Browsing by Author "Esser, Michael J."

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    Cortical 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.
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    Mitochondria, Inflammation, and T-Cell Metabolism in a Rat Model of Pediatric Mild Traumatic Brain Injury
    (2020-07-24) Fraunberger, Erik Albert; Esser, Michael J.; Shutt, Timothy E.; Gallagher, Clare N.; Yeates, Keith Owen; Kurrasch, Deborah M.; Noble-Haeusslein, Linda J.
    Representing approximately 20,000 emergency department visits in Canada every year, pediatric traumatic brain injury (TBI) can be an intractable medical problem with limited treatment options. While most research has been directed towards the devastating, moderate-severe end of the TBI spectrum, most clinical injuries present as mild with minimal duration of loss of consciousness and lack of macroscopic damage to neural tissue. The pediatric population is especially vulnerable to the consequences of these milder injuries as developmental processes and long-term functioning can be impacted by negative cognitive and emotional changes persisting for up to and beyond one month after injury. Although we have some understanding of TBI pathophysiology including diffuse axonal injury, mitochondrial dysfunction, and cerebral blood flow dysregulation, there is still no clear understanding as to how the developing brains responds and adapts to injury. This thesis takes up the challenge of studying a mild, heterogeneous injury using a juvenile rat TBI model. It begins to unravel some of the complex pathophysiological patterns after pediatric mTBI from the perspectives of mitochondrial function, inflammation, and T-cell metabolism. First, we documented females having greater mitochondrial oxygen consumption in brain cells 21 days after a single mTBI, offering insight into one mechanism for persistent impairments in females following pediatric mTBI. Second, we highlight inflammatory changes to the understudied cerebellum, show cytokines as poor biomarkers of mTBI, and illustrate dynamic changes in inflammation after pediatric mTBI using network analysis. Third, we found preliminary evidence of metabolic changes in CD4+ T-cells starting at 24h post-mTBI, revealing possible upstream changes to observed inflammation previously shown only at 4-7 days after injury. Seeing changes in substrate oxidation patterns presaging inflammation may reveal nascent benefits to targeting metabolism to alter inflammation for therapeutic intervention. Collectively, the work in this thesis significantly advances our knowledge of pediatric mTBI pathophysiology, introduces new ways to interpret inflammation data, and paves the way for the investigation of novel pathways for therapeutic intervention.
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    Neurophysiological and diffusion tensor imaging correlates of mild traumatic brain injury in children
    (2018-07-24) King, Regan; Kirton, Adam; Barlow, Karen; Lebel, Catherine A.; Esser, Michael J.; Federico, Paolo
    Children typically recover quickly following a mild traumatic brain injury (mTBI), however up to 15% of children continue to experience symptoms past three months post injury. Currently, underlying mechanisms of persistent post-concussive symptoms (PPCS) in children are unknown. The present thesis uses transcranial magnetic stimulation (TMS) and diffusion tensor imaging (DTI) to characterize the structural and functional characteristics of PPCS in 98 children (aged 8-18) with mTBI, over time. The Post-concussive Symptom Inventory (PCSI) was used to classify post-concussive symptoms in participants as symptomatic or asymptomatic. Twenty-six healthy controls were included for comparison. Neurophysiological data assessing cortical inhibition and facilitation were evaluated alongside symptom status. Associations between symptom status and DTI measures of water diffusion and anisotropy were also assessed in the corticospinal tract (CST), motor fibers of the corpus callosum (CC), and uncinate fasciculus (UF). Differences in neurophysiology were noted between healthy controls and children with mTBI in both inhibitory and excitatory TMS paradigms, further differentiating by symptom status. Differences in inhibitory paradigms were also noted over time. Fractional anisotropy (FA) differed as well in the UF, but not in the CST or CC, of symptomatic children compared to controls. No differences in diffusion metrics were observed over time. In summary, these findings suggest an indirect association of neurophysiology and white matter structure in mTBI recovery. Further exploration of neurophysiological and imaging correlates of PPCS are required to improve recovery and treatment outcomes of mTBI.
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    Temporal expression pattern of cytokines and other markers of brain injury in term infants with hypoxic ischemic injury
    (2018-09-13) Goswami, Ipsita Roy; Esser, Michael J.; Mineyko, Aleksandra; Pittman, Q. J.; Yusuf, Kamran; Khorshid, Mohammad
    Hypoxic Ischemic Encephalopathy (HIE) is the most common cause of perinatal brain injury. Treatment is available, therapeutic hypothermia (TH), but reliable tools are needed to determine early after birth who will benefit most. Cytokines, as indicators of brain injury, are potential biomarkers and are best studied by understanding network changes. This study sought to identify the cytokine molecular signatures associated with abnormal MRI or death in neonates with HIE. Multiplex immunoassay was used to quantify cytokine levels at multiple timepoints from birth to 96 hours of life. Machine learning algorithms were used for pattern identification to gain mechanistic insights. Cord blood levels of IL-6, IFNγ, IL-1ra, G-CSF, FGF-b and MCP-1 were significantly elevated in neonates with HIE compared to controls. Neonates with abnormal MRI or death had elevated cord blood IL-10 and MCP1 levels, high serum IL1ra and G-CSF levels at 24 hours, and low PDGF and IP10 levels at all time points. Further, in neonates with adverse outcomes IL-10, G-CSF, MCP1, IL-6, TNF-α, IL-8, and IL-1ra levels were elevated, while IL-4, PDGF, MIP1a, IL-15, IP10, and IFN-γ were lower at all time points. Conversely, the combinations of TNF-α levels < 74.4 pg/ml with IL8 levels > 0.85 pg/ml and IFN-γ levels > 0.04 pg/ml in cord blood predicted normal MRI (sensitivity 100%, specificity 37.5%). Similarly, IL-10 levels > 36.7 pg/ml or a combination of IL-6 levels < 8.46 pg/ml and IL-8 levels > 59.5 pg/ml at 24 hours were predictive of unfavorable outcome (sensitivity 95.2%, specificity of 62.5%). Regardless of the encephalopathy grading, TH shifted the cytokine balance towards neurotrophic factors (G-CSF) and Th2 cytokines (IL-4, IL-5, IL-10) around 24 hours of life followed by a reversal towards Th1 cytokines (IL-2, TNF-α and IFN-γ) after termination of TH. This general analysis of the peripheral cytokines in HIE delineates the principal drivers of the cytokine network that may serve as biomarkers. Upregulation of proinflammatory cytokines accompanied by active modulation of anti-inflammatory cytokines could account for the variations in patient-specific innate compensatory response that ultimately characterizes the short-term clinical outcome.
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    Temporal profile of blood cytokine levels and placental pathology in extremely preterm infants
    (2020-04-26) Zein, Hussein; Esser, Michael J.; Bründler, Marie Anne; Kirton, Adam; Mohammad, Khorshid
    Objective: To evaluate the relationship between placental pathology and the temporal profiles of “cytokine” (cytokines, chemokines and growth factors) levels in extremely preterm infants. Study design: A prospective cohort study of preterm infants born before 29 weeks gestational age (GA) and admitted to the neonatal intensive care unit (NICU) between June 2017 and July 2018 (n=55). Levels of 27 cytokines were measured in blood obtained from the umbilical cord at birth, 24-72 hours, and 21-28 days of life. Cytokine levels were determined using the Bio-Rad Multiplex Immunoassay System. Placental pathology per the 2016 Amsterdam consensus criteria and grouped as normal (N), inflammation (I), vasculopathy (V), or combined vasculopathy and inflammation (V+I). Results: Complete data was available from 42 patients. Cord blood median levels of cytokines differed between groups with the highest levels observed in group V+I as compared to groups N, I and V for the following: Eotaxin (p = 0.038), G-CSF (p = 0.023), IFN-γ (p = 0.002), IL-1ra (p < 0.001), IL-4 (p = 0.005), IL-8 (p = 0.010), MCP-1 (p = 0.011), and TNFα (p = 0.002). Post hoc analysis revealed sex differences in group I, with higher median levels of FGF-basic (p = 0.03), G-CSF (p = 0.048), IL1b (p = 0.038), IL-1ra (p = 0.005), IL-8 (p = 0.005), MIP-1α (p = 0.048) and TNFα (p = 0.048) in females. Conclusion: Specific types of placental pathology may be associated with differential cytokine profiles in extremely preterm infants. Sampling from cord blood may help assess the pathological status of the placenta and potentially infer outcome risks for the infant.