Grappling with the complexities of brain health, we dive into the world of traumatic brain injuries (TBIs), a prevalent yet puzzling health issue affecting millions each year. These injuries, varying from mild to severe, initiate a series of hidden yet significant changes in the brain. The story becomes more intricate as we consider the aftermath, where the effects evolve over time, often remaining undetected at first glance. Our exploration seeks to illuminate these hidden aftermaths, revealing the critical changes that occur following an injury.
Researchers led by Dr. Gerben van Hameren and Professor Alon Friedman from Dalhousie University, along with their team, have embarked on an in-depth investigation into the link between mitochondrial dysfunction and vascular impairment following TBI. Their groundbreaking study, published in Neurobiology of Disease, sheds light on the cascading consequences that follow a traumatic event to the brain.
Dr. Gerben van Hameran said: “Mitochondria are important components of almost all human cells. Their best-known role is to provide energy so that the cell can function optimally. In that process, mitochondria produce reactive oxygen species, which can be damaging, but can also be useful, for example in immune processes or as messenger molecules. Mitochondria also play a function managing the amount of calcium in a cell.”
TBI, a major health concern worldwide, unfolds in two phases: the immediate primary injury and the following secondary injury that develops over time. Dr. van Hameren explained, “Traumatic brain injury (TBI) is a major global source of health issues affecting 40 million people annually. TBI-related injury is classified as primary or secondary. Primary injury occurs instantaneously and may involve brain bruises, blood clots within the skull, damage to the brain’s white matter, and disruption of the brain’s cell structure. In contrast, secondary injury develops in the minutes, hours, or days after impact. The mechanisms behind secondary injury are complex and not well understood”.
Their study used a moderate TBI model, involving a method to simulate head impacts, which showed immediate drops in blood oxygen levels and significant declines in neurological health, as indicated by lower neurological severity scores (NSS). Dr. van Hameren elaborated, “We first assessed functional, anatomical, and behavioral outcomes following a simulated moderate head impact. This moderate impact resulted in 2.5% mortality. In surviving animals, we measured a drop in blood oxygen levels acutely upon impact. Behavioral analysis showed reduced neurological health scores at 20 min after head impacts. At 48 h following impact, the distribution of neurological health scores was bimodal”.
A critical discovery of this study was the frequent occurrence (approximately 50.9%) of Cortical Spreading Depolarization (CSD) immediately following TBI, linked to substantial declines in neurological health. “Consistent with previous studies, we recorded CSDs and associated spreading depression of brain activity in both hemispheres immediately following TBI,” Dr. van Hameren noted, “These CSDs were seen as a near shift in the voltage along with a suppression of the brain’s electrical signal. Recordings with two electrodes or a change in optical signaling through the skull confirmed the spread of the event”. He also said that “In the Friedman lab, we study how traumatic brain injury can lead to damage to the blood-brain barrier and how blood-brain barrier leakage is related to brain disorders, in particular epilepsy. In several of our studies (Aboghazleh et al., 2021; Parker et al., 2022) we noticed the importance of cortical spreading depolarization. Since only 50% of head injuries result in spreading depolarization, this phenomenon may be the most important factor in long-term outcome. “
Further examination of mitochondrial behavior during CSD revealed an increase in mitochondrial Reactive Oxygen Species (ROS), particularly near large blood vessels. “Despite the narrowing of blood vessels and reduced blood flow following CSD, no low oxygen levels were measured. We hypothesized that oxygen use by mitochondria is impaired in these TBI animals,” Dr. van Hameren clarified.
Electron microscopy offered a more detailed view of the blood vessel and mitochondrial changes post-TBI. “Following TBI, blood vessels in the brain appeared constricted with reduced roundness compared to controls. We also observed signs of damage to the internal structures of mitochondria, primarily in support cells and cells that control blood vessel tone from TBI-brains but not in nerve or lining cells,” Dr. van Hameren observed, highlighting the specific vulnerability of certain brain cell types to TBI-induced changes.
The study concludes that mitochondrial dysfunction significantly contributes to the abnormal blood vessel responses observed during increased metabolic demands, such as CSD and seizures following TBI. Dr. van Hameren emphasized, “Mitochondrial dysfunction underlies abnormal blood vessel response to increased metabolic demand such as that during CSD and seizures. Mitochondrial and blood vessel dysfunction during CSD could therefore underlie poor TBI outcome”.
This research represents a significant milestone in understanding the complex inner workings of TBI, leading the way for targeted strategies to reduce secondary damage and improve outcomes for those affected.
Gerben van Hameren, Jamil Muradov, Anna Minarik, Refat Aboghazleh, Sophie Orr, Shayna Cort, Keiran Andrews, Caitlin McKenna, Nga Thy Pham, Mark A. MacLean, Alon Friedman. “Mitochondrial dysfunction underlies impaired neurovascular coupling following traumatic brain injury”, Neurobiology of Disease, 2023. DOI: https://doi.org/10.1016/j.nbd.2023.106269
About the Authors
Gerben van Hameren is a Dutch neuroscientist with expertise in mitochondrial function in the nervous system. After a Bachelor’s degree in Biomedical Sciences and Master’s degree in Fundamental Neuroscience from Maastricht University, he performed his PhD thesis on mitochondrial dysfunction in peripheral neuropathies at the Institute for Neuroscience of Montpellier, France. There, he measured mitochondrial ROS and ATP using adeno-associated viruses and multiphoton microscopy in sciatic and saphenous nerves in vivo to study Charcot-Marie-Tooth disease and demyelination.
Currently a post-doctoral researcher at Dalhousie University, Halifax, Canada, he investigates mitochondrial and vascular dysfunction in rats following brain injury, seizures, and cortical spreading depolarization. For this work, he was funded by Mitacs and received a CURE Epilepsy Taking flight award.
Alon Friedman is a Professor of Neuroscience and holds the Dennis Chair in Epilepsy Research at Dalhousie University in Halifax and also is a Professor in the Department of Brain and Cognitive Sciences, at Ben-Gurion University of the Negev in Israel. He completed his medical and doctoral training at Ben-Gurion University and did his residency training in neurosurgery at Soroka University Medical Center in Israel. He did his post-doctoral training at the Charité Medical University in Berlin as an Alexander von-Humboldt fellow.
His work has been recognized by multiple international awards, the most prominent being the international Michael prize for Epilepsy Research, the Mercator Professorship at the Charité Medical University in Berlin, and the Foulkes Foundation Research Award.
His research is focused on exploring the interactions between the vascular and neuronal systems within the CNS and specifically on the involvement of microvascular pathology and blood-brain barrier dysfunction in the pathogenesis of injury-related epilepsy and neurodegeneration.