发表机构
Faculty of Engineering, University of Southern Denmark; Faculty of Science, University of Southern Denmark（南丹麦大学工程学院; 南丹麦大学理学院）
机构由 AI 辅助整理，请以论文原文为准。AI 中文总结
本研究开发图计算框架分析人类皮质类器官刺激诱发的网络动力学，发现重复刺激可抑制并空间收缩诱发反应，且该效应可与发育成熟区分开。
AI 中文摘要
人类皮质类器官为早期神经回路形成提供了可实验研究的模型，但其活动是否反映结构化信息处理而非自发同步尚不明确。我们开发了一套图计算框架来量化刺激诱发的传播，该框架包含：刺激条件功能图、作为系统识别工具的图约束动力学（图神经网络）模型、通过可观测传播深度限制整合深度的生物消息传递原理，以及一组图级指标。我们对三个类器官的纵向高密度微电极阵列（HD-MEA）记录完整实施了该方案。一旦恢复真实采集采样率和刺激时序，诱发反应被证实为快速、近同步的网络爆发，无可见向外传播（峰潜伏期与距离斜率为0）。因此传播/整合深度指标（Deff、可达性指数、dmax）不适用，且在可用试次数量下无法可靠估计每日连接图，这一负面结果对将此类指标应用于类器官数据具有方法论意义。围绕同步性、反应群体规模和共享变异性重新分析后，发现了经对照验证的现象：每日重复刺激会逐步抑制并空间收缩诱发反应。重复刺激可重塑类器官网络是已知结论，但每次制备均接受刺激的纵向设计无法将其与发育成熟区分开。我们通过发育匹配的未接受过刺激的对照打破了这一混淆：在第7天，首次接受刺激的类器官激活了93%的阵列，而接受过5次刺激的类器官仅激活了10%。
英文摘要
Human cortical organoids provide an experimentally accessible model of early neural circuit formation, yet whether their activity reflects structured information processing rather than spontaneous synchronization is unclear. We developed a graph-computational framework to quantify stimulus-evoked propagation. This includes stimulus-conditioned functional graphs, a graph-constrained dynamical (graph-neural-network) model used as a system-identification tool, a biological message-passing principle bounding integration depth by observable propagation depth, and a suite of graph-level metrics. We carried this program out in full on longitudinal HD-MEA recordings from three organoids. Once the true acquisition sampling rate and stimulus timing were recovered, the evoked response proved to be a fast, near-synchronous network burst with no measurable outward propagation (peak-latency vs. distance slope = 0). The propagation/integration-depth metrics (Deff ,reachability index, dmax) therefore do not apply, and per-day connectivity graphs were not reliably estimable at the available trial count, a negative result with methodological consequences for applying such metrics to organoid data. Reframing around synchrony, response-population size and shared variability revealed a control-validated phenomenon, i.e., repeated daily stimulation progressively depressed and spatially contracted the evoked response. That repeated stimulation reshapes organoid networks is established, but longitudinal designs in which every preparation is stimulated cannot separate this from developmental maturation. We break that confound with a developmentally-matched, stimulation-naive control, where at day 7, an organoid receiving its first-ever stimulation engaged 93% of the array, whereas organoids with five prior sessions engaged 10%.
