Persistent post-traumatic headache: a migrainous loop or not? The preclinical evidence

DOI: https://doi.org/10.1186/s10194- 020- 01135- 0

Abstract-Summary Due to the high prevalence of this disorder, several preclinical studies have been conducted using different animal models of mild TBI to reproduce conditions that engender PTH.

Despite representing a simplification of a complex disorder and displaying dif- ferent limitations concerning the human condition, animal models are still a main- stay to study in vivo the mechanisms of PTH and have provided valuable insight into the pathophysiology and possible treatment strategies.

Despite its high prevalence, PTH is not entirely understood, and the differential contribution of pathophysiological mechanisms, also observed in other conditions like migraine, has to be clarified.

The knowledge of currently available models is necessary to all researchers who

want to investigate PTH and contribute to unravel its mechanisms.

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5 Future Directions

Background: Definition, Epidemiology, Why Animal Models Are Needed? According to the International Classification of Headache Disorders 3 [ICHD-3], PTH attributed to traumatic head injury is a secondary headache that develops within 7 days after head or neck trauma (or after regaining consciousness following the trauma) [28].

In a large cohort study about the occurrence of post-concussion symptoms after complicated and uncomplicated mild traumatic brain injury (mTBI) it was seen that headache could be present at 3 and 6 months post-injury, as well as dizziness, noise sensitivity, fatigue/tiring more easily, feeling depressed/tearful, feeling frustrated or impatient, forgetfulness/poor memory, poor concentration, taking longer to think and restlessness [29].

A recent multicentric study noted that mild or worse PTH after uncomplicated mTBI (no intracranial abnormalities in CT scans) was present in 30% of patients at 3 months and in 27% at 6 months [29] and a pre-injury history of headache are sig- nificantly related to a higher risk of developing PTH [30–32].

Animal models of mTBI and concussion are being used for studying PTH.

Main Text It seems that all the studies mentioned above strongly corroborate the hypothesis that common pathways, especially those involving CGRP, are present in both migraine and PTH, raising the question whether the two conditions could represent a continuum within a spectrum of headache disorders, especially considering that animal models of PTH have achieved reproducing migraine-like features, as seen in humans.

Although chronic migraine animal models evaluating specific response to murine anti-CGRP drugs are lacking and human, and animal models are not directly com- parable, the coexistence of other different mechanisms in chronic migraine and per- sistent PTH could still be supposed and should be further investigated.

Current PTH animal models have shown impaired cognitive activities as well as altered responses to BLS, suggestive of migraine-like features as observed in human PTH studies [33].

Conclusions PTH is a common and disabling condition, for which we still need to clarify general pathogenesis and crucial mechanisms.

Animal models have provided relevant information on the pathophysiology of

PTH, but detailed underlying mechanisms are not fully understood.

In order to better define the relation between migraine and PTH, and to improve specific knowledge that could lead to targeted treatments, animal models should be tailored to accurately resemble human features and be systematically used to seek similarities and differences between these two bothering conditions.

Acknowledgement A machine generated summary based on the work of Benemei, Silvia; Labastida- Ramírez, Alejandro; Abramova, Ekaterina; Brunelli, Nicoletta; Caronna, Edoardo; Diana, Paola; Gapeshin, Roman; Hofacker, Maxi Dana; Maestrini, Ilaria; Pías,

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Post-concussion Syndrome

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Enrique Martínez; Mikulenka, Petr; Tikhonova, Olga; Martelletti, Paolo; MaassenVanDenBrink, Antoinette 2020 in The Journal of Headache and Pain.

Persistent post-traumatic headache: a migrainous loop or not? The clinical evidence