657 research outputs found

    Activation of the pro-resolving receptor Fpr2 attenuates inflammatory microglial activation

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    Poster number: P-T099 Theme: Neurodegenerative disorders & ageing Activation of the pro-resolving receptor Fpr2 reverses inflammatory microglial activation Authors: Edward S Wickstead - Life Science & Technology University of Westminster/Queen Mary University of London Inflammation is a major contributor to many neurodegenerative disease (Heneka et al. 2015). Microglia, as the resident immune cells of the brain and spinal cord, provide the first line of immunological defence, but can become deleterious when chronically activated, triggering extensive neuronal damage (Cunningham, 2013). Dampening or even reversing this activation may provide neuronal protection against chronic inflammatory damage. The aim of this study was to determine whether lipopolysaccharide (LPS)-induced inflammation could be abrogated through activation of the receptor Fpr2, known to play an important role in peripheral inflammatory resolution. Immortalised murine microglia (BV2 cell line) were stimulated with LPS (50ng/ml) for 1 hour prior to the treatment with one of two Fpr2 ligands, either Cpd43 or Quin-C1 (both 100nM), and production of nitric oxide (NO), tumour necrosis factor alpha (TNFα) and interleukin-10 (IL-10) were monitored after 24h and 48h. Treatment with either Fpr2 ligand significantly suppressed LPS-induced production of NO or TNFα after both 24h and 48h exposure, moreover Fpr2 ligand treatment significantly enhanced production of IL-10 48h post-LPS treatment. As we have previously shown Fpr2 to be coupled to a number of intracellular signaling pathways (Cooray et al. 2013), we investigated potential signaling responses. Western blot analysis revealed no activation of ERK1/2, but identified a rapid and potent activation of p38 MAP kinase in BV2 microglia following stimulation with Fpr2 ligands. Together, these data indicate the possibility of exploiting immunomodulatory strategies for the treatment of neurological diseases, and highlight in particular the important potential of resolution mechanisms as novel therapeutic targets in neuroinflammation. References Cooray SN et al. (2013). Proc Natl Acad Sci U S A 110: 18232-7. Cunningham C (2013). Glia 61: 71-90. Heneka MT et al. (2015). Lancet Neurol 14: 388-40

    The mechanisms of tinnitus: perspectives from human functional neuroimaging

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    In this review, we highlight the contribution of advances in human neuroimaging to the current understanding of central mechanisms underpinning tinnitus and explain how interpretations of neuroimaging data have been guided by animal models. The primary motivation for studying the neural substrates of tinnitus in humans has been to demonstrate objectively its representation in the central auditory system and to develop a better understanding of its diverse pathophysiology and of the functional interplay between sensory, cognitive and affective systems. The ultimate goal of neuroimaging is to identify subtypes of tinnitus in order to better inform treatment strategies. The three neural mechanisms considered in this review may provide a basis for TI classification. While human neuroimaging evidence strongly implicates the central auditory system and emotional centres in TI, evidence for the precise contribution from the three mechanisms is unclear because the data are somewhat inconsistent. We consider a number of methodological issues limiting the field of human neuroimaging and recommend approaches to overcome potential inconsistency in results arising from poorly matched participants, lack of appropriate controls and low statistical power

    The thalamocortical symphony:How thalamus and cortex play together in schizophrenia and plasticity

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    The work presented in this thesis aimed at investigating the function and mechanism of corticothalamic-thalamocortical network in schizophrenia and experience-dependent plasticity, further discussed their possible connection.In Chapter 2, we examined the effects of low-dose ketamine on the corticothalamic circuit (CTC) system. Our findings reveal that ketamine induces abnormal spindle activity and gamma oscillations in the CTC system. Notably, ketamine also leads to a transition in thalamic neurons from burst-firing to tonic action potential mode, which may underlie deficits in spindle oscillations. Chapter 3 addresses sensory perception deficits in schizophrenia, emphasizing disruptions in beta and gamma frequency oscillations due to signal-to-noise ratio imbalances. Chapter 4 explores experience-dependent plasticity, highlighting the role of thalamic synaptic inhibition in ocular dominance plasticity and the influence of cortical feedback. Chapter 5 investigates the involvement of endocannabinoids, particularly CB1 receptors, in inhibitory synaptic maturation and ocular dominance plasticity within the primary visual cortex.The general discussion raises the possibility of a link between neural plasticity and schizophrenia, particularly during the transformative phase of adolescence when the brain undergoes significant changes. An abnormal balance between inhibition and excitation, influenced by GABAergic maturation deficits, connectivity disruptions, and altered perceptual information transfer, may contribute to the development of schizophrenia.This thesis offers valuable insights into the intricate mechanisms underlying schizophrenia, with a particular focus on the CTC circuit, NMDA receptors, and endocannabinoids in the context of neuronal plasticity and cognitive function

    The thalamocortical symphony:How thalamus and cortex play together in schizophrenia and plasticity

    Get PDF
    The work presented in this thesis aimed at investigating the function and mechanism of corticothalamic-thalamocortical network in schizophrenia and experience-dependent plasticity, further discussed their possible connection.In Chapter 2, we examined the effects of low-dose ketamine on the corticothalamic circuit (CTC) system. Our findings reveal that ketamine induces abnormal spindle activity and gamma oscillations in the CTC system. Notably, ketamine also leads to a transition in thalamic neurons from burst-firing to tonic action potential mode, which may underlie deficits in spindle oscillations. Chapter 3 addresses sensory perception deficits in schizophrenia, emphasizing disruptions in beta and gamma frequency oscillations due to signal-to-noise ratio imbalances. Chapter 4 explores experience-dependent plasticity, highlighting the role of thalamic synaptic inhibition in ocular dominance plasticity and the influence of cortical feedback. Chapter 5 investigates the involvement of endocannabinoids, particularly CB1 receptors, in inhibitory synaptic maturation and ocular dominance plasticity within the primary visual cortex.The general discussion raises the possibility of a link between neural plasticity and schizophrenia, particularly during the transformative phase of adolescence when the brain undergoes significant changes. An abnormal balance between inhibition and excitation, influenced by GABAergic maturation deficits, connectivity disruptions, and altered perceptual information transfer, may contribute to the development of schizophrenia.This thesis offers valuable insights into the intricate mechanisms underlying schizophrenia, with a particular focus on the CTC circuit, NMDA receptors, and endocannabinoids in the context of neuronal plasticity and cognitive function

    Sensorimotor Processing in Post-Stroke Fatigue

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    Chronic pathological fatigue is a highly debilitating symptom with a significant impact on quality of life of stroke survivors. Despite its high prevalence, research into the mechanisms that underlie post-stroke fatigue is lacking. This thesis outlines how changes in cortical neurophysiology results in alterations in sensorimotor processing associated with the perception of effort and how prolonged experience of high effort can subsequently result in chronic pathological fatigue. I show that the perception of effort for what are usually low effort activities is altered in non-depressed, chronic stroke survivors with minimal physical impairment. Low effort voluntary contractions are perceived as more effortful in stroke survivors with high fatigue compared to those with low fatigue. Sensory attenuation, the ability to attend away from predictable sensory input, is thought to underlie altered effort perception. If one is unable to attend away from predictable sensory input associated with a voluntary movement, this will give rise to the perception of higher effort afforded to the movement. I show that stroke survivors with high fatigue do not show reduced sensory attenuation of sensory input arising from mechanoreceptors as quantified using a force matching task and suggest that high effort afforded to simple voluntary movements may be a result of reduced sensory attenuation of information arising from within the body, namely proprioceptive afferent information from the contracting muscle. Using TMS, I show that cortical excitability both at rest and during movement preparation is altered in stroke survivors with high fatigue and propose that cortical excitability reflects the degree of sensory attenuation at the level of the sensorimotor cortex. Finally, I show that neuromodulatory techniques such as transcranial direct current stimulation, are potential tools that can be used to reduce fatigue severity by potentially resetting cortical neurophysiology and reducing perceived effort. Overall, the data provides some evidence in support of the sensory attenuation model of fatigue and provides a novel insight into the mechanisms implicated in post- stroke fatigue

    Investigating the Cortical, Metabolic and Behavioral Effects of Transcranial Direct Current Stimulation in Preparation for Combined Rehabilitation

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    The goal of this thesis was to determine the cortical reorganization that occurs in patients with cervical spondylotic myelopathy (CSM) after surgical decompression and to implement this knowledge into a new rehabilitation strategy. Transcranial direct current stimulation (tDCS) is a non-invasive technique to modulate human behavior. Due to the novel electrode montage used, it was first pertinent that we determine how tDCS would modulate cortical, metabolic and motor behavior in healthy individuals. We observed the longitudinal functional adaptations that occur in patients with CSM using functional MRI. Enhanced excitation of supplementary motor area (SMA) was observed following surgical decompression and associated with increased function following surgery. This novel finding of enhanced excitation of motivated us to use a bihemispheric tDCS protocol, exciting bilateral motor areas to provide optimal motor enhancement. This novel tDCS electrode montage, targeting the SMA and primary motor cortex (M1) was implemented in healthy older adults to determine its effects on enhancing manual dexterity. Furthermore, to determine the frequency with which to apply tDCS, a single and tri session protocol was used. We observed a differential pattern of action with anti-phase and in-phase motor tasks during multisession tDCS. We used ultra-high field (7T) MRI to examined the metabolic changes that occur following tDCS. After the stimulation period we observed no significant metabolite modulation. A trend towards an increase in the NAA/tCr ratio, with a concomitant decrease in the absolute concentration of tCr was observed. Finally, we examined the functional connectivity before, during and after tDCS with the use of resting-state fMRI at 7T. We observed enhanced connectivity within right sensorimotor area after stimulation compared to during stimulation. This result confirmed that cortical modulations differ during versus after tDCS, signifying that optimal modulation of behaviour may be after the stimulation period. Furthermore, we observed an enhanced correlation between motor regions and the caudate, both during and after stimulation. In conclusion, we observed novel cortical adaptations in CSM patients after surgical decompression, which led us to believe that bihemispheric tDCS of M1-SMA network would result in optimal motor enhancement and warrants further investigation in CSM and other neurological disorders

    The relationship between cortical beta oscillations and motor learning

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    The ability to learn and retain new motor skills is pivotal for everyday life activities and motor rehabilitation after stroke. However, people show considerable individual differences in motor learning. Understanding the neurophysiological processes underlying these individual differences is of significant scientific and clinical importance. At a mechanistic level, oscillations in the beta frequency range (15–30 Hz), fundamental for motor control, reflect underlying cortical inhibitory and excitatory mechanisms. As such, they may provide appropriate biomarkers with which to bridge the gap between cellular and behavioural accounts of cortical plasticity in both healthy and diseased states. This thesis explores the interplay between cortical beta oscillations and individual differences in short-term motor learning within the context of healthy ageing and after stroke. First, I assess the test-retest reliability of resting and movement-related beta estimates in a group of healthy subjects across several weeks. By demonstrating that EEG-derived power measures of beta activity are highly reliable, I validate the notion that these measures reflect meaningful individual differences that can be utilized in basic research and in the clinic. Second, I probe the neurophysiological mechanisms underlying natural inter-individual differences in short-term motor learning. I demonstrate comparable motor learning ability between young and elderly individuals, despite age-related alterations in beta activity. Implementing a multivariate approach, I show that beta dynamics explain some of the individual differences in post-training tracking performance. Third, I extend this line of research by focusing on stroke-related inter-individual variations in motor learning. Employing the same tasks and analyses, I demonstrate preserved, albeit reduced motor learning ability and no aberrant beta activity after stroke. Beta dynamics explained some of the individual differences in stroke patients’ performance 24 hours after training, and may thus offer novel targets for therapeutic interventions
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