Moskowitz Michael A
Harvard Medical School, Departments of Radiology and Neurology, Center for Systems Biology, Massachusetts General Hospital, Boston, MA, USA.
Cephalalgia. 2025 Sep;45(9):3331024251370629. doi: 10.1177/03331024251370629. Epub 2025 Sep 2.
Cortical spreading depolarization (depression) underlies migrainous aura and is posited to cause its headache. At times, aura may start before headache, auras may start at the same time as, or shortly after headache onset, or sometimes without any headache at all. We suggest that the extent of spread and not the spread limited to eloquent cortex, is the key variable in the genesis of headache. Consistent with this notion, a first human case studied electrophysiologically showed that cortical spreading depolarization spreads extensively and silentlyWe propose a Buildup Hypothesis to explain headache generation in migraine with aura. Buildup occurs because cortical spreading depression releases noxious chemicals from cortical cells that accumulate in tissues and cerebrospinal fluid to reach levels sufficient to trigger pial afferents and cause pain. The extent of silent (or relatively silent) spread determines significant buildup. This Buildup Hypothesis helps to explain (1) typical and shorter latencies between end of aura and headache onset (approximately 0-20 minutes) and (2) why headache may not develop after aura (insufficient buildup), and also addresses temporal discrepancies such as headaches starting before an aura (i.e. subclinical spread with buildup in advance of aura). Hence, aura and headache are distinct consequences of cortical spreading depolarization.
皮层扩散性去极化（抑制）是偏头痛先兆的基础，并被认为是导致偏头痛头痛的原因。有时，先兆可能在头痛之前开始，先兆可能与头痛发作同时开始，或在头痛发作后不久开始，或者有时根本没有任何头痛。我们认为，扩散的范围而非仅限于明确皮层的扩散，是头痛发生的关键变量。与此观点一致，首例经电生理学研究的人类病例表明，皮层扩散性去极化广泛且无声地扩散。我们提出一个累积假说，以解释有先兆偏头痛中头痛的产生。累积的发生是因为皮层扩散性抑制从皮层细胞释放有害化学物质，这些化学物质在组织和脑脊液中积累，达到足以触发软膜传入神经并引起疼痛的水平。无声（或相对无声）扩散的程度决定了显著的累积。这个累积假说有助于解释：（1）先兆结束与头痛发作之间典型且较短的延迟（约0 - 20分钟），以及（2）为什么先兆后可能不会出现头痛（累积不足），并且还解决了诸如头痛在先兆之前开始（即亚临床扩散且在先兆之前累积）等时间差异问题。因此，先兆和头痛是皮层扩散性去极化的不同后果。
