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Research Focus

Traumatic brain injury (TBI) leads to significant morbidity and mortality. The primary injury is a direct result of mechanical forces applied to the brain that may induce hemorrhage, contusion, and axonal shearing. Primary injury can be targeted only with preventative measures. Secondary injury is prolonged, diffuse, and involves a pathophysiological sequence of events including cascades of excitatory neurotransmitter release, mitochondrial damage, changes in protein expression, and cell death. The cascade of changes associated with secondary injury leads to the morbidity of TBI. Patients with TBI experience symptoms that include headaches, dizziness, and cognitive disability with difficulties in attention, executive function, learning, and memory. It is this secondary injury that is poised for intervention, but to date, there are no successful treatments for TBI associated cognitive deficits. As a result, millions of people each year are unable to return to their pre-injury independence and productivity because of a TBI. The failure to develop successful treatments for post-injury cognitive deficits is, in part, due to a lack of a clearly defined target for intervention. The Department of Neurosurgery Neurotrauma Laboratory explores different mechanisms of dysfunction after TBI to identify future therapeutic targets.

Hippocampal Dysfunction

The hippocampus is a critical structure in cognition, particularly learning and memory, and therefore is a suitable brain region for targeted intervention. Human case reports and animal studies show that injury to the hippocampal formation produces anterograde amnesia. After TBI, a hippocampal subfield, the dentate gyrus, is particularly vulnerable. The dentate gyrus sits at the beginning of the tri-synaptic circuit of memory formation, and is necessary for encoding multiple inputs, and contextual pattern separation. The unique role of the dentate gyrus in learning and memory is in part due to its ability to generate new neurons in adulthood, a process demonstrated in rodents, non-human primates, and humans. The process of neurogenesis requires a coordinated sequence of events including cell proliferation, neuronal fate specification, migration, maturation, and appropriate integration into the hippocampal circuitry.

The coordinated events leading to successful new neuron integration is an important part of the recovery process, as complete disruption of adult neurogenesis impairs cognitive recovery. After a TBI, the number of maturing neurons is disturbed, as immature neurons are susceptible to cell death, yet there is a concomitant increase in the rate of new cell formation, reflecting a global increase in neurogenesis. Many new neurons extend axons and exhibit electrical signaling after experimental TBI. Yet there is evidence by our group and others that injury-induced neurogenesis generates abnormal new neurons that inappropriately migrate, mature, and integrate, thus contributing to cognitive dysfunction. In our laboratory we explore the generation and integration of new neurons after experimental TBI to identify mechanisms behind aberrant neurogenesis and hence potential therapeutic targets.

Metabolic Damage and Recovery

Early after TBI, brain metabolism is disrupted due to unregulated ion release, mitochondrial damage, and interruption of molecular trafficking. This metabolic disruption causes at least part of the TBI pathology. Maintaining ionic gradients required for neurotransmission is energetically costly and accounts for 80-85% of brain energy usage. Neuronal activation in response to environmental stimuli and cognitive effort initiates additional glucose uptake and metabolic activity. Although the link between brain metabolism and early post-injury cognitive symptoms is well established, the role of metabolic dysregulation in chronic symptomology is unclear. Our research indicates that while the supply of metabolic substrates is maintained in chronic TBI, the utilization/regulation of metabolic resources is altered. These changes reflect both compensatory and ongoing pathological processes that may negatively impact the brain’s ability to mobilize resources to completely meet the demands of neurotransmission and cognitive processing. Research in the Neurotrauma Research laboratory seeks to identify rational strategies to normalize brain metabolic balance based on molecular changes occurring in metabolic pathways at both acute and chronic time points after TBI.

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University of Cincinnati
College of Medicine
Department of Neurosurgery
PO Box 670515
Cincinnati Ohio 45267-0515