Secondary TMS outcome measure cortical excitability has prev

Secondary TMS outcome measure cortical excitability has previously been shown to decrease following TBI (De Beaumont et al., 2007; Chistyakov et al., 2001; Bernabeu et al., 2009; Livingston et al., 2010), yet we demonstrated no such change following ball heading. The reason why changes were seen in cortical inhibition and not cortical excitability may be due to the different levels of muscle contractile force applied during recording of the two parameters (20% MVC for excitability vs. 100% MVC for inhibition, see the introduction for its justification). Furthermore, it should be noted that measuring cortical excitability is a less straightforward procedure than corticomotor inhibition as it requires MEP normalization to maximal motor nerve response (Goodall et al., 2009). Primary outcome measure TMS corticomotor inhibition was thought to be most sensitive to quantifying electrophysiological changes based on a recent systematic review (Major et al., 2015), and is a direct measure of changes to Z-VEID-FMK function. Future work should include a control activity, such as body movement without head impact. However, the current pattern of results leaves little doubt that the changes in brain function were related to head impact rather than physical activity. The force of maximal knee contraction was not reduced after heading, therefore the absence of a physical exercise control group it is highly unlikely to explain the effect on corticomotor inhibition or memory function. Nevertheless, a future extension of this work can focus on the acute effects of heading now that the transience of the effect has been established, and would be well placed to reveal the mechanisms underlying these brain changes through a cross-over design that includes a control activity. Furthermore, because it is likely that sub-concussive impacts are more general in nature (i.e. they do not affect single muscles) future work should assess corticomotor inhibition in a larger number of muscles, possibly encompassing both upper and lower limbs. Further study into the dynamic metabolic processes as a direct result of soccer heading is required. Implementing the use of magnetic resonance spectroscopy in future studies could help determine short-term alterations in GABA and glutamate responses. With regard to changes in GABA, because of the use of single-pulse TMS in this study, we were only able to report on the activity of GABAB, while the use of paired-pulse TMS in future work can distinguish modulation of GABAA and GABAB. Critically, however, the sensitivity of the current primary outcome measure suggests that corticomotor inhibition through future dose-response studies has the potential to provide the evidence-base to guide safe engagement in contact-sports, such as soccer.
Conclusion
Funding and Acknowledgements This work was supported by the National Institute for Health Research (NIHR) Brain Injury Healthcare Technology Cooperative. This work was supported by existing funding awarded to L.W. as part of Framework 7 programme of the European Union (CENTER-TBI, Grant number: 602150-2). The work made use of a TMS coil to which the company Smartfish contributed £1500 for purchase of. T.DiV.\'s postgraduate study is support by the research office of Stirling University. W.S. is supported by a NHS Research Scotland Career Researcher Fellowship. D.I.D. and M.I. are members of SINAPSE – see www.sinapse.ac.uk.
Declaration
Author Contributions
Introduction Gulf War Illness (GWI) is a disorder that affects multiple systems and is manifested by various combinations and severities of at least 6 different kinds of symptoms, including Neurological-Cognitive-Mood (NCM), pain, fatigue, skin rashes, gastrointestinal, and respiratory symptoms (Institute of Medicine, 2000, 2006, 2010). Based on the presence of such symptoms, criteria have been developed to establish the diagnosis of GWI (Fukuda et al., 1998; Steele, 2000). The cause (or causes) of GWI are unknown, as is the pathophysiology of the disorder. Diverse lines of evidence have implicated three major factors as triggers, including (i) various vaccinations (Georgopoulos et al., 2015; Israeli, 2012; Toubi, 2012), (ii) various chemical exposures (Institute of Medicine, 2000; Steele et al., 2015) and (iii) various kinds of stress, and, typically, combinations thereof, since all GW veterans were vaccinated, exposed to low doses of nerve gas, and subjected to strenuous basic training. Beyond specific effects of each one of these factors (White et al., 2016), a common denominator shared by all is their effects on the immune system. These effects are diverse, depending on the factor. Vaccinations obviously target the immune system by inducing immune responses to the pathogens, but also to the adjuvants, contained in the vaccines (Israeli, 2012; Toubi, 2012); chemical exposure to subclinical levels of sarin have been shown to depress immune function (Henderson et al., 2001); and stress has since long been identified as affecting immune function (see reviews by O\'Leary, 1990; Webster Marketona and Glasera, 2008). Recent studies have documented immune dysfunction in GWI (Whistler et al., 2009), and even identified an immunosuppressant (methotrexate) as an optimal possible treatment for GWI (Craddock et al., 2015).