Publications by authors named "Charlotte J Stagg"

72 Publications

Recent advances in the role of excitation-inhibition balance in motor recovery post-stroke.

Fac Rev 2021 23;10:58. Epub 2021 Jun 23.

Wellcome Centre for Integrative Neuroimaging, FMRIB, Nuffield Department of Clinical Neurosciences, University of Oxford; Medical Research Council Brain Network Dynamics Unit, University of Oxford, Oxford, UK.

Stroke affects millions of people worldwide each year, and stroke survivors are often left with motor deficits. Current therapies to improve these functional deficits are limited, making it a priority to better understand the pathophysiology of stroke recovery and find novel adjuvant options. The excitation-inhibition balance undergoes significant changes post-stroke, and the inhibitory neurotransmitter γ-aminobutyric acid (GABA) appears to play an important role in stroke recovery. In this review, we summarise the most recent studies investigating GABAergic inhibition at different stages of stroke. We discuss the proposed role of GABA in counteracting glutamate-mediated excitotoxicity in hyperacute stroke as well as the evidence linking decreased GABAergic inhibition to increased neuronal plasticity in early stroke. Then, we discuss two types of interventions that aim to modulate the excitation-inhibition balance to improve functional outcomes in stroke survivors: non-invasive brain stimulation (NIBS) and pharmacological interventions. Finding the optimal NIBS administration or adjuvant pharmacological therapies would represent an important contribution to the currently scarce therapy options.
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http://dx.doi.org/10.12703/r/10-58DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8265564PMC
June 2021

An In-vivo 1H-MRS short-echo time technique at 7T: Quantification of metabolites in chronic multiple sclerosis and neuromyelitis optica brain lesions and normal appearing brain tissue.

Neuroimage 2021 Sep 30;238:118225. Epub 2021 May 30.

Wellcome Centre for Integrative Neuroimaging, FMRIB, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, OX3 9DU, United Kingdom; School of Health Sciences, Purdue University, 550 Stadium Mall Drive, West Lafayette, IN 47907, (765) 494-1419, United States; Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, United States.

Magnetic Resonance Spectroscopy (MRS) allows for the non-invasive quantification of neurochemicals and has the potential to differentiate between the pathologically distinct diseases, multiple sclerosis (MS) and AQP4Ab-positive neuromyelitis optica spectrum disorder (AQP4Ab-NMOSD). In this study we characterised the metabolite profiles of brain lesions in 11 MS and 4 AQP4Ab-NMOSD patients using an optimised MRS methodology at ultra-high field strength (7T) incorporating correction for T2 water relaxation differences between lesioned and normal tissue. MS metabolite results were in keeping with the existing literature: total N-acetylaspartate (NAA) was lower in lesions compared to normal appearing brain white matter (NAWM) with reciprocal findings for myo-Inositol. An unexpected subtlety revealed by our technique was that total NAA differences were likely driven by NAA-glutamate (NAAG), a ubiquitous CNS molecule with functions quite distinct from NAA though commonly quantified together with NAA in MRS studies as total NAA. Surprisingly, AQP4Ab-NMOSD showed no significant differences for total NAA, NAA, NAAG or myo-Inositol between lesion and NAWM sites, nor were there any differences between MS and AQP4Ab-NMOSD for a priori hypotheses. Post-hoc testing revealed a significant correlation between NAWM Ins:NAA and disability (as measured by EDSS) for disease groups combined, driven by the AP4Ab-NMOSD group. Utilising an optimised MRS methodology, our study highlights some under-explored subtleties in MRS profiles, such as the absence of myo-Inositol concentration differences in AQP4Ab-NMOSD brain lesions versus NAWM and the potential influence of NAAG differences between lesions and normal appearing white matter in MS.
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http://dx.doi.org/10.1016/j.neuroimage.2021.118225DOI Listing
September 2021

New Mechanistic Insights, Novel Treatment Paradigms, and Clinical Progress in Cerebrovascular Diseases.

Front Aging Neurosci 2021 28;13:623751. Epub 2021 Jan 28.

Unidad de Investigación Neurovascular, Departamento Farmacología y Toxicología, Facultad de Medicina, Instituto Universitario de Investigación en Neuroquímica, Universidad Complutense de Madrid, Madrid, Spain.

The past decade has brought tremendous progress in diagnostic and therapeutic options for cerebrovascular diseases as exemplified by the advent of thrombectomy in ischemic stroke, benefitting a steeply increasing number of stroke patients and potentially paving the way for a renaissance of neuroprotectants. Progress in basic science has been equally impressive. Based on a deeper understanding of pathomechanisms underlying cerebrovascular diseases, new therapeutic targets have been identified and novel treatment strategies such as pre- and post-conditioning methods were developed. Moreover, translationally relevant aspects are increasingly recognized in basic science studies, which is believed to increase their predictive value and the relevance of obtained findings for clinical application.This review reports key results from some of the most remarkable and encouraging achievements in neurovascular research that have been reported at the 10th International Symposium on Neuroprotection and Neurorepair. Basic science topics discussed herein focus on aspects such as neuroinflammation, extracellular vesicles, and the role of sex and age on stroke recovery. Translational reports highlighted endovascular techniques and targeted delivery methods, neurorehabilitation, advanced functional testing approaches for experimental studies, pre-and post-conditioning approaches as well as novel imaging and treatment strategies. Beyond ischemic stroke, particular emphasis was given on activities in the fields of traumatic brain injury and cerebral hemorrhage in which promising preclinical and clinical results have been reported. Although the number of neutral outcomes in clinical trials is still remarkably high when targeting cerebrovascular diseases, we begin to evidence stepwise but continuous progress towards novel treatment options. Advances in preclinical and translational research as reported herein are believed to have formed a solid foundation for this progress.
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http://dx.doi.org/10.3389/fnagi.2021.623751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876251PMC
January 2021

FSL-MRS: An end-to-end spectroscopy analysis package.

Magn Reson Med 2021 06 6;85(6):2950-2964. Epub 2020 Dec 6.

Wellcome Centre for Integrative Neuroimaging, FMRIB, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom.

Purpose: We introduce FSL-MRS, an end-to-end, modular, open-source MRS analysis toolbox. It provides spectroscopic data conversion, preprocessing, spectral simulation, fitting, quantitation, and visualization.

Methods: The FSL-MRS package is modular. Its programs operate on data in a standard format (Neuroimaging Informatics Technology Initiative [NIfTI]) capable of storing single-voxel and multivoxel spectroscopy, including spatial orientation information. The FSL-MRS toolbox includes tools for preprocessing of raw spectroscopy data, including coil combination, frequency and phase alignment, and filtering. A density matrix simulation program is supplied for generation of basis spectra from simple text-based descriptions of pulse sequences. Fitting is based on linear combination of basis spectra and implements Markov chain Monte Carlo optimization for the estimation of the full posterior distribution of metabolite concentrations. Validation of the fitting is carried out on independently created simulated data, phantom data, and three in vivo human data sets (257 single-voxel spectroscopy and 8 MRSI data sets) at 3 T and 7 T. Interactive HTML reports are automatically generated by processing and fitting stages of the toolbox. The FSL-MRS package can be used on the command line or interactively in the Python language.

Results: Validation of the fitting shows low error in simulation (median error of 11.9%) and in phantom (3.4%). Average correlation between a third-party toolbox (LCModel) and FSL-MRS was high (0.53-0.81) in all three in vivo data sets.

Conclusion: The FSL-MRS toolbox is designed to be flexible and extensible to new forms of spectroscopic acquisitions. Custom fitting models can be specified within the framework for dynamic or multivoxel spectroscopy. It is available as part of the FMRIB Software Library.
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http://dx.doi.org/10.1002/mrm.28630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116822PMC
June 2021

A single, clinically relevant dose of the GABA agonist baclofen impairs visuomotor learning.

J Physiol 2021 01 4;599(1):307-322. Epub 2020 Nov 4.

Wellcome Centre for Integrative Neuroimaging, FMRIB, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.

Key Points: Baclofen is a GABA agonist prescribed as a treatment for spasticity in stroke, brain injury and multiple sclerosis patients, who are often undergoing concurrent motor rehabilitation. Decreasing GABAergic inhibition is a key feature of motor learning and so there is a possibility that GABA agonist drugs, such as baclofen, could impair these processes, potentially impacting rehabilitation. Here, we examined the effect of 10 mg of baclofen, in 20 young healthy individuals, and found that the drug impaired retention of visuomotor learning with no significant effect on motor sequence learning. Overall baclofen did not alter transcranial magnetic stimulation-measured GABA inhibition, although the change in GABA inhibition correlated with aspects of visuomotor learning retention. Further work is needed to investigate whether taking baclofen impacts motor rehabilitation in patients.

Abstract: The GABA agonist baclofen is taken daily as a treatment for spasticity by millions of stroke, brain injury and multiple sclerosis patients, many of whom are also undergoing motor rehabilitation. However, decreases in GABA are suggested to be a key feature of human motor learning, which raises questions about whether drugs increasing GABAergic activity may impair motor learning and rehabilitation. In this double-blind, placebo-controlled study, we investigated whether a single 10 mg dose of the GABA agonist baclofen impaired motor sequence learning and visuomotor learning in 20 young healthy participants of both sexes. Participants trained on visuomotor and sequence learning tasks using their right hand. Transcranial magnetic stimulation (TMS) measures of corticospinal excitability, GABA (short-interval intracortical inhibition 2.5 ms) and GABA (long-interval intracortical inhibition 150 ms) receptor activation were recorded from left M1. Behaviourally, baclofen caused a significant reduction of visuomotor aftereffect (F  = 6.133, P = 0.014) and retention (F  = 4.138, P = 0.044), with no significant changes to sequence learning. There were no overall changes to TMS measured GABAergic inhibition with this low dose of baclofen. This result confirms the causal importance of GABA inhibition in mediating visuomotor learning and suggests that chronic baclofen use could negatively impact aspects of motor rehabilitation.
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http://dx.doi.org/10.1113/JP280378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611062PMC
January 2021

Neurophysiological signatures of hand motor response to dual-transcranial direct current stimulation in subacute stroke: a TMS and MEG study.

J Neuroeng Rehabil 2020 06 11;17(1):72. Epub 2020 Jun 11.

Institute of Brain Science, Brain Research Center, National Yang-Ming University, No.155, Sec. 2, Linong St., Beitou Dist, Taipei City, 112, Taiwan.

Background: Dual transcranial direct current stimulation (tDCS) to the bilateral primary motor cortices (M1s) has potential benefits in chronic stroke, but its effects in subacute stroke, when behavioural effects might be expected to be greater, have been relatively unexplored. Here, we examined the neurophysiological effects and the factors influencing responsiveness of dual-tDCS in subacute stroke survivors.

Methods: We conducted a randomized sham-controlled crossover study in 18 survivors with first-ever, unilateral subcortical ischaemic stroke 2-4 weeks after stroke onset and 14 matched healthy controls. Participants had real dual-tDCS (with an ipsilesional [right for controls] M1 anode and a contralesional M1 [left for controls] cathode; 2 mA for 20mins) and sham dual-tDCS on separate days, with concurrent paretic [left for controls] hand exercise. Using transcranial magnetic stimulation (TMS) and magnetoencephalography (MEG), we recorded motor evoked potentials (MEPs), the ipsilateral silent period (iSP), short-interval intracortical inhibition, and finger movement-related cortical oscillations before and immediately after tDCS.

Results: Stroke survivors had decreased excitability in ipsilesional M1 with a relatively excessive transcallosal inhibition from the contralesional to ipsilesional hemisphere at baseline compared with controls, as quantified by decreased MEPs and increased iSP duration. Dual-tDCS led to increased MEPs and decreased iSP duration in ipsilesional M1. The magnitude of the tDCS-induced MEP increase in stroke survivors was predicted by baseline contralesional-to-ipsilesional transcallosal inhibition (iSP) ratio. Baseline post-movement synchronization in α-band activity in ipsilesional M1 was decreased after stroke compared with controls, and its tDCS-induced increase correlated with upper limb score in stroke survivors. No significant adverse effects were observed during or after dual-tDCS.

Conclusions: Task-concurrent dual-tDCS in subacute stroke can safely and effectively modulate bilateral M1 excitability and inter-hemispheric imbalance and also movement-related α-activity.
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http://dx.doi.org/10.1186/s12984-020-00706-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291576PMC
June 2020

Intention to learn modulates the impact of reward and punishment on sequence learning.

Sci Rep 2020 06 1;10(1):8906. Epub 2020 Jun 1.

Wellcome Trust Centre for Integrative Neuroimaging, FMRIB, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.

In real-world settings, learning is often characterised as intentional: learners are aware of the goal during the learning process, and the goal of learning is readily dissociable from the awareness of what is learned. Recent evidence has shown that reward and punishment (collectively referred to as valenced feedback) are important factors that influence performance during learning. Presently, however, studies investigating the impact of valenced feedback on skill learning have only considered unintentional learning, and therefore the interaction between intentionality and valenced feedback has not been systematically examined. The present study investigated how reward and punishment impact behavioural performance when participants are instructed to learn in a goal-directed fashion (i.e. intentionally) rather than unintentionally. In Experiment 1, participants performed the serial response time task with reward, punishment, or control feedback and were instructed to ignore the presence of the sequence, i.e., learn unintentionally. Experiment 2 followed the same design, but participants were instructed to intentionally learn the sequence. We found that punishment significantly benefitted performance during learning only when participants learned unintentionally, and we observed no effect of punishment when participants learned intentionally. Thus, the impact of feedback on performance may be influenced by goal of the learner.
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http://dx.doi.org/10.1038/s41598-020-65853-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264311PMC
June 2020

Guidelines for TMS/tES clinical services and research through the COVID-19 pandemic.

Brain Stimul 2020 Jul - Aug;13(4):1124-1149. Epub 2020 May 12.

Department of Physiological Sciences, Federal University of Espírito Santo, Vitória, ES, Brazil.

Background: The COVID-19 pandemic has broadly disrupted biomedical treatment and research including non-invasive brain stimulation (NIBS). Moreover, the rapid onset of societal disruption and evolving regulatory restrictions may not have allowed for systematic planning of how clinical and research work may continue throughout the pandemic or be restarted as restrictions are abated. The urgency to provide and develop NIBS as an intervention for diverse neurological and mental health indications, and as a catalyst of fundamental brain research, is not dampened by the parallel efforts to address the most life-threatening aspects of COVID-19; rather in many cases the need for NIBS is heightened including the potential to mitigate mental health consequences related to COVID-19.

Objective: To facilitate the re-establishment of access to NIBS clinical services and research operations during the current COVID-19 pandemic and possible future outbreaks, we develop and discuss a framework for balancing the importance of NIBS operations with safety considerations, while addressing the needs of all stakeholders. We focus on Transcranial Magnetic Stimulation (TMS) and low intensity transcranial Electrical Stimulation (tES) - including transcranial Direct Current Stimulation (tDCS) and transcranial Alternating Current Stimulation (tACS).

Methods: The present consensus paper provides guidelines and good practices for managing and reopening NIBS clinics and laboratories through the immediate and ongoing stages of COVID-19. The document reflects the analysis of experts with domain-relevant expertise spanning NIBS technology, clinical services, and basic and clinical research - with an international perspective. We outline regulatory aspects, human resources, NIBS optimization, as well as accommodations for specific demographics.

Results: A model based on three phases (early COVID-19 impact, current practices, and future preparation) with an 11-step checklist (spanning removing or streamlining in-person protocols, incorporating telemedicine, and addressing COVID-19-associated adverse events) is proposed. Recommendations on implementing social distancing and sterilization of NIBS related equipment, specific considerations of COVID-19 positive populations including mental health comorbidities, as well as considerations regarding regulatory and human resource in the era of COVID-19 are outlined. We discuss COVID-19 considerations specifically for clinical (sub-)populations including pediatric, stroke, addiction, and the elderly. Numerous case-examples across the world are described.

Conclusion: There is an evident, and in cases urgent, need to maintain NIBS operations through the COVID-19 pandemic, including anticipating future pandemic waves and addressing effects of COVID-19 on brain and mind. The proposed robust and structured strategy aims to address the current and anticipated future challenges while maintaining scientific rigor and managing risk.
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http://dx.doi.org/10.1016/j.brs.2020.05.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217075PMC
July 2020

β-Oscillations Reflect Recovery of the Paretic Upper Limb in Subacute Stroke.

Neurorehabil Neural Repair 2020 05 23;34(5):450-462. Epub 2020 Apr 23.

Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan.

. Recovery of upper limb function post-stroke can be partly predicted by initial motor function, but the mechanisms underpinning these improvements have yet to be determined. Here, we sought to identify neural correlates of post-stroke recovery using longitudinal magnetoencephalography (MEG) assessments in subacute stroke survivors. . First-ever, subcortical ischemic stroke survivors with unilateral mild to moderate hand paresis were evaluated at 3, 5, and 12 weeks after stroke using a finger-lifting task in the MEG. Cortical activity patterns in the β-band (16-30 Hz) were compared with matched healthy controls. All stroke survivors (n=22; 17 males) had improvements in action research arm test (ARAT) and Fugl-Meyer upper extremity (FM-UE) scores between 3 and 12 weeks. At 3 weeks post-stroke the peak amplitudes of the movement-related ipsilesional β-band event-related desynchronization (β-ERD) and synchronization (β-ERS) in primary motor cortex (M1) were significantly lower than the healthy controls (p<0.001) and were correlated with both the FM-UE and ARAT scores (r=0.51-0.69, p<0.017). The decreased β-ERS peak amplitudes were observed both in paretic and non-paretic hand movement particularly at 3 weeks post-stroke, suggesting a generalized disinhibition status. β-ERS at week 3 post-stroke correlated with the FM-UE score at 12 weeks (r=0.54, p=0.03) but no longer significant when controlling for the FM-UE score at 3 weeks post-stroke. Although early β-band activity does not independently predict outcome at 3 months after stroke, it mirrors functional changes, giving a potential insight into the mechanisms underpinning recovery of motor function in subacute stroke.
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http://dx.doi.org/10.1177/1545968320913502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250642PMC
May 2020

Author Correction: A tool for functional brain imaging with lifespan compliance.

Nat Commun 2019 Dec 4;10(1):5628. Epub 2019 Dec 4.

Sir Peter Mansfield Imaging Centre, School of Physics and Astronomy, University of Nottingham, University Park, Nottingham, NG7 2RD, United Kingdom.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41467-019-13752-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893010PMC
December 2019

Alcohol consumption is associated with reduced creatine levels in the hippocampus of older adults.

Psychiatry Res Neuroimaging 2020 01 16;295:111019. Epub 2019 Nov 16.

Department of Psychiatry, University of Oxford, Oxford, UK; Global Brain Health Institute, Department of Neurology, University of California San Francisco, San Francisco, California, USA.

Besides its well established susceptibility to ageing, the hippocampus has also been shown to be affected by alcohol consumption. Proton spectroscopy (H-MRS) of the hippocampus, particularly at high-field 7T MRI, may further our understanding of these associations. Here, we aimed to examine how hippocampal metabolites varied with age and alcohol consumption. Hippocampal metabolite spectra were acquired in 37 older adults using 7T H-MRS, from which we determined the absolute concentration of N-acetylaspartate (NAA), creatine, choline, myo-inositol, glutamate and glutamine. Thirty participants (mean age = 70.4 ± 4.7 years) also had self-reported data on weekly alcohol consumption. Total choline inversely correlated with age, although this did not survive multiple comparisons correction. Crucially, adults with a higher weekly alcohol consumption had significantly lower levels of creatine, suggesting a deficit in their hippocampal metabolism. These findings add to an increasing body of evidence linking alcohol to hippocampal function.
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http://dx.doi.org/10.1016/j.pscychresns.2019.111019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6961205PMC
January 2020

A tool for functional brain imaging with lifespan compliance.

Nat Commun 2019 11 5;10(1):4785. Epub 2019 Nov 5.

Sir Peter Mansfield Imaging Centre, School of Physics and Astronomy, University of Nottingham, University Park, Nottingham, NG7 2RD, United Kingdom.

The human brain undergoes significant functional and structural changes in the first decades of life, as the foundations for human cognition are laid down. However, non-invasive imaging techniques to investigate brain function throughout neurodevelopment are limited due to growth in head-size with age and substantial head movement in young participants. Experimental designs to probe brain function are also limited by the unnatural environment typical brain imaging systems impose. However, developments in quantum technology allowed fabrication of a new generation of wearable magnetoencephalography (MEG) technology with the potential to revolutionise electrophysiological measures of brain activity. Here we demonstrate a lifespan-compliant MEG system, showing recordings of high fidelity data in toddlers, young children, teenagers and adults. We show how this system can support new types of experimental paradigm involving naturalistic learning. This work reveals a new approach to functional imaging, providing a robust platform for investigation of neurodevelopment in health and disease.
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http://dx.doi.org/10.1038/s41467-019-12486-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6831615PMC
November 2019

Dopamine depletion effects on cognitive flexibility as modulated by tDCS of the dlPFC.

Brain Stimul 2020 Jan - Feb;13(1):105-108. Epub 2019 Aug 31.

Department of Psychology, Sociology and Politics, Sheffield Hallam University, Sheffield, UK. Electronic address:

Background: Recent evidence suggests that transcranial direct current stimulation (tDCS) may interact with the dopaminergic system to affect cognitive flexibility. Objective/hypotheses: We examined whether putative reduction of dopamine levels through the acute phenylalanine/tyrosine depletion (APTD) procedure and excitatory anodal tDCS of the dorsolateral prefrontal cortex (dlPFC) are causally related to cognitive flexibility as measured by task switching and reversal learning.

Method: A double-blind, sham-controlled, randomised trial was conducted to test the effects of combining anodal tDCS and depletion of catecholaminergic precursor tyrosine on cognitive flexibility.

Results: Anodal tDCS and tyrosine depletion had a significant effect on task switching, but not reversal learning. Whilst perseverative errors were significantly improved by anodal tDCS, the APTD impaired reaction times. Importantly, the combination of APTD and anodal tDCS resulted in cognitive performance which did not statistically differ to that of the control condition.

Conclusions: Our results suggest that the effects of tDCS on cognitive flexibility are modulated by dopaminergic tone.
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http://dx.doi.org/10.1016/j.brs.2019.08.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116421PMC
June 2020

Relating diffusion tensor imaging measurements to microstructural quantities in the cerebral cortex in multiple sclerosis.

Hum Brain Mapp 2019 10 29;40(15):4417-4431. Epub 2019 Jul 29.

Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom.

To investigate whether the observed anisotropic diffusion in cerebral cortex may reflect its columnar cytoarchitecture and myeloarchitecture, as a potential biomarker for disease-related changes, we compared postmortem diffusion magnetic resonance imaging scans of nine multiple sclerosis brains with histology measures from the same regions. Histology measurements assessed the cortical minicolumnar structure based on cell bodies and associated axon bundles in dorsolateral prefrontal cortex (Area 9), Heschl's gyrus (Area 41), and primary visual cortex (V1). Diffusivity measures included mean diffusivity, fractional anisotropy of the cortex, and three specific measures that may relate to the radial minicolumn structure: the angle of the principal diffusion direction in the cortex, the component that was perpendicular to the radial direction, and the component that was parallel to the radial direction. The cellular minicolumn microcircuit features were correlated with diffusion angle in Areas 9 and 41, and the axon bundle features were correlated with angle in Area 9 and to the parallel component in V1 cortex. This may reflect the effect of minicolumn microcircuit organisation on diffusion in the cortex, due to the number of coherently arranged membranes and myelinated structures. Several of the cortical diffusion measures showed group differences between MS brains and control brains. Differences between brain regions were also found in histology and diffusivity measurements consistent with established regional variation in cytoarchitecture and myeloarchitecture. Therefore, these novel measures may provide a surrogate of cortical organisation as a potential biomarker, which is particularly relevant for detecting regional changes in neurological disorders.
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http://dx.doi.org/10.1002/hbm.24711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6772025PMC
October 2019

Therapeutic non-invasive brain stimulation in amyotrophic lateral sclerosis: rationale, methods and experience.

J Neurol Neurosurg Psychiatry 2019 10 9;90(10):1131-1138. Epub 2019 May 9.

Nuffield Department of Clinical Neurosciences, Oxford University, Oxford, UK

The neurodegenerative syndrome amyotrophic lateral sclerosis (ALS) is characterised by increased cortical excitability, thought to reflect pathological changes in the balance of local excitatory and inhibitory neuronal influences. Non-invasive brain stimulation (NIBS) has been shown to modulate cortical activity, with some protocols showing effects that outlast the stimulation by months. NIBS has been suggested as a potential therapeutic approach for disorders associated with changes in cortical neurophysiology, including ALS. This article reviews NIBS methodology, rationale for its application to ALS and progress to date.
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http://dx.doi.org/10.1136/jnnp-2018-320213DOI Listing
October 2019

Learning to optimize perceptual decisions through suppressive interactions in the human brain.

Nat Commun 2019 01 28;10(1):474. Epub 2019 Jan 28.

Department of Psychology, University of Cambridge, Cambridge, CB2 3EB, UK.

Translating noisy sensory signals to perceptual decisions is critical for successful interactions in complex environments. Learning is known to improve perceptual judgments by filtering external noise and task-irrelevant information. Yet, little is known about the brain mechanisms that mediate learning-dependent suppression. Here, we employ ultra-high field magnetic resonance spectroscopy of GABA to test whether suppressive processing in decision-related and visual areas facilitates perceptual judgments during training. We demonstrate that parietal GABA relates to suppression of task-irrelevant information, while learning-dependent changes in visual GABA relate to enhanced performance in target detection and feature discrimination tasks. Combining GABA measurements with functional brain connectivity demonstrates that training on a target detection task involves local connectivity and disinhibition of visual cortex, while training on a feature discrimination task involves inter-cortical interactions that relate to suppressive visual processing. Our findings provide evidence that learning optimizes perceptual decisions through suppressive interactions in decision-related networks.
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http://dx.doi.org/10.1038/s41467-019-08313-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6349878PMC
January 2019

Differential impact of reward and punishment on functional connectivity after skill learning.

Neuroimage 2019 04 8;189:95-105. Epub 2019 Jan 8.

Laboratory of Brain and Cognition, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, 20814, USA.

Reward and punishment shape behavior, but the mechanisms underlying their effect on skill learning are not well understood. Here, we tested whether the functional connectivity of premotor cortex (PMC), a region known to be critical for learning of sequencing skills, is altered after training when reward or punishment is given during training. Resting-state fMRI was collected in two experiments before and after participants trained on either a serial reaction time task (SRTT; n = 36) or force-tracking task (FTT; n = 36) with reward, punishment, or control feedback. In each experiment, training-related change in PMC functional connectivity was compared across feedback groups. In both tasks, we found that reward and punishment differentially affected PMC functional connectivity. On the SRTT, participants trained with reward showed an increase in functional connectivity between PMC and cerebellum as well as PMC and striatum, while participants trained with punishment showed an increase in functional connectivity between PMC and medial temporal lobe connectivity. After training on the FTT, subjects trained with control and reward showed increases in PMC connectivity with parietal and temporal cortices after training, while subjects trained with punishment showed increased PMC connectivity with ventral striatum. While the results from the two experiments overlapped in some areas, including ventral pallidum, temporal lobe, and cerebellum, these regions showed diverging patterns of results across the two tasks for the different feedback conditions. These findings suggest that reward and punishment strongly influence spontaneous brain activity after training, and that the regions implicated depend on the task learned.
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http://dx.doi.org/10.1016/j.neuroimage.2019.01.009DOI Listing
April 2019

Catecholaminergic modulation of indices of cognitive flexibility: A pharmaco-tDCS study.

Brain Stimul 2019 Mar - Apr;12(2):290-295. Epub 2018 Dec 7.

Department of Psychology, Sociology and Politics, Sheffield Hallam University, Sheffield, UK. Electronic address:

Background: Dopaminergic activity within the dorsolateral prefrontal cortex (dlPFC) has been implicated in the control of cognitive flexibility. Much of the evidence for a causative relationship between cognitive flexibility and dopamine has come from animal studies, whilst human data have largely been correlational.

Objective/hypothesis: The current study examines whether changes in dopamine levels through tyrosine administration and suppression of dlPFC activity via cathodal tDCS could be causally related to cognitive flexibility as measured by task switching and reversal learning.

Methods: Using a crossover, double-blind, sham controlled, counterbalanced, randomized trial, we tested the effects of combining cathodal tDCS with tyrosine, a catecholaminergic precursor, with appropriate drug and tDCS placebo controls, on two measures of cognitive flexibility: probabilistic reversal learning, and task switching.

Results: While none of the manipulations had an effect on task switching, there was a significant main effect of cathodal tDCS and tyrosine on reversal learning. Reversal learning performance was significantly worsened by cathodal tDCS compared with sham tDCS, whilst tyrosine significantly improved performance compared with placebo. However, there was no significant tDCS × drugs interaction. Interestingly, and as predicted by our model, the combined administration of tyrosine with cathodal tDCS resulted in performance that was equivalent to the control condition (i.e. tDCS sham + placebo).

Conclusions: Our results suggest a causative role for dopamine signalling and dorsolateral prefrontal cortex activity in regulating indices of cognitive flexibility in humans.
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http://dx.doi.org/10.1016/j.brs.2018.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116420PMC
June 2019

Visual training in hemianopia alters neural activity in the absence of behavioural improvement: a pilot study.

Ophthalmic Physiol Opt 2018 09;38(5):538-549

Oxford Centre for Functional MRI of the Brain (FMRIB), Wellcome Centre for Integrative Neuroimaging, University of Oxford, Oxford, UK.

Background: Damage to the primary visual cortex (V1) due to stroke often results in permanent loss of sight affecting one side of the visual field (homonymous hemianopia). Some rehabilitation approaches have shown improvement in visual performance in the blind region, but require a significant time investment.

Methods: Seven patients with cortical damage performed 400 trials of a motion direction discrimination task daily for 5 days. Three patients received anodal transcranial direct current stimulation (tDCS) during training, three received sham stimulation and one had no stimulation. Each patient had an assessment of visual performance and a functional magnetic resonance imaging (fMRI) scan before and after training to measure changes in visual performance and cortical activity.

Results: No patients showed improvement in visual function due to the training protocol, and application of tDCS had no effect on visual performance. However, following training, the neural response in motion area hMT+ to a moving stimulus was altered. When the stimulus was presented to the sighted hemifield, activity decreased in hMT+ of the damaged hemisphere. There was no change in hMT+ response when the stimulus was presented to the impaired hemifield. There was a decrease in activity in the inferior precuneus after training when the stimulus was presented to either the impaired or sighted hemifield. Preliminary analysis of tDCS data suggested that anodal tDCS interacted with the delivered training, modulating the neural response in hMT+ in the healthy side of the brain.

Conclusion: Training can affect the neural responses in hMT+ even in the absence of change in visual performance.
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http://dx.doi.org/10.1111/opo.12584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282990PMC
September 2018

The dynamics of cortical GABA in human motor learning.

J Physiol 2019 01 2;597(1):271-282. Epub 2018 Nov 2.

Wellcome Centre for Integrative Neuroimaging, Oxford Centre for fMRI of the Brain, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, OX3 7DU, UK.

Key Points: The ability to learn new motor skills is supported by plasticity in the structural and functional organisation of the primary motor cortex in the human brain. Changes inhibitory to signalling by GABA are thought to be crucial in inducing motor cortex plasticity. This study used magnetic resonance spectroscopy (MRS) to quantify the concentration of GABA in human motor cortex during a period of motor learning, as well as during a period of movement and a period at rest. We report evidence for a reduction in the MRS-measured concentration of GABA specific to learning. Further, the GABA concentration early in the learning task was strongly correlated with the magnitude of subsequent learning: higher GABA concentrations were associated with poorer learning. The results provide initial insight into the neurochemical correlates of cortical plasticity associated with motor learning, specifically relevant in therapeutic efforts to induce cortical plasticity during recovery from stroke.

Abstract: The ability to learn novel motor skills is a central part of our daily lives and can provide a model for rehabilitation after a stroke. However, there are still fundamental gaps in our understanding of the physiological mechanisms that underpin human motor plasticity. The acquisition of new motor skills is dependent on changes in local circuitry within the primary motor cortex (M1). This reorganisation has been hypothesised to be facilitated by a decrease in local inhibition via modulation of the neurotransmitter GABA, but this link has not been conclusively demonstrated in humans. Here, we used 7 T magnetic resonance spectroscopy to investigate the dynamics of GABA concentrations in human M1 during the learning of an explicit, serial reaction time task. We observed a significant reduction in GABA concentration during motor learning that was not seen in an equivalent motor task lacking a learnable sequence, nor during a passive resting task of the same duration. No change in glutamate was observed in any group. Furthermore, M1 GABA measured early in task performance was strongly correlated with the degree of subsequent learning, such that greater inhibition was associated with poorer subsequent learning. This result suggests that higher levels of cortical inhibition may present a barrier that must be surmounted in order to achieve an increase in M1 excitability, and hence encoding of a new motor skill. These results provide strong support for the mechanistic role of GABAergic inhibition in motor plasticity, raising questions regarding the link between population variability in motor learning and GABA metabolism in the brain.
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http://dx.doi.org/10.1113/JP276626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6312422PMC
January 2019

Hippocampal Functional Dynamics Are Clinically Implicated in Autoimmune Encephalitis With Faciobrachial Dystonic Seizures.

Front Neurol 2018 4;9:736. Epub 2018 Sep 4.

Physiological Neuroimaging Group, Wellcome Centre for Integrative Neuroimaging, FMRIB, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom.

This is the first study to investigate functional brain activity in patients affected by autoimmune encephalitis with faciobrancial dystonic seizures (FBDS). Multimodal 3T MRI scans, including structural neuroimaging (T1-weighted, diffusion weighted) and functional neuroimaging (scene-encoding task known to activate hippocampal regions), were performed. This case series analysis included eight patients treated for autoimmune encephalitis with FBDS, scanned during the convalescent phase of their condition (median 1.1 years post-onset), and eight healthy volunteers. Compared to controls, 50% of patients showed abnormal hippocampal activity during scene-encoding relative to familiar scene-viewing. Higher peak FBDS frequency was significantly related to lower hippocampal activity during scene-encoding ( = 0.02), though not to markers of hippocampal microstructure (mean diffusivity, = 0.3) or atrophy (normalized volume, = 0.4). During scene-encoding, stronger within-medial temporal lobe (MTL) functional connectivity correlated with poorer Addenbrooke's Cognitive Examination-Revised memory score ( = 0.03). These findings suggest that in autoimmune encephalitis, frequent seizures may have a long-term impact on hippocampal activity, beyond that of structural damage. These observations also suggest a potential approach to determine on-going MTL performance in this condition to guide long-term management and future clinical trials.
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http://dx.doi.org/10.3389/fneur.2018.00736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6131496PMC
September 2018

"Luteal Analgesia": Progesterone Dissociates Pain Intensity and Unpleasantness by Influencing Emotion Regulation Networks.

Front Endocrinol (Lausanne) 2018 23;9:413. Epub 2018 Jul 23.

Wellcome Centre for Integrative Neuroimaging, FMRIB, Nuffield Department of Clinical Neurosciences, Nuffield Division of Anaesthetics, University of Oxford, Oxford, United Kingdom.

Pregnancy-induced analgesia is known to occur in association with the very high levels of estradiol and progesterone circulating during pregnancy. In women with natural ovulatory menstrual cycles, more modest rises in these hormones occur on a monthly basis. We therefore hypothesized that the high estradiol high progesterone state indicative of ovulation would be associated with a reduction in the pain experience. We used fMRI and a noxious thermal stimulus to explore the relationship between sex steroid hormones and the pain experience. Specifically, we assessed the relationship with stimulus-related activity in key regions of networks involved in emotion regulation, and functional connectivity between these regions. We demonstrate that physiologically high progesterone levels are associated with a reduction in the affective component of the pain experience and a dissociation between pain intensity and unpleasantness. This dissociation is related to decreased functional connectivity between the inferior frontal gyrus and amygdala. Moreover, we have shown that in the pre-ovulatory state, the traditionally "male" sex hormone, testosterone, is the strongest hormonal regulator of pain-related activity and connectivity within the emotional regulation network. However, following ovulation the traditionally "female" sex hormones, estradiol and progesterone, appear to dominate. We propose that a phenomenon of "luteal analgesia" exists with potential reproductive advantages.
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http://dx.doi.org/10.3389/fendo.2018.00413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6064935PMC
July 2018

Modulating Regional Motor Cortical Excitability with Noninvasive Brain Stimulation Results in Neurochemical Changes in Bilateral Motor Cortices.

J Neurosci 2018 08 20;38(33):7327-7336. Epub 2018 Jul 20.

Nuffield Department of Clinical Neurosciences, Functional Magnetic Resonance Imaging of the Brain (FMRIB), Wellcome Centre for Integrative Neuroimaging, University of Oxford, Oxford, OX3 9DU, United Kingdom, and

Learning a novel motor skill is dependent both on regional changes within the primary motor cortex (M1) contralateral to the active hand and also on modulation between and within anatomically distant but functionally connected brain regions. Interregional changes are particularly important in functional recovery after stroke, when critical plastic changes underpinning behavioral improvements are observed in both ipsilesional and contralesional M1s. It is increasingly understood that reduction in GABA in the contralateral M1 is necessary to allow learning of a motor task. However, the physiological mechanisms underpinning plasticity within other brain regions, most importantly the ipsilateral M1, are not well understood. Here, we used concurrent two-voxel magnetic resonance spectroscopy to simultaneously quantify changes in neurochemicals within left and right M1s in healthy humans of both sexes in response to transcranial direct current stimulation (tDCS) applied to left M1. We demonstrated a decrease in GABA in both the stimulated (left) and nonstimulated (right) M1 after anodal tDCS, whereas a decrease in GABA was only observed in nonstimulated M1 after cathodal stimulation. This GABA decrease in the nonstimulated M1 during cathodal tDCS was negatively correlated with microstructure of M1:M1 callosal fibers, as quantified by diffusion MRI, suggesting that structural features of these fibers may mediate GABA decrease in the unstimulated region. We found no significant changes in glutamate. Together, these findings shed light on the interactions between the two major network nodes underpinning motor plasticity, offering a potential framework from which to optimize future interventions to improve motor function after stroke. Learning of new motor skills depends on modulation both within and between brain regions. Here, we use a novel two-voxel magnetic resonance spectroscopy approach to quantify GABA and glutamate changes concurrently within the left and right primary motor cortex (M1) during three commonly used transcranial direct current stimulation montages: anodal, cathodal, and bilateral. We also examined how the neurochemical changes in the unstimulated hemisphere were related to white matter microstructure between the two M1s. Our results provide insights into the neurochemical changes underlying motor plasticity and may therefore assist in the development of further adjunct therapies.
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http://dx.doi.org/10.1523/JNEUROSCI.2853-17.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6096041PMC
August 2018

Physiology of Transcranial Direct Current Stimulation.

J ECT 2018 09;34(3):144-152

Department of Clinical Neurophysiology, University Medical Center Göttingen, University of Göttingen, Göttingen.

Direct current stimulation is a neuromodulatory noninvasive brain stimulation tool, which was first introduced in animal and human experiments in the 1950s, and added to the standard arsenal of methods to alter brain physiology as well as psychological, motor, and behavioral processes and clinical symptoms in neurological and psychiatric diseases about 20 years ago. In contrast to other noninvasive brain stimulation tools, such as transcranial magnetic stimulation, it does not directly induce cerebral activity, but rather alters spontaneous brain activity and excitability by subthreshold modulation of neuronal membranes. Beyond acute effects on brain functions, specific protocols are suited to induce long-lasting alterations of cortical excitability and activity, which share features with long-term potentiation and depression. These neuroplastic processes are important foundations for various cognitive functions such as learning and memory formation and are pathologically altered in numerous neurological and psychiatric diseases. This explains the increasing interest to investigate transcranial direct current stimulation (tDCS) as a therapeutic tool. However, for tDCS to be used effectively, it is crucial to be informed about physiological mechanisms of action. These have been increasingly elucidated during the last years. This review gives an overview of the current knowledge available regarding physiological mechanisms of tDCS, spanning from acute regional effects, over neuroplastic effects to its impact on cerebral networks. Although knowledge about the physiological effects of tDCS is still not complete, this might help to guide applications on a scientifically sound foundation.
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http://dx.doi.org/10.1097/YCT.0000000000000510DOI Listing
September 2018

Motor Cortical Gamma Oscillations: What Have We Learnt and Where Are We Headed?

Curr Behav Neurosci Rep 2018 27;5(2):136-142. Epub 2018 Apr 27.

1Wellcome Centre for Integrative Neuroimaging, FMRIB, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, OX3 9DU UK.

Purpose Of Review: An increase in oscillatory activity in the -frequency band (approximately 50-100 Hz) has long been noted during human movement. However, its functional role has been difficult to elucidate. The advent of novel techniques, particularly transcranial alternating current stimulation (tACS), has dramatically increased our ability to study oscillations. Here, we review our current understanding of the role of oscillations in the human motor cortex, with reference to activity outside the motor system, and evidence from animal models.

Recent Findings: Evidence for the neurophysiological basis of human oscillations is beginning to emerge. Multimodal studies, essential given the necessarily indirect measurements acquired in humans, are beginning to provide convergent evidence for the role of oscillations in movement, and their relationship to plasticity.

Summary: Human motor cortical oscillations appear to play a key role in movement, and relate to learning. However, there are still major questions to be answered about their physiological basis and precise role in human plasticity. It is to be hoped that future research will take advantage of recent technical advances and the physiological basis and functional significance of this intriguing and important brain rhythm will be fully elucidated.
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http://dx.doi.org/10.1007/s40473-018-0151-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5962618PMC
April 2018

Metabolite-cycled density-weighted concentric rings k-space trajectory (DW-CRT) enables high-resolution 1 H magnetic resonance spectroscopic imaging at 3-Tesla.

Sci Rep 2018 05 17;8(1):7792. Epub 2018 May 17.

Wellcome Centre for Integrative Neuroimaging, FMRIB Division, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, OX3 9DU, UK.

Magnetic resonance spectroscopic imaging (MRSI) is a promising technique in both experimental and clinical settings. However, to date, MRSI has been hampered by prohibitively long acquisition times and artifacts caused by subject motion and hardware-related frequency drift. In the present study, we demonstrate that density weighted concentric ring trajectory (DW-CRT) k-space sampling in combination with semi-LASER excitation and metabolite-cycling enables high-resolution MRSI data to be rapidly acquired at 3 Tesla. Single-slice full-intensity MRSI data (short echo time (TE) semi-LASER TE = 32 ms) were acquired from 6 healthy volunteers with an in-plane resolution of 5 × 5 mm in 13 min 30 sec using this approach. Using LCModel analysis, we found that the acquired spectra allowed for the mapping of total N-acetylaspartate (median Cramer-Rao Lower Bound [CRLB] = 3%), glutamate+glutamine (8%), and glutathione (13%). In addition, we demonstrate potential clinical utility of this technique by optimizing the TE to detect 2-hydroxyglutarate (long TE semi-LASER, TE = 110 ms), to produce relevant high-resolution metabolite maps of grade III IDH-mutant oligodendroglioma in a single patient. This study demonstrates the potential utility of MRSI in the clinical setting at 3 Tesla.
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http://dx.doi.org/10.1038/s41598-018-26096-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5958083PMC
May 2018

Modulation of Long-Range Connectivity Patterns via Frequency-Specific Stimulation of Human Cortex.

Curr Biol 2017 Oct 28;27(19):3061-3068.e3. Epub 2017 Sep 28.

Wellcome Centre for Integrative Neuroimaging, FMRIB, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK; Oxford Centre for Human Brain Activity, Wellcome Centre for Integrative Neuroimaging, Department of Psychiatry, University of Oxford, Oxford OX3 7JX, UK. Electronic address:

There is increasing interest in how the phase of local oscillatory activity within a brain area determines the long-range functional connectivity of that area. For example, increasing convergent evidence from a range of methodologies suggests that beta (20 Hz) oscillations may play a vital role in the function of the motor system [1-5]. The "communication through coherence" hypothesis posits that the precise phase of coherent oscillations in network nodes is a determinant of successful communication between them [6, 7]. Here we set out to determine whether oscillatory activity in the beta band serves to support this theory within the cortical motor network in vivo. We combined non-invasive transcranial alternating-current stimulation (tACS) [8-12] with resting-state functional MRI (fMRI) [13] to follow both changes in local activity and long-range connectivity, determined by inter-areal blood-oxygen-level-dependent (BOLD) signal correlation, as a proxy for communication in the human cortex. Twelve healthy subjects participated in three fMRI scans with 20 Hz, 5 Hz, or sham tACS applied separately on each scan. Transcranial magnetic stimulation (TMS) at beta frequency has previously been shown to increase local activity in the beta band [14] and to modulate long-range connectivity within the default mode network [15]. We demonstrated that beta-frequency tACS significantly changed the connectivity pattern of the stimulated primary motor cortex (M1), without changing overall local activity or network connectivity. This finding is supported by a simple phase-precession model, which demonstrates the plausibility of the results and provides emergent predictions that are consistent with our empirical findings. These findings therefore inform our understanding of how local oscillatory activity may underpin network connectivity.
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http://dx.doi.org/10.1016/j.cub.2017.08.075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5640151PMC
October 2017

Neurochemical changes underpinning the development of adjunct therapies in recovery after stroke: A role for GABA?

J Cereb Blood Flow Metab 2018 09 20;38(9):1564-1583. Epub 2017 Sep 20.

1 Nuffield Department of Clinical Neurosciences, Oxford Centre for FMRI of the Brain (FMRIB), Wellcome Centre for Integrative Neuroimaging (WIN), University of Oxford, Oxford, UK.

Stroke is a leading cause of long-term disability, with around three-quarters of stroke survivors experiencing motor problems. Intensive physiotherapy is currently the most effective treatment for post-stroke motor deficits, but much recent research has been targeted at increasing the effects of the intervention by pairing it with a wide variety of adjunct therapies, all of which aim to increase cortical plasticity, and thereby hope to maximize functional outcome. Here, we review the literature describing neurochemical changes underlying plasticity induction following stroke. We discuss methods of assessing neurochemicals in humans, and how these measurements change post-stroke. Motor learning in healthy individuals has been suggested as a model for stroke plasticity, and we discuss the support for this model, and what evidence it provides for neurochemical changes. One converging hypothesis from animal, healthy and stroke studies is the importance of the regulation of the inhibitory neurotransmitter GABA for the induction of cortical plasticity. We discuss the evidence supporting this hypothesis, before finally summarizing the literature surrounding the use of adjunct therapies such as non-invasive brain stimulation and SSRIs in post-stroke motor recovery, both of which have been show to influence the GABAergic system.
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http://dx.doi.org/10.1177/0271678X17727670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125966PMC
September 2018

Consensus statement on current and emerging methods for the diagnosis and evaluation of cerebrovascular disease.

J Cereb Blood Flow Metab 2018 09 17;38(9):1391-1417. Epub 2017 Aug 17.

10 Department of Radiology, University Medical Center Utrecht, Utrecht, The Netherlands.

Cerebrovascular disease (CVD) remains a leading cause of death and the leading cause of adult disability in most developed countries. This work summarizes state-of-the-art, and possible future, diagnostic and evaluation approaches in multiple stages of CVD, including (i) visualization of sub-clinical disease processes, (ii) acute stroke theranostics, and (iii) characterization of post-stroke recovery mechanisms. Underlying pathophysiology as it relates to large vessel steno-occlusive disease and the impact of this macrovascular disease on tissue-level viability, hemodynamics (cerebral blood flow, cerebral blood volume, and mean transit time), and metabolism (cerebral metabolic rate of oxygen consumption and pH) are also discussed in the context of emerging neuroimaging protocols with sensitivity to these factors. The overall purpose is to highlight advancements in stroke care and diagnostics and to provide a general overview of emerging research topics that have potential for reducing morbidity in multiple areas of CVD.
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http://dx.doi.org/10.1177/0271678X17721830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125970PMC
September 2018

A Mechanistic Link from GABA to Cortical Architecture and Perception.

Curr Biol 2017 Jun 25;27(11):1685-1691.e3. Epub 2017 May 25.

Oxford Centre for fMRI of the Brain, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 9DU, UK; Oxford Centre for Human Brain Activity, Department of Psychiatry, University of Oxford, Oxford OX3 7JX, UK.

Understanding both the organization of the human cortex and its relation to the performance of distinct functions is fundamental in neuroscience. The primary sensory cortices display topographic organization, whereby receptive fields follow a characteristic pattern, from tonotopy to retinotopy to somatotopy [1]. GABAergic signaling is vital to the maintenance of cortical receptive fields [2]; however, it is unclear how this fine-grain inhibition relates to measurable patterns of perception [3, 4]. Based on perceptual changes following perturbation of the GABAergic system, it is conceivable that the resting level of cortical GABAergic tone directly relates to the spatial specificity of activation in response to a given input [5-7]. The specificity of cortical activation can be considered in terms of cortical tuning: greater cortical tuning yields more localized recruitment of cortical territory in response to a given input. We applied a combination of fMRI, MR spectroscopy, and psychophysics to substantiate the link between the cortical neurochemical milieu, the tuning of cortical activity, and variability in perceptual acuity, using human somatosensory cortex as a model. We provide data that explain human perceptual acuity in terms of both the underlying cellular and metabolic processes. Specifically, higher concentrations of sensorimotor GABA are associated with more selective cortical tuning, which in turn is associated with enhanced perception. These results show anatomical and neurochemical specificity and are replicated in an independent cohort. The mechanistic link from neurochemistry to perception provides a vital step in understanding population variability in sensory behavior, informing metabolic therapeutic interventions to restore perceptual abilities clinically.
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http://dx.doi.org/10.1016/j.cub.2017.04.055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5462622PMC
June 2017
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