Brain organoids represent a powerful tool for studying human neurological diseases, particularly those that affect brain growth and structure. However, many diseases manifest with clear evidence of physiological and network abnormality in the absence of anatomical changes, raising the question of whether organoids possess sufficient neural network complexity to model these conditions. Here, we explore the network-level functions of brain organoids using calcium sensor imaging and extracellular recording approaches that together reveal the existence of complex network dynamics reminiscent of intact brain preparations. We demonstrate highly abnormal and epileptiform-like activity in organoids derived from induced pluripotent stem cells from individuals with Rett syndrome, accompanied by transcriptomic differences revealed by single-cell analyses. We also rescue key physiological activities with an unconventional neuroregulatory drug, pifithrin-α. Together, these findings provide an essential foundation for the utilization of brain organoids to study intact and disordered human brain network formation and illustrate their utility in therapeutic discovery.

脑类器官是研究人类神经系统疾病的强大工具，特别是那些影响大脑生长和结构的疾病。然而，许多疾病在没有解剖学变化的情况下表现出明显的生理和网络异常证据，这就提出了类器官是否具有足够的神经网络复杂性来模拟这些条件的问题。在这里，我们使用钙传感器成像和细胞外记录方法探索大脑类器官的网络级功能，这些方法共同揭示了复杂网络动态的存在，让人想起完整的大脑准备工作。我们证明，来自雷特综合征个体的诱导多能干细胞的类器官具有高度异常和癫痫样活性，并伴有单细胞分析揭示的转录组差异。我们还使用非常规神经调节药物 Pifithrin-α 来挽救关键的生理活动。总之，这些发现为利用大脑类器官来研究完整和无序的人类大脑网络形成并说明其在治疗发现中的效用提供了重要的基础。