Browsing by Author "Gallagher, Clare"
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- ItemOpen AccessCerebrovascular pressure reactivity and brain tissue oxygen monitoring provide complementary information regarding the lower and upper limits of cerebral blood flow control in traumatic brain injury: a CAnadian High Resolution-TBI (CAHR-TBI) cohort study(2022-12-23) Gomez, Alwyn; Sekhon, Mypinder; Griesdale, Donald; Froese, Logan; Yang, Eleen; Thelin, Eric P.; Raj, Rahul; Aries, Marcel; Gallagher, Clare; Bernard, Francis; Kramer, Andreas H.; Zeiler, Frederick A.Abstract Background Brain tissue oxygen tension (PbtO2) and cerebrovascular pressure reactivity monitoring have emerged as potential modalities to individualize care in moderate and severe traumatic brain injury (TBI). The relationship between these modalities has had limited exploration. The aim of this study was to examine the relationship between PbtO2 and cerebral perfusion pressure (CPP) and how this relationship is modified by the state of cerebrovascular pressure reactivity. Methods A retrospective multi-institution cohort study utilizing prospectively collected high-resolution physiologic data from the CAnadian High Resolution-TBI (CAHR-TBI) Research Collaborative database collected between 2011 and 2021 was performed. Included in the study were critically ill TBI patients with intracranial pressure (ICP), arterial blood pressure (ABP), and PbtO2 monitoring treated in any one of three CAHR-TBI affiliated adult intensive care units (ICU). The outcome of interest was how PbtO2 and CPP are related over a cohort of TBI patients and how this relationship is modified by the state of cerebrovascular reactivity, as determined using the pressure reactivity index (PRx). Results A total of 77 patients met the study inclusion criteria with a total of 377,744 min of physiologic data available for the analysis. PbtO2 produced a triphasic curve when plotted against CPP like previous population-based plots of cerebral blood flow (CBF) versus CPP. The triphasic curve included a plateau region flanked by regions of relative ischemia (hypoxia) and hyperemia (hyperoxia). The plateau region shortened when cerebrovascular pressure reactivity was disrupted compared to when it was intact. Conclusions In this exploratory analysis of a multi-institution high-resolution physiology TBI database, PbtO2 seems to have a triphasic relationship with CPP, over the entire cohort. The CPP range over which the plateau exists is modified by the state of cerebrovascular reactivity. This indicates that in critically ill TBI patients admitted to ICU, PbtO2 may be reflective of CBF.
- ItemOpen AccessCortical Excitability after Mild Traumatic Brain Injury in Children(2015-12-04) Seeger, Trevor; Barlow, Karen; Kirton, Adam; Dunn, Jeff; Gallagher, Clare; Esser, MichaelIntroduction: Mild traumatic brain injury is frequently complicated by post-concussive syndrome. It is unknown why these symptoms persist, but recent research suggests that cortical excitability may play a role. Objectives: To determine if cortical excitability is different in pediatric mTBI, and if it correlates with symptom persistence. Methods:This was a cross-sectional controlled cohort study. Cortical excitability was measured using a variety of TMS paradigms in children with (symptomatic) and without (asymptomatic) persistent symptoms at one month post injury. The primary outcome measure was the corticalsilent period (cSP) (thought to represent GABAergic inhibition). Results: 57 children with mTBI (44% male; age 14.23 (SD:2.49)) and 28 controls were compared. cSP was similar between groups (F(2, 70)=0.53, p=0.591). There were no other significant group differences in cortical excitability. Conclusions: TMS was well tolerated in children with mTBI. Cortical excitability is similar to normal children at one-month following the injury.
- ItemOpen AccessCortical excitability after pediatric mild traumatic brain injury(Elsevier, 2016-11-19) Seeger, Trevor A.; Kirton, Adam; Esser, Michael J.; Gallagher, Clare; Dunn, Jeff F.; Zewdie, Ephrem Takele; Damji, Omar; Ciechanski, Patrick; Barlow, Karen M.Introduction: Mild traumatic brain injury (mTBI) outcomes are variable, and 10e15% may suffer from prolonged symptoms beyond 3 months that impair the child's return to normal activities. Neurophysiological mechanisms of mTBI are incompletely understood, particularly in children, but alterations in cortical excitability have been proposed to underlie post-concussion syndrome. Improved understanding is required to advance interventions and improve outcomes. Objective/Hypothesis: To determine if cortical excitability is altered in children with mTBI, and its association with clinical symptoms. Methods: This was a cross-sectional controlled cohort study. School-aged children (8e18 years) with mTBI were compared to healthy controls. Cortical excitability was measured using multiple TMS paradigms in children with (symptomatic) and without (recovered) persistent symptoms one-month post-injury. Primary outcome was the cortical silent period (cSP), a potential neurophysiological biomarker of GABAergic inhibition. Secondary outcomes included additional TMS neurophysiology, safety and tolerability. Associations between neurophysiology parameters and clinical symptoms were evaluated. Results: Fifty-three children with mTBI (55% male; mean age 14.1 SD: 2.4 years; 35 symptomatic and 27 asymptomatic participants) and 28 controls (46% male; mean age 14.3 SD: 3.1 years) were enrolled. cSP duration was similar between groups (F (2, 73) ¼ 0.55, p ¼ 0.582). Log10 long interval intracortical inhibition (LICI) was reduced in symptomatic participants compared to healthy controls (F (2, 59) ¼ 3.83, p ¼ 0.027). Procedures were well tolerated with no serious adverse events. Conclusions: TMS measures of cortical excitability are altered at one month in children with mTBI. Long interval cortical inhibition is decreased in children who remain symptomatic at one month post-injury.
- ItemOpen AccessPrognostic value of near-infrared spectroscopy regional oxygen saturation and cerebrovascular reactivity index in acute traumatic neural injury: a CAnadian High-Resolution Traumatic Brain Injury (CAHR-TBI) Cohort Study(2024-03-14) Gomez, Alwyn; Froese, Logan; Griesdale, Donald; Thelin, Eric P.; Raj, Rahul; van Iperenburg, Levi; Tas, Jeanette; Aries, Marcel; Stein, Kevin Y.; Gallagher, Clare; Bernard, Francis; Kramer, Andreas H.; Zeiler, Frederick A.Abstract Background Near-infrared spectroscopy regional cerebral oxygen saturation (rSO2) has gained interest as a raw parameter and as a basis for measuring cerebrovascular reactivity (CVR) due to its noninvasive nature and high spatial resolution. However, the prognostic utility of these parameters has not yet been determined. This study aimed to identify threshold values of rSO2 and rSO2-based CVR at which outcomes worsened following traumatic brain injury (TBI). Methods A retrospective multi-institutional cohort study was performed. The cohort included TBI patients treated in four adult intensive care units (ICU). The cerebral oxygen indices, COx (using rSO2 and cerebral perfusion pressure) as well as COx_a (using rSO2 and arterial blood pressure) were calculated for each patient. Grand mean thresholds along with exposure-based thresholds were determined utilizing sequential chi-squared analysis and univariate logistic regression, respectively. Results In the cohort of 129 patients, there was no identifiable threshold for raw rSO2 at which outcomes were found to worsen. For both COx and COx_a, an optimal grand mean threshold value of 0.2 was identified for both survival and favorable outcomes, while percent time above − 0.05 was uniformly found to have the best discriminative value. Conclusions In this multi-institutional cohort study, raw rSO2was found to contain no significant prognostic information. However, rSO2-based indices of CVR, COx and COx_a, were found to have a uniform grand mean threshold of 0.2 and exposure-based threshold of − 0.05, above which clinical outcomes markedly worsened. This study lays the groundwork to transition to less invasive means of continuously measuring CVR.
- ItemOpen AccessStability and a-complementation of M15 B-galactosidase from escherichia coli(1994) Gallagher, Clare; Huber, R. EugeneM15 B-Galactosidase from Escherichia coli is an inactive variant of Bgalactosidase with a deletion of residues 11-41. The protein can become active by the addition of a peptide derived from the N-terminal end of the wild type protein, by a process termed a-complementation. A fusion protein system was developed which allowed for the production and purification of a-peptide. This significantly decreased the time required to obtain pure peptide. The peptide produced in this way was also found to complement to a higher activity than the chemically cleaved (by cyanogen bromide) peptide from wild type B-galactosidase. Factors which affected the a-complementation of M15 B-galactosidase were investigated for their effects on activation (a-complementation). It was found that NaCl and B-mercaptoethanol increased the activation. Mg2+ increased the activity at low concentration but inhibited activation at high concentrations. The equilibrium between monomers and dimers was investigated. From experiments done at a series of protein concentrations, the Kd for monomer-dimer equilibrium was found to be 2.78 ± 0.76 x 10-7 M. The concentration of the protein was important in the equilibrium. Mg2+, NaCl and B-mercaptoethanol were shown to lower the Kd. The pH also affected the monomer-dimer equilibrium. The stability of M15 B-galactosidase was examined by thermal denaturation. The uncomplemented protein was found to have a lower temperature of activity loss than wild type protein. The complemented protein was more stable to heat than the uncomplemented M15 B-galactosidase if Mg2+ was present. The complemented enzyme lost activity non-cooperatively. The conformational stability of the M15 B-galactosidase protein was examined by urea denaturation. Unfolding intermediates of wild type Bgalactosidase were stabilized by Mg2+ and NaCl. For the M15 Bgalactosidase, NaCl stabilizes the intermediate structures but there was minimal stabilization by Mg2+. Complementation of the M15 B-galactosidase did not appear to increase the AG(H2O). The binding of a-peptide to the protein was found to be a 1:1 ratio of peptide per monomer ofM15 B-galactosidase with both dimers and tetramers. It was also shown that the peptide derived from the fusion protein formed distinct states of tetramers. The a-complementation process did not alter the binding of substrate to enzyme. The catalytic activity was, however, altered.
- ItemOpen AccessThe Interrogation of Traumatic Brain Injury with MR Spectroscopy and Molecular Imaging(2016) Lama, Sanju; Sutherland, Garnette; Tomanek, Boguslaw; Colicos, Michael; Zygun, David; Gallagher, ClareMetabolic perturbations in early acute severe traumatic brain injury (TBI) using magnetic resonance (MR) spectroscopy, and the prospects of molecular imaging of repetitive mild TBI, form the driving principles of this thesis work. Brain metabolism is thought to be maintained by neuronal-glial metabolic coupling, whereby glia take up glutamate from the synaptic cleft for conversion into glutamine, triggering glial glycolysis and lactate production. This lactate is shuttled into neurons and further metabolized. Using a weight drop model of severe TBI and MR spectroscopy with infusion of 13C labeled glucose, lactate and acetate, this portion of the thesis investigated the hypothesis that neuronal-glial metabolism is uncoupled following severe TBI. High resolution MR spectroscopy revealed significant labeling of lactate irrespective of the infused substrate and decreased labelling of other metabolites. Histopathology, while showing features of severe brain injury, also stained positive for tau. A microtubule associated protein, tau has been shown to accumulate in brains following TBI, particularly those related to sports and combat. It was further hypothesized that tau could be visualized through the administration of a unique anti-tau single domain antibody (sdAb)-nanoparticle complex. Through llama immunization, tau specific sdAbs were isolated, panned and characterized for bioconjugation to MR sensitive NaDyF4-NaGdF4 nanoparticles, towards non-invasive imaging of tau in vivo. At a ratio of ~4 sdAbs per nanoparticle, the complex was able to cross the neuronal membrane and bind to intracellular tau in live hippocampal neuronal cultures. Preliminary in vivo studies, establishing the model for repetitive mild TBI showed considerable tau staining within the entorhinal cortex, dentate gyrus and hippocampal CA3 sector sparing CA1. While there were some T1 changes in MR imaging, clinical translation will require further tests for sdAb – nanoparticle affinity to both tau and hyperphosphorylated tau, optimal dosage and safety, toxicology and clearance profile. It may be concluded that the early increase in brain lactate or lactate storm marks severe TBI; and tau abnormality and associated disrupted axonal transport, may be the hallmark of repetitive mild TBI, making it a potential MR visible biomarker for TBI. These concepts may guide future diagnostic and therapeutic directions.