Department of Neurosurgery, Massachusetts General Hospital, Charlestown, MA, United States; Department of Neurosurgery, Harvard Medical School, Boston, MA, United States.
Department of Neurosurgery, Massachusetts General Hospital, Charlestown, MA, United States.
Neurobiol Dis. 2021 Jul;154:105334. doi: 10.1016/j.nbd.2021.105334. Epub 2021 Mar 19.
The pathophysiology of extensive cortical tissue destruction observed in hemispheric hypodensity, a severe type of brain injury observed in young children, is unknown. Here, we utilize our unique, large animal model of hemispheric hypodensity with multifactorial injuries and insults to understand the pathophysiology of this severe type of traumatic brain injury, testing the effect of different stages of development. Piglets developmentally similar to human infants (1 week old, "infants") and toddlers (1 month old, "toddlers") underwent injuries and insults scaled to brain volume: cortical impact, creation of mass effect, placement of a subdural hematoma, seizure induction, apnea, and hypoventilation or a sham injury while anesthetized with a seizure-permissive regimen. Piglets receiving model injuries required overnight intensive care. Hemispheres were evaluated for damage via histopathology. The pattern of damage was related to seizure duration and hemorrhage pattern in "toddlers" resulting in a unilateral hemispheric pattern of damage ipsilateral to the injuries with sparing of the deep brain regions and the contralateral hemisphere. While "infants" had the equivalent duration of seizures as "toddlers", damage was less than "toddlers", not correlated to seizure duration, and was bilateral and patchy as is often observed in human infants. Subdural hemorrhagewas associate with adjacent focal subarachnoid hemorrhage. The percentage of the hemisphere covered with subarachnoid hemorrhage was positively correlated with damage in both developmental stages. In "infants", hemorrhage over the cortex was associated with damage to the cortex with sparing of the deep gray matter regions; without hemorrhage, damage was directed to the hippocampus and the cortex was spared. "Infants" had lower neurologic scores than "toddlers". This multifactorial model of severe brain injury caused unilateral, wide-spread destruction of the cortex in piglets developmentally similar to toddlers where both seizure duration and hemorrhage covering the brain were positively correlated to tissue destruction. Inherent developmental differences may affect how the brain responds to seizure, and thus, affects the extent and pattern of damage. Study into specifically how the "infant" brain is resistant to the effects of seizure is currently underway and may identify potential therapeutic targets that may reduce evolution of tissue damage after severe traumatic brain injury.
在半球低密度中观察到的广泛皮质组织破坏的病理生理学，这是一种在幼儿中观察到的严重脑损伤类型，目前尚不清楚。在这里，我们利用我们独特的、多因素损伤和刺激的半球低密度大型动物模型来了解这种严重类型的创伤性脑损伤的病理生理学，测试不同发育阶段的效果。发育上类似于人类婴儿（1 周龄，“婴儿”）和学步儿童（1 月龄，“学步儿童”）的仔猪接受了与脑容量成比例的损伤和刺激：皮质冲击、形成质量效应、放置硬膜下血肿、癫痫发作诱导、呼吸暂停和低通气或在癫痫发作允许的方案下麻醉时进行假损伤。接受模型损伤的仔猪需要过夜重症监护。通过组织病理学评估半球损伤情况。损伤模式与“学步儿童”中的癫痫发作持续时间和出血模式有关，导致同侧半球单侧损伤模式，深部脑区和对侧半球不受影响。虽然“婴儿”的癫痫发作持续时间与“学步儿童”相同，但损伤小于“学步儿童”，与癫痫发作持续时间无关，且呈双侧和斑片状，这在人类婴儿中很常见。硬膜下血肿与相邻的局灶性蛛网膜下腔出血有关。两个发育阶段的蛛网膜下腔出血覆盖的半球百分比与损伤呈正相关。在“婴儿”中，皮质上的出血与皮质损伤有关，而深部灰质区域不受影响；没有出血时，损伤指向海马体，皮质不受影响。“婴儿”的神经评分低于“学步儿童”。这种严重脑损伤的多因素模型在发育上类似于学步儿童的仔猪中引起单侧、广泛的皮质破坏，其中癫痫发作持续时间和覆盖大脑的出血均与组织破坏呈正相关。固有发育差异可能会影响大脑对癫痫发作的反应方式，从而影响损伤的程度和模式。目前正在研究“婴儿”大脑如何对癫痫发作产生抵抗力，这可能会确定潜在的治疗靶点，以减少严重创伤性脑损伤后组织损伤的发展。
