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 (lCMR_Glc) 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. lCMR_Glc 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.

Keywords: 2DG; concussion; glucose metabolism; hyperthermia; mild TBI; repetitive concussion; traumatic brain injury.

Figure 1

Quantitative autoradiographic images of local cerebral metabolic rate of glucose (lCMR_Glc) displayed in pseudocolor. Each coronal level (with reference to bregma) is the average of n = 7 or 8 brains from the three experimental groups: sham (n = 7), normothermia traumatic brain injury (TBI; n = 8), and hyperthermia TBI (n = 8). After repetitive mild concussive TBI (3× over 7 days), there was a bilateral decrease in glucose utilization in both normothermic and, to a greater extent, hyperthermic animals in all nine bregma levels analyzed. Left hemisphere is shown on the left.

Figure 2

Stacked images of all nine bregma levels in mirrored orientations to show qualitative intergroup differences.

Figure 3

Eight out of nine bregma levels showed significantly decreased ¹⁴C-2-deoxy-d-glucose (2DG) values bilaterally in normothermic and hyperthermic repetitive mTBI animals relative to uninjured sham control animals. * p < 0.05, ** p < 0.01, *** p < 0.001, and **** p < 0.0001. CA: cornu ammonis/hippocampus, Cg: cingulate cortex, Cor: cortical strip, CPu: caudate putamen, M1: primary motor cortex, M2: secondary motor cortex), PtA: parietal association cortex, RS: retrosplenial cortex, STR: striatum, and VM: visual cortex.

Figure 4

Schematic of three representative coronal sections (+0.7, −3.8, −7.3 mm relative to bregma) showing the 10 autoradiographic regions of interest: CA: cornu ammonis/hippocampus, Cg: cingulate cortex, Cor: cortical strip, CPu: caudate putamen, M1: primary motor cortex, M2: secondary motor cortex, PtA: parietal association cortex, RS: retrosplenial cortex, STR: striatum, and VM: visual cortex.