Using transcranial brain stimulation to prevent cortical spreading depression

描述（由申请人提供）：限制中风或创伤性脑损伤后的脑损伤程度对于最大限度地减少功能缺陷非常重要。皮质扩散性抑制（Cortically Spreading Depression，CoSD）是一种重复的、缓慢移动的波，出现在脑损伤后，并扩大缺血性卒中、出血性卒中和创伤性脑损伤后神经元死亡的区域。CoSD也与有先兆和脑震荡的偏头痛有关。因此，预防CoSD的能力将能够减少脑损伤的扩大并减轻与CoSD相关的症状，但药理学干预是全身性的，通常具有显著的副作用。该项目的目标是测试有针对性的非侵入性脑刺激可以减少或阻断CoSD的假设。该假设是基于这样的想法，即CoSD的传播机制可能会被经颅直流电刺激（tDCS）的神经效应抵消。CoSD波的传播部分由细胞外钾浓度的增加介导，这产生持续的去极化，随后是一段时间的神经元不活动。阴极经颅直流电刺激（tDCS）产生了广泛的超极化的底层神经元，因此有可能“钳位”大量的神经元的膜电位，并阻止CoSD波。初步数据显示，CoSD被阴极tDCS阻断。在第一组拟议的实验中，氯化钾将被施加到麻醉大鼠的额叶皮层以诱导CoSD，并且波将被记录在枕叶皮层中，具有经层多触点记录电极。TDCS将应用于放置在额部和枕部区域之间的颅电极，以检验阴极而非阳极或假tDCS将阻断CoSD的假设。将改变tDCS电流大小和电极尺寸，以确定可以防止CoSD的最佳条件。第二组实验将在相同模型中在tDCS期间诱导CoSD，并将测量整个大脑的局部脑葡萄糖摄取。这些实验将测试阴极而非阳极或假tDCS停止CoSD波并保护经颅电极下方和远端的神经元免受CoSD影响的假设。此外，由于可以以相对高的分辨率分析整个大脑，这些实验将评估跨皮层的保护作用的空间范围和幅度，以及测试阴极tDCS将减少CoSD在中脑、丘脑和纹状体中的远端效应的假设。总之，这些实验将提供tDCS阻断CoSD波的第一个证据，并将定义最佳刺激条件。这些结果将为使用tDCS对抗神经系统疾病的临床试验提供基础，其中CoSD发挥着重要作用，并将作为更完整的动物实验的基础，以更全面地研究中风和创伤性脑损伤模型。鉴于tDCS的低成本和便携性及其靶向特定脑区的能力，这些数据将对CoSD发挥作用的神经系统疾病的治疗产生直接影响。

DESCRIPTION (provided by applicant): Limiting the extent of brain damage after stroke or traumatic brain injury is important to minimize functional deficits. Cortical spreading depression (CoSD) is a repetitive, slow moving wave that appears after brain damage and expands the area of neuronal death after ischemic stroke, hemorrhagic stroke, and traumatic brain injury. CoSD has also been implicated in migraine with aura and concussion. The ability to prevent CoSD would therefore be able to reduce the expansion of brain damage and mitigate symptoms related to CoSD, but pharmacological interventions are systemic and typically have significant side effects. The goal of this project is test the hypothesis that targeted non-invasive brain stimulation can reduce or block CoSD. The hypothesis is based on the idea that the mechanism underlying propagation of CoSD may be countered by the neural effects of transcranial direct current stimulation (tDCS). The propagation of the CoSD wave is mediated in part by an increase in extracellular potassium concentration, which produces a sustained depolarization followed by a period of neuronal inactivity. Cathodal transcranial direct current stimulation (tDCS) produces a widespread hyperpolarization of underlying neurons, and therefore has the potential to 'clamp' the membrane potential of large numbers of neurons and block the CoSD wave. Preliminary data shows that CoSD is blocked by cathodal tDCS. In the first set of proposed experiments, potassium chloride will be applied to the frontal cortex of the anesthetized rat to induce CoSD, and the wave will be recorded in occipital cortex with a translaminar multicontact recording electrode. TDCS will be applied to a cranial electrode placed between the frontal and occipital areas to test the hypothesis that cathodal, but not anodal or sham tDCS will block CoSD..The tDCS current magnitude and electrode size will be varied to determine the optimal conditions under which CoSD can be prevented. The second set of experiments will induce CoSD during tDCS in the same model and will measure local cerebral glucose uptake throughout the entire brain. These experiments will test the hypothesis that cathodal, but not anodal or sham tDCS halts the CoSD wave and protects neurons under and distal to the transcranial electrode from the effects of the CoSD. Moreover, since the whole brain can be analyzed at relatively high resolution, these experiments will evaluate the spatial extent and magnitude of the protective effect across the cortex, as well as to test the hypothesis that cathodal tDCS will reduce the distant effects of CoSD in the midbrain, thalamus, and striatum. Together, these experiments will provide the first evidence that tDCS blocks the CoSD wave and will define the optimal stimulation conditions to do so. Results will provide the basis for clinical trials using tDCS against neurological disorders in which CoSD plays a major role, and will serve as the basis for more complete animal experiments to more fully investigate models of stroke and traumatic brain injury. Given the low cost and portability of tDCS and its ability to target specific brain regions, these data will have direct implications for the treatmen of neurological conditions in which CoSD plays a role.