metabolic sequelae were elucidated by the activity. We used a guinea-pig brain cortical tissue slice model using targeted receptor ligands ((RS)-(tetrazol-5-yl)glycine (TZG), (5S,10R)-(+)-5-methyl-10, 11-dihydro-5H-dibenzo[ a, d]cyclohepten-5, 10-imine maleate (MK-801, dizocilpine), cis-4-[phosphomethyl]-piperidine-2-carboxylic acid (CGS 19755), (RS)-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, (2S, 3S, 4S)-2-carboxy-4-(1-methylethenyl)-3-pyrrolidineacetic acid (kainate) and D-serine (D-Ser), as well as compounds (quinolinic acid and kynurenic acid (KynA)) involved in some neuroinflammatory responses. The data were derived using 13 C and 1 H NMR spectroscopy, and analysed by metabolomic approaches and multivariate statistics. The metabolic effects of agonists at the three major classes of iGluR were easily separated from each other using this method. The classical N-methyl-D-aspartate receptor agonist TZG and the antagonist CGS 19755 produced excitatory and inhibitory metabolic responses, respectively, while the blocker MK-801 resulted in a significant decrease in net metabolism and produced the largest decrease in all metabolite pool sizes seen by any glutamatergic ligand we have studied. Quinolinic acid and KynA produced similar acute metabolic responses, which were unlike those to TZG or CGS 19755, but similar to that of D-Ser. D-Ser was highly stimulatory of net flux into the Krebs cycle. These data show that the metabolic response to iGluR perturbation in vitro is a sensitive discriminator of function.

Group I and II metabotropic glutamate receptors alter brain cortical metabolic and glutamate/glutamine cycle activity: a ¹³C NMR spectroscopy and metabolomic study

Publisher: Wiley

Date: 14-12-2004

DOI: 10.1111/J.1471-4159.2004.02880.X

Abstract: Metabotropic glutamate receptors (mGluR) modulate neuronal function. Here, we tested the effect on metabolism of a range of Group I and II mGluR ligands in Guinea pig brain cortical tissue slices, applying 13C NMR spectroscopy and metabolomic analysis using multivariate statistics. The effects of Group I agonists (S)-3,5-dihydroxyphenylglycine (DHPG) and (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) depended upon concentration and were mostly stimulatory, increasing both net metabolic flux through the Krebs cycle and glutamate/glutamine cycle activity. Only the higher (50 microm) concentrations of CHPG had the opposite effect. The Group I antagonist (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA), consistent with its neuroprotective role, caused significant decreases in metabolism. With principal components analysis of the metabolic profiles generated by these ligands, the effects could be separated by two principal components. Agonists at Group II mGluR [(2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG IV) and 2R,4R-4-aminopyrrolidine-2,4-dicarboxylate (APDC)] generally stimulated metabolism, including glutamate/glutamine cycling, although this varied with concentration. The antagonist (2S)-alpha-ethylglutamic acid (EGLU) stimulated astrocyte metabolism with minimal impact on glutamate/glutamine cycling. (RS)-1-Aminophosphoindan-1-carboxylic acid (APICA) decreased metabolism at 5 microm but had a stimulatory effect at 50 microm. All ligand effects were separated from control and from each other using two principal components. The ramifications of these findings are discussed.

Time-to-Onset latency in fMRI: Fast detection of delayed activation

Publisher: IEEE

Date: 05-2011

DOI: 10.1109/ICASSP.2011.5946506

Brain Activity: Connectivity, Sparsity, and Mutual Information

Publisher: Institute of Electrical and Electronics Engineers (IEEE)

Date: 04-2015

DOI: 10.1109/TMI.2014.2358681

Metabolic abnormalities in developmental dyslexia detected by 1H magnetic resonance spectroscopy

Publisher: Elsevier BV

Date: 06-1998

DOI: 10.1016/S0140-6736(97)99001-2

Abstract: Literature is limited on HIV and colorectal cancer (CRC) in sub-Saharan Africa despite it being the epicentre of the HIV epidemic. To compare clinicopathological features and outcome of CRC in HIV-negative and HIV-positive patients. Retrospective analysis of a prospective CRC database. Demographic details, HIV status, anatomical site, disease stage, treatment and follow-up were documented. Of 715 patients with CRC, 145 and 570 tested positive and negative respectively for HIV. Median age was 45 (IQR 36-53 and 57 (IQR 45-66) years among HIV-positive and HIV-negative patients respectively (p<0.0001). Tumour differentiation differed between the two groups (p=0.003) but staging was not different (p=0.6). Surgical resection rate was 52% for HIV-positive patients versus 59% for HIV-negative patients (p=0.07). Median follow-up was 9 (IQR 2-20.5) months for HIV-positive patients and 12 (IQR 6-29) months for HIV-negative patients (p=0.154). Recurrence rate was 14.7% among HIV positive patients and 6.8% in HIV negative patients (p=0.089). When compared with HIV-negative patients, HIV-positive patients with CRC presented at a younger age and tended to have lower surgical resection rates. There was no difference between the two groups with CRC in terms of anatomical sub-site distribution, disease staging and recurrence rates.

Covertly active and progressing neurochemical abnormalities in suppressed HIV infection

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 2018

DOI: 10.1212/NXI.0000000000000430

Abstract: To assess whether HIV-related brain injury is progressive in persons with suppressed HIV infection. Seventy-three HIV+ virally suppressed men and 35 HIV− men, screened for psychiatric and alcohol/drug use disorders, underwent neuropsychological evaluation and proton magnetic resonance spectroscopy ( 1 H-MRS) at baseline and after and 23 ± 5 months. 1 H-MRS included brain regions known to be vulnerable to HIV and aging: frontal white matter (FWM), posterior cingulate cortex (PCC), and caudate area (CA). Major brain metabolites such as creatine (Cr: marker of cellular energy), N -acetyl aspartate (NAA: marker of neuronal integrity), choline (marker of cellular membrane turnover), glutamate/glutamine (excitatory/inhibitory neurotransmitter), and myo -Inositol (mI: marker of neuroinflammation) were calculated with reference to water signal. Neurocognitive decline was corrected for practice effect and baseline HIV-associated neurocognitive disorder (HAND) status. Across the study period, 44% had intact cognition, 42% stable HAND (including the single case that improved), 10% progressing HAND, and 4% incident HAND. When analyzing the neurochemical data per neurocognitive trajectories, we found decreasing PCC Cr in all subgroups compared with controls ( p 0.002). In addition, relative to the HIV− group, stable HAND showed decreasing FWM Cr, incident HAND showed steep FWM Cr reduction, whereas progressing HAND had a sharply decreasing PCC NAA and reduced but stable CA NAA. When analyzing the neurochemical data at the group level (HIV+ vs HIV− groups), we found stable abnormal metabolite concentrations over the study period: decreased FWM and PCC Cr (both p 0.001), decreased PCC NAA and CA NAA (both p 0.05) and PCC mI increase ( p 0.05). HIV duration and historical HAND had modest effects on metabolite changes. Our study reveals covertly active or progressing HIV-related brain injury in the majority of this virally suppressed cohort, reflecting ongoing neuropathogenic processes that are only partially worsened by historical HAND and HIV duration. Longer-term studies will be important for determining the prognosis of these slowly evolving neurochemical abnormalities.

Abnormalities in brain biochemistry associated with lack of dystrophin: studies of the mdx mouse

Publisher: Elsevier BV

Date: 02-2002

DOI: 10.1016/S0960-8966(01)00253-X

Abstract: Biochemical abnormalities have been reported in dystrophin-deficient muscle of boys with Duchenne (severe Xp21) muscular dystrophy or in the murine (mdx) model of the disease. These abnormalities include altered energy metabolism and responses to osmotic shock. In contrast, the situation in brain is less well understood and it is probable that dystrophin is playing a different role (or roles) in this organ. In this study we conclude that the elevation in choline-containing compounds reported in mdx brain is confined to cerebellum and hippoc us in older (> 6 months) mice. We report alterations in glucose metabolism in mdx brain under normal, awake conditions, and a reduced response of brain metabolism to the gamma-aminobutyric acid(A) receptor agonist muscimol. Using brain cortical slices we found no difference in the response of dystrophic tissue to hypoosmotic shock, but increased, substrate-dependent oxygen consumption rates at low oxygen partial pressures.

Stereospecificity of Substrate Usage by Glyoxalase 1: Nuclear Magnetic Resonance Studies of Kinetics and Hemithioacetal Substrate Conformation

Publisher: American Chemical Society (ACS)

Date: 29-03-1994

DOI: 10.1021/BI00178A011

Abstract: The specificity of glyoxalase 1 for the diastereomers of its hemithioacetal substrate [which forms spontaneously between an alpha-keto aldehyde and reduced glutathione (GSH)] was investigated by exploiting the differences between their 1H NMR spectra at pH* 4.4. The 1H NMR spectra of the hemithioacetals of glutathione with phenylglyoxal or methylglyoxal were assigned with the aid of conventional decoupling and two-dimensional NMR spectroscopic techniques. The rate of interconversion of the diastereomers was determined at 30 degrees C from the results of an inversion-transfer technique and found to be 0.30 +/- 0.04 s-1 (+/- sd) in the case of phenylglyoxal and 0.15 +/- 0.02 s-1 in the case of methylglyoxal. Stereopreference of the enzyme was tested by the addition of large amounts of yeast glyoxalase 1 to a reaction mixture glyoxalase 1 preferentially operated on one diastereomer of the phenylglyoxal hemithioacetal but the diastereomers of methylglyoxal appeared to be operated upon indiscriminately. From computer models of the kinetics of possible reaction schemes, a mechanism involving glyoxalase 1 catalysis of both diastereomers of the hemithioacetals was shown to be the most consistent with the experimental data. Estimates of internuclear distances in the diastereomers, obtained from 2D NMR spectra were used in "dynamical simulated annealing" calculations to generate likely structures of the substrates. Relative ring-current shifts obtained from 1D NMR spectra were used, together with a ring-current shift algorithm, to select structures with compatible conformations. We conclude that the rate of conversion of substrate by the enzyme is dependent upon the overall conformation of the substrate molecule, rather than merely its stereochemical configuration (R or S).

Resistance training improves cardiac output, exercise capacity and tolerance to positive airway pressure in Fontan physiology

Publisher: Elsevier BV

Date: 09-2013

DOI: 10.1016/J.IJCARD.2012.10.012

Abstract: Subjects with Fontan-type circulation have no sub-pulmonary ventricle and thus depend exquisitely on the respiratory bellows and peripheral muscle pump for cardiac filling. We hypothesised that resistance training to augment the peripheral muscle pump might improve cardiac filling, reduce inspiratory-dependence of IVC return to the heart and thus improve exercise capacity and cardiac output on constant positive airway pressure (CPAP). Eleven Fontan subjects (32+/-2 years, mean+/-SEM) had cardiac magnetic resonance imaging (MRI) and exercise testing (CPET) six underwent 20 weeks of high-intensity resistance training others were non-exercising controls. After training, CPET was repeated. Four trainers had MRI with real-time flow measurement at rest, exercise and on CPAP in the trained state and following a 12-month detrain. In the trained state, muscle strength increased by 43% (p=0.002), as did total muscle mass (by 1.94 kg, p=0.003) and peak VO2 (by 183 ml/min, p=0.02). After detraining, calf muscle mass and peak workload had fallen significantly (p<0.03 for both) as did peak VO2 (2.72 vs. 2.18 l/min, p<0.001) and oxygen pulse, a surrogate for SV (16% lower, p=0.005). Furthermore after detraining, SV on MRI decreased at rest (by 11 ml, p=0.01) and during moderate-intensity exercise (by 16 ml, p=0.04) inspiratory-dependent IVC blood return during exercise was 40% higher (p=0.02). On CPAP, cardiac output was lower in the detrained state (101 vs. 77 ml/s, p=0.03). Resistance muscle training improves muscle mass, strength and is associated with improved cardiac filling, stroke volume, exercise capacity and cardiac output on CPAP, in adults with Fontan-type circulation.

Chronic Pain: Lost Inhibition?

Publisher: Society for Neuroscience

Date: 24-04-2013

DOI: 10.1523/JNEUROSCI.0174-13.2013

Abstract: Human brain imaging has revealed that acute pain results from activation of a network of brain regions, including the somatosensory, insular, prefrontal, and cingulate cortices. In contrast, many investigations report little or no alteration in brain activity associated with chronic pain, particularly neuropathic pain. It has been hypothesized that neuropathic pain results from misinterpretation of thalamocortical activity, and recent evidence has revealed altered thalamocortical rhythm in in iduals with neuropathic pain. Indeed, it was suggested nearly four decades ago that neuropathic pain may be maintained by a discrete central generator, possibly within the thalamus. In this investigation, we used multiple brain imaging techniques to explore central changes in subjects with neuropathic pain of the trigeminal nerve resulting in most cases (20 of 23) from a surgical event. In iduals with chronic neuropathic pain displayed significant somatosensory thalamus volume loss (voxel-based morphometry) which was associated with decreased thalamic reticular nucleus and primary somatosensory cortex activity (quantitative arterial spin labeling). Furthermore, thalamic inhibitory neurotransmitter content was significantly reduced (magnetic resonance spectroscopy), which was significantly correlated to the degree of functional connectivity between the somatosensory thalamus and cortical regions including the primary and secondary somatosensory cortices, anterior insula, and cerebellar cortex. These data suggest that chronic neuropathic pain is associated with altered thalamic anatomy and activity, which may result in disturbed thalamocortical circuits. This disturbed thalamocortical activity may result in the constant perception of pain.

Brain mitochondrial dysfunction and driving simulator performance in untreated obstructive sleep apnea

Publisher: Wiley

Date: 15-09-2021

DOI: 10.1111/JSR.13482

Abstract: It is challenging to determine which patients with obstructive sleep apnea (OSA) have impaired driving ability. Vulnerability to this neurobehavioral impairment may be explained by lower brain metabolites levels involved in mitochondrial metabolism. This study compared markers of brain energy metabolism in OSA patients identified as vulnerable vs resistant to driving impairment following extended wakefulness. 44 patients with moderate‐severe OSA underwent 28hr extended wakefulness with three 90min driving simulation assessments. Using a two‐step cluster analysis, objective driving data (steering deviation and crashes) from the 2nd driving assessment (22.5 h awake) was used to categorise patients into vulnerable (poor driving, n = 21) or resistant groups (good driving, n = 23). 1 H magnetic resonance spectra were acquired at baseline using two scan sequences (short echo PRESS and longer echo‐time asymmetric PRESS), focusing on key metabolites, creatine, glutamate, N ‐acetylaspartate (NAA) in the hippoc us, anterior cingulate cortex and left orbito‐frontal cortex. Based on cluster analysis, the vulnerable group had impaired driving performance compared with the resistant group and had lower levels of creatine (PRESS p = ns, APRESS p = 0.039), glutamate, (PRESS p 0.01, APRESS p 0.01), NAA (PRESS p = 0.038, APRESS p = 0.035) exclusively in the left orbito‐frontal cortex. Adjusted analysis, higher glutamate was associated with a 21% (PRESS) and 36% (APRESS) reduced risk of vulnerable classification. Brain mitochondrial bioenergetics in the frontal brain regions are impaired in OSA patients who are vulnerable to driving impairment following sleep loss. These findings provide a potential way to identify at risk OSA phenotype when assessing fitness to drive, but this requires confirmation in larger future studies.

Metabolomic Approaches to Defining the Role(s) of GABAρ Receptors in the Brain

Publisher: Springer Science and Business Media LLC

Date: 11-01-2015

DOI: 10.1007/S11481-014-9579-4

Abstract: The inhibitory neurotransmitter γ-aminobutyric acid (GABA) acts through various types of receptors in the central nervous system. GABAρ receptors, defined by their characteristic pharmacology and presence of ρ subunits in the channel structure, are poorly understood and their role in the cortex is ill-defined. Here, we used a targeted pharmacological, NMR-based functional metabolomic approach in Guinea pig brain cortical tissue slices to identify a distinct role for these receptors. We compared metabolic fingerprints generated by a range of ligands active at GABAρ and included these in a principal components analysis with a library of other metabolic fingerprints obtained using ligands active at GABAA and GABAB, with inhibitors of GABA uptake and with compounds acting to inhibit enzymes active in the GABAergic system. This enabled us to generate a metabolic "footprint" of the GABAergic system which revealed classes of metabolic activity associated with GABAρ which are distinct from other GABA receptors. Antagonised GABAρ produce large metabolic effects at extrasynaptic sites suggesting they may be involved in tonic inhibition.

Frequency drift in MR spectroscopy at 3T

Publisher: Elsevier BV

Date: 11-2021

DOI: 10.1016/J.NEUROIMAGE.2021.118430

Fine-Grained Mapping of Cortical Somatotopies in Chronic Complex Regional Pain Syndrome

Publisher: Society for Neuroscience

Date: 30-09-2019

DOI: 10.1523/JNEUROSCI.2005-18.2019

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. SIGNIFICANCE STATEMENT This study shows that the spatial map of the fingers in somatosensory cortex is largely preserved in chronic complex regional pain syndrome (CRPS). These findings challenge the treatment rationale for restoring somatotopic representations in complex regional pain syndrome patients.

Details matter in quality science. Adopting a checklist for magnetic resonance spectroscopy can help you get them right

Publisher: Wiley

Date: 10-12-2022

DOI: 10.1111/JNC.15725

Abstract: The ISMRM study group on magnetic resonance spectroscopy has produced recommendations for reporting methods. The Journal of Neurochemistry has decided to encourage the use of the checklist for these standards by authors and reviewers in order to improve reproducibility and reliability of the science, make it easier for reviewers and to help educate the scientific community. Here, we explain why getting the details right is important. image

Metabolic Profiling of Genetic Disorders: A Multitissue 1H Nuclear Magnetic Resonance Spectroscopic and Pattern Recognition Study into Dystrophic Tissue

Publisher: Elsevier BV

Date: 06-2001

DOI: 10.1006/ABIO.2001.5096

Brain aging and cardiovascular factors in HIV: a longitudinal volume and shape MRI study

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 10-01-2022

DOI: 10.1097/QAD.0000000000003165

Brain bioenergetics and cognitive ability.

Publisher: S. Karger AG

Date: 2003

DOI: 10.1159/000073509

Abstract: We obtained sup /sup P magnetic resonance spectra from the brains in vivo of 101 males (range 6–72 years). In addition, cognitive test data were obtained from 42 boys (6–13 years) and from 26 adult males (22–56 years) of this test group. Significant correlations were observed in both adults and children between various inorganic phosphate (Pi)-containing sup /sup P peak ratios [e.g. Pi/adenosine triphosphate (ATP)] and (predominantly verbal) cognitive tasks. No change in the Pi/ATP ratio was observed across the age range studied. Brain pH was shown to decrease significantly with age in a relationship best described by a decaying exponential. This indicated that brain pH does not stabilize at adult values until at least the late teens. We explored the possibility of a relationship between brain pH and neuronal density. In particular, we noted that our previous observation of a relationship between pH and IQ in children was not readily detected in the adult populations, whereas phosphorus metabolite ratios (in particular, those containing Pi) were found to correlate with (predominantly verbal) cognitive task performance in both adults and children. We assessed how these observations may be interpreted in the context of a metabolic vs. histological debate.

HIV brain latency as measured by CSF BcL11b relates to disrupted brain cellular energy in virally suppressed HIV infection

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 03-2019

DOI: 10.1097/QAD.0000000000002076

Corpus Callosum Morphology and Its Relationship to Cognitive Function in Neurofibromatosis Type 1

Publisher: SAGE Publications

Date: 08-02-2010

DOI: 10.1177/0883073809350723

Abstract: Neurofibromatosis type 1 (NF1) is associated with cognitive dysfunction and structural brain abnormalities such as an enlarged corpus callosum. This study aimed to determine the relationship between corpus callosum morphology and cognitive function in children with neurofibromatosis type 1 using quantitative neuroanatomic imaging techniques. Children with neurofibromatosis type 1 (n = 46) demonstrated a significantly larger total corpus callosum and corpus callosum index compared with control participants (n = 30). A larger corpus callosum index in children with neurofibromatosis type 1 was associated with significantly lower IQ, reduced abstract concept formation, reduced verbal memory, and diminished academic ability, specifically reading and math. Our results suggest an enlarged corpus callosum in children with neurofibromatosis type 1 is associated with cognitive impairment and may provide an early structural marker for the children at risk of cognitive difficulties. Cognitive deficits associated with structural brain abnormalities in neurofibromatosis type 1 are unlikely to be reversible and so may not respond to proposed pharmacological therapies for neurofibromatosis type 1-related cognitive impairments.

Strategies for studies of neurotoxic mechanisms involving deficient transport of L-glutamate: antisense knockout in rat brain in vivo and changes in the neurotransmitter metabolism following inhibitio

Publisher: Elsevier BV

Date: 11-2000

DOI: 10.1016/S0361-9230(00)00372-5

Abstract: This communication briefly reviews characteristics of glutamate transport in the central nervous system and is involved in the aetiology of slow neurodegenerative diseases. Data in the literature suggest that antisense oligonucleotides targeted against glutamate transporters and administered in vivo over a period of days could be used to test the hypothesis. Data from our laboratory have indicated that single intraventricular doses of antisense oligonucleotides can also results in significant reductions in the numbers of substrate binding sites associated with glutamate transporters and may even cause subtle changes in their characteristics. In order to study metabolism in brain tissue, we have used 13C-nuclear magnetic resonance spectroscopy to analyse extracts of slices of guinea pig cerebral cortex exposed to glutamate transport inhibitor L-anti,endo-methanopyrrolidine dicarboxylate (L-a,e-MPDC). The results have shown-for the first time in an experimental model that preserves the relationship between glia and neurones within the context of brain tissue-that inhibition of L-glutamate transport can exert a significant influence on neurotransmitter-related metabolism. These findings suggest that metabolic disturbances caused by deficient glutamate transport could play a significant role in the death of neurones under pathological conditions in vivo.

Brain abnormalities in Duchenne muscular dystrophy: phosphorus-31 magnetic resonance spectroscopy and neuropsychological study

Publisher: Elsevier BV

Date: 05-1995

DOI: 10.1016/S0140-6736(95)90923-0

Abstract: Duchenne muscular dystrophy (DMD) is one of a range of muscular dystrophies caused by abnormalities of the short arm of the X chromosome (Xp21), which often cause mental retardation in addition to progressive muscular weakness. Normal dystrophin expression is lacking in both skeletal muscle and brain of affected subjects. Phosphorus-31 magnetic resonance spectroscopy has shown several abnormalities in skeletal muscle in DMD. We looked for similar abnormalities in brain in patients with DMD and related the findings to neuropsychological test results. We studied by magnetic resonance spectroscopy 19 boys (aged 76-167 months) diagnosed as having DMD and 19 control boys of similar age (87-135 months). Intelligence quotient (IQ) was assessed with the Wechsler Intelligence Scale for children. The DMD patients had significantly higher values than the controls in the brain ratios of inorganic phosphate to adenosine triphosphate (mean 0.53 [SD 0.21] vs 0.36 [0.09], p = 0.003), to phosphomonoesters (0.40 [0.07] vs 0.29 [0.07], p = 0.0001), and to phosphocreatine (0.44 [0.10] vs 0.37 [0.08], p = 0.02). There were significant differences between the DMD patients and the controls in full-scale IQ (76 [16] vs 101 [16], p = 0.0001), performance IQ (78 [17] vs 94 [14], p = 0.003), and verbal IQ (78 [17] vs 106 [17], p = 0.0001). These altered metabolite ratios parallel the findings in dystrophic muscle and suggest bioenergetic similarities in tissues that lack dystrophin.

Correction to: L-Aspartate, L-Ornithine and L-Ornithine-L-Aspartate (LOLA) and Their Impact on Brain Energy Metabolism (Neurochemical Research, (2020), 45, 6, (1438-1450), 10.1007/s11064-020-03044-9)

Publisher: Springer Science and Business Media LLC

Date: 07-07-2020

DOI: 10.1007/S11064-020-03087-Y

γ-Hydroxybutyrate and the GABAergic footprint: a metabolomic approach to unpicking the actions of GHB

Publisher: Wiley

Date: 30-07-2010

DOI: 10.1111/J.1471-4159.2010.06901.X

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 concentrations > 30 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.

Memory training alters hippocampal neurochemistry in healthy elderly

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 07-2003

DOI: 10.1097/00001756-200307180-00010

Glyoxalase 2 deficiency in the erythrocytes of a horse: 1H NMR studies of enzyme kinetics and transport of S-lactoylglutathione

Publisher: Elsevier BV

Date: 12-1991

DOI: 10.1016/0003-9861(91)90137-8

Abstract: In mammalian red blood cells the metabolism of methylglyoxal, and some alpha-ketoaldehydes, takes place via two, generally, highly active enzymes, glyoxalase 1 and 2. The 1H NMR spin-echo spectra of horse erythrocytes, and the various reactants in the glyoxalase system, were characterized as a prelude to obtaining series of spectra in time courses of methylglyoxal metabolism. We characterized the kinetics of the enzyme system in red cells from a normal horse and also from one which had very low activity of glyoxylase 2. The kinetics of the reaction scheme, with methylglyoxal as the starting substrate, were obtained from 1H NMR spectra and analyzed with a computer model of the scheme. The most salient feature of the normal system was the very high feed-forward inhibition (KiHTA = 0.1 microM) of glyoxalase 2 by the hemithioacetal which is the substrate of glyoxalase 1. The glyoxalase-2-deficient red cells were used to test whether S-lactoylglutathione is transported from red cells via the glutathione-S-conjugate transporter this transport appeared not to occur. Because methylglyoxal is extremely rapidly removed (half-life, approximately 5 min) from normal red cells, it is difficult to assess the effect of this compound on glycolysis but the slow decline evident in the deficient cells allowed a study of the effects on L-lactate production no effects were apparent.

Creatine as a booster for human brain function. How might it work?

Publisher: Elsevier BV

Date: 10-2015

DOI: 10.1016/J.NEUINT.2015.08.010

Abstract: Creatine, a naturally occurring nitrogenous organic acid found in animal tissues, has been found to play key roles in the brain including buffering energy supply, improving mitochondrial efficiency, directly acting as an anti-oxidant and acting as a neuroprotectant. Much of the evidence for these roles has been established in vitro or in pre-clinical studies. Here, we examine the roles of creatine and explore the current status of translation of this research into use in humans and the clinic. Some further possibilities for use of creatine in humans are also discussed.

Disruption to normal excitatory and inhibitory function within the medial prefrontal cortex in people with chronic pain

Publisher: Wiley

Date: 26-07-2021

DOI: 10.1002/EJP.1838

Abstract: Growing evidence indicates a link between changes in the medial prefrontal cortex and the pathophysiology of chronic pain. In particular, chronic pain is associated with altered medial prefrontal anatomy and biochemistry. Due to the comorbid affective disorders seen across all pain conditions, the medial prefrontal cortex is a region of significance as it is involved in emotional processing. We have recently reported that a decrease in medial prefrontal N ‐acetylaspartate and glutamate is associated with increased emotional dysregulation, indicating there are neurotransmitter imbalances in chronic pain. Therefore, we compared medial prefrontal neurochemistry in 24 people with chronic pain conditions to 24 age and sex‐matched healthy controls with no history of chronic pain. GABA‐edited MEGA‐PRESS was used to measure GABA + levels, and short TE PRESS was used to measure glutamate levels in the medial prefrontal cortex. Psychometric measures regarding pain intensity a week before scanning, during the scan and the total duration of chronic pain, were also recorded and compared to measured GABA + and glutamate levels. This study reveals that the presence of chronic pain is associated with significant decreases in medial prefrontal GABA + and glutamate. These findings support the hypothesis that chronic pain is associated with altered medial prefrontal biochemistry. The dysregulation of glutamatergic and GABAergic neurotransmitter systems supports a model of disinhibition of chronic pain, which may play a key role in both the experience of persistent pain and its associated affective disturbances. This study reveals a significant reduction in γ‐aminobutyric acid (GABA + ) and glutamate within the medial prefrontal cortex in chronic pain sufferers. While the current findings should be considered with reference to a small s le size, the disruption to normal excitatory and inhibitory medial prefrontal cortex function may be key in the development and maintenance of chronic pain and comorbid mental health disorders.

Three-dimensional skeletal muscle architecture in the lower legs of living human infants

Publisher: Elsevier BV

Date: 06-2023

DOI: 10.1016/J.JBIOMECH.2023.111661

A new role for α‐ketoglutarate dehydrogenase complex: regulating metabolism through post‐translational modification of other enzymes

Publisher: Wiley

Date: 04-06-2015

DOI: 10.1111/JNC.13150

An investigation of neuronal integrity in severe paediatric traumatic brain injury

Publisher: Informa UK Limited

Date: 12-2004

DOI: 10.1080/09297040490909279

Abstract: Magnetic Resonance Spectroscopy (MRS) and its association with neuropsychological functioning was examined in the chronic injury phase of paediatric traumatic brain injury (TBI). Fifteen children, aged 10-16 years, with severe TBIs were compared with 15 controls, matched for age and gender. The TBI group was found to have significantly lower levels of -acetyl aspartate (NAA) and Choline (Cho) in the right frontal lobe and generally displayed reduced performances on neuropsychological tests. A correlation between metabolites and reaction times was also obtained. Findings indicate a role of proton MRS as a measure of neuronal integrity following severe paediatric TBI and suggest a potential association of MRS with specific neuropsychological impairments.

A Novel Finger Illusion Reveals Reduced Weighting of Bimanual Hand Cortical Representations in People With Complex Regional Pain Syndrome

Publisher: Elsevier BV

Date: 02-2019

DOI: 10.1016/J.JPAIN.2018.08.008

Abstract: Complex regional pain syndrome (CRPS) is associated with deficits in sensorimotor control. Herein we have used a novel finger illusion to investigate whether CRPS is associated with reduced weighting of bimanual hand representations. The illusion normally induces a compelling feeling that the hands are close together when in fact they are 12 cm apart. People with CRPS and age, gender, and dominant hand-matched controls tested the illusion in the midline then on either side of the midline. The illusion had 2 variants the passive pincer-grip position, without contact (no grasp condition) and with contact (grasp condition) of the artificial finger. The primary outcome was the perceived vertical distance between the index fingers. Twenty people with CRPS and 20 controls participated (mean age 44.4 ± 11.7 years). During the no grasp condition, participants with CRPS perceived the vertical distance significantly closer to the actual 12 cm (mean 8.0 cm, 95% confidence interval 6.5-9.5 cm), than controls did (mean 6.4 cm, 95% confidence interval 5.5-7.2 cm]). That is, the illusion was weaker in people with CRPS than in controls during no grasp. There was no such difference during grasp that is, both groups showed the predicted illusion response. There was no effect of hand placement relative to midline or relative to the opposite hand. We conclude that people with unilateral CRPS have lower weighting of bimanual hand representation than controls have, independent of hand location. However, adding additional cutaneous input returns those with CRPS to the expected performance. We suggest the results have clear clinical and research implications. PERSPECTIVE: An abnormal weighting of bilateral hand representation may reflect a vulnerability for chronic CRPS, an adaptation to the disease, and/or a potential therapeutic target. That addition of cutaneous input immediately normalizes the problem points to the possible role of bimanual tasks in prevention or rehabilitation.

Brain function in Duchenne muscular dystrophy

Publisher: Oxford University Press (OUP)

Date: 2002

DOI: 10.1093/BRAIN/AWF012

Abstract: Duchenne muscular dystrophy (DMD) is the second most commonly occurring genetically inherited disease in humans. It is an X-linked condition that affects approximately one in 3300 live male births. It is caused by the absence or disruption of the protein dystrophin, which is found in a variety of tissues, most notably skeletal muscle and neurones in particular regions of the CNS. Clinically DMD is characterized by a severe pathology of the skeletal musculature that results in the premature death of the in idual. An important aspect of DMD that has received less attention is the role played by the absence or disruption of dystrophin on CNS function. In this review we concentrate on insights into this role gained from investigation of boys with DMD and the genetically most relevant animal model of DMD, the dystrophin-deficient mdx mouse. Behavioural studies have shown that DMD boys have a cognitive impairment and a lower IQ (average 85), whilst the mdx mice display an impairment in passive avoidance reflex and in short-term memory. In DMD boys, there is evidence of disordered CNS architecture, abnormalities in dendrites and loss of neurones, all associated with neurones that normally express dystrophin. In the mdx mouse, there have been reports of a 50% decrease in neurone number and neural shrinkage in regions of the cerebral cortex and brainstem. Histological evidence shows that the density of GABA(A) channel clusters is reduced in mdx Purkinje cells and hippoc al CA1 neurones. At the biochemical level, in DMD boys the bioenergetics of the CNS is abnormal and there is an increase in the levels of choline-containing compounds, indicative of CNS pathology. The mdx mice also display abnormal bioenergetics, with an increased level of inorganic phosphate and increased levels of choline-containing compounds. Functionally, DMD boys have EEG abnormalities and there is some preliminary evidence that synaptic function is affected adversely by the absence of dystrophin. Electrophysiological studies of mdx mice have shown that hippoc al neurones have an increased susceptibility to hypoxia. These recent findings on the role of dystrophin in the CNS have implications for the clinical management of boys with DMD.

Effects of L-glutamate transport inhibition by a conformationally restricted glutamate analogue (2S,1'S,2'R)-2-(Carboxycyclopropyl)glycine (L-CCG III) on metabolism in brain tissue in vitro analysed by NMR spectroscopy

Publisher: Springer Science and Business Media LLC

Date: 2002

DOI: 10.1023/A:1014842303583

Abstract: (2S,1'S,2'R)-2-(Carboxycyclopropyl)glycine (L-CCG III) was a substrate of Na(+)-dependent glutamate transporters (GluT) in Xenopus laevis oocytes (IC50 to approximately 13 and to approximately 2 microM for, respec tively, EAAT 1 and EAAT 2) and caused an apparent inhibition of [3H]L-glutamate uptake in "mini-slices" of guinea pig cerebral cortex (IC50 to approximately 12 microM). In slices (350 microM) of guinea pig cerebral cortex, 5 microM L-CCG III increased both the flux of label through pyruvate carboxylase and the fractional enrichment of glutamate, GABA, glutamine and lactate, but had no effect on total metabolite pool sizes. At 50 microM L-CCG III decreased incorporation of 13C from [3-13C]-pyruvate into glutamate C4, glutamine C4, lactate C3 and alanine C3. The total metabolite pool sizes were also decreased with no change in the fractional enrichment. Furthermore, L-CCG III was accumulated in the tissue, probably via GluT. At lower concentration, L-CCG III would compete with L-glutamate for GluT and the changes probably reflect a compensation for the "missing" L-glutamate. At 50 microM, intracellular L-CCG III could reach > 10 mM and metabolism might be affected directly.

Long reach of the NAAG family tree

Publisher: Wiley

Date: 16-11-2020

DOI: 10.1111/JNC.15213

Modulation of brain metabolism by very low concentrations of the commonly used drug delivery vehicle dimethyl sulfoxide (DMSO)

Publisher: Wiley

Date: 12-09-2007

DOI: 10.1002/JNR.21477

Abstract: Dimethyl sulfoxide (DMSO) has long been used in studies as a vehicle to enhance the solubility and transport of ligands in biological systems. The effects of this drug on the outcomes of such studies are still unclear, with concentrations of DMSO reported as "safe" varying considerably. In the present work, we investigated the effects of very low concentrations of DMSO on the brain metabolism of [3-(13)C]pyruvate and D-[1-(13)C]glucose using (1)H/(13)C NMR spectroscopy and a guinea pig cortical brain slice model. Our results show that DMSO is accumulated by brain slices. DMSO at all concentrations [0.000025%-0.25% (v/v)] increased the metabolic rate when [3-(13)C]pyruvate was used as a substrate and also in the presence of D-[1-(13)C]glucose (0.00025%-0.1% DMSO). These results are consistent with DMSO stimulating respiration, which it may do through altering the kinetics of ATP-requiring reactions. Our results also emphasize that there is no practical concentration of DMSO that can be used in metabolic experiments without effect. Therefore, care should be taken when evaluating the actions of drugs administered in combination with DMSO.

For want of a nail. ramifications of a single gene deletion, dystrophin, in the brain of the mouse.

Publisher: IMR Press

Date: 2004

DOI: 10.2741/1209

Abstract: Lack of expression of a single gene, dystrophin, causes the severe, progressive muscle wasting and mental deficits characteristic of Duchenne muscular dystrophy. In this work, we investigated the impact of dystrophin deletion on expression of other genes in the brain cortex, hippoc us and cerebellum using the murine homologue, the mdx mouse, and RT-PCR. Expression of the brain glucose transporters GLUT1 and GLUT2 was found to be decreased, as were some subunits of the GABAA and nicotinic acetylcholine receptors. Genes involved in bioenergetic homeostasis, such as the mitochondrial creatine kinase and the gamma subunit of ATP synthase were also found to be abnormally expressed, while expression of the structural proteins beta-dystrobrevin and rapsyn was also significantly affected. We relate these findings to known functional deficits and discuss the possible mechanisms behind the altered gene expression.

Inhibition of glutamine transport depletes glutamate and GABA neurotransmitter pools: further evidence for metabolic compartmentation

Publisher: Wiley

Date: 04-2003

DOI: 10.1046/J.1471-4159.2003.01713.X

Abstract: The role of glutamine and alanine transport in the recycling of neurotransmitter glutamate was investigated in Guinea pig brain cortical tissue slices and prisms, and in cultured neuroblastoma and astrocyte cell lines. The ability of exogenous (2 mm) glutamine to displace 13C label supplied as [3-13C]pyruvate, [2-13C]acetate, l-[3-13C]lactate, or d-[1-13C]glucose was investigated using NMR spectroscopy. Glutamine transport was inhibited in slices under quiescent or depolarising conditions using histidine, which shares most transport routes with glutamine, or 2-(methylamino)isobutyric acid (MeAIB), a specific inhibitor of the neuronal system A. Glutamine mainly entered a large, slow turnover pool, probably located in neurons, which did not interact with the glutamate/glutamine neurotransmitter cycle. This uptake was inhibited by MeAIB. When [1-13C]glucose was used as substrate, glutamate/glutamine cycle turnover was inhibited by histidine but not MeAIB, suggesting that neuronal system A may not play a prominent role in neurotransmitter cycling. When transport was blocked by histidine under depolarising conditions, neurotransmitter pools were depleted, showing that glutamine transport is essential for maintenance of glutamate, GABA and alanine pools. Alanine labelling and release were decreased by histidine, showing that alanine was released from neurons and returned to astrocytes. The resultant implications for metabolic compartmentation and regulation of metabolism by transport processes are discussed.

Neurobiological and Cognitive Profile of Young Binge Drinkers: a Systematic Review and Meta-Analysis

Publisher: Springer Science and Business Media LLC

Date: 09-2019

DOI: 10.1007/S11065-019-09411-W

β-Hydroxybutyrate in the Brain: One Molecule, Multiple Mechanisms

Publisher: Springer Science and Business Media LLC

Date: 08-11-2016

DOI: 10.1007/S11064-016-2099-2

Abstract: β-Hydroxybutyrate (βOHB), a ketone body, is oxidised as a brain fuel. Although its contribution to energy metabolism in the healthy brain is minimal, it is an interesting metabolite which is not only oxidised but also has other direct and collateral effects which make it a molecule of interest for therapeutic purposes. In brain βOHB can be produced in astrocytes from oxidation of fatty acids or catabolism of amino acids and is metabolised in the mitochondria of all brain cell types although uptake across the blood brain barrier is a metabolic control point. βOHB possesses an intrinsic high heat of combustion, making it an efficient mitochondrial fuel, where it can alter the NAD

L-Aspartate, L-Ornithine and L-Ornithine-L-Aspartate (LOLA) and Their Impact on Brain Energy Metabolism

Publisher: Springer Science and Business Media LLC

Date: 18-05-2020

DOI: 10.1007/S11064-020-03044-9

Hippocampal area metabolites relate to severity and cognitive function in obstructive sleep apnea

Publisher: Elsevier BV

Date: 11-2004

DOI: 10.1016/J.SLEEP.2004.08.004

Abstract: Obstructive sleep apnea (OSA) is associated with intermittent hypoxia and cognitive decrements. As the hippoc us is particularly susceptible to hypoxia, we hypothesized that it may show biochemical abnormalities, and they may relate to apnea severity. Eight males with OSA and five age-matched controls underwent neurocognitive testing before and after polysomnography and proton magnetic resonance spectra were obtained from the left hippoc al area of all subjects. In the left hippoc al area, N-acetyl-containing/creatine-containing compounds was significantly increased in OSA (P=0.04). Inspection of these compounds with respect to the water resonance indicated that this was most likely due to a decrease in creatine-containing compounds rather than any change in N-acetyl-containing compounds. Lower levels of hippoc al creatine-containing compounds were correlated with worse OSA severity and neurocognitive performance. We suggest the changes in creatine levels in the hippoc al area represent adjustments to brain bioenergetics, similar to those seen in ischemic preconditioning, and may reflect the different susceptibility of these tissues to hypoxic damage in OSA.

Alanine metabolism, transport, and cycling in the brain

Publisher: Wiley

Date: 14-05-2007

DOI: 10.1111/J.1471-4159.2007.04654.X

Abstract: Brain glutamate/glutamine cycling is incomplete without return of ammonia to glial cells. Previous studies suggest that alanine is an important carrier for ammonia transfer. In this study, we investigated alanine transport and metabolism in Guinea pig brain cortical tissue slices and prisms, in primary cultures of neurons and astrocytes, and in synaptosomes. Alanine uptake into astrocytes was largely mediated by system L isoform LAT2, whereas alanine uptake into neurons was mediated by Na(+)-dependent transporters with properties similar to system B(0) isoform B(0)AT2. To investigate the role of alanine transport in metabolism, its uptake was inhibited in cortical tissue slices under depolarizing conditions using the system L transport inhibitors 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid and cycloleucine (1-aminocyclopentanecarboxylic acid cLeu). The results indicated that alanine cycling occurs subsequent to glutamate/glutamine cycling and that a significant proportion of cycling occurs via amino acid transport system L. Our results show that system L isoform LAT2 is critical for alanine uptake into astrocytes. However, alanine does not provide any significant carbon for energy or neurotransmitter metabolism under the conditions studied.

EFFECTS OF GLUTAMATE TRANSPORT SUBSTRATES AND GLUTAMATE RECEPTOR LIGANDS ON THE ACTIVITY OF Na⁺/K⁺‐ATPase IN BRAIN TISSUE IN VITRO

Publisher: Wiley

Date: 11-2004

DOI: 10.1111/J.1440-1681.2004.04090.X

Abstract: 1. It has been suggested that Na+/K(+)-ATPase and Na(+)-dependent glutamate transport (GluT) are tightly linked in brain tissue. In the present study, we have investigated Na+/K(+)-ATPase activity using Rb+ uptake by 'minislices' (prisms) of the cerebral cortex. This preparation preserves the morphology of neurons, synapses and astrocytes and is known to possess potent GluT that has been well characterized. Uptake of Rb+ was determined by estimating Rb+ in aqueous extracts of the minislices, using atomic absorption spectroscopy. 2. We determined the potencies of several known substrates/inhibitors of GluT, such as L-trans-pyrrolidine-2,4-dicarboxylate (LtPDC), DL-threo-3-benzyloxyaspartic acid, (2S,3S,4R)-2-(carboxycyclopropyl)-glycine (L-CCG III) and L-anti,endo-3,4-methanopyrrolidine dicarboxylic acid, as inhibitors of [3H]-L-glutamate uptake by cortical prisms. In addition, we established the susceptibility of GluT, measured as [3H]-L-glutamate uptake in brain cortical prisms, to the inhibition of Na+/K(+)-ATPase by ouabain. Then, we tested the hypothesis that the Na+/K(+)-ATPase (measured as Rb+ uptake) can respond to changes in the activity of GluT produced by using GluT substrates as GluT-specific pharmacological tools. 3. The Na+/K(+)-ATPase inhibitor ouabain completely blocked Rb+ uptake (IC50 = 17 micromol/L), but it also potently inhibited a fraction of GluT (approximately 50% of [3H]-L-glutamate uptake was eliminated IC50 < 1 micromol/L). 4. None of the most commonly used GluT substrates and inhibitors, such as L-aspartate, D-aspartate, L-CCG III and LtPDC (all at 500 micromol/L), produced any significant changes in Rb+ uptake. 5. The N-methyl-D-aspartate (NMDA) receptor agonists (R,S)-(tetrazol-5-yl)-glycine and NMDA decreased Rb+ uptake in a manner compatible with their known neurotoxic actions. 6. None of the agonists or antagonists for any of the other major classes of glutamate receptors caused significant changes in Rb+ uptake. 7. We conclude that, even if a subpopulation of glutamate transporters in the rat cerebral cortex may be intimately linked to a fraction of Na+/K(+)-ATPase, it is not possible, under the present experimental conditions, to detect regulation of Na+/K(+)-ATPase by GluT.

Astrocytes, Metabolism, Signaling and Brain Drains: Introduction to the Special Issue in Honor of Gerald Dienel

Publisher: Springer Science and Business Media LLC

Date: 27-11-2015

DOI: 10.1007/S11064-015-1781-0

Kinetic analysis of the human erythrocyte glyoxalase system using 1H NMR and a computer model

Publisher: Wiley

Date: 10-1990

DOI: 10.1111/J.1432-1033.1990.TB19307.X

Abstract: 1H NMR was used with methylglyoxal, purified by an HPLC technique, to study the kinetics of the human erythrocyte glyoxalase system. 1H NMR enabled the direct measurement of the time-dependent changes in concentrations of the two hydrates of methylglyoxal, which have not previously been directly measurable, as well as measurement of substrates and products of the glyoxalase enzyme system in the human red blood cell. A computer model of the reaction scheme was developed and NMR data numerically analyzed, thus allowing a complete kinetic description of the reactions. The rate constants describing the chemical equilibria between the hydrated species of methylglyoxal were determined by this numerical analysis or by a saturation-transfer technique, and found to be much slower (by several orders of magnitude) than previously determined by other methods. The kinetic parameters describing the enzyme-catalyzed reactions were also determined from experiments using a dilute haemolysate that was added to solutions of methylglyoxal and reduced glutathione (GSH). The maximal velocity of glyoxalase 1 is threefold greater (Vmax = 70.4 +/- 4.7 mmol.min-1.1 packed cells-1) than glyoxalase 2(Vmax = 24 +/- 5 mmol.min-1.1 packed cells-1) and it exhibits threefold-greater affinity for its substrate (Km = 0.46 +/- 0.04 mM) than the second enzyme (Km = 1.5 +/- 0.4 mM). Both enzymes are subject to competitive inhibition glyoxalase 1 by reduced glutathione (KiGSH = 7.88 +/- 0.16 mM) and glyoxalase 2 by the hemithioacetal (HTA) of methylglyoxal and GSH (KiHTA = 0.29 +/- 0.04 mM).

Stability and nonreactivity of ergothioneine in human erythrocytes studied by1H NMR

Publisher: Wiley

Date: 06-1993

DOI: 10.1002/MRM.1910290617

Abstract: The N(CH3)3 resonance of ergothioneine in 1H spin-echo Fourier transform (SEFT) NMR spectra of red blood cells is usually a large singlet and it has been common practice to use this apparently unchanging resonance as an intensity reference. Recently, Reglinski et al. (Magn. Reson. Med. 6, 217-223 (1988)) have questioned this practice, reporting changes seen in the resonance in response to oxidative stress induced by arsenicals. We propose that the changes in the ergothioneine resonance that were reported are artifacts due to alterations in osmolality and magnetic susceptibility induced by the addition of nonisotonic solutions to red blood cell suspensions. These factors change the specific intensity of the intracellular resonances of all compounds. Ergothioneine was observed not to take part in any chemical reactions with arsenicals in free solution or in intact erythrocytes, and we conclude that ergothioneine may still be used as an internal intensity reference in 1H SEFT NMR spectra, bearing in mind the above physical factors.

The Art, Science, and Secrets of Scanning Young Children

Publisher: Elsevier BV

Date: 05-2023

DOI: 10.1016/J.BIOPSYCH.2022.09.025

Anodal transcranial direct current stimulation increases brain intracellular pH and modulates bioenergetics

Publisher: Oxford University Press (OUP)

Date: 09-2013

DOI: 10.1017/S1461145713000084

Abstract: Transcranial direct current stimulation is an emerging treatment for brain disorders but its mode of action is not well understood. We applied 10 min 1 mA anodal transcranial direct current stimulation (tDCS) inside the bore of a 3 T MRI scanner to the left dorsolateral prefrontal cortex of 13 healthy volunteers (aged 19–28 yr) in a blinded, sham-controlled, cross-over design. Brain bioenergetics were measured from the left temporo-frontal region using 31P magnetic resonance spectroscopy before, during and for 20 min following tDCS. Brain pH rose during tDCS and remained elevated afterwards. Phosphomonoesters were significantly decreased while inorganic phosphate (Pi) also fell. Partial-least squares discriminant analysis of the data revealed two significantly different subject groups: one where phosphocreatine (PCr), ATP and Pi fell along with a larger increase in pH and one where PCr and ATP increased along with a smaller increase in pH and a slower and more sustained decrease in Pi. Group membership was predicted by baseline pH and ATP. We interpreted the effects of tDCS as driving two biochemical processes: cellular consumption of ATP causing hydrolysis of PCr via the creatine kinase reaction driving the increase in pH synthesis of ATP and PCr by mitochondria with concomitant drop in Pi and phosphomonoester levels.

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 con

Publisher: Wiley

Date: 18-12-2013

DOI: 10.1111/JNC.12634

Hypo‐osmotic swelling‐activated release of organic osmolytes in brain slices: implications for brain oedema in vivo

Publisher: Wiley

Date: 15-06-2001

DOI: 10.1046/J.1471-4159.2001.00403.X

Abstract: A decrease in the intracellular levels of osmotically active species has invariably been seen after swelling of mammalian brain tissue preparations. The exact identity of the species, and the manner of their decrease, remain to be described. We investigated the swelling-activated decrease of organic osmolytes in rat cortical brain slices using (1)H- and (31)P-magnetic resonance spectroscopy. We found that acute hypo-osmotic shock causes decreases in the levels of a range of intracellular amino acids and amino acid derivatives, N-acetyl-aspartate, creatine, GABA, glutamate, hypotaurine, and also in the levels of the methylamines glycerol-phosphorylcholine, phosphorylcholine and choline. Incubation of cortical slices with the anion channel blockers niflumic acid and tamoxifen caused inhibition of organic osmolyte efflux, suggesting that such osmolyte efflux occurs through anion channels. Intracellular phosphocreatine was also seen to decrease during acute hypo-osmotic superfusion, although intracellular ATP remained constant. In addition, the acidification of an intracellular compartment was observed during hypo-osmotic superfusion. Our results suggest a link between brain energy reserve and brain osmoregulation.

White matter measures are near normal in controlled HIV infection except in those with cognitive impairment and longer HIV duration (vol 23, pg 539, 2017)

Publisher: Springer Science and Business Media LLC

Date: 28-07-2017

DOI: 10.1007/S13365-017-0542-Z

Alterations of GABA and glutamate–glutamine levels in premenstrual dysphoric disorder: A 3T proton magnetic resonance spectroscopy study

Publisher: Elsevier BV

Date: 2015

DOI: 10.1016/J.PSCYCHRESNS.2014.10.020

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 ((1)H 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 (1)H 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.

Training the brain and its connections to muscles.

Publisher: American Physiological Society

Date: 15-07-2013

DOI: 10.1152/JAPPLPHYSIOL.00503.2013

Cerebellar morphology in developmental dyslexia.

Publisher: Elsevier BV

Date: 2002

DOI: 10.1016/S0028-3932(01)00216-0

Abstract: Recent evidence has suggested cerebellar anomalies in developmental dyslexia. Therefore, we investigated cerebellar morphology in subjects with documented reading disabilities. We obtained T1-weighted magnetic resonance images in the coronal and sagittal planes from 11 males with prior histories of developmental dyslexia, and nine similarly-aged male controls. Proton magnetic resonance spectra (TE=136ms, TR=2.4s) were obtained bilaterally in the cerebellum. Phonological decoding skill was measured using non-word reading. Handedness was assessed using both the Annett questionnaire of hand preference and Annett's peg moving task. Cerebellar symmetry was observed in the dyslexics but there was significant asymmetry (right grey matter>left grey matter) in controls. The interpretation of these results depended whether a motor- or questionnaire-based method was used to determine handedness. The degree of cerebellar symmetry was correlated with the severity of dyslexics' phonological decoding deficit. Those with more symmetric cerebella made more errors on a nonsense word reading measure of phonological decoding ability. Left cerebellar metabolite ratios were shown to correlate significantly with the degree of cerebellar asymmetry (P<0.05) in controls. This relationship was absent in developmental dyslexics. Cerebellar morphology reflects the higher degree of symmetry found previously in the temporal and parietal cortex of dyslexics. The relationship of cerebellar asymmetry to phonological decoding ability and handedness, together with our previous finding of altered metabolite ratios in the cerebellum of dyslexics, lead us to suggest that there are alterations in the neurological organisation of the cerebellum which relate to phonological decoding skills, in addition to motor skills and handedness.

Reduced cytosolic acidification during exercise suggests defective glycolytic activity in skeletal muscle of patients with Becker muscular dystrophy

Publisher: Oxford University Press (OUP)

Date: 1999

DOI: 10.1093/BRAIN/122.1.121

Abstract: Becker muscular dystrophy is an X-linked disorder due to mutations in the dystrophin gene, resulting in reduced size and/or content of dystrophin. The functional role of this subsarcolemma protein and the biochemical mechanisms leading to muscle necrosis in Becker muscular dystrophy are still unknown. In particular, the role of a bioenergetic deficit is still controversial. In this study, we used 31p magnetic resonance spectroscopy (31p-MRS) to investigate skeletal muscle mitochondrial and glycolytic ATP production in vivo in 14 Becker muscular dystrophy patients. Skeletal muscle glycogenolytic ATP production, measured during the first minute of exercise, was similar in patients and controls. On the other hand, during later phases of exercise, skeletal muscle in Becker muscular dystrophy patients was less acidic than in controls, the cytosolic pH at the end of exercise being significantly higher in Becker muscular dystrophy patients. The rate of proton efflux from muscle fibres of Becker muscular dystrophy patients was similar to that of controls, pointing to a deficit in glycolytic lactate production as a cause of higher end-exercise cytosolic pH in patients. The maximum rate of mitochondrial ATP production was similar in muscle of Becker muscular dystrophy patients and controls. The results of this in vivo 31P-MRS study are consistent with reduced glucose availability in dystrophin-deficient muscles.

Network comparison with frequency domain persistent homology

Publisher: IEEE

Date: 04-2016

DOI: 10.1109/ISBI.2016.7493328

Dynamic changes in brain bioenergetics during obstructive sleep apnea

Publisher: SAGE Publications

Date: 13-05-2009

DOI: 10.1038/JCBFM.2009.57

Abstract: Repetitive collapse of the upper airway during obstructive sleep apnea/hypopnea (OSA) exposes the brain of sufferers to frequent, transient, hypoxic episodes. The loss of cerebrovascular reactivity in sleep, and particularly in OSA, means that physiologic compensatory mechanisms may not ensure adequate brain oxygen levels. This 31 P magnetic resonance spectroscopy study, of 13 males with severe, untreated OSA undertaken after overnight sleep deprivation, represents the first, seconds time-scale analysis of human brain bioenergetics during transient hypoxia and demonstrates that a moderate degree of oxygen desaturation during sleep has significant effects on brain bioenergetic status. Oxygen desaturation % of sleeping baseline resulted in decreases in brain adenosine triphosphate levels ( P 0.01), and increases in inorganic phosphate ( P 0.0001) with no concomitant changes in phosphocreatine or brain pH. This indicates that the mechanism of adenosine triphosphate depletion in these patients is different to that observed in normoxic, awake working brain. These data show that the buffering capacity of phosphocreatine and the creatine kinase system is not active in mild transient hypoxia and that cerebrovascular compensatory mechanisms are not adequate to prevent decrements in brain high-energy phosphates in OSA. Transient hypoxia experienced during sleep may impair brain function more than previously thought.

Direct mapping of T*₂ signal changes induced by Transcranial Direct Current Stimulation

Publisher: IEEE

Date: 04-2013

DOI: 10.1109/ISBI.2013.6556664

RE: Magnetic resonance spectroscopy of the brain: review of metabolites and clinical applications

Publisher: Elsevier BV

Date: 10-2009

DOI: 10.1016/J.CRAD.2009.06.003

Changes in hepatic glutathione metabolism in diabetes.

Publisher: American Diabetes Association

Date: 03-1991

DOI: 10.2337/DIAB.40.3.344

Abstract: Glutathione is important in the regulation of the redox state, and a decline in its tissue level has often been considered to be indicative of increased oxidative stress in diabetes. In this study of diabetic rats, the level of hepatic glutathione was normal unless food intake was restricted. Thus, the previous report of a reduction in hepatic glutathione in diabetes is likely to be the result of food deprivation rather than diabetes alone. In contrast to changes characteristic of oxidative stress, the efflux of glutathione in bile from diabetic animals was significantly decreased, whereas hepatic mixed disulfides were unchanged, and the hepatic γ-glutamyltransferase activity was considerably increased. These changes were not reproduced by food deprivation. The decrease in biliary excretion of glutathione in diabetes may reflect an attempt to conserve glutathione by activation of the hepatic γ-glutamyl cycle. We conclude that the disturbances of glutathione metabolism in diabetes are not typical of those seen in oxidative stress or food restriction.

Brain activity: Conditional dissimilarity and persistent homology

Publisher: IEEE

Date: 04-2015

DOI: 10.1109/ISBI.2015.7164127

Emerging Concepts in Vector Development for Glial Gene Therapy: Implications for Leukodystrophies

Publisher: Frontiers Media SA

Date: 22-06-2021

DOI: 10.3389/FNCEL.2021.661857

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.

Combining MR elastography and diffusion tensor imaging for the assessment of anisotropic mechanical properties: A phantom study

Publisher: Wiley

Date: 17-09-2012

DOI: 10.1002/JMRI.23797

Abstract: To investigate the anisotropic elasticity of soft tissues using MR elastography (MRE) combined with diffusion tensor imaging (DTI). The storage moduli parallel (μ(‖)) and perpendicular (μ(⊥)) to the local fiber orientation were calculated assuming a transversely isotropic model. The local fiber orientation was provided by DTI. The proposed technique was validated against rheometry using anisotropic viscoelastic phantoms with various fiber volume fractions (V(f) = 0%, 15%, and 35%) and bovine skeletal muscle s les. The anisotropic ratio (μ(‖)/μ(⊥)) as measured by MRE correlated well with rheometry for all s les (R(2) = 0.809). The combined MRE/DTI technique was also able to differentiate different levels of mechanical anisotropy with the mechanical anisotropy (μ(‖)/μ(⊥)) of the V(f) = 35% phantoms being significantly higher than the V(f) = 15% and the isotropic (V(f) = 0%) phantoms. The bovine muscle s les showed significantly higher mechanical anisotropy than all phantoms. This study has demonstrated the feasibility of the proposed imaging technique for characterizing mechanical anisotropy of anisotropic materials and biological tissues, and validated the mechanical anisotropy results.

Oral creatine monohydrate supplementation improves brain performance: a double–blind, placebo–controlled, cross–over trial

Publisher: The Royal Society

Date: 22-10-2003

DOI: 10.1098/RSPB.2003.2492

Magnetic Resonance-Based Metabolomics for Understanding Neurological Disorders: Current Status and Statistical Considerations

Publisher: Bentham Science Publishers Ltd.

Date: 11-2012

DOI: 10.2174/2213235X130102

Delayed labelling of brain glutamate after an intra-arterial [13C]glucose bolus: evidence for aerobic metabolism of guinea pig brain glycogen store

Publisher: Elsevier BV

Date: 07-1999

DOI: 10.1016/S0167-4889(99)00067-1

Abstract: Glycogen in glial cells is the largest store of glucose equivalents in the brain. Here we describe evidence that brain glycogen contributes to aerobic energy metabolism of the guinea pig brain in vivo. Five min after an intra-arterial bolus injection of d-[U-14C]glucose, 28+/-11% of the radioactivity in brain tissue was associated with the glycogen fraction, indicating that a significant proportion of labelled glucose taken up by the brain is converted to glycogen shortly after bolus infusion. Incorporation of 13C-label into lactate generated by brains made ischaemic after d-[1-13C]glucose injection confirms that these glucose equivalents can be mobilised for anaerobic glucose metabolism. Aerobic metabolism was monitored by following the time course of 13C-incorporation into glutamate in guinea pig cortex and cerebellum in vivo. After an intra-arterial bolus injection of d-[1-13C]glucose, glutamate labelling reached a maximum 40-60 min after injection, suggesting that a slowly metabolised pool of labelled glucose equivalents was present. As the concentration of 13C-labelled glucose in blood was shown to decrease below detectable levels within 5 min of bolus injection, this late phase of glutamate labelling must occur with mobilisation of a brain storage pool of labelled glucose equivalents. We interpret this as evidence that glucose equivalents in glycogen may contribute to energy metabolism in the aerobic guinea pig brain.

Now I know my ABC. A systems neurochemistry and functional metabolomic approach to understanding the GABAergic system

Publisher: Wiley

Date: 07-04-2009

DOI: 10.1111/J.1471-4159.2009.05803.X

Abstract: Here, we describe use of a reductionist brain model, the brain tissue slice, to generate snapshots of functional metabolism in response to a pharmacological (GABAergic) perturbation. Tissue slices prepared from Guinea pig cerebral cortex were incubated for 1 h in the presence of [3-13C]-pyruvate and ligands with affinity for GABA receptors. The resultant patterns of 13C flux and metabolite levels were measured by 13C/1H NMR spectroscopy, generating 'metabolic fingerprints' for each ligand. Effects of agonists and effectors at GABA receptors (A, B, and C types) were examined, compared to those of exogenous GABA and evaluated using multivariate statistical models. Data clusterings did not directly correlate with GABA receptor types but produced at least five distinct groups ranked according to their affinity for GABA. As our experimental model retains, to a large extent, the structure and function of normal brain tissue, the generated database can be used to assess GABAergic ligands and make unique inferences relevant to their modes of action in brain.

Elevation of cell-associated HIV-1 transcripts in CSF CD4+ T cells, despite effective antiretroviral therapy, is linked to brain injury.

Publisher: Proceedings of the National Academy of Sciences

Date: 21-11-2022

DOI: 10.1073/PNAS.2210584119

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 (

Statistical integration of 1H NMR and MRS data from different biofluids and tissues enhances recovery of biological information from individuals with HIV-1 infection

Publisher: American Chemical Society (ACS)

Date: 04-2011

DOI: 10.1021/PR1010263

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 s les. Here we extend this concept to identify novel metabolic correlations between different biofluids and tissues from the same in iduals. We acquired NMR data from blood plasma and cerebrospinal fluid (CSF) (N = 19) from HIV-1-infected in iduals, 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.

Upper limb function is normal in patients with restless legs syndrome (Willis-Ekbom Disease)

Publisher: Elsevier BV

Date: 04-2015

DOI: 10.1016/J.CLINPH.2014.07.010

Abstract: Restless legs syndrome, now called Willis-Ekbom Disease (RLS/WED), is a sensorimotor-related sleep disorder. Little is known of the effect of RLS/WED on motor function. The current study investigated upper limb function in RLS/WED patients. We hypothesised that RLS/WED patients exhibit subtle changes in tremor litude but normal dexterity and movement speed and rhythmicity compared to healthy controls. RLS/WED patients (n=17, 59 ± 7 years) with moderate disease and healthy controls (n=17, 58 ± 6 years) completed screening tests and five tasks including object manipulation, maximal pinch grip, flexion and extension of the index finger (tremor assessment), maximal finger tapping (movement speed and rhythmicity assessment), and the grooved pegboard test. Force, acceleration, and/or first dorsal interosseus EMG were recorded during four of the tasks. Task performance did not differ between groups. Learning was evident on tasks with repeated trials and the magnitude of learning did not differ between groups. Hand function, tremor, and task learning were unaffected in RLS/WED patients. Patients manipulated objects in a normal manner and exhibited normal movement speed, rhythmicity, and tremor. Further research is needed to assess other types of movement in RLS/WED patients to gain insight into the motor circuitry affected and the underlying pathophysiology.

Metabolite profiling of the intraerythrocytic malaria parasitePlasmodium falciparumby¹H NMR spectroscopy

Publisher: Wiley

Date: 19-11-2008

DOI: 10.1002/NBM.1323

Abstract: NMR spectroscopy was used to identify and quantify compounds in extracts prepared from mature trophozoite-stage Plasmodium falciparum parasites isolated by saponin-permeabilisation of the host erythrocyte. One-dimensional (1)H NMR spectroscopy and four two-dimensional NMR techniques were used to identify more than 50 metabolites. The intracellular concentrations of over 40 metabolites were estimated from the (1)H NMR spectra of extracts prepared by four extraction methods: perchloric acid, methanol/water, methanol/chloroform/water, and methanol alone. The metabolites quantified included: the majority of the biological alpha-amino acids 4-aminobutyric acid mono-, di- and tri-carboxylic acids nucleotides polyamines myo-inositol and phosphocholine and phosphoethanolamine. The parasites also contained a significant concentration (up to 12 mM) of the exogenous buffering agent, HEPES. Although the metabolite profiles obtained with each extraction method were broadly similar, perchloric acid was found to have significant advantages over the other extraction media.

Understanding Your Inhibitions: Modulation of Brain Cortical Metabolism by GABA_B Receptors

Publisher: SAGE Publications

Date: 07-02-2007

DOI: 10.1038/SJ.JCBFM.9600453

Abstract: Although the impact of neuronal excitation on the functional activity of brain is well understood, the nature of functional responses to inhibitory modulation is far from clear. In this work, we investigated the effects of modulation of the metabotropic GABA B receptor on brain metabolism using a targeted neuropharmacological, 1 H/ 13 C nuclear magnetic resonance spectroscopy, and metabolomic approach. While agonists at GABA B receptors (Baclofen and SKF 97541) generally decreased metabolic activity, mild agonist action could also stimulate metabolism. Less potent antagonists (CGP 35348, Phaclofen) significantly decreased metabolic activity, while more potent antagonists (CGP 52432 and SCH 50911) had opposite, stimulatory, effects. Examination of the data by principal components analysis showed clear isions of the effects into excitatory and inhibitory components. GABAergic modulation can, therefore, have stimulatory, inhibitory, or even neutral net effects on metabolic activity in brain tissue. This is consistent with GABAergic activity being context dependent, and this conclusion should be taken into account when evaluating functional imaging data involving modulation of neuronal inhibition.

Toluene inhalation in adolescent rats reduces flexible behaviour in adulthood and alters glutamatergic and GABAergic signalling

Publisher: Wiley

Date: 09-11-2016

DOI: 10.1111/JNC.13858

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 hippoc us, 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.

A Chip Off the Old Block: The Brain Slice as a Model for Metabolic Studies of Brain Compartmentation and Neuropharmacology

Publisher: Springer New York

Date: 2014

DOI: 10.1007/978-1-4939-1059-5_10

1 H NMR of compounds with low water solubility in the presence of erythrocytes: effects of emulsion phase separation

Publisher: Springer Science and Business Media LLC

Date: 09-04-2001

DOI: 10.1007/S002490000108

Abstract: When lipophilic compounds like diethyl phthalate (DEP) were added to water, two sets of resonances appeared in the 1H NMR spectrum, whereas when added in concentrations above approximately 3.5 mM to erythrocytes in a high haematocrit suspension, only one set of resonances was observed at the low-frequency position. The appearance of one set of resonances at lower frequency was found to be common to a series of lipophilic compounds in erythrocytes. The appearance of the NMR spectra is ascribed to the existence of an emulsion, meaning two different phases of a compound: a "droplet" (resonances to lower frequency) and aqueous dissolved phase (resonances to higher frequency). The absence of the resonances from the dissolved phase in erythrocyte solution is ascribed to exchange broadening. The absolute chemical shift of the compound in its "droplet" phase was also measured using a cylindrical/spherical microcell. This arrangement mimicked the geometry of the dissolved versus the phase-separated species and thus obviated the effect of a difference in magnetic susceptibility between the "droplet" solute and its aqueous solution. Factors influencing the formation of emulsion phases such as erythrocytes, haemoglobin and smaller proteins were investigated they are found to be effective in the order given.

The relationship between thalamic GABA content and resting cortical rhythm in neuropathic pain

Publisher: Wiley

Date: 17-01-2018

DOI: 10.1002/HBM.23973

Dichloroacetate (DCA) reduces brain lactate but increases brain glutamine in experimental cerebral malaria: A ¹H-NMR study

Publisher: Informa UK Limited

Date: 04-2000

DOI: 10.1179/135100000101535492

Abstract: Recent findings that levels of brain lactate and alanine were elevated in murine cerebral malaria led us to investigate the effect of dichloroacetate (DCA 60 mg/kg), an activator of pyruvate dehydrogenase, on the levels of brain metabolites, and on the survival of mice infected with Plasmodium berghei ANKA which normally causes lethal cerebral malaria. DCA significantly reduced brain lactate and alanine levels when administered to infected mice, had no effect on the TCA cycle-related metabolites glutamate, GABA and aspartate and was associated with increased brain glutamine levels: 40% of mice thus treated survived the normally lethal infection.

CRPS Is Not Associated with Altered Sensorimotor Cortex GABA or Glutamate

Publisher: Society for Neuroscience

Date: 2020

DOI: 10.1523/ENEURO.0389-19.2020

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 in iduals 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 s le 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.

Understanding your inhibitions: effects of GABA and GABA_A receptor modulation on brain cortical metabolism

Publisher: Wiley

Date: 04-12-2008

DOI: 10.1111/J.1471-4159.2008.05742.X

Abstract: A targeted neuropharmacological, (1)H/(13)C NMR spectroscopy and multivariate statistical approach was used to examine the effects of exogenous GABA and ligands at the GABA(A) receptor family on brain metabolism in the Guinea pig cortical tissue slice. All ligands at GABA(A) receptors generated metabolic patterns which were distinct from one another with the major variance in the data arising because of metabolic work (shown by net flux into Krebs cycle byproducts and increased metabolic pool sizes). Three major clusters of metabolic signatures were identified which corresponded to: (i) activity at phasic (synaptic) GABA(A) receptors, dominated by alpha1-containing receptors and responsive to GABA at 10 micromol/L (ii) activity at perisynaptic receptors, dominated by response to high (40 micromol/L) GABA and the superagonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-3-ol hydrochloride, and C, activity at extrasynaptic receptors, dominated by response to low (0.1-1.0 micromol/L) GABA, zolpidem (400 nmol/L) and the non-specific allosteric modulator RO19-4603 (1 nmol/L). These results highlight the utility of a different but robust approach to study of the GABAergic system using metabolic systems analysis.

Piece of mind; a full systems approach is required

Publisher: Cambridge University Press (CUP)

Date: 04-2007

DOI: 10.1017/S0140525X07001276

Abstract: Intelligence studies are confounded by an inability to image the mind, as well as by heterogeneity in intelligence constructs, gender, and age. The ghost (of future, not past) sitting at the table is a molecular one. Biochemistry and molecular biology factors can contribute to or take away from intelligence to a great and not yet fully explored extent.

A comprehensive guide to MEGA-PRESS for GABA measurement

Publisher: Elsevier BV

Date: 05-2023

DOI: 10.1016/J.AB.2023.115113

The effects of large neutral amino acid supplements in PKU: An MRS and neuropsychological study

Publisher: Elsevier BV

Date: 05-2007

DOI: 10.1016/J.YMGME.2007.02.002

Abstract: To determine the effects of large neutral amino acid (LNAA) supplements on brain and plasma phenylalanine (Phe) levels and other metabolites in early treated subjects with classical phenylketonuria (PKU), and to investigate the relationship between these metabolites and neuropsychological performance. This was a prospective, double blind, cross over study consisting of four two-week phases with a 4 week washout period. Sixteen subjects (7 males), with classical PKU were recruited into the study and completed all 4 phases. Each phase consisted of either the LNAA supplement or placebo, and either the patient's usual medical product or not. Subjects were instructed to follow their usual Phe restricted diet, maintain energy intake and complete a 3-day food record during each phase. At the end of each phase, brain Phe and other metabolites were measured by proton magnetic resonance spectroscopy (MRS), and plasma amino acids quantified. A detailed neuropsychological assessment was performed on the same day as the MRS and plasma collection. There was no correlation between plasma and brain Phe, but few of the plasma Phe readings were over 1200 micromol/L. Plasma Phe decreased with LNAA supplementation when patients were not taking their medical formula. LNAA supplementation had a specific impact on executive functions particularly in verbal generativity and cognitive flexibility. Measures of attention were better on medical product, with or without LNAA supplements. LNAA supplementation was associated with a trend to a lowering of plasma Phe levels. LNAA supplementation had a specific impact on executive functions particularly in verbal generativity and flexibility. For in iduals already complying with diet and PKU medical product, additional supplementation with LNAA is of limited value. LNAA supplementation may be of benefit to those unable to comply with PKU medical product by reducing plasma Phe, perhaps by competing with Phe at the level of transport across the gut.

Neuroscience Research Australia

Location: Australia

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University Of New South Wales

Location: Australia

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University Of New South Wales

Location: No location found

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Neuroscience Research Australia

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Discovery Projects - Grant ID: DP0985147

Start Date: 2009

End Date: 12-2012

Amount: $565,000.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE100100055

Start Date: 2011

End Date: 12-2011

Amount: $400,000.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP180101702

Start Date: 05-2018

End Date: 12-2021

Amount: $429,397.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0989541

Start Date: 2009

End Date: 12-2010

Amount: $1,000,000.00

Funder: Australian Research Council

Special Research Initiatives - Grant ID: SR0354494

Start Date: 2004

End Date: 02-2004

Amount: $10,000.00

Funder: Australian Research Council

Linkage Projects - Grant ID: LP0667490

Start Date: 2006

End Date: 12-2010

Amount: $650,000.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE120100027

Start Date: 04-2012

End Date: 12-2013

Amount: $320,000.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP0557664

Start Date: 02-2005

End Date: 12-2007

Amount: $360,000.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE170100021

Start Date: 05-2017

End Date: 12-2018

Amount: $2,168,000.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0560916

Start Date: 2005

End Date: 12-2006

Amount: $323,400.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0453295

Start Date: 01-2004

End Date: 12-2005

Amount: $369,697.00

Funder: Australian Research Council