Thalamic inflammation after brain trauma is associated with thalamo-cortical white matter damage

Background Traumatic 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. Findings Using [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. Conclusions These findings support a link between axonal damage and persistent inflammation after brain injury

Comparison of methods for automated lesion identification in stroke patients

Introduction Lesion - Symptom mapping forms the foundation to our understanding of the function of different parts of the brain. As the science of neuro-imaging has developed, the detail and quality of images produced on scanning patients have improved. The result is that a single scan can produce a wealth of data. The manual analysis and interpretation of this data have thus become a time consuming and laborious affair. Manual analysis also has the drawback of being highly subjective and user dependent. This has resulted in the development of automated methods for the interpretation of such data. Before data could be analysed, it must be pre-processed into a format that can be optimally used by these methods. This step involves the normalisation, segmentation and spatial smoothing of patient scans. Scans must be pre- processed before automated analysis can be done. The use of automated methods is supposed to make data interpretation quick, reliable and reproducible. 1.2 Aim In this study the smoothing aspect of pre-processing will first be looked at. Here different smoothing levels will be used to try and decide on a value for optimal smoothing. Once this is decided analyses using three automated lesion identification methods will be done. The methods include Voxel Based Morphometry (VBM), Posterior Probability Mapping (PPM) and Fuzzy Clustering with fixed Prototypes (FCP). Parameters for the optimal functioning of these methods will be determined and suggestions will also be made as to which method may be the best and under what circumstances. 1.3 Results The optimal Full Width at Half Maximum (FWHM) value for smoothing was found to be 8mm. When the methods were looked at the following could be said: VBM: Analyses produced results in all 5 patients and Results only produced one level of information. PPM: The optimal probability threshold was determined to be 0.5 Analysis provides two levels of information. Lesions were identified with sharper borders and Analyses required the longest computer processing time. FCP: An a value of 0.5 provides the best results. Lesions identified with less sharp (i.e. fuzzy) borders - method possibly more sensitive and Analyses required the least computer processing time. 1.4 Conclusion This study provides further evidence that smoothing must be carried out on all scans to enable accurate and reliable lesion identification. An optimal FWHM of 8mm was determined. The study also determines an optimal value of 0.5 for the probability threshold in PPM analysis. An optimal a value of 0.5 was also found for FCP analysis. VBM proved to be the easiest method to use while PPM estimated the confidence to declare a tissue as abnormal and FCP was the most sensitive to lesion presence. Further work, however, should be done to further investigate the probability threshold for PPM and a value for FCP

Professional identity development of pre-clerkship medical students: a critical analysis

This dissertation examines how the undergraduate medical education learning environment shapes the development of “the good doctor” professional identity amongst pre-clerkship medical students. The research addresses the gap in scholarship on how the hidden curriculum shapes medical professional identity. The research highlights how the beliefs and practices of students are shaped not by a value-neutral curriculum, but out of and in response to official ideologies perpetuated in the broader learning environment (the “culture” of medical school) in ways that are often hidden. This research was based on a two-year longitudinal critical ethnographic case study of one Canadian medical school. Data collection included focus groups with a core group of students during their first two years of medical school. This was supplemented by interviews with administrative staff and faculty, and observation of the medical school governance meetings. Undergraduate medical education training was examined from students’ perspectives, focusing on how the formal, informal, and hidden curricula shape professional identity. The critical theoretical frameworks of Pierre Bourdieu and Michel Foucault were used to analyze the complex relations of power and influence in pre-clerkship education. Particular attention was paid to how power intersects with the culture of medicine as the identity of a medical professional is constructed. The results show how official ideologies of what it means to be “the good doctor” as prescribed in the national CanMEDS roles and mandated locally through medical school governance structures, are in conflict with and resisted through the counter-ideologies promoted through the hidden curriculum. This research has important implications for curriculum planning in medical education. The findings provide compelling evidence that the formal curriculum must be designed to account for the effects of a hidden curriculum. Specific recommendations are: (1) Medical students would benefit from having a pedagogical space in the formal curriculum to critically reflect on their experiences and the various ideologies and counter-ideologies of “the good doctor” that are shaping their identity; and (2) Establishing communities of practice as a pedagogical space model, would be a useful framework for facilitating this approach, supporting students to navigate the hidden curriculum and negotiate their own professional identity

Neuroinflammation, Mast Cells, and Glia: Dangerous Liaisons

The perspective of neuroinflammation as an epiphenomenon following neuron damage is being replaced by the awareness of glia and their importance in neural functions and disorders. Systemic inflammation generates signals that communicate with the brain and leads to changes in metabolism and behavior, with microglia assuming a pro-inflammatory phenotype. Identification of potential peripheral-to-central cellular links is thus a critical step in designing effective therapeutics. Mast cells may fulfill such a role. These resident immune cells are found close to and within peripheral nerves and in brain parenchyma/meninges, where they exercise a key role in orchestrating the inflammatory process from initiation through chronic activation. Mast cells and glia engage in crosstalk that contributes to accelerate disease progression; such interactions become exaggerated with aging and increased cell sensitivity to stress. Emerging evidence for oligodendrocytes, independent of myelin and support of axonal integrity, points to their having strong immune functions, innate immune receptor expression, and production/response to chemokines and cytokines that modulate immune responses in the central nervous system while engaging in crosstalk with microglia and astrocytes. In this review, we summarize the findings related to our understanding of the biology and cellular signaling mechanisms of neuroinflammation, with emphasis on mast cell-glia interactions

Delayed mGluR5 activation limits neuroinflammation and neurodegeneration after traumatic brain injury

<p>Abstract</p> <p>Background</p> <p>Traumatic brain injury initiates biochemical processes that lead to secondary neurodegeneration. Imaging studies suggest that tissue loss may continue for months or years after traumatic brain injury in association with chronic microglial activation. Recently we found that metabotropic glutamate receptor 5 (mGluR5) activation by (<it>RS</it>)-2-chloro-5-hydroxyphenylglycine (CHPG) decreases microglial activation and release of associated pro-inflammatory factors <it>in vitro</it>, which is mediated in part through inhibition of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Here we examined whether delayed CHPG administration reduces chronic neuroinflammation and associated neurodegeneration after experimental traumatic brain injury in mice.</p> <p>Methods</p> <p>One month after controlled cortical impact traumatic brain injury, C57Bl/6 mice were randomly assigned to treatment with single dose intracerebroventricular CHPG, vehicle or CHPG plus a selective mGluR5 antagonist, 3-((2-Methyl-4-thiazolyl)ethynyl)pyridine. Lesion volume, white matter tract integrity and neurological recovery were assessed over the following three months.</p> <p>Results</p> <p>Traumatic brain injury resulted in mGluR5 expression in reactive microglia of the cortex and hippocampus at one month post-injury. Delayed CHPG treatment reduced expression of reactive microglia expressing NADPH oxidase subunits; decreased hippocampal neuronal loss; limited lesion progression, as measured by repeated T2-weighted magnetic resonance imaging (at one, two and three months) and white matter loss, as measured by high field <it>ex vivo </it>diffusion tensor imaging at four months; and significantly improved motor and cognitive recovery in comparison to the other treatment groups.</p> <p>Conclusion</p> <p>Markedly delayed, single dose treatment with CHPG significantly improves functional recovery and limits lesion progression after experimental traumatic brain injury, likely in part through actions at mGluR5 receptors that modulate neuroinflammation.</p

Cortical Gray Matter Injury in Encephalopathy of Prematurity: Link to Neurodevelopmental Disorders

Preterm-born infants frequently suffer from an array of neurological damage, collectively termed encephalopathy of prematurity (EoP). They also have an increased risk of presenting with a neurodevelopmental disorder (e.g., autism spectrum disorder; attention deficit hyperactivity disorder) later in life. It is hypothesized that it is the gray matter injury to the cortex, in addition to white matter injury, in EoP that is responsible for the altered behavior and cognition in these individuals. However, although it is established that gray matter injury occurs in infants following preterm birth, the exact nature of these changes is not fully elucidated. Here we will review the current state of knowledge in this field, amalgamating data from both clinical and preclinical studies. This will be placed in the context of normal processes of developmental biology and the known pathophysiology of neurodevelopmental disorders. Novel diagnostic and therapeutic tactics required integration of this information so that in the future we can combine mechanism-based approaches with patient stratification to ensure the most efficacious and cost-effective clinical practice

Cathepsin S acts via protease-activated receptor 2 to activate sensory neurons and induce itch-like behaviour

Chronic itch is a debilitating condition characterised by excessive scratching and is a symptom frequently reported in skin diseases such as atopic dermatitis. It has been proposed that release of the cysteine protease Cathepsin S (CatS) from skin keratinocytes or immune cells resident in or infiltrating the skin could act as a pruritogen in chronic itch conditions. CatS is known to activate protease-activated receptor 2 (PAR2). We therefore hypothesised that enzymatic activation of neuronally expressed PAR2 by CatS was responsible for activation of sensory neurons and transmission of itch signals. Intradermally-injected human recombinant (hr)-CatS or the PAR2 agonist, SLIGRL-NH2 behaved as pruritogens by causing scratching behaviour in mice. Hr-CatS-induced scratching behaviour was prevented by CatS inhibitors and PAR2 antagonists and reduced by 50% in TRPV1−/− mice compared with wild-type mice, whilst no significant reduction in scratching behaviour was observed in TRPA1−/− mice. Cultured dorsal root ganglion (DRG) cells showed an increase in [Ca2+]i following incubation with hr-CatS, and the percentage of neurons that responded to hr-CatS decreased in the presence of a PAR2 antagonist or in cultures of neurons from TRPV1−/− mice. Taken together, our results indicate CatS acts as a pruritogen via PAR2 activation in TRPV1-expressing sensory neurons