The current study investigated neurometabolic differences between 10 non-concussed athletes and 10 concussed athletes of similar age and education in the acute and chronic post-injury phases. In the DLPFC, NAA:Cr levels remained lower in the concussed group across time. All other comparisons in DLPFC revealed no significant differences or trends. Within the motor cortex there were variable changes depending upon the metabolic ratio in question. Concussed athletes demonstrated a recovery of Glu:Cr levels across time (Figure 3A). Levels of m-I/Cr were equal between control and concussed athletes in the acute post-injury phase but there was a significant difference in the chronic phase suggesting metabolic disruptions that emerged over time as opposed to being immediately reactionary to the injury. NAA/Cr levels in M1 tended to distinguish control and concussed athletes at both time points, suggesting a similar pattern as was seen in the DLPFC.
The profiles of Glu:Cr and m-I:Cr in the DLPFC demonstrate stability within and between groups. This is consistent with the findings of Shutter et al.  who found that Glu:Cr levels were not predictive of outcome in patients with good outcomes either immediately post-injury or eight months post-injury relative to controls. It is difficult to draw parallels with other findings involving either increases or decreases in Glu:Cr levels as other studies have taken spectra from different brain regions and in more severely injured populations [74, 75]. Though we have previously demonstrated changes in Glu:Cr in primary motor cortex, we did not see similar alterations in DLPFC suggesting that there are biomechanical influences that are present in primary motor cortex that are not present in prefrontal areas [53, 76]. Similarly, m-I:Cr levels were also very stable both across time and between groups.
The nature of the NAA:Cr findings was unexpected given the current literature implicating decreased levels of NAA:Cr [53, 54, 62, 77]. Indeed, past research investigating the time course of NAA alterations report mixed results as one moves chronologically further away from the point of injury. Vagnozzi and colleagues  report recovery within 30 days, except for those athletes who received a second concussive blow during the acute phase. We reported a similar finding in a group of 12 athletes who were scanned days after sustaining a concussion . Conversely, Cohen and colleagues  found that whole brain NAA levels remained depressed in patient groups that were days to over a year post injury. Other studies have found diminished NAA levels in similar brain regions ranging from days  to one month  to months  to a year  post-injury. Though our results are consistent with the latter group of studies showing continued depression of NAA:Cr levels, they are contrary to those of Vagnozzi and colleagues . The exact nature of why there is continued depression is not immediately evident, but a few explanations for these metabolic alterations are plausible. Firstly, the current study's sample is composed of student athletes. Though the athletes followed the return to play protocol as specified in the consensus statements [52, 72], they continued to take classes and in most cases resume practice within one week after the injury during the season in addition to continued physically demanding training in the months after the season when the follow-up data were obtained. This continued cognitive and physical effort may protract a full recovery [12, 52, 80] even when return to play protocols are properly followed such that a return to preconcussion levels does take place, but outside of the window used in the current study. Another possibility that may explain the continued metabolic depression is perhaps unique to contact sports like football and hockey. Even though no athletes reported a second concussion in a single season, sustaining subconcussive blows during practices and games may have also delayed metabolic recovery, even without resulting in a second injury as some studies suggest there are consequences, even if short lived, to sustaining multiple subconcussive blows [81, 82]. Finally, it is also possible that sustaining a concussion persistently lowers NAA:Cr levels. There is ample evidence to suggest this is the case after a mTBI [70, 77, 79]. Future studies charting the time course of metabolic injury and recovery need to be conducted in order to determine whether there is recovery, in whom there is recovery, and when the recovery occurs. Though the current study investigates sports concussion, which are not necessarily equivalent to mTBI, the comparison is still worth making until more data specific to sports concussion becomes available.
Results from primary motor cortex paint a more complex picture of the metabolic state of the brain after a concussion. While depressed in the acute phase, Glu:Cr levels in concussed athletes rebound to those of control athletes in the chronic phase, elegantly demonstrating metabolic recovery. There is no precedent for Glu:Cr recovery in the mildly brain injured population, let alone in the sports literature. However, given the seemingly short lived metabolic disturbance of glutamate levels as illustrated in the neurometabolic cascade , we predicted just such a recovery. What remains to be further explored is when exactly between the injury and the 6-month post injury time point as measured in the current study does Glu:Cr concentration achieve physiologically typical levels and whether this metabolic resolution corresponds to symptom recovery. The reasons for affected Glu:Cr levels in M1 but not in DLPFC are not immediately apparent. However, examination of the literature investigating the biomechanics of mTBI show that the rotational forces associated with concussion suggest that M1 is consistently vulnerable to shear strain [19, 76, 83–85].
M-I:Cr in M1 also showed a complex pattern of results. While there are no differences in the acute phase, there appears to be a pathological increase in m-I:Cr in the chronic phase. Other studies investigating either mixed TBI groups  or severe TBI [69, 74] though in different brain regions, have noted increased concentrations of m-I months and years after injury. The current data are consistent in this respect, but why these differences are not seen in the acute post injury phase is not immediately apparent. One possible explanation may be that there are two different mechanisms that help to regulate osmotic pressure in neurons and glia. Within the acute post-trauma phase this is primarily regulated by the rapid transport of Na+, K+, H+, and Cl- across the plasma membrane [86, 87]. Indeed, such an account is supported by the neurometabolic cascade as described by Giza and Hovda  where axonal swelling is indicative of hypernatremia . To offset the ensuing water loss, the brain accumulates m-I to avoid a rapid over correction which could have devastating consequences to the brain . Such a fast acting mechanism would preclude any observable changes in m-I in the acute phase which is in line with the current study's results. However, long term changes in cellular tonicity are offset by the transport of non-perturbing osmolytes that do not alter the electrophysiological state of the cell, namely m-I . The increase in m-I might also be indicative of gliosis [see 90 for review]. Myo-Inositol increase in association with decreased NAA:Cr ratios has been associated with gliosis in other populations , while other work suggestions that gliosis is not necessarily related to altered neurometabolism . Other studies investigating TBI also report increased m-I:Cr levels in both severe [69, 74] and mild injuries . In addition to TBI, other pathologies that have been associated to increased levels of m-I include drug addiction and stroke [see 67 for a complete review]. Though many questions remain as to the functional significance of such an increase in m-I, we are the first to report such an effect in the sports concussion population. Further confirmation is needed to confirm the robustness of this finding in a larger sample as well as the temporal nature of the changes.
The breadth of the metabolic changes in M1 (increases in m-I/Cr and Glu/Cr) within the concussed athletes in the chronic post-injury phase as well as the significant decrease of Glu:Cr in the acute phase may be due to the biomechanics of how the brain moves within the skull when a rotation force is applied [76, 85, 92]. The respective impacts of rotational and linear forces in producing a concussion [76, 85, 92–94] suggest that M1 is consistently vulnerable to the white matter injury of shear strain. The differential effects on Glu:Cr and m-I:Cr in M1 versus DLPFC are further corroborated by changes detected using diffusion tensor imaging where patients who had suffered a mTBI demonstrated reduced fractional anisotropy in the corticospinal tract indicating diffuse axonal injury where no such injury pattern was found in frontal regions .
NAA levels in M1 showed a statistical trend between concussed and control athletes. Indeed, the overwhelming evidence implicates diminished levels of NAA after a brain injury, whether it be mild [53, 54, 62, 70, 77–79, 95] or severe [60, 70, 74, 75, 78, 96, 97]. Though the current results were not statistically significant in M1, this is consistent with what the current study demonstrates in the DLPFC. Decreased levels of NAA may be reflective of diffuse axonal injury in white matter and neuronal loss in gray matter , but this is a less probable interpretation given the heterogeneous nature of the neuropathological response to trauma. Declines in NAA levels are linked to decreases in ATP where the greater the initial decrease, the lesser the observed recovery. Indeed, recovery is observed in all injuries that do not include the substantial permanent destruction of brain tissue. That is to say, neurological recovery may be observed in conjunction with varying degrees of metabolic recovery where the latter need not be complete in order to observe clinical recovery in the former . The persistent reduction in NAA:Cr levels observed in the current study may therefore be the consequence of a continued reduction of ATP due to the disruption of neuronal mitochondria due to the influx of Ca2+ and lactate, which is consistent with the observed post-injury cellular pathology ; furthermore, clinical signs seem to bear little relation to the neurometabolic anomalies observed in patients suggesting a highly variable relationship between injury severity and metabolic changes past the immediate (minutes) post-injury phase . It is thus conceivable, despite the findings of Vagnozzi et al (2008) that concussed athletes do have continued metabolic disruptions despite being clinically recovered in terms of their PCSS scores. That is to say, even though concussive injuries do not typically result in observable brain trauma (i.e. MRI, CT scan), and concussed individuals typically recover from a symptom standpoint within weeks after the injury, there is a sustained and persistent effect on cellular metabolism. The continued neurometabolic alterations observed in the current study may be reflective of other pathological processes such as gliosis or cell loss. Cell loss would seem to be less probable given the time frame of 6 months post injury used in the current study, though changes in volumetry have been shown as a consequence to mTBI while other studies have measured brain volume at one year post-injury [77, 99]. Indeed, a study investigating mTBI 6 months post injury showed atrophy only in participants who had positive MR findings  while another some three months post injury also failed to find differences in participants who had suffered a MTBI . Gliosis, as mentioned above is another possibility, but given that the current study observes an increase of m-I only in M1, it does not explain the persistence of metabolic disturbance observed in the DLPFC.