Department of Rehabilitation Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, People's Republic of China.
Department of Radiology, The First Affiliated Hospital of Nanchang University, Nanchang, People's Republic of China.
World Neurosurg. 2021 Aug;152:e321-e331. doi: 10.1016/j.wneu.2021.05.089. Epub 2021 May 29.
Previous studies have shown that deep brain stimulation (DBS) can improve the level of consciousness of comatose patients with traumatic brain injuries (TBIs). However, the most suitable targets for DBS are unknown, and the mechanisms underlying recovery remain to be determined. The aim of the present study was to assess the effects of lateral hypothalamic area-DBS (LHA-DBS) in comatose rats with TBIs.
A total of 55 Sprague-Dawley rats were randomly assigned to 5 groups: the control group, TBI group, stimulated (TBI+LHA-DBS) group, antagonist (TBI+SB334867+LHA-DBS) group, and antagonist control (TBI+saline+LHA-DBS) group. The rats in the control group had undergone a sham operation and anesthesia, without coma induction. Coma was induced using a free-fall drop method. The rats in the stimulated group received bilateral LHA stimulation (frequency, 200 Hz; voltage, 2-4 V; pulse width, 0.1 ms) for 1 hour, with 5-minute intervals between subsequent stimulations, which were applied alternately to the left and right sides of the lateral hypothalamus. The comatose rats in the antagonist group received an intracerebroventricular injection with an orexins receptor type 1 (OX1R) antagonist (SB334867) and then received LHA-DBS. A I-VI consciousness scale and electroencephalography were used to assess the level of consciousness in each group of rats after LHA-DBS. Western blotting and immunofluorescence were used to detect OX1R expression in the LHA and α1-adrenoceptor (α1-AR) subtype and gamma-aminobutyric acid β receptor (GABABR) expression in the prefrontal cortex.
In the TBI, stimulated, antagonist, and antagonist control groups, 5, 10, 6, and 9 rats were awakened. The electroencephalographic readings indicated that the proportion of δ waves was lower in the stimulated group than in the TBI and antagonist groups (P < 0.05). Western blotting and immunofluorescence analysis showed that OX1R expression was greater in the stimulated group than in the TBI group (P < 0.05). The expression of α1-AR was also greater in the stimulated group than in the TBI and antagonist groups (P < 0.05). In contrast, the GABABR levels in the stimulated group were lower than those in the TBI and antagonist groups (P < 0.05). A statistically significant difference was found between the antagonist and antagonist control groups.
Taken together, these results suggest that LHA-DBS promotes the recovery of consciousness in comatose rats with TBIs. Upregulation of α1-AR expression and downregulation of GABABR expression in the prefrontal cortex via the orexins and OX1R pathways might be involved in the wakefulness-promoting effects of LHA-DBS.
先前的研究表明，深部脑刺激（DBS）可以改善创伤性脑损伤（TBI）昏迷患者的意识水平。然而，最适合 DBS 的目标尚不清楚，其恢复的机制仍有待确定。本研究旨在评估外侧下丘脑 DBS（LHA-DBS）对 TBI 昏迷大鼠的影响。
将 55 只 Sprague-Dawley 大鼠随机分为 5 组：对照组、TBI 组、刺激组（TBI+LHA-DBS）、拮抗剂组（TBI+SB334867+LHA-DBS）和拮抗剂对照组（TBI+生理盐水+LHA-DBS）。对照组大鼠接受假手术和麻醉，但不诱导昏迷。使用自由落体跌落法诱导昏迷。刺激组大鼠接受双侧 LHA 刺激（频率 200 Hz；电压 2-4 V；脉冲宽度 0.1 ms），每次刺激之间间隔 5 分钟，交替刺激下丘脑的左右两侧。拮抗剂组大鼠接受脑室注射食欲素受体 1（OX1R）拮抗剂（SB334867），然后接受 LHA-DBS。使用 I-VI 意识量表和脑电图评估各组大鼠接受 LHA-DBS 后的意识水平。Western blot 和免疫荧光检测外侧下丘脑的 OX1R 表达和前额叶皮质的 α1-肾上腺素能受体（α1-AR）亚型和γ-氨基丁酸 B 受体（GABABR）表达。
在 TBI、刺激、拮抗剂和拮抗剂对照组中，有 5、10、6 和 9 只大鼠清醒。脑电图读数显示，刺激组的 δ 波比例低于 TBI 组和拮抗剂组（P<0.05）。Western blot 和免疫荧光分析显示，刺激组的 OX1R 表达高于 TBI 组（P<0.05）。刺激组的 α1-AR 表达也高于 TBI 组和拮抗剂组（P<0.05）。相反，刺激组的 GABABR 水平低于 TBI 组和拮抗剂组（P<0.05）。拮抗剂组和拮抗剂对照组之间存在统计学差异。
综上所述，这些结果表明，LHA-DBS 促进 TBI 昏迷大鼠意识的恢复。通过食欲素和 OX1R 途径，前额叶皮质中 α1-AR 表达的上调和 GABABR 表达的下调可能参与了 LHA-DBS 的促觉醒作用。
