Looking at transcontinental footrace history, the finisher rate ranges from 28% to 73% (Table 1). The Bunion Derbies of the early twentieth century showed the lowest rate due to lower standards regarding sports equipment, nutrition features, endurance-associated behavioral knowledge and the level of organization. These two Derbies had 150 starters in mean, much more than nowadays, indicating a high rate of rookies with little or no experience in ultra running. In the TEFR09, 31% of the participants (32% of the subjects) did not reach the finish line (Table 5, Figure 17). This is 18% more finishers than at the TEFR03. This could be attributed to the longer distance in 2003 (+540 km) from Lisbon to Moscow, implying a mean difference of 8.3 km per stage between the TEFR09 and the TEFR03. Apart from the TEFR03, running distances of modern transcontinental footraces (1992 to 2009) were approximately equally long and the finishing rate of 68% in the TEFR09 lies in the upper range of the published data (Table 1). Looking at the rate of participation, being more than 200% higher than the mean starter rate of all modern transcontinental footraces, the comparably high finishing rate indicates a professional organization and preparation of both the runners and organizers of the TEFR09.
Due to the diverse ways and possibilities to exercise long distance running (that is, area, length, altitude, distance, weather, indoor/outdoor, on/off-road, looped course, combinations with other disciplines and so on), it is extremely difficult to compare the performances of ultra athletes in the literature [107, 108, 145]. Regarding the present literature, an abundant variety of physiological, anthropometrical, pre-race and training variables seem to influence running performance and associated injuries, depending upon the length and duration of the races [146–150]. In MSUM, such as the TEFR09, the daily changing environmental conditions have a direct influence on stage performances. In the last days of the TEFR09 weather conditions became more and more difficult towards the destination, North Cape, leading to a marked decrease of mean running speed (Figure 18). Only their indomitable will not to drop out at the end of race after more than 4,000 km of running, kept many emaciated participants in the race.
Drop out and injuries
Due to the likely multifactorial nature of running injuries, very few firm conclusions can be made based on the existing studies. In general, there are intrinsic factors such as individual biomechanical abnormalities (that is, mal-alignments, muscle imbalance, stiffness, weakness, instability) or extrinsic (mostly avoidable) factors such as poor running technique, improper equipment and improper changes in training extent and mode or duration and frequency of the race burden contributing to overuse injuries . The one year prevalence of running injuries is 55% in male marathon runners; limb overuse injuries are the most common . In UM these entities become much more important. The most common injuries for runners are multiply cited in the literature: anterior knee pain (for example, patella-femoral syndrome), iliotibial band friction syndrome, tibial stress syndrome (shin splint/injuries), plantar fasciitis, Achilles tendonitis and meniscal injuries of the knee [152–156].
Approximately two thirds of NF dropped out of the race in the first half of the TEFR09 (Figure 17). As our results show, the reasons for premature resignation of subjects were different. Conforming to the literature [20, 22], in more than two thirds of the cases, overuse injuries of the lower and upper limb were the most common reasons (Table 5). However, these soft tissue overuse injuries occurred not only in less experienced ultra runners, but also in runners who had already successfully finished transcontinental races such as the TEFR03 or the 'Run Across America'. There were only a few subjects and runners without any overuse problems of the limbs in these 64 days. However, not every soft tissue overuse inflammation leads to the cessation of running. Most runners were able to 'overrun' these specific problems. They reduced running speed in adaptation to their problems, used topical application of anti-inflammatory medication and some of them took non-steroidal anti-inflammatory drugs for a few days. With adequate behavior many, but not all, athletes recovered and were able to continue the race. Presumably some athletes could handle more pain than others . An example is one extreme runner, an experienced 49-year-old male subject, who had multiple severe overuse-induced soft tissue inflammations with local muscle fiber rupture forcing him to frequently slow down his speed (Figure 7A). He also showed signs of exertional compartment syndrome, but did finish the TEFR09. His ordeal at the TEFR09 is reflected by the red line in Figure 18. Contrary to other reports, Achilles tendonitis or lower limb joint problems were not a reason for subjects to stop the TEFR09. Further results of module II research topics such as specific personality, temperament, character and pain perception will be presented soon.
Statement of principal findings
The relevance of results in field studies is determined by the appropriateness of the research questions and hypotheses, by the practicability of methods and measurements and the consistency of their specific implementation and by the correct interpretation of results. Due to the manifold open questions and unproven hypotheses in endurance running, the unique opportunity of doing real time observations of changes in the body of athletes while running at the upper limit in a MSUM was demanding.
The TEFR project was designed to explore inter-individual variability in adaption to the tremendous persisting physical endurance running load on the different organic and functional systems of the body with regard to the lack of breaks and time for regeneration.
All technical equipment was tested by the specific manufacturers on reliability and validity under normal clinical conditions and usage. But daily dismantling, transport and setting up of the mobile MRI hardware sets extraordinary demands which were initially not totally verifiable and calculable. Despite some technical problems and temporal defects (Table 3), our arrival at the North Cape demonstrated the feasibility of accompanying a large group of endurance runners (67) with a mobile MRI and all its necessary equipment ensuring permanent operability during the 64 stage ultra marathon.
Throughout the whole TEFR09 our time schedules for examinations adapted to the daily changing local circumstances and the athletes mental state and problems. To avoid additional stress for the subjects, they could not and were not forced to follow the study protocol strictly. However, the efficiency of this strategy was reflected in the high rate of compliance (98%) until the end of the TEFR09. Only one subject who finished the race left the study at stage 36 (km 2,448) due to personal and, explicitly, not study related problems. Consequently, the completion rate of planned examinations over the whole running distance of 4,486 km was only limited by the drop-out rate of the subjects from the TEFR09 (Table 4, Figure 16). In particular, specific implementation of stationary validated MRI protocols on the mobile MRI on the truck trailer by a team of MRI experts and training of the research staff on the mobile MRI before the start ensures practical experience with the experimental protocols under field conditions and makes modification of them possible where necessary.
Strengths of the study
The strengths of the TEFR project are the unique chance to do a field study with the large number of 44 subjects, the realization of tests and measurements with the modern technical gold-standard equipment MRI in a daily changing and increasingly harsh and inhospitable environment (Figure 14), the complete baseline control data and the high rate of test completion. Large subject numbers provide the statistical power to discriminate between and, identify associations with, different patterns of adaptation as well as to detect differences in response between subgroups. Matched subject race profiles and baseline measurements before the start of the TEFR09 control for variability of exposure to ascending running distance and, thereby, permit valid inter-individual comparison of responses to this burden (with subjects as their own controls), maximizing the signal (true physiological differences) to noise (variations in exposure) ratio.
The avoidance of invasive or interventional tests on the subjects' mechanisms during the TEFR09 and the descriptive nature of the data may be considered a weakness of this study. However, the variety of outputs from different measurement techniques (for example, functional and cine MRI, physical anthropometrical measurements and laboratory data including proteomics, plasma and urine biomarkers) allows observation of consistent patterns of response that may be strongly suggestive of particular mechanisms.
In module I, for example, measured data of T2*-mapping of joint cartilage (Figure 4 A and 4.2A/B) will allow conclusions on the influence of long distance running on the proteoglycans in the cartilage matrix based on the current experimental experiences [43–45, 157]. As in most other mobile MR associated examinations of other modules, additional laboratory analyses using specific parameters on collected blood and urine samples (for example, cartilage oligomeric matrix protein (COMP) [158–165] for joint cartilage research) will give further information for interpretation and verification of image related results.
Another example is the vascular cine MRI studies of module III. In humans, the relationships of blood flow changes to structure, function, and shear rate of conducting arteries have not been thoroughly examined. Therefore, the purpose of the vascular cine MRI study in module III (Figure 10) was to investigate these parameters of the elastic-type, common carotid artery (CCA) and the muscular-type, common femoral artery (CFA) in long-term running, assuming that the impact of activity-induced blood flow changes on conduit arteries, if any, should be seen in these highly endurance-trained athletes. These investigations using the gold standard method, MRI , enable further analyses on the current status of insights on the question of structural and functional vascular adaption and associated exercise-induced blood flow changes on endurance training based on sonographic B-mode measurements .
The manifold investigations of Knechtle et al. on ultra endurance athletes [15–22, 113, 145] focused on the question which anthropometric parameters of ultra athletes are predictors of ultra endurance performance. These authors postulated some direct connections between specific physical anthropometric markers and ultra endurance performance [16, 19, 166]. Examinations of module I and module IV (morphometry, body composition) of the TEFR project with its possibility of precise and differentiated morphometric analysis (for example, segmental and functional muscle volumetry) may be able to verify common experiences and to detect relationships between anthropometry and morphometry of endurance athletes and performance in MSUM.
All tissue systems - subcutaneous and visceral adipose tissues, muscles, ligaments, fascia, tendons, bones and cartilage - were studied with special quantitative and qualitative MR techniques. This should help explain how the different tissues react to the severe stress that continued for days and weeks without any pauses for regeneration or even resting phases as two marathon distances had to be completed every day.
Individual performance and ability to deal with injuries and overuse symptoms with regard to decision making for stopping MSUM is a complex psychosomatic process and more or less modulated by character traits. Strong changes of endocrine and metabolic status during marathon runs are described [78, 79]. Hormonal changes can influence pain sensation and show an influence on specific brain functions . Knowing this, investigations detecting reasons for dropping out of the race (14 subjects) can focus not only on MR image analysis, but must also include specific laboratory analysis and psychometric tests as done or planned in the TEFR project. Serotonin, tryptophan and endorphin are described for use as stress markers in UM . The relation of branched-chain to aromatic amino acids as a model (amino acid dysbalance hypothesis) to explain running-associated fatigue is described . The reduction of the pain sensation is known for cortisol . Considering all these particular mechanisms influencing performance and decision making in ultra athletes, the important dimension of laboratory analysis possibilities, in addition to MR data analysis, becomes obvious for the different parts of the TEFR project.
Overall, the possibility of cross-validations between physical, MR-graphic, -functional and laboratory follow-up data on multiple organic systems during a nearly ten-week ultra run is a unique strength of this study.
Weakness of the study
The main weakness of this study is the lack of a control group of non endurance experienced subjects. However, this is not a feasible option in field studies under race conditions including such an immense amount of physical and mental load. In order to explore the influence of pre-race running experience, we will undertake subgroup analyses investigating the influence of individual pre-race performances on our findings. In the pre-race pain study (project module II, MR group 2), we recruited a parallel age-related control group that was tested over the same pain scale and functional MRI protocol as the MSUM exposed subjects. This sub-group is, therefore, not confounded by self-selection due to prior endurance tolerance.
As the first attempt in MR research, we tried to perform H1-MR-spectroscopy for measurement of IMCL [140, 168, 169] with a mobile MRI on a truck trailer. MR spectroscopy needs a stable magnetic field and, therefore, a still and static environment around the scanner. Due to the daily changing position of the mobile MRI, the possibility and feasibility of manual shimming was not predictable. This is the only measurement with uncertain validity due to changing environmental conditions in the TEFR project.
Environmental factors, such as ambient weather conditions (Figure 14), subject de- or hyperhydration and concurrent illnesses may also have confounded results. However, indoor temperature (18.7°C, SD 3.0°C, range 11.7 to 28.5°C) and temperature in the MR trailer (20.5°C, SD 0.8°C, range 18.5 to 21.8°C) was much less variable than outdoor temperature (15.2°C, SD 4.7°C, range 3.7 to 25.1°C). All subjects were encouraged to maintain adequate
hydration (guided by the production of good quantities of pale urine). There was only one Japanese subject identified with a severe illness during the race, suffering from a severe cough which persisted from stage 12 till stage 32 (day of drop out).
Another weakness of the study was that there was only rough documentation of nutrition. Nutrition depended on food availability at the TEFR stages and was provided by the TEFR organization. The use of doping substances was forbidden by the terms of participation but not controlled. Runners did not agree to close measurement and documentation of food and caloric intake, because this would have meant too much disturbance of their daily running routine and compromised compliance due to additional stress conducted by the research work. Despite initial concerns, mobile MRI examinations did not result in additional stress for the athletes. On the contrary, most of them enjoyed relaxing in the MR scanner, having no other noises and people around them while listening to their favorite music via headphones.
Strengths and weakness in relation to other studies
In comparison to previous field, laboratory and radiological, especially stationary MR studies focusing on long distance running and its effects on the human body, our study is unique in several aspects: ultra-long distance running without any day of rest, cohort size of subjects and use of a mobile MRI throughout the whole race. This is the first MR-based follow-up ultra marathon field study that ensures unique data based on repeated measurements on ascending distance burden.
We explored the possibility of conducting this study with a stationary MRI in a fixed local setting. However, this is not realizable with a large cohort size, because not many ultra endurance athletes took the challenge to run ultra long distances in circles in local regions or stadiums day by day. For example, at the Sri Chinmoy Self-Transcendence 3,100 Mile Race over 5,649 laps of one extended city block in Jamaica, Queens, New York (http://www.3100.srichinmoyraces.org) only 10 to 14 participants started regularly. If a study like this is planned, it has to be adapted to the race circumstances and not the race conditions to the study. Only exceptional runners would be willing to take such a burden under laboratory conditions. It is the experience of the distance and the environment that motivates these athletes to run thousands of kilometers. In addition, such an approach might have incurred significant additional costs; our subjects were entirely self-funded, whereas volunteers in chamber studies often expect remuneration.
Unanswered questions and future research
Further research arising from this study will follow two themes. First, studies in patients to explore the validity of our model by applying the findings of this study to pathophysiological problems in a clinical setting. Second, collecting additional healthy volunteer data from subjects exposed to an ultra endurance burden (ultra marathon, ultra triathlon, ultra cycling and) in further field studies and chamber studies.
Whether it is possible to initiate future projects using this model of a mobile MRI field study is critical. First, this was a unique cohort size in transcontinental ultra running and it would be difficult to find a size like this again: the latest Run Across America (Table 1) had only 14 participants. Second, in addition to sufficient funding a bit of luck is necessary to finish a field study successfully when using a sensitive and high-maintenance technical piece of equipment such as a mobile MRI. Future studies might answer additional questions by using alternative or additional measurement techniques or undertaking novel intervention trials.