Department of Pediatrics, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
Neurocrit Care. 2022 Jun;37(Suppl 1):102-111. doi: 10.1007/s12028-022-01474-7. Epub 2022 Apr 4.
BACKGROUND: Cortical spreading depolarizations (CSDs) are associated with worse outcomes in many forms of acute brain injury, including traumatic brain injury (TBI). Animal models could be helpful in developing new therapies or biomarkers to improve outcomes in survivors of TBI. Recently, investigators have observed CSDs in murine models of mild closed head injury (CHI). We designed the currently study to determine additional experimental conditions under which CSDs can be observed, from mild to relatively more severe TBI. METHODS: Adult male C57Bl/6J mice (8-14 weeks old) were anesthetized with isoflurane and subjected to CHI with an 81-g weight drop from 152 or 183 cm. CSDs were detected with minimally invasive visible light optical intrinsic signal imaging. Cerebral blood flow index (CBFi) was measured in the 152-cm drop height cohort using diffuse correlation spectroscopy at baseline before and 4 min after CHI. Cognitive outcomes were assessed at 152- and 183-cm drop heights for the Morris water maze hidden platform, probe, and visible platform tests. RESULTS: CSDs occurred in 43% (n = 12 of 28) of 152-cm and 58% (n = 15 of 26) of 183-cm drop height CHI mice (p = 0.28). A lower baseline preinjury CBFi was associated with development of CSDs in CHI mice (1.50 ± 0.07 × 10 CHI without CSD [CSD-] vs. 1.17 ± 0.04 × 10 CHI with CSD [CSD+], p = 0.0001). Furthermore, in CHI mice that developed CSDs, the ratio of post-CHI to pre-CHI CBFi was lower in the hemisphere ipsilateral to a CSD compared with non-CSD hemispheres (0.19 ± 0.07 less in the CSD hemisphere, p = 0.028). At a 152-cm drop height, there were no detectable differences between sham injured (n = 10), CHI CSD+ (n = 12), and CHI CSD- (n = 16) mice on Morris water maze testing at 4 weeks. At a 183-cm drop height, CHI CSD+ mice had worse performance on the hidden platform test at 1-2 weeks versus sham mice (n = 15 CHI CSD+, n = 9 sham, p = 0.045), but there was no appreciable differences compared with CHI CSD- mice (n = 11 CHI CSD-). CONCLUSIONS: The data suggest that a lower baseline cerebral blood flow prior to injury may contribute to the occurrence of a CSD. Furthermore, a CSD at the time of injury can be associated with worse cognitive outcome under the appropriate experimental conditions in a mouse CHI model of TBI.
背景：皮质扩散性去极化（CSD）与许多形式的急性脑损伤（包括创伤性脑损伤）的预后较差有关。动物模型有助于开发新的治疗方法或生物标志物，以改善创伤性脑损伤幸存者的预后。最近，研究人员在轻度闭合性颅脑损伤（CHI）的小鼠模型中观察到 CSD。我们设计了目前的研究，以确定在轻度到相对更严重的 TBI 下可以观察到 CSD 的其他实验条件。
方法：成年雄性 C57Bl/6J 小鼠（8-14 周龄）用异氟烷麻醉，用 81-g 重的砝码从 152 或 183cm 高处坠落造成 CHI。用微创可见光光学固有信号成像检测 CSD。在 152cm 落高组中，使用漫反射相关光谱法在 CHI 前和 CHI 后 4 分钟测量脑血流指数（CBFi）。在 152 和 183cm 落高下，使用 Morris 水迷宫隐藏平台、探针和可见平台测试评估认知结果。
结果：在 152cm 和 183cm 落高的 CHI 小鼠中，CSD 分别发生在 43%（n=12/28）和 58%（n=15/26）（p=0.28）。较低的基线损伤前 CBFi 与 CHI 小鼠 CSD 的发生有关（CSD-组为 1.50±0.07×10，CSD+组为 1.17±0.04×10，p=0.0001）。此外，在发生 CSD 的 CHI 小鼠中，CSD 对侧半球的 CHI 后与 CHI 前 CBFi 比值较非 CSD 半球低（CSD 半球低 0.19±0.07，p=0.028）。在 152cm 落高下，4 周时，假损伤（n=10）、CHI CSD+（n=12）和 CHI CSD-（n=16）小鼠之间在 Morris 水迷宫测试中没有可检测到的差异。在 183cm 落高下，与假鼠（n=15 CHI CSD+，n=9 假鼠，p=0.045）相比，CHI CSD+小鼠在 1-2 周时隐藏平台测试的表现更差，但与 CHI CSD-小鼠（n=11 CHI CSD-）相比，差异不明显。
结论：数据表明，损伤前较低的基线脑血流可能导致 CSD 的发生。此外，在 TBI 小鼠 CHI 模型中，损伤时发生的 CSD 在适当的实验条件下可能与较差的认知结果有关。
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