Immunohistochemical staining with the hypoxia marker pimonidazole.
GFAP staining in the hippocampus
Dentate gyrus. PV positive interneurons (red), c-Fos activation (green)
Increased neuronal loss in injured mice exposed to be broad spectrum antibiotics
Research in our lab is focused on traumatic brain injury (TBI). Specifically we are focused on utilizing clinically relevant animal models of TBI to study the effects of secondary insults (such as intracranial hypertension, systemic hypotension, and systemic hypoxemia) after moderate and severe TBI. By further understanding the effects of secondary insults we hope to develop novel neuroprotective approaches and therapeutics that can improve outcomes following TBI.
Areas of Focus:
Delayed hypoxemia following traumatic brain injury: A new target for neuroprotective targets
To explicitly model the contribution of secondary brain hypoxia, we have developed a clinically relevant murine model of TBI with delayed hypoxemia. Our objective is to test therapeutics that may mitigate secondary injury from delayed hypoxemia following TBI. Utilizing a rigorous preclinical trial funnel design including adequate sample sizes, minimization of bias, validation/replication of results, clinically relevant long term outcomes, and testing of sex and genotype factors, we have established a framework for efficient testing of potential candidate therapeutics.
Acute stress and long-term maladaptive fear memory after traumatic brain injury.
Clinical research supports high rates of TBI-PTSD comorbidity and confirms TBI as a significant predictor in the development of PTSD. However, the biological mechanisms impacted following brain injury that may lead to increased PTSD risk are currently unknown. Maladaptive and abnormal fear memory has been associated with PTSD, which decreases one’s ability to restrict fear to the appropriate context. Altered hippocampal-amygdala circuitry may be a contributing factor to such pathologic memory. Utilizing our previously developed murine model of TBI with delayed hypoxemia, we aim to elucidate the underlying mechanism involved with abnormal fear response after TBI, which could provide a unique opportunity to develop pharmacological and non-pharmacological approaches that target clinically relevant long-term psychological dysfunction for TBI survivors.
Intestinal microbial modulation of traumatic brain injury
The influence of gut microbiota on TBI, tissue repair and subsequent neurological outcome is currently unknown. This knowledge gap is of paramount clinical significance as TBI patients are highly susceptible to alterations in gut microbiota due to frequent antibiotic administration, prolonged hospitalization and autonomic dysfunction. In collaboration with the laboratory of Ashley Steed, (microbial-host immunity) we are exploring the influence of gut microbial dysbiosis utilizing immunohistochemistry, flow cytometry, and behavioral assessments.
Stuart Friess M.D.
Division of Critical Care Medicine
Department of Pediatrics
Campus Box 8028
660 S. Euclid Avenue
St. Louis, MO 63110
Friess SH, Ichord RN, Owens K, Ralston J, Rizol R, Overall KL, Smith C, Helfaer MA, Margulies SS. Neurobehavioral functional deficits following closed head injury in the neonatal pig. Exp Neurol. 2007; 204(1):234-43. doi:10.1016/j.expneurol.2006.10.010 PMCID: PMC1892165 PMID: 17174304
Friess SH, Ichord RN, Ralston J, Ryall K, Helfaer MA, Smith C, Margulies SS. Repeated traumatic brain injury affects composite cognitive function in piglets. J Neurotrauma. 2009;26(7):1111-21. doi:10.1089/neu.2008.0845 PMCID: PMC2848948 PMID: 19275468
Friess SH, Smith C, Kilbaugh TJ, Frangos SG, Ralston J, Helfaer MA, Margulies SS. Early cerebral perfusion pressure augmentation with phenylephrine after traumatic brain injury may be neuroprotective in a pediatric swine model. Crit Care Med. 2012; 40(8):2400-6. doi:10.1097/CCM.0b013e31825333e6 PMCID: PMC3400930 PMID: 22809910
Bruins B, Kilbaugh TJ, Margulies SS, Friess SH. The anesthetic effects on vasopressor modulation of cerebral blood flow in an immature swine model. Anesth Analg. 2013; 116(4):838-44. doi:10.1213/ANE.0b013e3182860fe7 PMCID: PMC3606687 PMID: 23460561
Friess SH, Lapidus JB, Brody DL. Decompressive craniectomy reduces white matter injury after controlled cortical impact in mice. J Neurotrauma. 2015; 32(11):791-800. doi:10.1089/neu.2014.3564 PMID: 25557588
Parikh U, Williams M, Jacobs A, Pineda JA, Brody DL, Friess SH. Delayed Hypoxemia Following Traumatic Brain Injury Exacerbates White Matter Injury. J Neuropathol Exp Neurol. 2016. PMID: 27288907
Davies M, Jacobs A, Brody DL, Friess SH. Delayed Hypoxemia Following Traumatic Brain Injury Exacerbates Long-Term Behavioral Deficits. J Neurotrauma. 2018. PMID: 29149808