To revisit Aristides Leao’s original description of cortical spreading depression (CSD) and discuss contemporary evidence linking CSD mechanisms to calcitonin gene-related peptide (CGRP)-mediated migraine pathways.

In 1944, Brazilian neuroscientist Aristides Leao unexpectedly observed a slowly propagating wave of cortical electrical silence while studying epilepsy in rabbits, a finding later named cortical spreading depression (CSD). This phenomenon became the basis of migraine aura and inspired decades of research. As migraine therapeutics evolved, CGRP emerged as a central mediator of trigeminovascular inflammation and pain. Understanding how CSD interacts with CGRP reflects a continued effort to link Leao’s discovery and modern targeted therapy.

It was conducted a targeted review searching PubMed and Google Scholar (1944–2025) using the terms “spreading depression”, “CGRP” and “Aristides Leao” identified experimental and translational studies supporting the intersection between CSD and CGRP. Findings were organized across mechanistic and therapeutic perspectives to illustrate how Leao’s early experiments anticipated concepts now central to migraine research.

Leao’s observation marked a turning point in experimental neurophysiology. Over time, his description went from a laboratory curiosity to a core principle of neurology research. Decades later, as advances in molecular neuroscience identified CGRP as a central mediator of migraine pain, researchers revisited Leao’s work through a new lens. The neurovascular and inflammatory mechanisms of CSD were found to intersect with pathways influenced by CGRP. Their precise interaction is still under study, yet both are considered complementary elements in this context. Leao’s pioneering experiments continue to guide and inspire modern research, connecting his electrophysiologic phenomenon with the most updated practices in headache medicine.

The cortical spreading depression remains a key concept in the understanding of migraine pathophysiology beyond the description of aura. Highlighting this historical breakthrough as a bridge to the current therapeutic arsenal reinforces how mid-twentieth-century electrophysiology continues to guide twenty-first-century targeted therapy in neurology.