Despite growing concern regarding the long-term health of sports players who suffer from repetitive mTBIs, few studies have been conducted investigating the status of retired professional players at the levels of both brain and behaviour. To our knowledge, this is the first joint computerized neuropsychological and functional magnetic resonance imaging study in a cohort of NFL alumni and the first attempt to examine functional connectivity within this population. In accordance with previous behavioural studies, we observed only small differences for NFL alumni relative to controls when performing a computerized test of executive function. By contrast, results from the fMRI analyses revealed far more pronounced abnormalities in functional activation within the dorsal frontoparietal network. These in-vivo findings extend previous post-mortem and epidemiological studies by demonstrating that hyperfrontalility and frontoparietal hypoconnectivity are cumulative long-term consequences of repetitive mTBI.

The current study provides converging evidence to support the view that long-term cortical compensatory mechanisms work to counter the neurological impact of repetitive mTBI. For example, the NFL alumni exhibited pronounced hyperactivation within the same DLPFC regions that were engaged by controls during planning and retrieval. This hyperactivation was evident at all levels of planning complexity and for all levels of working-memory load, including those for which there was no significant difference in performance. The profile of activation within the DLPFC was also qualitatively different between groups as it scaled significantly according to planning demands in NFL alumni but not in controls. Moreover, frontopolar regions were selectively recruited in the NFL alumni during more difficult trials whereas in controls no such activation was evident. Thus, additional cortical resources were brought on line in NFL alumni in order to cope with heavier planning demands. The observation of frontal-lobe hyperactivation is consistent with results from previous research investigating functional brain activation in college athletes during the acute phase shortly after concussion24,25,26,27. However, the results presented here demonstrate that across the life span, hyperfrontality either persists or resurfaces.

The functional and affective connectivity analyses provide novel insights regarding the nature of the underlying abnormality. More specifically, in the PPI analysis the NFL alumni had greatly reduced functional connectivity within the dorsal frontoparietal network. The reduction in functional connectivity was not specific to certain psychological conditions as it was consistent across planning and counting trials. The GC analysis demonstrates that hypoconnectivity was not symmetrical throughout the frontoparietal network but rather, was characterised by significant reductions in affective connectivity to the DLPFC and FPC but not to the PC. Thus, it would appear that the NFL alumni suffer from a lack of dorsal frontoparietal network coherence and abnormal causal flow. This pattern of results fits particularly closely with an inefficiency model, in which long distance connectivity within the frontoparietal network is disrupted and as a consequence, frontal lobe sub-regions work harder when dealing with executive cognitive demands.

The strength of the neuroimaging results should be contrasted with the relative weakness of the behavioural differences. More specifically, a core aim of neuropsychological testing is the development of sensitive biomarkers that can be used to confirm neurological impairments. The results of the group level analyses suggest that when quantifying the long-term neurological impact of mTBIs, functional neuroimaging can provide more sensitive biomarkers than behavioural testing alone. For example, the behavioural differences that were observed in the SP task were barely significant at the group level. This result is in line with the broader sports-mTBI literature, in which reports of longer-term impairments are typically modest and hard to replicate21. By contrast, the functional neuroimaging results showed robust effects in terms of both hyperactivation and hypoconnectivity in NFL alumni. The hyperactivation was evident both when examining ROIs that focused on brain regions associated with task demands and when applying a stringent voxel-wise whole brain corrected threshold. It should be noted that the ROI analyses were specifically designed to match the behavioural analyses with respect to the design and therefore, the degrees of freedom of the group-level models. Thus, the greater sensitivity of the neuroimaging analyses cannot be accounted for by any increased statistical power inherent in the factorial model. Simple scaling of the fMRI signal also cannot account for the observed results, as hyperactivation differed qualitatively across groups and was specific to certain brain regions (i.e., DLPFC not PPC) under certain conditions (e.g. FPC under heavier planning loads). Moreover, connectivity measures were lower not higher in NFL alumni. Instead, the relative weakness of the behavioural results is most likely to be a consequence of cognitive coping strategies and cortical compensatory mechanisms that work to counter the behavioural consequences of an acquired executive impairment.

NFL alumni are a particularly difficult population to recruit for research studies of this type. However, they offer a unique opportunity to examine how individual differences in number of mTBIs suffered relate to individual differences in behavioural and neural abnormalities. Thus, it is particularly noteworthy that both hyperfrontality and hypoconnectivity were related to the total number of head collisions of great enough severity to warrant being removed from play. These correlational analyses effectively rule out lifestyle variables that may differ across the two groups as potential confounds and moreover, support the view that repetitive mTBIs have a cumulative impact in the longer term.

Indeed, more broadly, individuals who suffer from TBI often show little impairment on lab-based neuropsychological tests of executive function, yet the epidemiological data suggests that the longer-term outcomes for many such individuals are particularly poor16. In light of the current results, it seems likely that this inconsistency between assessments and outcomes is a consequence of similar cortical compensatory mechanisms operating in these related groups. Such compensatory mechanisms could adequately mask behavioural impairments in tests of executive function within the lab whilst failing to fully compensate in more complex real-world scenarios. In accordance with this view, it has previously been observed that the most commonly applied tests of executive function are poor predictors of real life executive impairments and therefore, lack both sensitivity and ecological validity17,18. This view fits particularly well with the current results, because whilst none of the NFL alumni tested here had previously been diagnosed with a cognitive impairment and cross-group behavioural differences were barely significant, many of them reported that they were experiencing distressing cognitive problems in every day life. Thus while they are not classified as patients based on behavioural assessments, we would suggest that they should be based on the conjunction of evidence from previous post-mortem studies, the self report of real life executive problems and the observation of pronounced functional brain abnormalities within a frontoparietal network that is affected in dysexecutive neurological and psychiatric populations19,28. More research is required in order to determine whether similar fMRI results are evident in other populations that suffer from mTBI and to gauge their prognostic value. However, the results presented here, suggest that measures of abnormal functional activation and functional connectivity may provide a useful supplement to traditional lab based behavioural assessments when confirming impairments.

In fact, biomarkers that may be used to confirm neurological abnormalities at the individual participant level are notoriously difficult to develop but are also of great potential value. For example, a sensitive marker of frontal-lobe dysfunction might be used to confirm an acquired executive impairment when negotiating financial compensation for the long-term side effects of acquired injuries. Consequently, it is notable that the functional neuroimaging analyses were far more effective than behavioural testing when subdividing NFL alumni and controls at the individual participant level. More specifically, when the 90th percentile was taken as the criterion for abnormal performance, ~15% and ~31% of the NFL alumni were classified as low performers on the SP task using accuracy and RT as measures respectively. By contrast, ~53% were classified as functionally abnormal based on hyperactivation within the DLPFC during planning. 92% were within the bottom 10 percentile based on the functional connectivity analysis. Furthermore, whereas DLPFC functional activation and functional connectivity were found to correlate strongly with the ranked number of times players were sent off field due to head injury, behavioural data failed to show a statistically significant relationship. Thus the brain imaging data can provide more accurate detection and assessment of the level of damage acquired. In such cases, the most convincing method for confirming that a neurological abnormality has been acquired, may be the decision of a previously trained learning machine that takes into account behavioural and imaging measures together. Once trained on one cohort, the machine could be used to pass an unbiased judgement on whether an individual is most similar to a control or retired NFL player in terms of their behavioural and functional activation profiles, thereby providing a polymarker. Here, the SVM was able to make this categorical decision with between 84% and 90% accuracy depending on the set of information that was input to the machine. Critically, the distance from the hyperplane that separates controls from NFL alumni, correlated significantly with the RTO measure, supporting the view that the parameters that guided this classification decision were related to mTBI. Future longitudinal studies should determine whether this polymarker can also provide an early warning sign of accumulating damage prior to the development of behavioural symptoms in an individual in order to warn them that preventative measures should be taken.

Several important limitations should be considered in the current study. Most notably, while none of the NFL alumni had been diagnosed with or treated for neurological or psychiatric conditions, they were a self-selecting population and as outlined above, many believed themselves to be suffering from cognitive deficits acquired during the courses of their careers. The observed frontal-lobe abnormalities were almost certainly related to repetitive mTBI as demonstrated by the significant relationship with the RTO measure. However, to estimate the overall proportion of all NFL alumni who suffer such long-term effects would require the testing of a larger-scale randomly sampled population. This study also did not have the resolution to differentiate between concussive and sub-concussive injuries. Nor could it accurately examine the relationship between milder impacts that did not lead to removal from play and functional abnormalities because no reliable estimate could be taken of their frequency. Determining the strength of this relationship would form a sensible focus for a longitudinal study and we suggest that the SP paradigm would provide a logical tool for this purpose.

The inherent limitations of accurately matching controls to NFL alumni should also be noted. NFL players are a unique group in many respects. By definition, they differ from controls physically and moreover, leading an NFL career will result in differences in a range of potentially confounding lifestyle factors. Indeed, we would argue that it is impossible to recruit a perfectly match set of controls for an NFL cohort. Consequently, the most appropriate way of ruling out potential confounds, is to examine individual differences in those factors that might be confounding. For example, one of the reviewers suggested that differences in baseline abilities might account for the cross-group differences in functional activation and connectivity. Measures of baseline intelligence were not available and whilst all but one participant completed college, measures of education level are hard to interpret in NFL alumni when one considers motivation and career path. It is important to note that individual differences in baseline IQ cannot be entirely ruled out in a cross-sectional study of this type. However, when individual differences in connectivity and activity were examined using both ROI and voxel-wise analyses in the control group, there was no significant relationship with task performance measures including overall accuracy and response time in ROI or voxel-wise whole brain analyses. Nor were any significant correlations observed when using education level as a predictor in the entire Applied FMRI normative cohort. Similarly, the normative controls were on average physically smaller than NFL alumni (indeed two additional NFL volunteers could not be scanned as they did not fit within the bore of the magnet). However, weight, head size and brain dimensions did not correlate significantly with DLPFC activation in the NFL or control groups. Nor was brain size significantly different across the NFL and control groups. The Applied fMRI normative cohort also includes both males and females. However, there were no statistically significant differences between functional activation within any of the ROIs examined here or with whole brain analysis when contrasting males and females within the normative cohort. Furthermore, contrasting NFL alumni with age matched male controls only (N = 13) still generated a robust cross-group effect in terms of DLPFC hyperactivation and hypoconnectivity. In fact, of the various correlations examined, only age, which was matched across groups, showed significant effects in controls, with a modest correlation in terms of DLPFC-PC connectivity (left t = 1.77 p < 0.05, right t = 1.72 p = 0.05). These modest effects of age, were dwarfed by the scale of the NFL-control effects and more importantly, stand in stark contrast to the reliability of the correlations with the RTO measure. Thus, whilst confounding variables cannot be entirely ruled out in a cross sectional study of this type, when the individual differences and cross group analyses are considered together, the results accord particularly closely with the hypothesis that exposure to repetitive mTBI during the course of the professional NFL career leads to abnormal frontal lobe function.

In summary, the results presented here provide novel evidence that cortical compensatory mechanism work to counteract disrupted dorsal executive network connectivity in purportedly healthy NFL alumni who have suffered repetitive mTBI during the course of their careers. These changes are important in light of the inconsistencies in the neuropsychological literature and the increased incidence of neurological disease and neurodegenerative mortality among NFL alumni and sufferers of mild to moderate TBI more broadly. The relationship between history of mTBI, abnormal frontoparietal function and long-term outcomes clearly merits further investigation. To this end, we believe that larger scale and longitudinal neuroimaging studies are warranted in this and other populations that suffer from multiple mTBIs. Such studies have the potential to derive the neural fingerprint of mTBI in order to provide an early warning sign when repeated injuries are accumulating towards long-term cognitive impairment.