Multiple Concussions: From Preclinic to Clinic

Concussion is classified within the category of mild traumatic brain injury, occurring any time an external force, unnecessarily acting directly to the head, causes a rapid acceleration-deceleration of the brain. It is prevalently encountered in both contact (American football, boxing, martial arts, soccer, ice hockey) and non-contact (horse riding, alpine sky, car and moto races) sports. On classical neuroradiological screening (CT scan, MRI), the largest majority of concussed patients is negative, although manifesting a well characterized plethora of early (loss of consciousness, confusion, headache, nausea, vomiting) and late (persistent headache, reduced capacity to concentrate, fatigue and disturbances of memory, sleep, character) clinical symptoms that, in those who had no previous history of concussion, spontaneously resolve in a relatively short period of time (1-2 weeks). Transitory cognitive disfunctions accompany the post-concussive period and disappear, after the first concussive episode, more or less together with that of clinical symptoms. What we learned in the last decades is that, part of the force acting at the time of impact, is absorbed by the “soft” brain tissue immediately triggering biochemical (alterations in enzyme activities and protein expressions), metabolic (mitochondrial dysfunction with energy deficit), molecular (alterations in gene and microRNA expressions) changes characterizing the well-known neurometabolic cascade of concussion, affecting numerous processes of nervous cell functions and lasting much longer than symptom resolution and neurocognitive healing.

To date, no easy to measure biomarkers of diagnostic and prognostic value are available to assess the “real” biochemical, metabolic and molecular healing of the post-concussed brain. Given this deficiency, it remains highly inappropriate to base the return-to-play decision for sports-related concussions solely on the disappearance of symptoms and the normalization of neurocognitive functions. Indeed, during the prolonged period of biochemical, metabolic, and molecular healing, the brain remains in a "window of vulnerability" to a second concussion, which, in the worst-case scenario, can lead to second impact syndrome, often resulting in fatal outcomes. In most cases, repeat concussions do not give rise to gross symptoms different from those of a single concussion. What is strikingly different is their duration. Additionally, there is no answer, to date, to the crucial question “how many are too many”. Nor it is currently understood when and how repeat concussions develop into chronic traumatic encephalopathy, of devastating consequences for the patients. Again, we are still searching for biomarkers of diagnostic and prognostic value to monitor repeat concussed patients, as well as of standardized animal models that may greatly help to clarify the molecular mechanisms of nervous cell damages of brain that experienced repeat concussions. Also, it would be of paramount importance in sports to clearly understand whether multiple sub-concussive episodes may develop into permanent damages of brain cell functions.

The aim of this Research Topic is to receive contributions (from preclinical and clinical research to review papers) that may contribute to fill the lack of knowledges on the aforementioned questions in the field of multiple concussions as well as sub-concussions. The Topic Editors are particularly interested in, though not limited to, the following subtopics:

- Evaluation of potential molecular biomarkers in patients with multiple concussions and their correlation with symptoms and neurocognitive tests
- Investigating the effects of sub-concussions in humans
- Preclinical models answering the question on “how many are too many”, and providing information on the point-of-no-return that will lead to irreversible neurodegeneration
- Preclinical models describing the potential molecular mechanisms that may contribute to the development of chronic traumatic encephalopathy.