Mild Hyperthermia Aggravates Glucose Metabolic Consequences in Repetitive Concussion

Abstract

Traumatic brain injury (TBI) is one of the leading causes of mortality and disability around the world. Mild TBI (mTBI) makes up approximately 80% of reported cases and often results in transient psychological abnormalities and cognitive disruption. At-risk populations for mTBI include athletes and other active individuals who may sustain repetitive concussive injury during periods of exercise and exertion when core temperatures are elevated. Previous studies have emphasized the impact that increased brain temperature has on adverse neurological outcomes. A lack of diagnostic tools to assess concussive mTBI limits the ability to effectively identify the post-concussive period during which the brain is uniquely susceptible to damage upon sustaining additional injury. Studies have suggested that a temporal window of increased vulnerability that exists corresponds to a period of injury-induced depression of cerebral glucose metabolism. In the current study, we sought to evaluate the relationship between repetitive concussion, local cerebral glucose metabolism, and brain temperature using the Marmarou weight drop model to generate mTBI. Animals were injured three consecutive times over a period of 7 days while exposed to either normothermic or hyperthermic temperatures for 15 min prior to and 1 h post each injury. A 14C-2-deoxy-d-glucose (2DG) autoradiography was used to measure local cerebral metabolic rate of glucose (lCMRGlc) in 10 diverse brain regions across nine bregma levels 8 days after the initial insult. We found that repetitive mTBI significantly decreased glucose utilization bilaterally in several cortical areas, such as the cingulate, visual, motor, and retrosplenial cortices, as well as in subcortical areas, including the caudate putamen and striatum, compared to sham control animals. lCMRGlc was significant in both normothermic and hyperthermic repetitive mTBI animals relative to the sham group, but to a greater degree when exposed to hyperthermic conditions. Taken together, we report significant injury-induced glucose hypometabolism after repetitive concussion in the brain, and additionally highlight the importance of temperature management in the acute period after brain injury.

Multimodal magnetic resonance imaging after experimental moderate and severe traumatic brain injury: A longitudinal correlative assessment of structural and cerebral blood flow changes

“…We did not observe progressive changes in gray matter CBF after a 4-month time point, indicating that injury-induced blood flow reduction was sustained out to one year, the end point of the present study-which is consistent with published reports on patients with moderate to severe TBI [65]. When CBF is pathologically reduced, there is disruption of metabolic processes and a mismatch between supply and demand for oxygen and glucose, leading to cell death, long-term impairment, and dysfunction [47,[66][67][68][69]. There is a significant positive correlation between injury-induced lowered CBF and cognitive deficits, even in mild TBI [70,71].…”

Multimodal magnetic resonance imaging of youth sport-related concussion reveals acute changes in the cerebellum, basal ganglia, and corpus callosum that resolve with recovery

“…We did, however, observe reduced connectivity between the caudate and each of the pallidum and thalamus in the recently concussed group, in addition to an acute day of MRI dependence in caudate CBF and pallidum ALFF. This is in agreement with a previous animal study of TBI reporting significant functional disturbances (injury-induced glucose hypometabolism) in areas including the caudate following repeated concussions, at eight days post first injury ( Blaya et al, 2020 ). Further evidence of disruption within the basal ganglia and thalamocortical pathways was shown in a recent study that described local and large-scale beta oscillatory dysfunction in male mTBI subjects, indicating disrupted information flow through cortico-basal ganglia-thalamic circuits ( Zhang et al, 2020 ).…”

Conservative Management of Acute Sports-Related Concussions: A Narrative Review

“…Vigorous exercise may lead to hyperthermia, which can exacerbate concussion-related glucose hypometabolism. Therefore, cooling after exercise may improve outcomes in this regard by reducing hyperthermia-related neurometabolic burden [117].…”