Traumatic brain injury (TBI) research has focused on moderate to severe injuries as their outcomes are significantly worse than those of a mild TBI (mTBI). However, recent epidemiological evidence has indicated that a series of even mild TBIs greatly increases the risk of neurodegenerative and psychiatric disorders. Neuropathological studies of repeated TBI have identified changes in neuronal ionic concentrations, axonal injury, and cytoskeletal damage as important determinants of later life neurological and mood compromise; yet, there is a paucity of data on the contribution of neurogliovascular dysfunction to the progression of repeated TBI and alterations of brain function in the intervening period.Methods: Here, we established a mouse model of repeated TBI induced via three electromagnetically actuated impacts delivered to the intact skull at three-day intervals and determined the long-term deficits in neurogliovascular functioning in Thy1-ChR2 mice. Two weeks post the third impact, cerebral blood flow and cerebrovascular reactivity were measured with arterial spin labelling magnetic resonance imaging. Neuronal function was investigated through bilateral intracranial electrophysiological responses to optogenetic photostimulation. Vascular density of the site of impacts was measured with in vivo two photon fluorescence microscopy. Pathological analysis of neuronal survival and astrogliosis was performed via NeuN and GFAP immunofluorescence.Results: Cerebral blood flow and cerebrovascular reactivity were decreased by 50±16% and 70±20%, respectively, in the TBI cohort relative to sham-treated animals. Concomitantly, electrophysiological recordings revealed a 97±1% attenuation in peri-contusional neuronal reactivity relative to sham. Peri-contusional vascular volume was increased by 33±2% relative to sham-treated mice. Pathological analysis of the peri-contusional cortex demonstrated astrogliosis, but no changes in neuronal survival.Conclusion: This work provides the first in-situ characterization of the long-term deficits of the neurogliovascular unit following repeated TBI. The findings will help guide the development of diagnostic markers as well as therapeutics targeting neurogliovascular dysfunction.
Abstract:We describe eleven mid-western Canadian aboriginal infants with a unique, progressive muscle disorder. All except one had muscle biopsy and/or autopsy. The infants were normal newborns who rapidly developed rigidity of all skeletal muscles, with early, respiratory insufficiency. Death occurred before 18 months of age. Electromyography showed increased insertion activity and profuse fibrillation potentials; motor unit potentials and interference pattern are normal until late in the course. Pathologic features include progressive, granular to powdery Z-band transformation, myofibrillar loss, and muscle regeneration. SDS-gel electrophoresis of one muscle sample revealed increased 54kDa and reduced 80kDa protein fractions. This disease differs from other conditions with Z-band alterations because of continuous muscle activity and relentless clinical progression. The clinical features, elevated serum creatine kinase, electromyographic and muscle biopsy findings suggest a dystrophic process. The recognition of this condition as an autosomal recessive disorder allows appropriate genetic counselling.Resume: Dystrophic musculaire hypertonique infantile fatale dont l'heredite est autosomale recessive chez les autochtones. Nous decrivons onze nourrissons autochtones de l'ouest canadien atteints d'une affection musculaire progressive. Tous sauf un ont eu une biopsie musculaire et/ou une autopsie. Les nourrissons 6taient normaux a la naissance. lis ont deVeloppe rapidement de la rigiditd de tous les muscles squelettiques avec une insuffisance respiratoire pr6coce et sont ddcfides avant Page de 18 mois. L'electromyographie a montre 1 une activity d'insertion augmentee et des potentiels de fibrillation en abondance; les potentiels de plaques motrices et le trace 1 interfdrentiel fitaient normaux jusqu'a un stade avance de la maladie. A l'anatomopathologie, on remarque une transformation progressive de granulaires a poudreuses des bandes en Z, une perte neurofibrillaire et une regeneration musculaire. L'electrophorese sur gel SDS d'un echantillon musculaire a reVele une augmentation de la fraction protdique de 54kD et une diminution de la fraction de 80kD. Cette maladie est diffeYente des autres affections ou Ton observe des alterations des bandes en Z a cause de Pactivite musculaire continue et de la progression clinique inexorable. Les caracteristiques cliniques, I'elevation de la creatine-kinase, les observations electromyographiques et anatomopathologiques suggerent qu'il s'agit d'un processus dystrophique. L'identification de cette affection comme etant une maladie autosomale recessive permet d'offrir une conseil gdn&ique approprie.
Although epidemiological evidence suggests significant sex and gender-based differences in stroke risk and recovery, females have been widely under-represented in preclinical stroke research. The neurovascular sequelae of brain ischemia in females, in particular, are largely uncertain. We set out to address this gap by a multimodal in vivo study of neurovascular recovery from endothelin-1 model of cortical focal-stroke in sham vs. ovariectomized female rats. Three weeks post ischemic insult, sham operated females recapitulated the phenotype previously reported in male rats in this model, of normalized resting perfusion but sustained peri-lesional cerebrovascular hyperreactivity. In contrast, ovariectomized (Ovx) females showed reduced peri-lesional resting blood flow, and elevated cerebrovascular responsivity to hypercapnia in the peri-lesional and contra-lateral cortices. Electrophysiological recordings showed an attenuation of theta to low-gamma phase-amplitude coupling in the peri-lesional tissue of Ovx animals, despite relative preservation of neuronal power. Further, this chronic stage neuronal network dysfunction was inversely correlated with serum estradiol concentration. Our pioneering data demonstrate dramatic differences in spontaneous recovery in the neurovascular unit between Ovx and Sham females in the chronic stage of stroke, underscoring the importance of considering hormonal-dependent aspects of the ischemic sequelae in the development of novel therapeutic approaches and patient recruitment in clinical trials.
1 Technical Efficacy: Stage 4 J. MAGN. RESON. IMAGING 2017;46:505-517.
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