A “SUBCONCUSSIVE” BLOW is one that does not meet the criteria for clinical diagnosis of concussion or mild traumatic brain injury (TBI), yet is hypothesized1 to have an adverse long-term effect in some individuals, particularly via repetitive occurrences. Subconcussive blows must be differentiated from mild TBI or concussions. Mild TBI is defined as disrupted brain functioning from any force to the head as evidenced by altered or lost consciousness, with various severity indices (length of coma, posttraumatic amnesia, or Glasgow Coma Scale score) that are of shorter duration or milder than more severe TBI. The most commonly utilized diagnostic criteria are those proposed by the American Congress of Rehabilitation Medicine.2 The term “concussion” is sometimes used to refer to a milder subcategory of mild TBI,3 particularly in the sports literature, but the term is typically used synonymously with “mild TBI.” The vast majority of mild TBI cases have normal findings on clinical neuroimaging (ie, CT and structural magnetic resonance imaging [MRI]). Indeed, some clinical diagnostic criteria for concussion require normal acute neuroimaging.4 The question then becomes whether “invisible” persistent structural injury is present.5,6 Increasing resources have been directed at finding objective physiological evidence of injury and potential correlates with cognitive and neuropsychiatric symptoms through newer or experimental neuroimaging techniques and other biomarkers.
Severity of TBI is determined at the time of injury and not (as is often erroneously done) by level of functioning at some later time point. Severity of TBI is a continuum, and the particular classification scheme used to designate a mild, moderate, or severe injury is somewhat arbitrary. As such, there has been much debate about how best to define concussion/mild TBI and the need for consistency in diagnostic criteria.7 Because it is sometimes impossible to determine with certainty whether or not a person has sustained a mild TBI, some argue that broad and inclusive criteria should be used to identify those at greater risk and to ensure proper evaluation and treatment (eg, McCrory et al3; Scholten et al8) For example, a recently published consensus statement on sports concussion encourages assessment and management of athletes showing features of concussion, which includes postconcussive symptoms (eg, headache, emotional lability) and sleep disturbance.3 Unlike moderate to severe TBI, diagnosis of mild TBI often cannot be corroborated with objective diagnostic tools used by medical or other health care personnel.
If the lower boundary of concussions is unclear, defining a “subconcussive blow” or a “subconcussion” is even more problematic. How does a “subconcussive blow” differ from any blow to the head? What force would be required to be designated a “subconcussive blow” as opposed to a less severe and nonclinical impact to the head? Furthermore, given that concussions may go undiagnosed at the time of the impact, when and how would subconcussive blows be diagnosed? Therefore, “head impacts” or “head impacts not associated with diagnosed concussion” are more accurate terms. Because a subconcussion cannot clearly be defined, it is largely an elusive theoretical construct at this point.
There is growing concern that repetitive head trauma, both those associated with diagnosed concussions and those not so associated, may cause brain pathology and lead to chronic traumatic encephalopathy (CTE). Chronic traumatic encephalopathy denotes a histopathologically defined condition, which has been proposed to be a secondary consequence of repetitive head trauma and to represent a degenerative condition that causes pronounced behavior changes and cognitive dysfunction.9 Its diagnosis is very controversial. Historically, the term “dementia pugilistica” or “punch drunk syndrome” denoted a similar entity, described in boxers with repetitive head trauma.10 Pathologically, the hallmark of CTE is tau-immunoreactive neurofibrillary tangles.11 However, in contrast to Alzheimer disease, the neurofibrillary tangles are unevenly distributed with a predilection for the depths of the sulci and around blood vessels,12 particularly early in the disease. Furthermore, deposition of beta-amyloid (Aß) plaques occurs in fewer than half the cases of traumatic encephalopathy reported to date.9
Just as there is controversy over the lower severity boundary for concussion, there also are no consensus criteria for the neuropathological or clinical criteria of CTE. The 2 prominent laboratories in this line of research have promulgated partially overlapping but different criteria.12,13 Similarly, anecdotal links among concussion, CTE, and clinical outcomes have yet to be scientifically established. For example, despite highly publicized cases suggesting a link between suicide and concussion, a recent review of the evidence concluded that “the current state of the science indicates that suppositions invoking a relationship between CTE and suicide must be viewed as speculative at this point in time.”14 Iverson notes15 that there are no published cross-sectional, epidemiological, or prospective studies showing a relation between contact sports and risk of suicide.
Despite the definitional and diagnostic problems with “subconcussions,” given the debate about the “lower threshold” of concussion and how inclusive versus restrictive one should be, there is increasing interest in “subconcussive” blows to the head. Concerns about the possible effects of repetitive head trauma and the development of CTE add to the importance of developing a clear scientific understanding of these issues. Does a blow that does not necessarily alter consciousness, either alone or repetitively, have some type of adverse impact, either in the short- or in the long-term? This would obviously have significant implications for those who participate in sports, particularly those with a higher rate of such blows (eg, boxing, football, soccer, etc), as well as for military veterans who have been exposed to repeated physical trauma (or potentially even high pressure blast waves) to the head. It might also suggest the need to lower the threshold of what constitutes a concussion.
Animal models suggest that a single blow with a level of force that typically does not cause cellular damage can nonetheless cause damage when repeated several times within short periods.16,17 Shulz et al16 used a paradigm wherein a “subconcussive” lateral fluid percussive force of 0.5 to 0.99 atmosphere (atm) was used based on previous work suggesting that forces of 1.00 to 1.50 atm caused concussion with functional impairments. They found that a single mild lateral fluid percussion injury administered with this lower level of “subconcussive” force did not produce significant differences between “subconcussive injured” rats and sham injured rats on axonal injury measures or on measures of cognitive, emotional (ie, validated measures of anxiety on the elevated plus maze, based on rodents' aversion to open spaces), or sensorimotor functioning. However, there was evidence of an acute neuroinflammatory response in the subconcussive group in the form of increased microglia/macrophages and reactive astrogliosis. Slemmer and Weber17 found that a 10% subthreshold stretch paradigm (which results in membrane deformation and axial strain or stretch) eventually caused damage when repeated multiple times within short periods (2-minute intervals). Notably, 5 or 6 insults were needed to cause damage, and damage was not associated with repetitive blows administered at longer intervals (ie, 1 hour). There were also significant increases in neuron-specific enolase after 6 consecutive injuries, a marker of brain injury, but no corresponding increase in S-100h protein (another biomarker of injury). As such, there is some evidence that repetitive, “subthreshold” force can cause injury but only with a certain number of repetitions in short succession.
On the contrary, other experimental animal research suggests that repetitive “subconcussive” blows may actually be protective in some circumstances. For example, Allen et al18 found that administering repetitive concussive insults (repetitive mild TBI was induced by dropping a weight from 2.5 cm above the dural surface 3 times with 3 days intervening each time) before inducing a severe TBI insult caused significant reduction in motor deficits compared to those observed in animals with severe TBI alone. These authors hypothesize that activation of some neurons and astrocytes in certain regions following repetitive injury may play a role in cortical reorganization and/or creation of alternate pathways in the brain. There is other evidence that a very mild “subconcussive” blow might actually be protective in some cases. For example, a “subconcussive” injury (3.4 mm) applied to mice hippocampal cells administered 24 hours before a “mild” injury (5.5 mm) significantly decreased S-100h protein (but not neuron-specific enolase).17 However, there may be differences in effects between glia and other cells in this type of paradigm (see Arundine et al, 200319). Further research on “preconditioning” is necessary. These findings at least suggest the possibility that there may be a period when a subconcussed brain is rendered better able to recover from a subsequent injury. As a whole, the animal literature suggests that any effect of repetitive subconcussive blows is likely to be complex, with many factors to consider including time between impacts, number of impacts, type of impact/force, type of outcome potentially affected, etc. The longer-term effects are also unknown.
Translating animal experimental findings to humans is difficult. Nevertheless, the animal literature cited above certainly raises the possibility that head impacts not associated with a diagnosed concussion can have some type of effect in human beings. Posttraumatic perturbation of metabolism resolves within 7 to 10 days in rats (which corresponds to the typical functional recovery in athletes after concussion20) but can last 2 to 4 weeks in humans.21 In general, human recovery is slower than that of rats.22 The questions about subconcussive blows then become as follows: how frequent, how close in time must they occur, how powerful the minimal force required, and how many blows are needed to sustain structural damage? In addition, what might the long-term consequences be, if any? This line of research in humans is really in its infancy and might best be studied via controlled study of athletes, particularly soccer players, who endure both “subthreshold” and concussive injuries. A meta-analysis20 examining “exposure” due to sports (ie, heading frequency in soccer or number of bouts in boxing) found a small but significant adverse impact of exposure on neuropsychological functioning (d = 0.31) overall. However, the majority of the studies in that analysis included participants with prior head injury, so the effect is likely inflated with respect to evaluating the potential effect of repetitive “subconcussive” impacts.
A recent review of the subconcussion literature1 in humans concluded that subconcussive blows can have a deleterious neurological effect over time. However, that review did not focus primarily on clinical outcomes and did not discuss in detail some contradictory findings in the literature to date. The purpose of the current review is to critically examine the extant literature on subconcussive blows with an emphasis on more short-term clinical outcomes because we are unaware of any studies of long-term outcomes. In addition, given the paucity of data on this emerging topic, only a formative, rather than systematic, review was possible.
PubMed was searched using the following terms: subconcussion, subconcussive, impact/concussion, and threshold/concussion. In addition, reference sections of known journal articles on the topic of subconcussive blows were searched. Only studies with human participants and studies that addressed clinical outcomes were included.
Twenty-two potential studies on clinical outcomes were identified, 9 of which were ultimately deemed relevant to the purpose of the review: 5 studies on symptom reporting/performance and 4 studies on neuroimaging. Thirteen studies were discarded because they either were conducted with animals or did not address clinical outcomes. All included studies were conducted with athletes. In addition, 9 studies on biomechanics of concussion are briefly reviewed below to provide context for the clinical findings.
Not surprisingly, human data in subconcussion studies come primarily from football players, who endure an average of 652 impacts to the helmet per season at the high school level with variability due to position (ie, linemen tend to have the most impacts).23 With respect to forces sustained to the head, Schnebel et al24 reported a range of 90 to 120gs in collegiate football players. Pellman et al25 found that a force in excess of 98gs is 75% specific to concussion in the National Football League. In contrast, others have found that the magnitude of impact to the helmet does not necessarily correlate with the probability of sustaining a concussion,26 suggesting that there is no “threshold effect” (or a certain force necessary) for concussion. Overall, most studies have found a wide range of impact magnitudes associated with concussion. Furthermore, rather than magnitude of force, a combination of biomechanical variables tends to better predict concussion (ie, linear acceleration, rotational acceleration, head injury criterion, impact location).27 However, Eckner et al28 compared cumulative impact histories prior to concussive impacts to the cumulative impact histories prior to the 3 largest magnitude nonconcussive impacts in the same athletes and found that the cumulative impact burden history prior to concussion was no different than the burden produced by impacts that did not result in concussion. This was true no matter what variable was examined—number of hits, cumulative force, or type of force (ie, linear vs rotational). Furthermore, there was no evidence of a window of vulnerability vis-à-vis nonconcussive impacts. Similarly, Guskiewicz et al,29 in a prospective study of 88 college football players with helmet telemetry over 5 seasons, found no relations between diagnosed concussion; linear or rotational impact magnitude (or impact location); and changes in postural stability, cognitive performance, or self-reported symptoms following injury. The authors concluded that something other than just force (both in terms of magnitude and location) determines the occurrence of concussion and subsequent cognitive/behavioral sequelae. On the contrary, Beckwith et al30–32 found that football players were hit more often and with greater impact on days when they were diagnosed with a concussion; when the concussion was diagnosed immediately after impact, the magnitudes of a variety of kinematic measures associated with the injury were elevated relative to those associated with the delayed diagnosis of concussion, though it is unclear to what extent delayed diagnoses were accurate. Clearly the role of prior head impact burden and the relation between biomechanical parameters and diagnosed concussion are not simple.
Performance and symptom reporting data
Other investigators have pursued clinical outcome studies of the neurological/neuropsychological impact of subconcussive blows. Broglio et al33 studied 95 high school football players over 4 seasons using a head impact telemetry system to record impacts to the helmet. In that time, there were a total of 101,994 impacts recorded and 19 athletes sustained a total of 20 concussions. Both cognitive and symptom reporting measures (using “ImPACT” computerized assessment34) were completed preseason and again within 24 hours of injury in those who sustained a concussion. The concussed athletes demonstrated acute declines in cognitive performance and increases in symptom reporting. However, there were no significant relations between changes in performance on cognitive tests and any of a number of impact exposure variables (including number of impacts, peak or cumulative linear acceleration, peak or cumulative rotational acceleration, impact severity or cumulative profile, time from game start until injury, or time from the previous impact), nor was there a relation between self-reported symptom severity and these impact exposure variables. Of nearly 100 statistical comparisons, there was only 1 marginally significant relation between the force of the injurious impact and change in impulse control, though it was not significant when corrections for multiple comparisons were applied.
Gysland et al35 studied 46 collegiate football players with cognitive, sensory, balance, and symptom self-report measures both before and after a single season during which a telemetry system recorded head impacts. Changes in performance were mostly independent of prior concussion history as well as the total number, magnitude, and location of sustained impacts over 1 season. Specifically, head-impact variables (including the total number of impacts, the total number of impacts greater than 90g, the total cumulative magnitude of impacts, and the total number of impacts to the top of the head) did not predict neurocognitive performance over time on the Automated Neuropsychological Assessment Metrics36 or the Standardized Assessment of Concussion37, nor did they predict changes in balance on the Sensory Organization Test38 or total symptom severity. Another measure of balance (the Balance Error Scoring System39) produced counter-intuitive and contradictory findings. That is, a higher number of impacts and higher number of prior concussions predicted improved balance over the course of the season, while a higher cumulative magnitude of head impacts predicted declining balance. Finally, while total symptom severity was not related to head impact variables, an increase in the number of symptoms reported was related to a higher number of severe head impacts (over 90g) and a higher number of impacts to the top of the head. As the authors point out, the increase in the number of symptoms reported over the season (0.90-1.45 symptoms) is less than 1 point and likely not clinically meaningful. This study, of course, does not address the potential effects of lifetime impact dose, though the authors did find that the amount of college football exposure (based on number of years played) was associated with poorer balance and increased symptom reporting. Miller et al40 similarly assessed 76 collegiate football players at preseason, mid-season, and postseason on neuropsychological measures and found no significant declines throughout the season on the Standardized Assessment of Concussion or ImPACT, despite likely repeated subconcussive impacts. These researchers did not measure head impacts so the relation between magnitude and number of blows was not directly assessed.
Finally, McAllister et al41 followed 214 collegiate football and hockey players from pre- to postseason and compared them to 45 noncontact sport athletes assessed at the same intervals. None of the athletes sustained a diagnosed concussion during the study period. They used a more extensive battery than prior studies, including the ImPACT battery (including self-reported symptom severity) as well as 7 other neuropsychological measures. They found no significant between-athlete group differences by time on a variety of cognitive measures, despite the contact athletes sustaining an average of 469 head impacts over the season with a maximum acceleration of 132 gs. They concluded that the number of head impacts does not have a widespread short-term detrimental effect. However, these authors did additional analyses to examine if there was a subset of individuals who did worse than expected at postseason, based on the noncontact athletes' preseason performance and test-retest interval. After conducting multiple comparisons, they found that a statistically significantly higher percentage (24% vs 3.6%) of athletes in the contact sport group performed below predicted performance on the learning trials of the California Verbal Learning Test, Second Edition,42 a verbal memory measure. However, performance on the California Verbal Learning Test was not significantly correlated with head impact exposure, though performances on 2 measures of speeded attention/psychomotor function were correlated with exposure (ie, Trails B and ImPACT reaction time). None of the other neuropsychological measures revealed any differences between groups.
Overall, studies employing cognitive/neuropsycho-logical assessment within a single season have failed to demonstrate any strong and consistent relations between number and severity of subconcussive blows and cognitive changes. There are just a few studies at this point, and they are not directly comparable. Gysland et al35 found an effect for total symptom severity and contradictory balance findings but included athletes who sustained concussions during the study season, while McAllister et al41 had 1 cognitive finding and did not include people with concussions during the study season (though it is unclear if this difference may have been due to differences in prior concussion history). As was suggested by the animal literature, human studies to date suggest than any effect of subconcussive blows is likely to be small and possibly nonreplicable, perhaps evident in a subset of individuals on select measures, and perhaps even beneficial in some cases. Further longer-term prospective study is needed to determine whether there is a cumulative dose effect. The difficulty, of course, is finding athletes with no history of concussion who nonetheless endure repeated subconcussive blows.
Recent studies that have included a neuroimaging component have demonstrated a potential cumulative effect of subconcussive blows, at least in a subset of individuals. Specifically, in a prospective study of 21 high-school football players who were assessed pre- and postseason (with some assessed in-season as well), 4 of the 8 nonconcussed players with subconcussive blows who were reassessed in-season had significant reductions on verbal and/or visual memory scores on the ImPACT battery and significantly decreased fMRI activation levels in the dorsolateral prefrontal cortex and cerebellum43 during working memory tasks. Furthermore, these players' cognitive and fMRI data were at least as impaired as 3 players who sustained a concussion during the season, although different areas of activation were noted via fMRI. All ImPACT scores were near ceiling during each assessment for all athletes. The 4 nonconcussed players with positive findings had a greater total number of collision events throughout the season than the concussed and nonconcussed (with no decline in cognitive performance) groups. Furthermore, while the total number of blows differentiated the groups, the median peak linear acceleration did not.44 The number of impacts experienced in the week immediately preceding in-season reassessment was significantly correlated with changes in fMRI activation in all players. Interestingly, the group with no concussion and no changes on cognitive measures had more collisions per player in each location on the helmet than the concussed group, suggesting that concussion was due to a particularly damaging single or smaller number of blows rather than a lowered concussion threshold from a cumulative subconcussive effect. These authors did not report pre-post season comparisons by group, nor did they report whether total season head impact variables correlated with cognitive performance variables. It is puzzling that ubiquitous “near ceiling” performance on cognitive testing nonetheless resulted in group differences. Thus, while there may be a subset of individuals who show acute clinical changes related to recent subconcussive impacts, the longer-term (or even season-specific) and functional implications remain unclear.
Recent work has also employed diffusion tensor imaging to investigate subconcussive blows. In a prospective cohort of 9 football/ice hockey high school athletes and 6 controls (some with minor orthopedic injuries, some without), changes in white matter, as detected using diffusion tensor imaging within 24 hours of injury, were most apparent in the 1 concussed athlete, followed by the nonconcussed athletes (with repetitive impacts), followed by the controls.45 Increases in symptom reporting over the study period correlated with the proportion of white matter voxels showing some kind of significant change (whether increased or decreased) in fractional anisotropy (FA) and mean diffusivity (MD), both markers of white matter integrity. The number of self-reported head hits was also significantly correlated with the proportion of white matter voxels showing some kind of significant change. However, the changes in FA and MD were in both directions (both increased and decreased), making interpretation difficult. However, the “subconcussive group” did not report more symptoms than the control group and did not perform any differently than controls on the ImPACT cognitive assessment battery (and in fact outperformed them on visual motor speed and reaction time). Thus, the subconcussive-relevant findings seem restricted to white matter changes of unclear structural or functional meaning. Unfortunately, this study relied on retrospective self-reported diaries for its assessment of subconcussive blows, further limiting interpretability. History of prior concussions in either group is also unknown in this study. Again, given that this study followed the athletes for only 1 season, the longer-term implications are unknown.
A larger study46 of the effects of exposure to repetitive head impacts over a single season on diffusivity measures compared 80 collegiate varsity football and ice hockey players who wore instrumented helmets and who did not sustain a concussion during the index season to 79 noncontact sport athletes (with no history of reported concussion). A significant (P = .011) athlete group difference was found for MD in the corpus callosum. Postseason FA differed (P = .001) in the amygdala (0.238 vs 0.233). Measures of head impact exposure correlated with white matter diffusivity measures in several brain regions including corpus callosum, amygdala, cerebellar white matter, hippocampus, and thalamus. In a group of both contact and noncontact athletes with poorer performance on a measure of verbal learning and memory, the magnitude of change in corpus callosum MD at postseason was greater than in those who did not perform poorly. The authors interpreted their findings as consistent with relations among head impact exposure, white matter diffusion measures, and cognition over the course of a single season, even in the absence of diagnosed concussion.
Although there is not a straightforward relation between various kinematic parameters and the probability of sustaining a diagnosed concussion, there is recent interest in the potential cumulative impact of repeated “subconcussive” blows. Evidence from human studies of the neurological/neuropsychological impact of subconcussive blows is currently quite limited. Findings to date suggest that any effect of subconcussive blows is likely to be small and perhaps only evident in a subset of individuals on select measures. Even in this subset, it is unclear if differences are clinically meaningful and/or enduring. The neuroimaging studies reviewed showed some functional and structural changes in a subset of individuals that seem to correlate with head impact exposure, but findings are not consistent across studies. Neuroimaging findings associated with subconcussive blows have shown FA and MD changes occur in both directions (both increased and decreased) and are poorly correlated with functional and symptom changes. Thus, as with the purely cognitive studies, the neuroimaging studies reveal that while there may be a subset of individuals who show acute clinical changes related to recent subconcussive impacts, the longer-term (or even season-specific) and functional implications remain unclear.
Given the small number of studies, and the disparate methodologies used, it is difficult to draw any firm conclusions at this point. Important methodological issues when studying the cumulative impact of subconcussive blows include controlling for prior concussion history (or preferably not including people with any history of concussion), using consistent protocols across studies, and comparing results within certain age ranges, given the possible differences in recovery by age.47 If effects are small and potentially dependent on moderating factors, inconsistent findings are likely. Measuring changes in cognition and symptoms has been challenging in the larger concussion literature. As discussed earlier, given the recent focus in the media on concussion and the concern about CTE (despite the lack of a clear and universally accepted operational CTE definition), it is important to proceed cautiously. Large prospective studies are needed to elucidate both the immediate and long-term effects of cumulative subconcussive head impacts. Certainly, research on the elderly suggests that positive neuroimaging findings and even brain pathology do not always correspond well with functional abnormalities. In 2 large epidemiological clinical-pathologic aging studies, brain pathology accounted for only 40% of the variance in cognitive decline.48 To be sure, any potential acute and possibly transient effects due to the cumulative effect of subconcussive blows, seen both within the brain and through behavior, may or may not have longer-term impact, depending on what is likely to be a large number of variables. Caution is warranted in interpreting and publicizing “brain injury” secondary to subconcussive blows, due to the huge implications for society as a whole. Prospective, controlled epidemiological study is needed to clarify the incidence of subconcussive blows and their short- and long-term effects.
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