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Abstract

This brief history of neurotrauma research at the University of California (UC), Davis, is based on a Keynote Address by the first author, which was presented at the UC Davis Symposium for Neurotrauma Advancement, Partnership, Strategy and Exploration (SyNAPSE) held on August 12, 2025, in Sacramento, California. This compendium describes a 58-year “journey” of clinical and laboratory neurotrauma research from multiple departments at UC Davis. This is a representative sample of UC Davis’s significant and often groundbreaking contributions to science, clinical innovation, and patient care related to neurotrauma. Importantly, the talented people responsible for this work are showcased.

Keywords

traumatic brain injury spinal cord injury human studies

Section 1: The Early Years, 1967–1996

Julian Youmans, MD, established the Department of Neurological Surgery in 1967 and served as Chair until 1982. During his early years at the University of California (UC), Davis, Professor Youmans prioritized neurotrauma research and assigned his residents to study cervical spine injuries that were incurred each summer by people jumping from the bridges spanning the American and Sacramento rivers, sometimes in too shallow water. Professor Youmans was an advocate of automobile safety and was instrumental in the enactment of seat belt laws. He also wrote the widely regarded definitive reference book of Neurological Surgery.¹

John Harris, MD (affectionately known as the “Ski-Doc”), performed America’s first observational, prospective medical/surgical study of TBI in alpine skiing. Dr. Harris served on the ski patrol for the 1960 Winter Olympics at Squaw Valley. In 1975, Professor Youmans appointed Dr. Harris to the UC Davis Neurosurgery faculty and inspired him to study Tahoe’s brain ski trauma experience in a rigorous, scientific, and prospective manner.² Dr. Harris’ research and advocacy were instrumental in establishing rule changes requiring helmet use in alpine ski competition and later for helmet requirements for recreational skiers. While serving as a staff neurosurgeon at Barton Memorial Hospital (Lake Tahoe, CA), he regularly flew his twin-engine Beechcraft to Sacramento Executive Airport to attend UC Davis Neurological Surgery grand rounds.

Barry French, MD, published a landmark study of CT and head trauma in 1977 when UC Davis was one of the first medical centers to have CT. He demonstrated an accuracy approaching 100% in the diagnosis of intra- and extra-cerebral hematomas.³ Dr. French also served as Acting Chair of UC Davis Neurosurgery during the leadership transition from Dr. Youmans to Dr. Franklin Wagner.

Franklin Wagner, MD, served as Chair from 1982 to 1989. He was a major participant in the National Spinal Cord Injury Studies clinical trials evaluating the acute administration of methylprednisolone,^4–6 Dr. Wagner also edited an influential book with Laurence Pitts, MD (UC San Francisco), that was a comprehensive review of contemporary management of neurotrauma.⁷

Section 2: TBI Laboratory Progress 1997–2024

In 1997, J. Paul Muizelaar, MD, PhD, was recruited from Wayne State University in Detroit to serve as Chair of UC Davis Neurological Surgery. Dr. Muizelaar brought a vision of building a state-of-the-art neurotrauma animal laboratory, modeled after his earlier experience at the Medical College of Virginia in Richmond. Dr. Muizelaar recruited Robert Berman, PhD, from Wayne State University to bring his expertise in neurochemistry and behavior to UC Davis. Together, they launched the Neurosurgery Neurotrauma Lab at the UC Davis Center for Neuroscience in Davis, CA. The following year, Bruce Lyeth, PhD, was recruited from the Medical College of Virginia to bolster the Neurotrauma Laboratory. Dr. Lyeth brought his extensive experience in TBI animal models, behavior, pharmacology, and small animal surgery to the growing neurotrauma laboratory. In 2000, UC Davis Neurosurgery became a charter member of the University of California Neurotrauma Consortium, which was initiated by David Hovda, PhD, at UCLA. The consortium hosted an annual research symposium of which UC Davis participated in each of the subsequent 24 years.

Intracranial Physiology

In 1999, Dr. Muizelaar recruited Marike Zwienenberg, MD, from Amsterdam to work with Drs. Berman and Lyeth as a laboratory Research Fellow prior to her entering the UC Davis Neurological Surgery residency program. In one of the first studies conducted in the new Neurotrauma Laboratory, Drs. Zwienenberg and Lyeth performed an intricate ICP study in a rat model of subdural hematoma. Dr. Zwienenberg simultaneously measured ICP using three different techniques in the same rats and validated the cortical placement of a Camino transducer against the gold standard intraventricular method, both of which were more accurate than the cistern magna measurements.⁸

Glutamate Excitotoxicity

The role of glutamate excitotoxicity in TBI was an early focus of the Neurotrauma Lab. Drs. Zwienenberg and Lyeth performed NIH RO1-funded studies expanding the targets for interventions to reduce glutamate excitotoxicity. They demonstrated that selectively manipulating different subtypes of metabotropic glutamate receptors (mGluRs) reduced neuronal cell death associated with experimental TBI in the rat. They used selective antagonists of excitatory mGluRs and selective agonists of inhibitory mGluRs and found that both strategies reduced neuronal cell death after experimental TBI in the rat.⁹

The excitotoxicity research theme continued with Jun-Feng Feng, MD, PhD, Gene Gurkoff, PhD, and Dr. Lyeth investigating a novel method to reduce glutamate excitotoxicity by targeting the peptide neurotransmitter, N-acetyl-aspartyl-glutamate (NAAG). NAAG is coreleased with glutamate in the synapse but only during intense neuronal activity (e.g., initiated by TBI). NAAG reduces excessive glutamate release by stimulating inhibitory presynaptic mGluR3 receptors. Importantly, the influence on synaptic glutamate is temporary because NAAG is rapidly inactivated by a peptidase in the synapse. The team administered a selective NAAG peptidase inhibitor (ZJ-43) that successfully increased and prolonged high levels of NAAG in the synapse.¹⁰ They subsequently demonstrated that post-TBI administration of a NAAG peptidase inhibitor abolished the detrimental effects of secondary hypoxia on hippocampal cell death in a fluid percussion model of TBI in the rat.¹¹ This study suggested the potential utility of this therapeutic strategy for treating secondary insults that may occur even hours after the primary TBI.

Astrocyte Pathology and Biomarkers

In 2003, Zhao Xueren, MD, and Dr. Lyeth published the first study examining astrocyte pathology after experimental TBI.¹² Astrocytes were labeled in brain section using GFAP immunohistochemistry at various times after lateral fluid percussion TBI in the rat or sham TBI (control). At 24 hours after TBI, there was a significant loss (60%) of astrocytes in the ipsilateral hippocampus. This publication led to NIH RO1 funding and had major impacts on the TBI field, initiating interest in glia pathology after TBI. Furthermore, this research set the stage for the later development of GFAP as a blood and CSF biomarker for TBI.

In 2005, Candace Floyd, PhD, further explored mechanisms of astrocyte pathology after TBI. Using a cell culture model of mechanical strain injury, Dr. Floyd revealed pathological elevations in intracellular sodium and calcium in astrocytes that could both be attenuated by pharmacologically blocking the reversal of the Na⁺/Ca ⁺⁺ exchanger.¹³ These findings revealed that reversal of the Na⁺/Ca⁺⁺ exchanger is an important pathological mechanism affecting astrocytes after TBI that could lead to novel treatment interventions.

As a follow-up to astrocyte pathology studies, Dr. Lyeth speculated that fragments of GFAP from damaged astrocytes might be found in blood and CSF and thus serve as a brain biomarker of TBI. In collaboration with Banyan Biomarkers, Inc., Huang Xianjian, MD, Ken Van, MS, and Dr. Lyeth measured large increases in GFAP in serum at 3- and 6-h after fluid percussion TBI in the rat, while CSF levels of GFAP were also significantly elevated at 24 h compared to sham TBI.¹⁴ This study contributed to the FDA approval of GFAP as a clinical biomarker for mild TBI. GFAP biomarkers have progressed to the point where the 2024 recommendations of the blood-based biomarker working group at NINDS include the use of blood GFAP as an approach to the triage, diagnosis, prognosis, and treatment of TBI.¹⁵ Serum GFAP biomarker measurement has recently been utilized to identify individuals at very low risk for mild traumatic intracranial injury on CT scans, potentially reducing unnecessary acute neuroimaging.¹⁶

Voltage-Gated Calcium Channels

Beginning in 2008, Dr. Berman, Kia Shahlaie, MD, PhD, and Dr. Gurkoff led the Neurotrauma Lab’s investigations into voltage-gated Ca²⁺ channels (VGCC) in experimental TBI. Opening of VGCCs is a major contributor to elevated intracellular Ca⁺⁺ ([Ca²⁺]_i) after TBI, as well as exacerbating glutamate release. This line of research led to NIH RO1 funding and a series of groundbreaking publications examining the effects of blocking VGCCs in TBI.

In 2010, Dr. Shahlaie performed intricate cell culture experiments examining the time course of [Ca²⁺]_i flux, as well as glutamate release and cell death in an in vitro neuronal–glial cell culture model of TBI. He first measured injury-dependent increases in [Ca²⁺]_i and then examined the effects of the N-Type Ca²⁺ channel blocker, SNX-185 (an omega-conotoxin analog). SNX-185 blocked the increase in [Ca²⁺]_i and increased neuronal survival over a wide range of injury magnitudes.¹⁷ Dr. Shahlaie argued for the continued investigation of this treatment strategy for the clinical management of TBI.

In 2012, Dr. Gurkoff continued to investigate the role of Ca²⁺ by subjecting a mixed neuronal-astrocyte cell culture to injury and discovering that TBI enhances the [Ca²⁺]_i response to application of glutamate. At 48-hours after a moderate biaxial strain injury, neurons were hyperresponsive to glutamate application, increasing 90% over the response to uninjured neurons.¹⁸ This study identified a potential mechanism for increased vulnerability to secondary insults as well as seizure susceptibility following TBI.

More recently, Morgan Jude, MD, Ali Izadi, PhD, and Gene Gurkoff, PhD, investigated the N-type VCCC blocker, ziconotide, in the fluid percussion rat TBI model. Previous attempts to translate intravenous ziconotide therapy to humans were halted due to peripheral side effects. However, ziconotide is FDA-approved for the treatment of severe pain syndromes when administered intrathecally. The team demonstrated that intraventricular ziconotide improves cognitive outcome in the rat injury model assessed with the novel object recognition task (submitted). Their findings support the concept that centrally delivered ziconotide can be a potential therapeutic agent to improve cognitive performance following TBI.

Theta Neuromodulation

In 2010, neurosurgery resident Mark Fedor, MD, and Dr. Berman examined hippocampal theta activity after TBI in the rat by implanting bilateral hippocampal electrodes to measure deep brain EEG while rats explored a new environment. Hippocampal theta rhythm is a well-studied correlate of memory function.^19–21 Drs. Fedor and Berman demonstrated that fluid injury reduced hippocampal EEG power by 30%, but only in the theta frequency band (6–10 Hz).²²

In 2013, neurosurgery resident Darrin Lee, MD, PhD, Drs. Gurkoff and Izadi hypothesized that if theta EEG is diminished after TBI, then application of theta stimulation to the hippocampus after TBI would improve injury-impaired cognition. They subsequently demonstrated that theta stimulation in the medial septal nucleus, which drives the hippocampus, improved cognitive function in TBI rats measured in the Barnes maze.²³ Uninjured rats quickly learned the more efficient peripheral and spatial search strategies to find the escape hole over 6 days. In contrast, TBI rats continued to persist using the random strategy, which is not dependent on hippocampal processing. Rats subjected to TBI plus theta stimulation performed indistinguishable to uninjured rats. These and subsequent studies established the laboratory as the world’s leader in the evaluation of changes in deep brain electrical activity following TBI and how these changes relate to cognitive outcome after injury. Drs. Gurkoff and Shahlaie leveraged these unique findings to develop an innovative, RO1-funded neuromodulation program.

Swine Model of TBI

In 2017, Rachel Russo, MD, was instrumental in developing a swine model of TBI while serving as a Major at Travis AFB (Fairfield, CA). Dr. Russo and the Travis group evaluated the effects of Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) in a swine polytrauma model of TBI plus hemorrhagic shock (25% blood loss). The REBOA procedure blocks arterial blood flow to the lower body to preserve cerebral blood flow during hemorrhagic shock. Russo’s experiment in swine TBI plus shock evaluated whether the resulting increase in blood pressure and CBF may worsen cerebral edema and increase ICP. They found that rapid resuscitation, and not the REBOA procedure, resulted in the largest increase in ICP.²⁴ Dr. Russo joined the UC Davis Department of Surgery (Division of Trauma) in 2020. The development of the swine gyrencephalic animal model provides a valuable source to further the studies of TBI in the UC Davis neurotrauma labs.

Section 3: SCI Laboratory Progress 2010–2024

In 2010, Dr. Floyd developed and characterized a graded model of C-5 hemicontusion spinal cord injury (SCI) in male rats. The cervical injury location was quite unique at that time, as the vast majority of rodent models of SCI impacted the mid-thoracic region. In contrast, epidemiological data indicate that most traumatic SCI patients have injuries at the cervical level. Dr. Floyd also found that delayed administration of a clinically relevant dose of 17β-estradiol is functionally protective in male rats. She suggested that 17β-estradiol may be an effective clinical therapeutic intervention for reducing secondary damage after SCI in males, which could be readily translated to clinical trials.²⁵ More recently, neurosurgery resident Jose Castillo, MD, characterized a rat C-5 hemicontusion cervical SCI model using a computer-controlled impact device. Measurements of multiple gross and fine motor skills, as well as histopathological assessment, produced graded responses relative to injury magnitude.²⁶ These studies further refined the rodent cervical SCI injury model.

Section 4: TBI Clinical Progress 1997–2024

In 1997, James Holmes, MD, MPH, in the Department of Emergency Medicine, published two very influential studies examining whether simple clinical criteria can be used to safely reduce the number of adult patients who require a CT scan after minor head trauma. The studied risk factors included severe headache, nausea, vomiting, and depressed skull fracture. These influential studies changed protocols, leading to a reduction in the number of patients exposed to X-ray radiation.²⁷

In a highly cited review publication, Dr. Muizelaar endeavored to identify factors that could be responsible for some of the discrepancies between the “successes” achieved in identifying neuroprotective agents in the laboratory and the “failures” in translating these results to neuroprotection in the clinical setting.²⁸ Dr. Muizelaar posed a thoughtful question: Have the previous and current methods of clinical trial design and evaluation led us to incorrectly reject beneficial therapies?

In 2008, Dr. Shahlaie initiated the UC Davis TBI Clinical Registry, a unique prospective real-world neurotrauma database. To date, the registry contains over 11,000 UC Davis patients, including both adults and children. The registry has become a rich source of patient data for retrospective inquiry and has resulted in dozens of publications by Dr. Kia Shahlaie, Zwienenberg, along with Ryan Martin, MD, and Krupa Savalia, MD, PhD. Examples of impactful studies from the database include a comparison of common patterns of intracranial injury in adult and pediatric TBI,²⁹ studying the impact of hyperoxia and functional outcomes,³⁰ and outcome prediction in severe pediatric TBI.³¹

In 2009, Nathan Kuppermann, MD, MPH, from the Department of Emergency Medicine, led a prospective cohort study to identify children at very low risk of clinically important brain injuries after head trauma that established the Pediatric Emergency Care Applied Research Network (PECARN) head injury rule and served as its inagural chair.³² This was a very large trial enrolling over 42,000 children at 25 hospitals. The PECARN head injury rule identified children who were at very low risk of clinically important TBIs by providing critical evidence for obtaining cranial CT in injured children and has guided clinicians across the world in their evaluation of head-injured children. More recently, Dr. Holmes led a large multicenter study that demonstrated that the PECARN head injury rule can also be used for all ages to safely decrease the use of cranial CT.³³

In 2011, Drs. Shahlaie and Muizelaar shed light on the problem of post-traumatic vasospasm, an underrecognized cause of ischemic damage after severe TBI. They performed a retrospective analysis of consecutive cases and found that fever on admission or the presence of small parenchymal contusions were independent risk factors for the development of vasospasm. They concluded that diffuse mechanical injury and activation of inflammatory pathways may be underlying mechanisms for the development of post-traumatic vasospasm and advised that a subset of patients with these risk factors may be an appropriate population for aggressive screening.³⁴

In 2014, Daniel Nishijima, MD (Department of Emergency Medicine), performed a systematic review and meta-analysis of emergency department patients with, or at risk, of intracranial hemorrhage secondary to TBI, examining whether the clot-stabilizing drug, tranexamic acid (TXA), would improve patients’ outcomes.³⁵ Pooled results from two randomized controlled clinical trials demonstrated that TXA significantly reduced intracranial hemorrhage progression and had a non-statistically significant improvement of clinical outcomes in patients with TBI. Dr. Nishijima followed this up with an exploratory analysis of the CRASH-2 (Clinical Randomization of an Antifibrinolytic in Significant Hemorrhage) trial evaluating TXA.³⁶ Analyses indicated that severely injured adult patients randomized within 3 h from injury demonstrated better functional outcomes with TXA compared with placebo. The results of these analyses suggest that administration of TXA could improve outcomes in TBI patients.

In 2019, Rachael Callcut, MD (Department of Surgery, Division of Trauma, Acute Care Surgery), led a large multicenter prospective study about why and how trauma patients die. While hemorrhage was the predominant early cause of death, at later time points (>24 h), TBI accounted for most deaths. Falls were the most common mechanism of injury, and TBI was nonsurvivable in 82% of cases.³⁷

In the past decade, UC Davis Neurological Surgery established its own dedicated neuro-ICU and critical care team consisting of Lara Zimmerman, MD, and Dr. Martin (arrived in 2016), Jeffrey Vitt, MD (arrived in 2020), and Dr. Savalia (arrived in 2022). The neurocritical care team has made use of the TBI Registry with several completed and ongoing research projects (e.g., PET imaging to investigate glial activation and neuroinflammation after TBI, causes of post-traumatic epilepsy, and a study examining the use of brain oxygenation in severe TBI).

Section 5: SCI Clinical Progress 2002–2024

In 2002, Dr. Holmes led a large multicenter trial evaluating the use of CT versus MRI in cervical spine injuries at a time when CT and MRI were evolving in their diagnostic use with SCI. He concluded that MRI was superior at identifying soft tissue injuries, whereas CT performed better in identifying bony injuries.³⁸ He followed this up with a systematic review and meta-analysis that demonstrated CT should be used instead of plain films to evaluate patients at risk for cervical spine injuries. This article led to protocol changes in which CT replaced plain film X-ray as the preferred diagnostic test to screen patients at risk for cervical spine injury.³⁹

Kee Kim, MD, has been involved in numerous clinical trials, including a recent study examining the benefits of a neurospinal scaffold for safety and neurological recovery in complete thoracic injury. The trial, which was a 24-month follow-up from the INSPIRE study, supports the safety and probable benefit of this scaffold implantation in complete thoracic SCI.⁴⁰

Allan Martin, MD, PhD, is actively involved in the new guidelines for the management of patients with traumatic SCI. Dr. Martin has coauthored several recent papers with recommendations on hemodynamic management,⁴¹ use of intraoperative neuromonitoring,⁴² and the role and timing of decompressive surgery.⁴³

Conclusions

UC Davis has a very rich history of neurotrauma 4research, a culture that was established by its founding Chair, Dr. Julian Youmans. This brief overview highlights representative samples of the numerous scientific discoveries and clinical innovations by our faculty, residents, students, and staff. The department’s neurotrauma mission is highly collaborative, combining the expertise of our basic and clinical scientists to evaluate how injury alters brain and spinal cord function in laboratory models and at the bedside. Our goal is to leverage our findings to develop innovative therapeutic strategies to improve the quality of life in our patients with TBI and SCI and to continue to lead advancements in neurotrauma research.

Consent Statement

Informed consent was obtained from all the participants whose pictures are in the article.

Footnotes

Author Disclosure Statement

The authors have no interests to disclose.

Funding Information

No funding was received for this article.

Abbreviations Used

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History of Neurotrauma Research at University of California,Davis

Abstract

Keywords

Section 1: The Early Years, 1967–1996

Section 2: TBI Laboratory Progress 1997–2024

Intracranial Physiology

Glutamate Excitotoxicity

Astrocyte Pathology and Biomarkers

Voltage-Gated Calcium Channels

Theta Neuromodulation

Swine Model of TBI

Section 3: SCI Laboratory Progress 2010–2024

Section 4: TBI Clinical Progress 1997–2024

Section 5: SCI Clinical Progress 2002–2024

Conclusions

Consent Statement

Footnotes

Author Disclosure Statement

Funding Information

Abbreviations Used

References