Georgia Sotiropoulou

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.

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.

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.

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.

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

Memory training alters hippocampal neurochemistry in healthy elderly

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 07-2003

DOI: 10.1097/00001756-200307180-00010

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.

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.

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

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.

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

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.

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.

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.

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.

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.

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.

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 (

Microphysics of Antarctic precipitation in climate models : recent advances and challenges

Publisher: Copernicus GmbH

Date: 23-03-2020

DOI: 10.5194/EGUSPHERE-EGU2020-2850

Abstract: & align=& quot justify& quot & & span& The current assessment of the Antarctic surface mass balance mostly relies on reanalysis products or climate model simulations. The ability of models to reproduce the precipitation field at the regional and continental scales not only depends on the simulation of the atmospheric dynamics over the Southern Ocean and of the advection of moisture towards the ice sheet, but also on the representation of the microphysical processes that govern the formation and growth of ice crystals and snowflakes. This presentation reviews recent studies to stress the importance and challenges of evaluating the precipitation microphysics over Antarctica in climate models. It also discusses how recent observational c aigns including ground-based remote-sensing instruments can help pinpoint key processes that should be represented in models. We then present tangible ex les of evaluation and improvement of microphysical schemes in the Polar WRF model thanks to radar and lidar observations acquired near Dumont d& #8217 Urville and Mawson stations on the Antarctic coast. Particular attention is devoted to three processes& : i) the sublimation of snowfall within the katabatic layer that considerably reduces the amount of precipitation that actually reaches the surface& ii) the snowflake aggregation responsible for rapid depletion of crystals within clouds& iii) the generation of supercooled liquid water in frontal clouds that leads to crystal/snowflake riming. Such studies, albeit preliminary, could pave the way for further evaluations of clouds and precipitation in climate models in different Antarctic contexts, especially in the cold and pristine atmosphere of the Plateau.& /span& & &

Measured ice nucleating particle concentrations improve the simulation of mid-level mixed-phase clouds over the high-latitude Southern Ocean

Publisher: Wiley

Date: 24-07-2020

DOI: 10.1002/ESSOAR.10503669.1

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.

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.

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.

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.

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.

Challenging and Improving the Simulation of Mid-Level Mixed-Phase Clouds Over the High-Latitude Southern Ocean

Publisher: American Geophysical Union (AGU)

Date: 07-04-2021

DOI: 10.1029/2020JD033490

Abstract: Climate models exhibit major radiative biases over the Southern Ocean owing to a poor representation of mixed‐phase clouds. This study uses the remote‐sensing dataset from the Measurements of Aerosols, Radiation and Clouds over the Southern Ocean (MARCUS) c aign to assess the ability of the Weather Research and Forecasting (WRF) model to reproduce frontal clouds off Antarctica. It focuses on the modeling of thin mid‐level supercooled liquid water layers which precipitate ice. The standard version of WRF produces almost fully glaciated clouds and cannot reproduce cloud top turbulence. Our work demonstrates the importance of adapting the ice nucleation parameterization to the pristine austral atmosphere to reproduce the supercooled liquid layers. Once simulated, droplets significantly impact the cloud radiative effect by increasing downwelling longwave fluxes and decreasing downwelling shortwave fluxes at the surface. The net radiative effect is a warming of snow and ice covered surfaces and a cooling of the ocean. Despite improvements in our simulations, the local turbulent circulation related to cloud‐top radiative cooling is not properly reproduced, advocating for the need to develop a parameterization for top‐down convection to capture the turbulence‐microphysics interplay at cloud top.

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.

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).

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.

A comprehensive guide to MEGA-PRESS for GABA measurement

Publisher: Elsevier BV

Date: 05-2023

DOI: 10.1016/J.AB.2023.115113

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.

Neuroscience Research Australia

Location: Australia

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University Of New South Wales

Location: Australia

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Neuroscience Research Australia

Location: No location found

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University Of New South Wales

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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: LE120100027

Start Date: 04-2012

End Date: 12-2013

Amount: $320,000.00

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

Discovery Projects - Grant ID: DP180101702

Start Date: 05-2018

End Date: 12-2021

Amount: $429,397.00

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: LE0560916

Start Date: 2005

End Date: 12-2006

Amount: $323,400.00

Funder: Australian Research Council