Abstract
In their interesting article, Young et al. (1) propose that each symptom or sign occurring in primary headache disorders is the result of the dysfunction of a ‘neuronal module’ and that links between certain modules are responsible for both the sequence of symptoms and the global phenotype of a given headache in a given individual.
As most ‘theories’ in Medicine, and especially in primary headaches, this one raises ambivalent feelings.
In the peer-review process both referees found the paper ‘fascinating’, but one strongly recommended it while the other firmly rejected it for publication.
Reinventing the wheel?
Are there still neurologists and neuroscientists who do not believe that the symptoms and signs of primary headache patients are due to neuronal dysfunctions? If the answer is no, as I hope, there is no doubt that the relevant structures are not single neurones, but neuronal circuits, which the authors call ‘modules’.
Once the trigeminal pain pathway is activated on one side, its connections i.a. with nucleus tractus solitarius, superior salivary nucleus, reticular formation, parabrachial nucleus, periaqueductal grey, hypothalamus and probably contralateral trigeminal nucleus caudalis can explain associated gastro-intestinal and autonomic symptoms, sensoriphobia and bilaterality. The difference in clinical phenotype between attacks in the same individual, between individual patients and possibly between disorders could chiefly be due to different degrees of activation in the pain-conducting pathways themselves and in their collateral projections to these various structures. Trigeminal pain being after all the common denominator between primary headaches, such a simplified view refers to known anatomical circuits and would not need ‘modules’.
The term ‘modules’ is known for the anatomo-functional organization of the cerebral cortex, where the columnar modules are linked to a discrete and precise neurological function. The modules proposed here are quite different as they refer to symptoms, many of which can be induced by a dysfunction or lesion in different regions of the nervous system: for instance, ptosis-miosis by a dysfunction in the hypothalamus, brain stem, spinal intermediolateral column at C8-D1, cervical sympathetic chain; nausea by a dysfunction in hypothalamus, nucleus tractus solitarius, vagus nerve. Moreover, the modules proposed by Young et al. (1) comprise both normal physiological functions such as autonomic control and biological rythms, and systems that are activated only in pathological conditions, such as aura (?), pain, allodynia, acouphobia, or nausea.
Adding a novel aspect?
The interesting aspect of the ‘modular theory’ presented here is that it allows for a sequential activation of modules (or neuronal circuits) as discussed above, but also for independent activation of neurones in different locations or for simultaneous activation of various modules by a single common trigger. In the realm of pathogenic theories presenting some primary headaches such as migraine as ‘central channelopathies’, this is interesting and thought-provoking. Ion channels, such as the voltage-dependant calcium channel dysregulated by CACNA1A mutations, are indeed widely distributed in the nervous system. If they are responsible for paroxysmal dysfunctions of neurones, this might in theory occur in different locations simultaneously or at different times, allowing for different clinical phenotypes and/or march of symptoms.
Circumstantial clinical evidence for such independent foci of recurrent neuronal dysfunction, however, exists only in migraine with aura, where the aura and the headache might evolve independently (2).
To sum up, the ‘modular headache theory’ described by Young et al. (1) has on the one hand a flair of ‘déjà vu’ by its reinvention of known functional neuroanatomy. On the other hand, it is thought-provoking and provides ideas for novel scientific research in primary headaches, which is after all its main purpose and the reason why it was accepted for publication in the ‘hypothesis’ section.