Can cortical spreading depression activate central trigeminovascular neurons without peripheral input? Pitfalls of a new concept.

For the past 25 years, it has been hotly debated whether cortical spreading depression (CSD), the underlying mechanism of aura, can trigger migraine headache through activation of the trigeminovascular pain pathway. According to one school of thought, CSD leads to a cascade of molecular events (1) that activate pain fibers in meningeal areas overlying the affected cortices (2). According to another school of thought, the aura (and therefore CSD) and the headache are coincidental events with no causal relationship (3). In the past 2 years, this debate has been put to rest by a wealth of scientific evidence that CSD is a noxious event that activates the trigeminovascular pathway (4,5). The recent publication by Lambert and colleagues opens yet a new debate on whether the activation of the central trigeminovascular neurons by CSD depends on peripheral input from meningeal nociceptors or central input from the cortex (6). In their study, the authors suggest that activation of brainstem trigeminovascular neurons by CSD can occur independently of peripheral input (6). This stands in sharp contrast to a large body of evidence for the critical role of peripheral nociceptors in the activation of central trigeminovascular neurons (4,5,7–11). Settling this issue is therefore critical, as it is relevant to the very biological underpinnings of migraine in general, and to the relationship between the aura and headache in particular. Unfortunately, as experts in the experimental techniques used in this study, we believe that the veracity of the findings are questionable, for a number of reasons. First, the recordings are not single units, as claimed, or even multi-units, but instead appear to reflect background electrical noise (e.g. Figure 5 lower trace; multiunit discharge appears only after the second arrow, but the rate meter registers high levels of activity before that point, even though no discharge is visible). Even the top panel in Figure 1, which is vastly better than the one shown in Figure 5, shows that firing of several neurons are registered into the data analysis system as coming from only one neuron (6). Second, the blockade of peripheral input to the spinal trigeminal nucleus is incomplete. For the study to be valid, a complete blockade of transmission of all action potentials from the dura to the spinal trigeminal nucleus should have been achieved. Only then could the authors conclude with any kind of certainty that the activation of brainstem trigeminovascular neurons by CSD was partially independent of peripheral input (1). As shown in Figure 2 (6), lignocaine injections in the trigeminal ganglion did not eliminate all neuronal responses to stimulation of the dura and skin. At that point, the study should have been stopped or redesigned as it could no longer refute the possibility that the activation seen in the spinal trigeminal nucleus after the induction of CSD was mediated solely by the peripheral input from meningeal nociceptors, whose activity, by the way, was increased by CSD in a similar manner (5). (Scientifically, there are two ways to explain the incomplete blockade of peripheral input from skin and dura to the spinal trigeminal nucleus: (a) incomplete inhibition of the trigeminal ganglion by the lignocaine injection, especially the difficult-toreach neurons in the ophthalmic division of the ganglion, and (b) peripheral input from intact sensory neurons in the 2nd and 3rd dorsal root ganglia.) Third, the blockade of peripheral input to the spinal trigeminal nucleus is assessed inadequately.