Physical exercise and traumatic brain injury: is it question of time?

Valentina Mastrorilli ,Stefano Farioli Vecchioli

Is it better to be safe than sorry? This Hamletic dilemma has always stimulated medical-scientific debates in numerous fields of biomedicine.And among these,the preventive-therapeutic approach to the treatment of brain trauma is one of the most striking examples.Traumatic brain injury (TBI) is a leading cause of brain damage among young and elderly populations with a very high hospitalization and death rate.TBI is characterized by two pathologically distinct but strictly consequential phases: a first characterized by an immediate and highly variable mechanical dysfunction of the brain tissue,which involves widespread cell death and tissue degeneration,followed by a second phase which can last from days to even years depending on the severity of the TBI and the patient’s pre-existing health status.Secondary processes,including inflammatory phenomena,oxidative stress associated with metabolic,vascular,and neuro-modulatory deficits,are very often responsible for neuromotor and psychological deficits leading to longterm disabilities (Kaur and Sharma,2018).In recent years,physical activity has emerged as one of the most promising non-pharmacological therapies in post-traumatic neuro-rehabilitation strategies (Coll-Andreu et al.,2022).However,pre-clinical experimental evidence and human clinical trials have not yet produced unequivocal results capable of establishing standardized therapeutic pathways based on post-traumatic exercise.The high diversity of short-and longterm consequences of head trauma,which can range from motor and cognitive problems to sleep-related problems and mood,up to the comorbidity of the onset of neurodegenerative diseases such as Alzheimer’s diasease,represents one of the main obstacles to determine how much and when physical therapy can bring benefits in a post-traumatic patient (Griesbach et al.,2018).Furthermore,in this context,the age and previous psycho-physical conditions of the traumatized patient must also be taken into account.These issues represent fundamental variables that can greatly modify the optimal conditions of physical activity capable of providing an effective therapeutic benefit.With reference to when to subject the patient to physical therapy,some preclinical studies have shown that a therapeutic approach based on very early physical activity post-trauma can lead to an aggravation of the progression of post-traumatic neuro-degenerative processes,due to various deleterious factors such as an increase in inflammatory phenomena,the hypersecretion of catabolic hormones,an altered ion homeostasis and Na+-K ATPase activity and finally the increase in metabolic demand within an already compromised brain (Griesbach,2011).Further clues concerning a deleterious effect of a premature approach to post-TBI physical activity come from studies in which a lack of increase in brain-derived neurotrophic factor (BDNF),cAMPresponse element binding protein,synapsin,and other signaling molecules involved in synaptic plasticity was observed in mice subjected to physical activity in a period very close to TBI,with consequent impairments in post-lesion cognitive abilities.Finally,the negative effect of early posttraumatic physical activity is also reflected in the abrogation of different endogenous compensatory mechanisms,suggesting that an engaging prematurely in post-TBI physical activity can induce a significant lowering of the endogenous mechanisms responsible for restoring cerebral homeostasis and the stimulation of reparative neuroplasticity (Coll-Andreu et al.,2022).

However,the therapeutic power of post-traumatic physical exercise is highly emphasized by other preclinical studies and clinical trials,which take into consideration physical activity applied several days after TBI.The main benefits provided by this low-cost,non-invasive,and easily implemented therapy are mainly due to the massive increase in essential components of neuroplasticity such as insulin-like growth factor-1,vascular endothelial growth factor,and above all BDNF (Coll-Andreu et al.,2022).In fact,many preclinical studies carried out on mouse models of TBI have clearly highlighted a direct correlation between post-TBI physical exercise and increased expression of BDNF in brain regions damaged by the lesion,with a consequent improvement in endogenous neuro-reparative potentials,ranging from reduced cell mortality,increased synaptic plasticity and neurogenesis up to a marked improvement in learning and memory abilities in mice subjected to TBI (Coll-Andreu et al.,2022).Another very important aspect that has recently emerged is the discovery of an anti-inflammatory action exerted by physical activity in pre-clinical models of TBI.In fact,one of the pathophysiological aspects characterizing TBI is represented by the activation in the perilesional regions of microglial cells,which initially play a critical role in the clearance of metabolic products and in debris removal,but which in the long run assume a pro-inflammatory phenotype and neurotoxic activity.In this context,it has been demonstrated that physical exercise plays a potent anti-inflammatory action in TBI animal models,through the reduction of the number of reactive microglial cells,the inhibition of the production of pro-inflammatory cytokines,and the up-regulation of the expression of genes able to stimulate the activation of an anti-inflammatory M2 microglial phenotype (Kim et al.,2022).

However,when we analyze the effect of posttraumatic physical therapy on humans,the situation is much more complex and varied.In fact,few studies have tackled this topic with somewhat heterogeneous results as regards study samples and diversity of outcome experimental data obtained.Ultimately,what emerges from the scientific literature is that physical activity is always preferable to rest following a traumatic event and that practicing moderate exercise following a head injury if not beneficial,may not be deleterious(Coll-Andreu et al.,2022).Neuroimaging studies have suggested that physical activity following TBI is able to positively modulate different neural substrates,such as structural connectivity and gray matter microstructure.In this regard,the existence of a common mechanism able to orchestrate these modifications,rather than the presence of different independent mechanisms,has been hypothesized.In fact,numerous evidences agree that the activity-induced neural modifications may be attributable to improvements in the angiogenesis process or changes in cerebral blood volume following exercise.In fact,it has been seen that TBI-dependent widespread reduction of cerebral blood flow (CBF) can be normalized by physical activity with a consequent improvement in prognosis,as observed in athletes with repetitive concussion (Zafonte et al.,2018).In this regard,physical activity in healthy people is able to significantly increase the regional CBF both in the early and late phases of exercise.From these considerations emerges the need to deepen the relationship between post-traumatic exercise and CBF modifications also by taking into consideration other markers of TBI recovery,such as the heart rate variability,in order to provide simpler and more effective diagnostic methods for evaluating neural recovery through CBF normalization.

Recently,a new line of research has emerged that analyses the effect of physical activity before TBI.It must immediately be said that these studies have no purely therapeutic value as it is impossible to predict a traumatic event,even if the continuous concussions during sporting activities and the extreme bone fragility responsible for falls in the elderly could in some way represent fields in which apply these preventive studies.Pre-clinical studies on mice models have clearly demonstrated that acute and/or continuous physical exercise preceding a traumatic event is able to promote numerous molecular and cellular adaptive responses that enormously increase neuronal resilience to brain damage and to ameliorate cognitive functions (Soltani et al.,2020).The phases immediately following the head injury (in the first 60–90 minutes) are the most critical for the survival of the patient affected by a severe TBI.In this period the primary damage mainly characterized by axonal damage,cell membrane disruption,and glutamate-induced excitotoxicity very often is responsible for a high mortality rate.In this context,a very recent study demonstrated that a period of pre-conditioning with physical activity was closely correlated not only with a significant reduction of the mortality rate but even with an increase of hippocampal BDNF production and an attenuation of spatial memory deficits in a mouse model analyzed 30 days following severe TBI (Kopczynski et al.,2023).This observation reveals an extremely important prophylaxis role of physical activity in a post-traumatic context and at the same time suggests how a physically active lifestyle is capable of erecting a sort of brain reserve capable of effectively counteracting the post-traumatic damages caused by TBI.In support of these observations,pre-clinical studies in mouse models have shown that running before TBI provides a series of neuroprotective and neuro-reparatory mechanisms,acting on the injured tissue,likely resulting in an even greater effect than what observed in post-TBI exercise sessions.These mechanisms include a reduction of edema and lesion-size,a decrease in neuronal death,in oxidative stress,and in microglial activation associated with a potent attenuation of post-traumatic inflammatory phenomena,leading to an improved recovery of sensorimotor performance and cognitive/affective functions (Soltani et al.,2020;Kopczynski et al.,2023).At the cellular level,the ability to respond to trauma is expressed through the modulation and reorganization of neuroplasticity processes in the attempt to restore neural homeostasis as much as possible within the damaged regions.In preclinical models,adult neurogenesis represents the form of neuroplasticity most responsive to TBI.In fact,numerous studies have highlighted a rapid activation of the neural stem cells (NSCs) and neural progenitors in a very short time after TBI with a consequent increase in the number of new neurons within the main neurogenic niches: The hippocampal dentate gyrus and the subventricular zone (Chang et al.,2016;Marzano et al.,2022).A very intriguing process intimately related to the post-TBI neurogenic response is the massive migration of new neurons from neurogenic niches to injured regions (Chang et al.,2016).The functional output of this cellular redirection is still being studied,even if several hypotheses converge on a trophic and neuro-reparative supporting role of these young neurons within the injured brain regions.However,the role of physical activity,one of the main pro-neurogenic external stimuli,in enhancing post-TBI neurogenic responses has always been poorly considered,and no study up to now has ever examined the role of physical activity before TBI on neurogenic response.In this regard,a recent paper has shown how the interaction between physical activity and p21 gene deletion before TBI plays an important role in subventricular neurogenic and migratory mechanisms in response to traumatic injury (Battistini et al.,2023).The p21 gene is one of the main regulators of the NSC quiescent/activation transition phase and its deletion induces an early hyper-activation and proliferation of NSCs in the postnatal age,followed by a gradual depletion of the NSC pool and a decline of neurogenic activity within the niches.Physical activity is able to reactivate the neurogenic potential of p21 ko NSCs and to trigger a potent increase of adult neurogenesis in the subventricular zone (Battistini et al.,2023).In this study,pre-conditioning with physical activity before the trauma results in a potent neurogenic response characterized by a strong increase of neural progenitors and a massive migration of stem cells and neuroblasts towards the injured cortical region,leading to a clear improvement of the specific functional responses of mice (Battistini et al.,2023).

In this framework,it appears somewhat complex to compare the effects of pre and post-TBI physical activity,due to the different TBI and physical exercise models utilized as well as the scares literature describing the processes underlying the pre-conditioning role of physical activity in humans.However,the observations here summarized support the hypothesis that preventive physical activity has a greater neuro-reparative power than that obtained by exercise after the trauma(Figure 1).Indeed,we hypothesize that constant and moderately intense physical activity during life could predispose the brain to a whole series of protective and repairing mechanisms ready to act immediately after the traumatic event,something that cannot be done with physical exercise following TBI.And it is widely known that the ability of the brain to react promptly to the first post-TBI phase is of pivotal importance in the sequence of events that distinguish the severity of the damage and the repercussions on the physical and mental state of the traumatized patient.Furthermore,it cannot be excluded that the psycho-physical conditions of a post-TBI patient are not ideal for letting physical activity suitable for improving the neural response to trauma,contrary to what happens in a healthy person who practices sport.In this regard,it has been reported that pre-injured exercise history of walking or jogging positively influenced home-based exercise adherence to rehabilitation programs,suggesting that even cultural aspects need to be taken into consideration (Hasset et al.,2011).In conclusion,we are talking about two sides of the same coin that are quite different and not easily comparable;however,the available scientific data confirms once again that leading a physically active life is excellent insurance even in the event of a head injury.

Figure 1｜Pre-and post-TBI physical activity differentially affects the brain.

Plaisant S.R.L.has no known competing financial interests or personal relationships that could have appeared to influence the work reported in this manuscript.No conflicts of interest exist between Plaisant S.R.L.and publication of this manuscript.

Valentina Mastrorilli#,Stefano Farioli Vecchioli*, #

Institute of Biochemistry and Cell Biology,Institute of Biochemistry and Cell Biology,National Research Council (IBBC/CNR),Monterotondo,Rome,Italy(Mastrorilli V,Farioli Vecchioli S)Plaisant S.R.L.,Rome,Italy (Mastrorilli V)

*Correspondence to:Stefano Farioli Vecchioli,PhD,stefano.fariolivecchioli@cnr.it.https://orcid.org/0000-0001-7059-7779(Stefano Farioli Vecchioli)#Both authors contributed equally to this work.

Date of submission:April 19,2023

Date of decision:May 25,2023

Date of acceptance:June 12,2023

Date of web publication:July 20,2023

https://doi.org/10.4103/1673-5374.380888

How to cite this article:Mastrorilli V,Farioli Vecchioli S (2024) Physical exercise and traumatic brain injury: is it question of time?Neural Regen Res 19(3):475-476.

Open access statement:This is an open access journal,and articles are distributed under the terms of the Creative Commons AttributionNonCommercial-ShareAlike 4.0 License,which allows others to remix,tweak,and build upon the work non-commercially,as long as appropriate credit is given and the new creations are licensed under the identical terms.

Open peer reviewers:Margalida Coll-Andreu,Universitat Autònoma de Barcelona,Spain;Nathan R Strogulski,the University of Dublin Trinity College,Ireland;Luis V Portela,Universidade Federal do Rio Grande do Sul,Brazil.

Additional file:Open peer review reports 1,2,and 3.