Repeated mild traumatic brain injury: mechanisms of cerebral vulnerability

Abstract

Among the 3.5 million annual new head injury cases is a subpopulation of children and young adults who experience repeated traumatic brain injury (TBI). The duration of vulnerability after a single TBI remains unknown, and biomarkers have yet to be determined. Decreases in glucose metabolism (cerebral metabolic rate of glucose [CMRglc]) are consistently observed after experimental and human TBI. In the current study, it is hypothesized that the duration of vulnerability is related to the duration of decreased CMRglc and that a single mild TBI (mTBI) increases the brain's vulnerability to a second insult for a period, during which a subsequent mTBI will worsen the outcome. Postnatal day 35 rats were given sham, single mTBI, or two mTBI at 24-h or 120-h intervals. (14)C-2-deoxy-D-glucose autoradiography was conducted at 1 or 3 days post-injury to calculate CMRglc. At 24 h after a single mTBI, CMRglc is decreased by 19% in both the parietal cortex and hippocampus, but approached sham levels by 3 days post-injury. When a second mTBI is introduced during the CMRglc depression of the first injury, the consequent CMRglc is depressed (36.5%) at 24 h and remains depressed (25%) at 3 days. In contrast, when the second mTBI is introduced after the metabolic recovery of the first injury, the consequent CMRglc depression is similar to that seen with a single injury. Results suggest that the duration of metabolic depression reflects the time-course of vulnerability to second injury in the juvenile brain and could serve as a valuable biomarker in establishing window of vulnerability guidelines.

FIG. 1.

Traumatic brain injury (TBI)-induced cerebral metabolic rate of glucose (CMRglc) depression. This graph shows a comparison of the CMRglc changes with time after various types of TBIs in different aged rats as measured by ¹⁴C-2-deoxy-D-glucose autoradiography (data from ^,,,,). FP, fluid percussion; PND, post-natal day; CCI, controlled cortical impact.

FIG. 2.

Diagrammatic representation of the central hypothesis. A single mild traumatic brain injury (mTBI) increases the brain's vulnerability to a second insult for a period, during which a subsequent mTBI will worsen outcome. A second injury introduced after this period of vulnerability will result in cerebral metabolic rate of glucose (CMRglc) changes similar to the first injury. ¹⁴C-2dg, ¹⁴C-2-deoxy-D-glucose.

FIG. 3.

Three coronal sections indicating the nine autoradiographic regions of interest measured. Fr1 (frontal cortex), Par1 (anterior parietal cortex), Hippo (whole hippocampus), CA1, CA3, Thal (thalamus), PrR (perirhinal cortex), Parietal cortex, Posterior parietal cortical strip. The black bar over parietal indicates the center of the impact site.

FIG. 4.

Average (±standard error of the means) changes in the cerebral metabolic rate of glucose (CMRglc) with time after single mild traumatic brain injury in both parietal and hippocampal CA1 regions, illustrating the recovery of metabolism by 3 days after injury.

FIG. 5.

The graph shows the average (±standard error of the mean) changes in the cerebral metabolic rate of glucose (CMRglc) between injury groups at 1 and 3 days post-injury in the contralateral and ipsilateral parietal cortex. *p<0.05; **p<0.01. RTBI, repeated traumatic brain injury.

FIG. 6.

The graph shows the average (±standard error of the mean) changes in the cerebral metabolic rate of glucose (CMRglc) between injury groups at 1 and 3 days post-injury in the contralateral and ipsilateral CA1 hippocampus. *p<0.05; **p<0.01. RTBI, repeated traumatic brain injury.

FIG. 7.

Time course of novel object task recovery are shown for sham, single, and repeated traumatic brain injury (RTBI) 24 h. The box plot shows the median percent time spent with the novel object at 1 and 3 days post-injury. Behavioral changes after RTBI 120 h were not conducted for this experiment. *p<0.05, **p<0.01 relative to sham animals.