Editors' ChoiceTraumatic Brain Injury

The brainstem and traumatic brain injury

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Science Translational Medicine  22 Jun 2016:
Vol. 8, Issue 344, pp. 344ec99
DOI: 10.1126/scitranslmed.aag2110

Traumatic brain injury (TBI) is commonly associated with impaired arousal immediately after injury. Individuals with chronic TBI also experience daytime sleepiness. Studies in rodents have revealed that the orexin system is acutely disrupted after TBI with both a decrease in orexin concentration and an altered diurnal oscillation. Orexin is an arousal-promoting neuropeptide released from neurons in the lateral and posterior hypothalamus that project to brainstem nuclei associated with arousal as well as to the cortex. Decreased orexin in patients with TBI may explain their increased somnolence. Although post-mortem studies in humans with fatal TBI have revealed brainstem lesions, it is not known whether arousal-promoting neurons are damaged.

To determine whether arousal-promoting nuclei in the brain are injured in individuals with severe TBI, Valko et al. performed postmortem examinations of brains from eight individuals with fatal TBI and 10 age-matched and sex-matched controls. All patients with fatal TBI were in a coma from the time of their injury until their death. The authors assessed five brainstem nuclei associated with arousal using immunohistochemistry and stereological cell counting: the locus coeruleus, the dorsal and median raphe nuclei, and the pedunculopontine and laterodorsal tegmental nuclei. In TBI patients, there was a loss of serotonergic neurons in the dorsal raphe nucleus (17% fewer compared with controls) and loss of noradrenergic neurons in the locus coeruleus (29% fewer than controls), but there were no differences in neuron numbers in other nuclei between TBI and control individuals. The authors also compared injury in the brainstem nuclei to injury in the hypothalamus and found that there was greater neuronal loss in the hypothalamus, including orexinergic neurons, than in the brainstem.

The study results do not fully account for the problems in arousal seen in patients suffering from TBI but do suggest that TBI leads to different patterns of injury in hypothalamic and brainstem neurons with the dorsal hypothalamus being most affected. Although injury to brainstem nuclei may play a role, the authors hypothesize that additional injury to the more injury-prone dorsal hypothalamus may be necessary for TBI-related dysfunction of the arousal system. Orexin-producing neurons promote wakefulness through brainstem nuclei, such as the locus coeruleus. These findings may explain the decrease in orexin found in animal models of TBI. Further research is needed to better characterize the pathophysiology of arousal dysfunction in TBI.

P. O. Valko et al., Damage to arousal-promoting brainstem neurons with traumatic brain injury. Sleep 39, 1249–1252 (2016). [Abstract]

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