Abstract
Dear Sir We thank Drs Brighina and Fierro for their interest in our work. The queries they raise are based mainly on studies in which phosphenes were used as indices of visual cortex activation. Since its first application in humans, transcranial magnetic stimulation (TMS) of the motor cortex has been extensively studied, because the peripheral electromyographic response offers an objective measure of cortical activation and allows to determine motor thresholds accurately. TMS studies of the visual cortex, by contrast, have to rely on subjective assessments of phosphenes or visual imagery tasks, which probably explains why they are less abundant and less reproducible. Moreover, the cerebral generators of phosphenes seem quite complex. It is most likely that both the optic radiations close to their termination in the dorsal parts of V1 and back-projecting fibres from V2 and V3 back to V1 generate phosphenes and scotomas (1). Finally, while the respective roles of inhibitory and excitatory interneurons as well as pyramidal neurons are well documented in the motor cortex, the precise interactions between these different actors are still poorely understood in the visual cortex. For example, Sparing et al. (2) recently found that the mechanisms underlying phosphene induction in the visual cortex are different from those underlying intracortical inhibition and facilitation in the motor cortex. To obtain an objective measure of visual cortex activation, we have therefore used the pattern-reversal visual evoked potential (PR-VEP) instead of studying magnetophosphenes once again.
Habituation of cortical evoked responses is a complex phenomenon depending on the balance between excitatory and inhibitory mechanisms. The interictal habituation deficit found in migraine could in theory be due to at least three different abnormalities: increased excitability (homosynaptic facilitation), decreased inhibition (heterosynaptic) or decreased cortical preactivation level. We have previously argued that the latter is the most likely explanation and provided a set of experimental data favouring this hypothesis: (i) the amplitude of cortical evoked potentials in the first blocks of a low number of averagings is normal or reduced (see Schoenen et al. for a review (3)); (ii) thalamo-cortical activation, as reflected by the early burst of high-frequency oscillations (HFO) in somatosensory evoked potentials is reduced, whereas intracortical inhibition, as indexed by the late HFO burst is normal (Coppola et al. (4)); (iii) if high-frequency rTMS would restore habituation in migraineurs by up-regulating cortical inhibitory circuits as suggested by Brighina anf Fierro, one would expect a decrease in amplitude of the PR-VEP first block and, if magnetophosphenes are reliable, an increase in phosphene threshold. The experimental data, however, show the exact opposite: an amplitude increase and a threshold decrease (see p. 147 of our article); (iv) the ictal (and immediate pre-ictal) normalization of evoked potential amplitudes and habituation is more likely to be induced by the effect of a modulatory system on cortical preactivation level than by a change in excitability of inhibitory interneurons. A good candidate for this is the raphe-cortical serotonergic pathway. As a matter of fact, the ictal normalization of habituation in a visual event-related potential was accompanied by a decrease in platelet 5-HT content, and thus an increase in the biologically active compartment of serotonin (Evers et al. (5)).
Taken together, these findings suggest that in migraine the cerebral cortex is dysexcitable because of an interictally reduced preactivation level of sensory (especially visual) areas, probably due to hypoactivation in subcortico-cortical aminergic pathways. However, Brighina and Fierro rightly emphasize that a role for intracortical inhibitory interneurons cannot be ruled out, the more so in that a reduction of cortical preactivation (and thus of lateral inhibition) may be associated with insufficient activation of these interneurons and that ascending aminergic systems have been shown to differentially affect subgroups of cortical GABAergic cells (Bacci et al. (6)). We therefore need more experimental data on migraine patients, in particular studies of PR-VEP habituation after modulation of intracortical inhibitory circuits by light deprivation or pharmacological agents.
Finally, whatever the cellular and molecular mechanisms might be for the effects of rTMS on the visual cortex, we agree with our colleagues on the therapeutic potential of this method in migraine.