Mild but isolated closed head injury is typically thought to have no long-term sequelae, with rapid recovery and no defined injury on a clinical head CT scan. Short-term neurological problems include changes in memory, alertness, cognitive function, concentration, but these typically recover within 7-10 days. This period has clear EEG, vascular and metabolic changes, which clear over time. However, if further traumatic brain injury [TBI] episodes occurs shortly after the first (within 1-2 days) then the outcome is more limited and multiple mild, TBI episodes may give rise to post-traumatic encephalopathy. Post-traumatic encephalopathy has components of axonal injury, microvascular changes due to local vessel shearing and subarachnoid hemorrhage, and neuronal damage. Our proposal will address mechanisms of brain dysfunction and treatment associated with multiple closed head injury episodes. Our hypothesis is that closely spaced closed head injury episodes (ie, every 24 hours, total of 3 occurrences) will result in chronic, irreversible behavioral, metabolic, neurovascular, and physiological changes to the brain, in comparison to more widely spaced (every 10 days) closed head injury episodes (also 3 occurrences). Further, we hypothesize that delayed brain stimulation, using either extracranial (diffuse) or intracranial (focused, fornix/septum) stimulation (for 1 month, at 3 months after the injury episodes) will enhance recovery responses, leading to improved memory and physiological function which outlasts the stimulation period. We will analyze underlying mechanisms of long-term impairment following repeated (X 3) mild, closed head injury (ie, concussion). This will be accomplished by comparing the outcome of three injury conditions: sham controls; animals exposed to repeat injury (3 total episodes) occurring over short a time interval (every 24 hours); and, animals exposed to repeat injury (also 3 episodes) occurring over longer time intervals (every 10 days). After a period of recuperation we will evaluate the effects of delayed (at 3 months after injury episodes) intermittent brain stimulation, using either extracranial electrodes or intracranial septal/fornix electrodes, with stimulation over 4 weeks to enhance recovery and hippocampal plasticity after the head injury. We will assess the outcome at 5-6 months with multiple types of behavioral testing and physiological analysis using a comprehensive, in vivo hippocampal physiological approach. Mechanisms to be studied in this acute, in vivo preparation will include assessment of brain metabolism, neurovascular coupling, hippocampal plasticity (long-term potentiation) and cholinergic innervation. We anticipate these data will help understand pathophysiology associated with repetitive concussion and possible treatment methods to enhance recovery of function and brain plasticity.
Recovery from closely spaced brain concussive injuries evolves over months and can result in significant residual cognitive damage. This issue is critical for a large number of veterans and highly relevant to treatment, since many have incurred head injuries. Stimulation of the brain through either extracranial or intracranial electrodes (ie, fornix/septum) may improve memory, but a significant question is whether a limited period of brain stimulation during early recovery may permanently enhance circuitry formation in the hippocampus, even after stimulation ceases. Our study focuses on delayed brain stimulation during a critical period of recovery and whether this limited stimulation can lead to persistent improvement in brain circuitry which outlasts the stimulation. This study may provide evidence whether a clinically applicable, common form of treatment now in use (brain stimulation) can improve head injury outcome.
| Galeffi, Francesca; Degan, Simone; Britz, Gavin et al. (2016) Dysregulation of oxygen hemodynamic responses to synaptic train stimulation in a rat hippocampal model of subarachnoid hemorrhage. J Cereb Blood Flow Metab 36:696-701 |
| Krucoff, Max O; Rahimpour, Shervin; Slutzky, Marc W et al. (2016) Enhancing Nervous System Recovery through Neurobiologics, Neural Interface Training, and Neurorehabilitation. Front Neurosci 10:584 |
