To determine the effects of a combination therapy with BoNT-A and atogepant (Ato) on the responsiveness of central trigeminovascular neurons (in SpV) to CSD. 

We showed recently that cortical spreading depression (CSD) activates 2 distinct trigeminovascular pathways, one that is blocked by CGRP-mAbs, consisting of peripheral Ad nociceptors and central high-threshold (HT) neurons, and a second one that is blocked by onabotulinumtoxinA (BoNT-A), consisting of peripheral C-fiber and central wide-dynamic-range (WDR) neurons.

All neurons: In control animals, a single wave of CSD activated 70% of all central trigeminovascular neurons, whereas in the BoNT-A/Ato group, it activated only 8.3% (X2= 0.002).  In the control group, mean firing increased >230% 1 and 2h after CSD.  In the BoNT-A/Ato group, mean firing remained unchanged after CSD. 

HT neurons: CSD activated 80% of the neurons in the control group, and 16.6% in the BoNT-A/Ato group (X2= 0.035).  The mean firing increased 162.1 (1h) and 251.1% (2h) after CSD in the control group and remained unchanged in the BoNT-A/Ato group.

WDR neurons: CSD activated 60% of the neurons in the control group, and 0% in the BoNT-A/Ato group (X2= 0.026).  The mean firing increased 542.9 (1h) and 199.4% (2h) after CSD in the control group and remained unchanged in the BoNT-A/Ato group.

The findings raise the possibility that chronic migraine patients may benefit from treatment approach that combines drugs that block the trigeminovascular Ad-HT pathway (i.e., Ato or any other CGRP modulator) and the C-WDR pathway (i.e., BoNT-A).