Imperial College London

DrGregoryScott

Faculty of MedicineDepartment of Brain Sciences

Honorary Clinical Lecturer
 
 
 
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gregory.scott99

 
 
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C3NL, Burlington DanesBurlington DanesHammersmith Campus

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Summary

 

Publications

Publication Type
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61 results found

Sandrone S, Scott G, Anderson WJ, Musunuru Ket al., 2021, Active learning-based STEM education for in-person and online learning, CELL, Vol: 184, Pages: 1409-1414, ISSN: 0092-8674

Journal article

Beppi C, Violante IR, Scott G, Sandrone Set al., 2021, EEG, MEG and neuromodulatory approaches to explore cognition: Current status and future directions, BRAIN AND COGNITION, Vol: 148, ISSN: 0278-2626

Journal article

Mallas E-J, De Simoni S, Scott G, Jolly A, Hampshire A, Li L, Bourke N, Roberts S, Gorgoraptis N, Sharp Det al., 2021, Abnormal dorsal attention network activation in memory impairment after traumatic brain injury, Brain: a journal of neurology, Vol: 144, Pages: 114-127, ISSN: 0006-8950

Memory impairment is a common, disabling effect of traumatic brain injury. In healthy individuals, successful memory encoding is associated with activation of the dorsal attention network as well as suppression of the default mode network. Here, in traumatic brain injurypatients we examined whether: i) impairments in memory encoding are associated with abnormal brain activation in these networks; ii) whether changes in this brain activity predict subsequent memory retrieval; and iii) whether abnormal white matter integrity underpinningfunctional networks is associated with impaired subsequent memory. 35 patients with moderate-severetraumatic brain injury aged 23-65 years (74% males) in the post-acute/chronic phase after injury and 16 healthy controls underwent functional MRI during performance of an abstract image memory encoding task. Diffusion tensor imaging was used to assess structural abnormalities across patient groups compared to 28 age-matched healthy controls. Successful memory encoding across all participants was associated with activation of the dorsal attention network, the ventral visual stream and medial temporal lobes. Decreased activation was seen in the default mode network. Patients with preserved episodic memory demonstrated increased activation in areas of the dorsal attention network.Patients with impaired memory showed increased left anterior prefrontal activity. White matter microstructure underpinning connectivity between core nodes of the encoding networks was significantly reduced in patients with memory impairment. Our results show for the first time that patients with impaired episodic memory show abnormal activation of key nodes within the dorsal attention network and regions regulating default mode network activity during encoding. Successful encoding was associated with an opposite direction of signal

Journal article

Graham NSN, Jolly A, Zimmerman K, Bourke NJ, Scott G, Cole JH, Schott JM, Sharp DJet al., 2020, Diffuse axonal injury predicts neurodegeneration after moderate-severe traumatic brain injury, Brain: a journal of neurology, Vol: 143, Pages: 3685-3698, ISSN: 0006-8950

Traumatic brain injury is associated with elevated rates of neurodegenerative diseases such as Alzheimer's disease and chronic traumatic encephalopathy. In experimental models, diffuse axonal injury triggers post-traumatic neurodegeneration, with axonal damage leading to Wallerian degeneration and toxic proteinopathies of amyloid and hyperphosphorylated tau. However, in humans the link between diffuse axonal injury and subsequent neurodegeneration has yet to be established. Here we test the hypothesis that the severity and location of diffuse axonal injury predicts the degree of progressive post-traumatic neurodegeneration. We investigated longitudinal changes in 55 patients in the chronic phase after moderate-severe traumatic brain injury and 19 healthy control subjects. Fractional anisotropy was calculated from diffusion tensor imaging as a measure of diffuse axonal injury. Jacobian determinant atrophy rates were calculated from serial volumetric T1 scans as a measure of measure post-traumatic neurodegeneration. We explored a range of potential predictors of longitudinal post-traumatic neurodegeneration and compared the variance in brain atrophy that they explained. Patients showed widespread evidence of diffuse axonal injury, with reductions of fractional anisotropy at baseline and follow-up in large parts of the white matter. No significant changes in fractional anisotropy over time were observed. In contrast, abnormally high rates of brain atrophy were seen in both the grey and white matter. The location and extent of diffuse axonal injury predicted the degree of brain atrophy: fractional anisotropy predicted progressive atrophy in both whole-brain and voxelwise analyses. The strongest relationships were seen in central white matter tracts, including the body of the corpus callosum, which are most commonly affected by diffuse axonal injury. Diffuse axonal injury predicted substantially more variability in white matter atrophy than other putative clinical or ima

Journal article

Jolly A, Scott G, Sharp D, Hampshire Aet al., 2020, Distinct patterns of structural damage underlie working memory and reasoning deficits after traumatic brain injury, Brain: a journal of neurology, Vol: 143, Pages: 1158-1176, ISSN: 0006-8950

It is well established that chronic cognitive problems after traumatic brain injury (TBI) relate to diffuse axonal injury (DAI) and the consequent widespread disruption of brain connectivity. However, the pattern of DAI varies between patients and they have a correspondingly heterogeneous profile of cognitive deficits. This heterogeneity is poorly understood, presenting a non-trivial challenge for prognostication and treatment. Prominent amongst cognitive problems are deficits in working memory and reasoning. Previous functional magnetic resonance imaging (fMRI) in controls has associated these aspects of cognition with distinct, but partially overlapping, networks of brain regions. Based on this, a logical prediction is that differences in the integrity of the white matter tracts that connect these networks should predict variability in the type and severity of cognitive deficits after TBI.We use diffusion-weighted imaging, cognitive testing and network analyses to test this prediction. We define functionally distinct sub-networks of the structural connectome by intersecting previously published fMRI maps of the brain regions that are activated during our working memory and reasoning tasks, with a library of the white-matter tracts that connect them. We examine how graph theoretic measures within these sub-networks relate to the performance of the same tasks in a cohort of 92 moderate-severe TBI patients. Finally, we use machine learning to determine whether cognitive performance in patients can be predicted using graph theoretic measures from each sub-network.Principal component analysis of behavioural scores confirm that reasoning and working memory form distinct components of cognitive ability, both of which are vulnerable to TBI. Critically, impairments in these abilities after TBI correlate in a dissociable manner with the information-processing architecture of the sub-networks that they are associated with. This dissociation is confirmed when examining degree

Journal article

Jolly AE, Raymont V, Cole JH, Whittington A, Scott G, De Simoni S, Searle G, Gunn RN, Sharp DJet al., 2019, Dopamine D2/D3 receptor abnormalities after traumatic brain injury and their relationship to post-traumatic depression, NeuroImage: Clinical, Vol: 24, ISSN: 2213-1582

ObjectiveTo investigate dopamine D2/D3 receptor availability following traumatic brain injury (TBI) and their relationship to the presence of DSM-IV Major Depressive Disorder (MDD) and patterns of axonal injury.MethodsTwelve moderate-severe TBI patients and 26 controls were imaged using [11C]PHNO positron emission tomography (PET) and structural magnetic resonance imaging (MRI). TBI patients and a second group of 32 controls also underwent diffusion tensor imaging (DTI) and neuropsychological assessment. Patients included six with post-injury MDD (TBI-MDD) and six without (TBI-NON). Non-displaceable binding potential (BPND) [11C]PHNO values were used to index D2/D3 receptor availability, and were calculated using a reference region procedure. Differences in BPND were examined using voxelwise and region-of-interest analyses. White matter microstructure integrity, quantified by fractional anisotropy (FA), was assessed and correlated with BPND.ResultsLower [11C]PHNO BPND was found in the caudate across all TBI patients when compared to controls. Lower [11C]PHNO BPND was observed in the caudate of TBI-MDD patients and increased [11C]PHNO BPND in the Amygdala of TBI-NON patients compared to controls. There were no significant differences in [11C]PHNO BPND between TBI-MDD and TBI-NON patients. Furthermore, DTI provided evidence of axonal injury following TBI. The uncinate fasciculus and cingulum had abnormally low FA, with the uncinate particularly affected in TBI-MDD patients. Caudate [11C]PHNO BPND correlated with FA within the nigro-caudate tract.Conclusions[11C]PHNO BPND is abnormal following TBI, which indicates post-traumatic changes in D2/D3 receptors. Patterns of [11C]PHNO BPND seen in patients with and without MDD suggest that further research would be beneficial to determine whether the use of dopaminergic treatment might be effective in the treatment of post-traumatic depression.

Journal article

Jenkins PO, De Simoni S, Bourke NJ, Fleminger J, Scott G, Towey DJ, Svensson W, Khan S, Patel MC, Greenwood R, Friedland D, Hampshire A, Cole JH, Sharp DJet al., 2019, Stratifying drug treatment of cognitive impairments after traumatic brain injury using neuroimaging, Brain, Vol: 142, Pages: 2367-2379, ISSN: 1460-2156

Cognitive impairment is common following traumatic brain injury. Dopaminergic drugs can enhance cognition after traumatic brain injury, but individual responses are highly variable. This may be due to variability in dopaminergic damage between patients. We investigate whether measuring dopamine transporter levels using 123I-ioflupane single-photon emission computed tomography (SPECT) predicts response to methylphenidate, a stimulant with dopaminergic effects. Forty patients with moderate-severe traumatic brain injury and cognitive impairments completed a randomized, double-blind, placebo-controlled, crossover study. 123I-ioflupane SPECT, MRI and neuropsychological testing were performed. Patients received 0.3 mg/kg of methylphenidate or placebo twice a day in 2-week blocks. Subjects received neuropsychological assessment after each block and completed daily home cognitive testing during the trial. The primary outcome measure was change in choice reaction time produced by methylphenidate and its relationship to stratification of patients into groups with normal and low dopamine transporter binding in the caudate. Overall, traumatic brain injury patients showed slow information processing speed. Patients with low caudate dopamine transporter binding showed improvement in response times with methylphenidate compared to placebo [median change = -16 ms; 95% confidence interval (CI): -28 to -3 ms; P = 0.02]. This represents a 27% improvement in the slowing produced by traumatic brain injury. Patients with normal dopamine transporter binding did not improve. Daily home-based choice reaction time results supported this: the low dopamine transporter group improved (median change -19 ms; 95% CI: -23 to -7 ms; P = 0.002) with no change in the normal dopamine transporter group (P = 0.50). The low dopamine transporter group also improved on self-reported and caregiver apathy assessments (P = 0.03 and P = 0.02, respectively). Both groups reported improvements in fatigue (P = 0.03

Journal article

Scott G, Carhart-Harris R, 2019, Psychedelics as a treatment for disorders of consciousness, Neuroscience of Consciousness, Vol: 2019, Pages: 1-8, ISSN: 2057-2107

Based on its ability to increase brain complexity, a seemingly reliable index of conscious level, we proposetesting the capacity ofthe classic psychedelic, psilocybin,to increase conscious awarenessin patients with disorders of consciousness.We alsoconfrontthe considerable ethical and practical challengesthis proposal must address, if this hypothesis is to be directly assessed.

Journal article

Jenkins PO, De Simoni S, Bourke N, Fleminger J, Scott G, Towey D, Svensson W, Khan S, Patel M, Greenwood R, Cole J, Sharp DJet al., 2018, Dopaminergic abnormalities following traumatic brain injury, Brain, Vol: 141, Pages: 797-810, ISSN: 1460-2156

Traumatic brain injury can reduce striatal dopamine levels. The cause of this is uncertain, but is likely to be related to damage to the nigrostriatal system. We investigated the pattern of striatal dopamine abnormalities using 123I-Ioflupane single-photon emission computed tomography (SPECT) scans and their relationship to nigrostriatal damage and clinical features. We studied 42 moderate–severe traumatic brain injury patients with cognitive impairments but no motor parkinsonism signs and 20 healthy controls. 123I-Ioflupane scanning was used to assess dopamine transporter levels. Clinical scan reports were compared to quantitative dopamine transporter results. Advanced MRI methods were used to assess the nigrostriatal system, including the area through which the nigrostriatal projections pass as defined from high-resolution Human Connectome data. Detailed clinical and neuropsychological assessments were performed. Around 20% of our moderate–severe patients had clear evidence of reduced specific binding ratios for the dopamine transporter in the striatum measured using 123I-Ioflupane SPECT. The caudate was affected more consistently than other striatal regions. Dopamine transporter abnormalities were associated with reduced substantia nigra volume. In addition, diffusion MRI provided evidence of damage to the regions through which the nigrostriatal tract passes, particularly the area traversed by dopaminergic projections to the caudate. Only a small percentage of patients had evidence of macroscopic lesions in the striatum and there was no relationship between presence of lesions and dopamine transporter specific binding ratio abnormalities. There was also no relationship between reduced volume in the striatal subregions and reduced dopamine transporter specific binding ratios. Patients with low caudate dopamine transporter specific binding ratios show impaired processing speed and executive dysfunction compared to patients with normal levels. Taken toge

Journal article

Cole JH, Jolly A, De Simoni S, Bourke N, patel M, Scott G, Sharp Det al., 2018, Spatial patterns of progressive brain volume loss after moderate-severe traumatic brain injury, Brain, Vol: 141, Pages: 822-836, ISSN: 1460-2156

Traumatic brain injury leads to significant loss of brain volume, which continues into the chronic stage. This can be sensitively measured using volumetric analysis of magnetic resonance imaging. Here we: (i) investigated longitudinal patterns of brain atrophy; (ii) tested whether atrophy is greatest in sulcal cortical regions, and (iii) showed how atrophy could be used to power intervention trials aimed at slowing neurodegeneration. In 61 moderate/severe traumatic brain injury patients (mean age = 41.55 years ± 12.77) and 32 healthy controls (mean age = 34.22 years ± 10.29), cross-sectional and longitudinal (one-year follow-up) brain structure was assessed using voxel-based morphometry on T1-weighted scans. Longitudinal brain volume changes were characterised using a novel neuroimaging analysis pipeline that generates a Jacobian determinant metric, reflecting spatial warping between baseline and follow-up scans. Jacobian determinant values were summarised regionally and compared with clinical and neuropsychological measures. Traumatic brain injury patients showed lower grey and white matter volume in multiple brain regions compared to controls at baseline. Atrophy over one year was pronounced following traumatic brain injury. Traumatic brain injury patients lost a mean (± standard deviation) of 1.55% ± 2.19 of grey matter volume per year, 1.49% ± 2.20 of white matter volume or 1.51% ± 1.60 of whole brain volume. Healthy controls lost 0.55% ± 1.13 of grey matter volume and gained 0.26% ± 1.11 of white matter volume; equating to a 0.22% ± 0.83 reduction in whole brain volume. Atrophy was greatest in white matter, where the majority (84%) of regions were affected. This effect was independent of and substantially greater than that of ageing. Increased atrophy was also seen in cortical sulci compared to gyri. There was no relationship between atrophy and time since injury or age at baseline. Atrophy rates we

Journal article

Scott GPT, Zetterberg H, Jolly A, Cole JH, De Simoni S, Jenkins PO, Feeney C, Owen DR, Lingford-Hughes A, Howes O, Patel MC, Goldstone AP, Gunn RN, Blennow K, Matthews PM, Sharp DJet al., 2017, Minocycline reduces chronic microglial activation after brain trauma but increases neurodegeneration, Brain, Vol: 141, Pages: 459-471, ISSN: 1460-2156

Survivors of a traumatic brain injury can deteriorate years later, developing brain atrophy and dementia. Traumatic brain injury triggers chronic microglial activation, but it is unclear whether this is harmful or beneficial. A successful chronic-phase treatment for traumatic brain injury might be to target microglia. In experimental models, the antibiotic minocycline inhibits microglial activation. We investigated the effect of minocycline on microglial activation and neurodegeneration using PET, MRI, and measurement of the axonal protein neurofilament light in plasma. Microglial activation was assessed using 11C-PBR28 PET. The relationships of microglial activation to measures of brain injury, and the effects of minocycline on disease progression, were assessed using structural and diffusion MRI, plasma neurofilament light, and cognitive assessment. Fifteen patients at least 6 months after a moderate-to-severe traumatic brain injury received either minocycline 100 mg orally twice daily or no drug, for 12 weeks. At baseline, 11C-PBR28 binding in patients was increased compared to controls in cerebral white matter and thalamus, and plasma neurofilament light levels were elevated. MRI measures of white matter damage were highest in areas of greater 11C-PBR28 binding. Minocycline reduced 11C-PBR28 binding (mean Δwhite matter binding = −23.30%, 95% confidence interval −40.9 to −5.64%, P = 0.018), but increased plasma neurofilament light levels. Faster rates of brain atrophy were found in patients with higher baseline neurofilament light levels. In this experimental medicine study, minocycline after traumatic brain injury reduced chronic microglial activation while increasing a marker of neurodegeneration. These findings suggest that microglial activation has a reparative effect in the chronic phase of traumatic brain injury.

Journal article

Datta G, Colasanti A, Kalk N, Owen DR, Scott G, Rabiner EI, Gunn R, Lingford-Hughes A, Malik O, Ciccarelli O, Nicholas R, Nie L, Battaglini M, De Stefano N, Matthews Pet al., 2017, [(11)C]PBR28 or [(18)F]PBR111 detect white matter inflammatory heterogeneity in multiple sclerosis, Journal of Nuclear Medicine, Vol: 58, Pages: 1477-1482, ISSN: 1535-5667

Objective: To assess microglial activation in lesions and in normal appearing white matter of multiple sclerosis (MS) patients using positron emission tomography (PET). Methods: 34 MS patients (7 with secondary progressive MS (SPMS), 27 with relapsing remitting MS (RRMS)) and 30 healthy volunteers, genetically stratified for translocator protein (TSPO), binding status underwent PET scanning with TSPO radioligands ((11)C-PBR28 or (18)F-PBR111). Regional TSPO availability was measured as a distribution volume ratio (DVR) relative to the caudate (a pseudo-reference region). White matter lesions (WML) were classified as "active" (DVR highest in the lesion), "peripherally active" (peri-lesional DVR highest), "inactive" (DVR highest in surrounding normal appearing white matter, NAWM) or "undifferentiated" (similar DVR across lesion, peri-lesional and NAWM volumes). Results: The mean DVR in NAWM of patients was greater than that of the healthy volunteer white matter for both radioligands. Uptake for individual WML in patients was heterogeneous, but the median WML DVR and NAWM DVR for individual patients were strongly correlated (ρ = 0.94, P = 4x10-11). A higher proportion of lesions were inactive in patients with SPMS (35 %) than RRMS (23 %), but active lesions were found in all patients, including those on highly efficacious treatments. Conclusion: TSPO radioligand uptake was increased in brains of MS patients relative to healthy controls with two TSPO radiotracers. WML showed heterogeneous patterns of uptake. Active lesions were found in patients with both RRMS and SPMS. Their independent prognostic significance needs further investigation.

Journal article

Feeney C, Sharp DJ, Hellyer PJ, Jolly AE, Cole JH, Scott G, Baxter D, Jilka S, Ross E, Ham TE, Jenkins PO, Li LM, Gorgoraptis N, Midwinter M, Goldstone APet al., 2017, Serum IGF-I levels are associated with improved white matter recovery after TBI., Annals of Neurology, Vol: 82, Pages: 30-43, ISSN: 0364-5134

OBJECTIVE: Traumatic brain injury (TBI) is a common disabling condition with limited treatment options. Diffusion tensor imaging (DTI) measures recovery of axonal injury in white matter (WM) tracts after TBI. Growth hormone deficiency (GHD) after TBI may impair axonal and neuropsychological recovery, and serum IGF-I may mediate this effect. We conducted a longitudinal study to determine the effects of baseline serum IGF-I concentrations on WM tract and neuropsychological recovery after TBI. METHODS: Thirty-nine adults after TBI (84.6% male; age median 30.5y; 87.2% moderate-severe; time since TBI median 16.3 months, n=4 with GHD) were scanned twice, 13.3 months (12.1-14.9) apart, and 35 healthy controls scanned once. Symptom and quality of life questionnaires and cognitive assessments were completed at both visits (n=33). Our main outcome measure was fractional anisotropy (FA), a measure of WM tract integrity, in a priori regions of interest: splenium of corpus callosum (SPCC), and posterior limb of internal capsule (PLIC). RESULTS: At baseline, FA was reduced in many WM tracts including SPCC and PLIC following TBI compared to controls, indicating axonal injury, with longitudinal increases indicating axonal recovery. There was a significantly greater increase in SPCC FA over time in patients with serum IGF-I above vs. below the median-for-age. Only the higher IGF-I group had significant improvements in immediate verbal memory recall over time. INTERPRETATION: WM recovery and memory improvements after TBI were greater in patients with higher serum IGF-I at baseline. These findings suggest that GH/IGF-I system may be a potential therapeutic target following TBI. This article is protected by copyright. All rights reserved.

Journal article

Donat CK, Scott G, Gentleman S, Sastre Met al., 2017, Microglial activation in traumatic brain injury, Frontiers in Aging Neuroscience, Vol: 9, ISSN: 1663-4365

Microglia have a variety of functions in the brain, including synaptic pruning, CNS repair and mediating the immune response against peripheral infection. Microglia rapidly become activated in response to CNS damage. Depending on the nature of the stimulus, microglia can take a number of activation states, which correspond to altered microglia morphology, gene expression and function. It has been reported that early microglia activation following traumatic brain injury (TBI) may contribute to the restoration of homeostasis in the brain. On the other hand, if they remain chronically activated, such cells display a classically activated phenotype, releasing pro-inflammatory molecules, resulting in further tissue damage and contributing potentially to neurodegeneration. However, new evidence suggests that this classification is over-simplistic and the balance of activation states can vary at different points. In this article, we review the role of microglia in TBI, analyzing their distribution, morphology and functional phenotype over time in animal models and in humans. Animal studies have allowed genetic and pharmacological manipulations of microglia activation, in order to define their role. In addition, we describe investigations on the in vivo imaging of microglia using translocator protein (TSPO) PET and autoradiography, showing that microglial activation can occur in regions far remote from sites of focal injuries, in humans and animal models of TBI. Finally, we outline some novel potential therapeutic approaches that prime microglia/macrophages toward the beneficial restorative microglial phenotype after TBI.

Journal article

Datta G, Violante IR, Scott G, Zimmerman K, Santos-Ribeiro A, Rabiner EA, Gunn RN, Malik O, Ciccarelli O, Nicholas R, Matthews PMet al., 2016, Translocator positron-emission tomography and magnetic resonance spectroscopic imaging of brain glial cell activation in multiple sclerosis., Multiple Sclerosis, Vol: 23, Pages: 1469-1478, ISSN: 1352-4585

BACKGROUND: Multiple sclerosis (MS) is characterised by a diffuse inflammatory response mediated by microglia and astrocytes. Brain translocator protein (TSPO) positron-emission tomography (PET) and [myo-inositol] magnetic resonance spectroscopy (MRS) were used together to assess this. OBJECTIVE: To explore the in vivo relationships between MRS and PET [(11)C]PBR28 in MS over a range of brain inflammatory burden. METHODS: A total of 23 patients were studied. TSPO PET imaging with [(11)C]PBR28, single voxel MRS and conventional magnetic resonance imaging (MRI) sequences were undertaken. Disability was assessed by Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite (MSFC). RESULTS: [(11)C]PBR28 uptake and [ myo-inositol] were not associated. When the whole cohort was stratified by higher [(11)C]PBR28 inflammatory burden, [ myo-inositol] was positively correlated to [(11)C]PBR28 uptake (Spearman's ρ = 0.685, p = 0.014). Moderate correlations were found between [(11)C]PBR28 uptake and both MRS creatine normalised N-acetyl aspartate (NAA) concentration and grey matter volume. MSFC was correlated with grey matter volume (ρ = 0.535, p = 0.009). There were no associations between other imaging or clinical measures. CONCLUSION: MRS [ myo-inositol] and PET [(11)C]PBR28 measure independent inflammatory processes which may be more commonly found together with more severe inflammatory disease. Microglial activation measured by [(11)C]PBR28 uptake was associated with loss of neuronal integrity and grey matter atrophy.

Journal article

Scott G, Mahmud M, Owen DR, Johnson MRet al., 2016, Microglial positron emission tomography (PET) imaging in epilepsy: applications, opportunities and pitfalls, Seizure-European Journal of Epilepsy, Vol: 44, Pages: 42-47, ISSN: 1059-1311

Neuroinflammation is increasingly implicated in epileptogenesis and epilepsy. Microglia are an important mediator of central nervous system inflammation, and the development of positron emission tomography (PET) radioligands which bind the Translocator Protein (TSPO), an outer mitochondrial membrane protein expressed by microglia, has enabled in vivo measurement of neuroinflammation. Here, we outline the principles and potential pitfalls of TSPO PET imaging in relation to epilepsy, and opportunities for using TSPO imaging as a biomarker for future anti-inflammatory based therapeutics in epilepsy.

Journal article

De Simoni S, Grover PJ, Jenkins PO, Honeyfield L, Quest R, Scott G, Wilson WH, Majewska P, Waldman AD, Patel MC, Sharp DJet al., 2016, Disconnection between the default mode network and medial temporal lobes in post-traumatic amnesia, Brain, Vol: 139, Pages: 3137-3150, ISSN: 0006-8950

Post-traumatic amnesia is very common immediately after traumatic brain injury. It is characterised by a confused, agitated state and a pronounced inability to encode new memories and sustain attention. Clinically, post-traumatic amnesia is an important predictor of functional outcome. However, despite its prevalence and functional importance, the pathophysiology of post-traumatic amnesia is not understood. Memory processing relies on limbic structures such as the hippocampus, parahippocampus and parts of the cingulate cortex. These structures are connected within an intrinsic connectivity network, the Default Mode Network. Interactions within the Default Mode Network can be assessed using resting state functional magnetic resonance imaging, which can be acquired in confused patients unable to perform tasks in the scanner. Here we used this approach to test the hypothesis that the mnemonic symptoms of post-traumatic amnesia are caused by functional disconnection within the Default Mode Network. We assessed whether the hippocampus and parahippocampus showed evidence of transient disconnection from cortical brain regions involved in memory processing. 19 traumatic brain injury patients were classified into post-traumatic amnesia and traumatic brain injury control groups, based on their performance on a paired associates learning task. Cognitive function was also assessed with a detailed neuropsychological test battery. Functional interactions between brain regions were investigated using resting-state functional magnetic resonance imaging. Together with impairments in associative memory patients in post-traumatic amnesia demonstrated impairments in information processing speed and spatial working memory. Patients in post-traumatic amnesia showed abnormal functional connectivity between the parahippocampal gyrus and posterior cingulate cortex. The strength of this functional connection correlated with both associative memory and information processing speed and normal

Journal article

Peress L, Violante IR, Scott G, Zimmerman K, Sharp D, Nicholas R, Raffel Jet al., 2016, Thalamic magnetic resonance spectroscopy in highly active multiple sclerosis, 32nd Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS), Publisher: SAGE PUBLICATIONS LTD, Pages: 210-211, ISSN: 1352-4585

Conference paper

Feeney C, Scott GP, Cole JH, Sastre M, Goldstone AP, Leech Ret al., 2016, Seeds of neuroendocrine doubt, Nature, Vol: 535, Pages: E1-E2, ISSN: 0028-0836

Journal article

Fagerholm ED, Scott G, Shew WL, Song C, Leech R, Knöpfel T, Sharp DJet al., 2016, Cortical Entropy, Mutual Information and Scale-Free Dynamics in Waking Mice, Cerebral Cortex, Vol: 26, Pages: 3945-3952, ISSN: 1460-2199

Some neural circuits operate with simple dynamics characterized by one or a few well-defined spatiotemporal scales (e.g. central pattern generators). In contrast, cortical neuronal networks often exhibit richer activity patterns in which all spatiotemporal scales are represented. Such "scale-free" cortical dynamics manifest as cascades of activity with cascade sizes that are distributed according to a power-law. Theory and in vitro experiments suggest that information transmission among cortical circuits is optimized by scale-free dynamics. In vivo tests of this hypothesis have been limited by experimental techniques with insufficient spatial coverage and resolution, i.e., restricted access to a wide range of scales. We overcame these limitations by using genetically encoded voltage imaging to track neural activity in layer 2/3 pyramidal cells across the cortex in mice. As mice recovered from anesthesia, we observed three changes: (a) cortical information capacity increased, (b) information transmission among cortical regions increased and (c) neural activity became scale-free. Our results demonstrate that both information capacity and information transmission are maximized in the awake state in cortical regions with scale-free network dynamics.

Journal article

Feeney C, Scott G, Raffel J, Roberts S, Coello C, Jolly A, Searle G, Goldstone AP, Brooks DJ, Nicholas RS, Trigg W, Gunn RN, Sharp DJet al., 2016, Kinetic analysis of the translocator protein positron emission tomography ligand [18F]GE-180 in the human brain, European Journal of Nuclear Medicine and Molecular Imaging, Vol: 43, Pages: 2201-2210, ISSN: 1619-7089

PURPOSE: PET can image neuroinflammation by targeting the translocator protein (TSPO), which is upregulated in activated microglia. The high nonspecific binding of the first-generation TSPO radioligand [(11)C]PK-11195 limits accurate quantification. [(18)F]GE-180, a novel TSPO ligand, displays superior binding to [(11)C]PK-11195 in vitro. Our objectives were to: (1) evaluate tracer characteristics of [(18)F]GE-180 in the brains of healthy human subjects; and (2) investigate whether the TSPO Ala147Thr polymorphism influences outcome measures. METHODS: Ten volunteers (five high-affinity binders, HABs, and five mixed-affinity binders, MABs) underwent a dynamic PET scan with arterial sampling after injection of [(18)F]GE-180. Kinetic modelling of time-activity curves with one-tissue and two-tissue compartment models and Logan graphical analysis was applied to the data. The primary outcome measure was the total volume of distribution (V T) across various regions of interest (ROIs). Secondary outcome measures were the standardized uptake values (SUV), the distribution volume and SUV ratios estimated using a pseudoreference region. RESULTS: The two-tissue compartment model was the best model. The average regional delivery rate constant (K 1) was 0.01 mL cm(-3) min(-1) indicating low extraction across the blood-brain barrier (1 %). The estimated median V T across all ROIs was also low, ranging from 0.16 mL cm(-3) in the striatum to 0.38 mL cm(-3) in the thalamus. There were no significant differences in V T between HABs and MABs across all ROIs. CONCLUSION: A reversible two-tissue compartment model fitted the data well and determined that the tracer has a low first-pass extraction (approximately 1 %) and low V T estimates in healthy individuals. There was no observable dependency on the rs6971 polymorphism as compared to other second-generation TSPO PET tracers. Investigation of [(18)F]GE-180 in populations with neuroinflammatory disease is nee

Journal article

Campos-Pires R, Armstrong S, Sebastiani A, Luh C, Gruss M, Radyushkin K, Hirnet T, Engelhard K, Franks NP, Thal SC, Dickinson Ret al., 2016, Xenon provides short-term and long-term neuroprotection in a rodent model of traumatic brain injury, International Brain Injury Association’s Eleventh World Congress on Brain Injury, Publisher: Taylor & Francis, Pages: 653-653, ISSN: 1362-301X

Conference paper

Zimmerman K, Scott G, Violante I, Feeney C, Sharp Det al., 2016, Magnetic resonance spectroscopy of the thalamus in chronic traumatic brain injury, International Brain Injury Association’s Eleventh World Congress on Brain Injury, Publisher: Taylor &; Francis, Pages: 660-661, ISSN: 1362-301X

Conference paper

Scott G, Gunn RN, Matthews PM, Sharp DJet al., 2016, Minocycline reduces microglial activation after traumatic brain injury measured using [11C]-PBR28 positron emission tomography, International Brain Injury Association’s Eleventh World Congress on Brain Injury, Publisher: Taylor & Francis, Pages: 686-687, ISSN: 1362-301X

Conference paper

Dinov M, Lorenz R, Scott G, Fagerholm E, Sharp D, Leech Ret al., 2016, Novel modeling of task versus rest brain state predictability using a dynamic time warping spectrum: comparisons and contrasts with other standard measures of brain dynamics, Frontiers in Computational Neuroscience, Vol: 10, ISSN: 1662-5188

Dynamic time warping, or DTW, is a powerful and domain-general sequence alignment method for computing a similarity measure. Such dynamic programming-based techniques like DTW are now the backbone and driver of most bioinformatics methods and discoveries. In neuroscience it has had far less use, though this has begun to change. We wanted to explore new ways of applying DTW, not simply as a measure with which to cluster or compare similarity between features but in a conceptually different way. We have used DTW to provide a more interpretable spectral description of the data, compared to standard approaches such as the Fourier and related transforms. The DTW approach and standard discrete Fourier transform (DFT) are assessed against benchmark measures of neural dynamics. These include EEG microstates, EEG avalanches and the sum squared error (SSE) from a multilayer perceptron (MLP) prediction of the EEG timeseries, and simultaneously acquired FMRI BOLD signal. We explored the relationships between these variables of interest in an EEG-FMRI dataset acquired during a standard cognitive task, which allowed us to explore how DTW differentially performs in different task settings. We found that despite strong correlations between DTW and DFT-spectra, DTW was a better predictor for almost every measure of brain dynamics. Using these DTW measures, we show that predictability is almost always higher in task than in rest states, which is consistent to other theoretical and empirical findings, providing additional evidence for the utility of the DTW approach.

Journal article

Jamall O, Feeney C, Zaw-Linn J, Malik A, Niemi M, Tenorio-Jimenez C, Ham TE, Jilka SR, Jenkins PO, Scott G, Li LM, Gorgoraptis N, Baxter D, Sharp DJ, Goldstone APet al., 2016, Prevalence and correlates of vitamin D deficiency in adults after traumatic brain injury, Clinical Endocrinology, Vol: 85, Pages: 636-644, ISSN: 1365-2265

Objectives: Traumatic brain injury (TBI) is a major cause of long-term disability with variable recovery. Preclinicalstudies suggest that vitamin D status influences recovery after TBI. However, there is no publishedclinical data on links between vitamin D status and TBI outcomes. To determine the: (i) prevalence ofvitamin D deficiency/insufficiency, and associations of vitamin D status with (ii) demographic factors andTBI severity, and with (iii) cognitive function, symptoms and quality of life, in adults after TBI.Design: Retrospective audit of patients seen between July 2009 and March 2015. Serum vitamin D (25-hydroxy-cholecalciferol) was categorised as deficient (<40nmol/L), insufficient (40-70nmol/L) or replete(>70nmol/L).Patients: 353 adults seen in tertiary hospital clinic (75.4% lighter-skinned, 74.8% male, age median 35.1y,range 26.6-48.3y), 0.3-56.5 months after TBI (74.5% moderate-severe).Measurements: Serum vitamin D concentrations; Addenbrooke’s Cognitive Examination (ACE-R), BeckDepression Inventory II (BDI-II), SF-36 Quality of Life, Pittsburgh Sleep Quality Index.Results: 46.5% of patients after TBI had vitamin D deficiency and 80.2% insufficiency/deficiency. Patientswith vitamin D deficiency had lower ACE-R scores than those vitamin D replete (mean effect size ± SEM 4.5± 2.1, P=0.034), and higher BDI-II scores than those vitamin D insufficient (4.5 ± 1.6, P=0.003), correcting forage, gender, time since TBI, TBI severity. There was no association between vitamin D status and markers ofTBI severity, sleep or quality of life.Conclusion: Vitamin D deficiency is common in patients after TBI and associated with impaired cognitivefunction and more severe depressive symptoms.

Journal article

Scott GPT, Ramlackhansingh A, Edison P, Hellyer PJ, Cole J, Veronese M, Leech R, Greenwood RJ, Turkheimer F, Gentleman S, Heckemann RA, Matthews PM, Brooks D, Sharp DJet al., 2016, Amyloid pathology and axonal injury after brain trauma, Neurology, Vol: 86, Pages: 821-828, ISSN: 0028-3878

Objective: To image amyloid-β (Aβ) plaque burden in long-term survivors of traumatic brain injury (TBI), test whether traumatic axonal injury and Aβ are correlated, and compare the spatial distribution of Aβ to Alzheimer’s disease.Methods: Patients 11 months to 17 years after moderate-severe TBI had 11C-Pittsburgh compound-B (PIB) PET, structural and diffusion MRI and neuropsychological examination. Healthy aged controls and AD patients had PET and structural MRI. Binding potential (BPND) images of 11C-PIB, which index Aβ plaque density, were computed using an automatic reference region extraction procedure. Voxelwise and regional differences in BPND were assessed. In TBI, a measure of white matter integrity, fractional anisotropy (FA), was estimated and correlated with 11C-PIB BPND.Results: 28 participants (9 TBI, 9 controls, 10 AD) were assessed. Increased 11C-PIB BPND was found in TBI versus controls in the posterior cingulate cortex (PCC) and cerebellum. Binding in the PCC increased with decreasing FA of associated white matter tracts, and increased with time since injury. Compared to AD, binding after TBI was lower in neocortical regions, but increased in the cerebellum. Conclusions: Increased Aβ burden was observed in TBI. The distribution overlaps with, but is distinct from, that of AD. This suggests a mechanistic link between TBI and the development of neuropathological features of dementia, which may relate to axonal damage produced by the injury.

Journal article

Scott G, Hellyer PJ, Ramlackhansingh AF, Brooks DJ, Matthews PM, Sharp DJet al., 2015, Thalamic inflammation after brain trauma is associated with thalamo-cortical white matter damage, Journal of Neuroinflammation, Vol: 12, ISSN: 1742-2094

BackgroundTraumatic brain injury can trigger chronic neuroinflammation, which may predispose to neurodegeneration. Animal models and human pathological studies demonstrate persistent inflammation in the thalamus associated with axonal injury, but this relationship has never been shown in vivo.FindingsUsing [11C]-PK11195 positron emission tomography, a marker of microglial activation, we previously demonstrated thalamic inflammation up to 17 years after traumatic brain injury. Here, we use diffusion MRI to estimate axonal injury and show that thalamic inflammation is correlated with thalamo-cortical tract damage.ConclusionsThese findings support a link between axonal damage and persistent inflammation after brain injury.

Journal article

Li LM, Leech R, Scott GT, Malhotra P, Seemungal B, Sharp DJet al., 2015, The effect of oppositional parietal transcranial direct current stimulation on lateralized brain functions, European Journal of Neuroscience, Vol: 42, Pages: 2904-2914, ISSN: 1460-9568

Cognitive functions such as numerical processing and spatial attention show varying degrees of lateralization. Transcranial direct current stimulation (tDCS) can be used to investigate how modulating cortical excitability affects performance of these tasks. This study investigated the effect of bi-parietal tDCS on numerical processing, spatial and sustained attention. It was hypothesized that tDCS would have distinct effects on these tasks because of varying lateralization (numerical processing left, spatial attention right) and that these effects are partly mediated by modulation of sustained attention. A single-blinded, crossover, sham-controlled study was performed. Eighteen healthy right-handed participants performed cognitive tasks during three sessions of oppositional parietal tDCS stimulation: sham; right anodal with left cathodal (RA/LC); and right cathodal with left anodal (RC/LA). Participants performed a number comparison task, a modified Posner task, a choice reaction task (CRT) and the rapid visual processing task (RVP). RA/LC tDCS impaired number comparison performance compared with sham, with slower responses to numerically close numbers pairs. RA/LC and RC/LA tDCS had distinct effects on CRT performance, specifically affecting vigilance level during the final block of the task. No effect of stimulation on the Posner task or RVP was found. It was demonstrated that oppositional parietal tDCS affected both numerical performance and vigilance level in a polarity-dependent manner. The effect of tDCS on numerical processing may partly be due to attentional effects. The behavioural effects of tDCS were specifically observed under high task demands, demonstrating the consequences of an interaction between stimulation type and cognitive load.

Journal article

Shanahan MP, Hellyer P, Sharp DJ, Scott G, Leech Ret al., 2015, Cognitive flexibility through metastable neural dynamics is disrupted by damage to the structural connectome, Journal of Neuroscience, Vol: 35, Pages: 9050-9063, ISSN: 0270-6474

Current theory proposes that healthy neural dynamics operate in a metastable regime, where brain regions interact to simultaneously maximize integration and segregation. Metastability may confer important behavioral properties, such as cognitive flexibility. It is increasingly recognized that neural dynamics are constrained by the underlying structural connections between brain regions. An important challenge is, therefore, to relate structural connectivity, neural dynamics, and behavior. Traumatic brain injury (TBI) is a pre-eminent structural disconnection disorder whereby traumatic axonal injury damages large-scale connectivity, producing characteristic cognitive impairments, including slowed information processing speed and reduced cognitive flexibility, that may be a result of disrupted metastable dynamics. Therefore, TBI provides an experimental and theoretical model to examine how metastable dynamics relate to structural connectivity and cognition. Here, we use complementary empirical and computational approaches to investigate how metastability arises from the healthy structural connectome and relates to cognitive performance. We found reduced metastability in large-scale neural dynamics after TBI, measured with resting-state functional MRI. This reduction in metastability was associated with damage to the connectome, measured using diffusion MRI. Furthermore, decreased metastability was associated with reduced cognitive flexibility and information processing. A computational model, defined by empirically derived connectivity data, demonstrates how behaviorally relevant changes in neural dynamics result from structural disconnection. Our findings suggest how metastable dynamics are important for normal brain function and contingent on the structure of the human connectome.

Journal article

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