cooler skin along the tibiae. This problem became even more visible following a sportspecific warm up program, indicating a low metabolic activity around the affected structures (Figure 6b). In addition, the athlete had a history of osteochondrosis at the tibial tuberosity of both knees. Especially following exercise, the tibial tuberosity on both knees

The following example of a 25-year old professional football player represents an incidental finding. Images were taken within the scope of a team screening. On the injury questionnaire, no acute problems were reported. Upon enquiry no signs of venous disease were reported. However, the subject´s right greater saphenous vein appeared very clearly as an area of increased warmth on the thermogram that may indicate a vascular dilatation with beginning venous insufficiency (Figure 7). Further observational research will determine if

The thermogram of a 26-year old professional football player represents a problem in the Achilles region (Figure 8). This athlete reported a feeling of morning stiffness on the musculotendinosus junction on his left leg. The thermograms showed a side-to-side

this abnormality predict future problems prior to the onset of symptoms.

Fig. 7. Infrared image of the medial aspect of the right leg

Fig. 8. Infrared image from the dorsal view of the lower leg

difference in the affected area of 1.7° C.

appeared as a cold area.

Epidemiological studies have shown an alarmingly high incidence of knee, foot, ankle and lower leg injuries in recreational and competitive runners. Most of these injuries were overuse injuries including stress fractures, shin splints, patellar tendinitis and, most prevalently Achilles tendinitis (Hreljac, 2005). The following thermograms were taken of a 22-year old competitive middle distance runner who runs 40-100km a week (Figure 9). He reported pain in his right Achilles tendon that occurs gradually, especially during exercise. The athlete was diagnosed with midportion Achilles tendinopathy with mild morphological abnormalities. At the time the images were taken, there was a small but noticeable pain at rest and no swelling. The average temperature of the ROI on the right side was 1.6° C lower compared to the non-affected side. The lower temperature may indicate lower metabolic activity due to affected tissue with a loss of normal fiber structure.

Fig. 9. Infrared image from the dorsal view of the lower legs with ROI

Following a treatment period of 8.5 weeks, including electro-physical and physiotherapeutic treatment, thermograms were taken again under resting conditions (Figure 10a) and following a 45-minute run of low intensity (Figure 10b). The side-to-side temperature difference dropped to 0.6°C before exercise, indicating better metabolic activity of the affected side. Following exercise, the right Achilles tendon junction was colder compared to the left one, with a temperature difference of 1.0°C. The athlete reported no pain at rest or following exercise. The regular treatment seemed to improve the Achilles tendon metabolism. However, the impaired metabolic activity following the sport-specific exercise needs to be further addressed with continuing therapy to prevent recurrent problems.

Fig. 10. Infrared image of the lower legs with ROI

The Application of Medical Infrared Thermography in Sports Medicine 267

Traumatic injuries usually involve a long, costly rehabilitation period, and they are challenging for the athlete. An injured athlete is under pressure to return to competition as soon as possible. High-quality treatment can reduce the duration and negative impact of the rehabilitation period. It is well known that richly vascularized areas heal faster compared to poorly vascularized areas (Singer et al., 1999). MIT may give information about the state of vascularization and the on-going healing process to ensure the most effective treatment and provide recovery information to decrease the likelihood of re-injury by returning to the

Knee injuries, especially ruptures of the anterior cruciate ligament (ACL), represent a significant problem in professional alpine skiing (Flørenes et al., 2009) as illustrated by the case of a 21-year-old skier. At 16 years the skier ruptured his left anterior cruciate ligament, medial collateral ligament and the medial meniscus. Since that time, he has suffered from periodic pain, predominantly around the patellae. At age 20 years he was diagnosed with articular cartilage, damage grade three. According to the International Cartilage Repair Society, grade three indicates that the lesion affects more than 50% of the cartilage layer. The average temperature difference of the left patellae was found to be 1.6°C lower compared to the right side (Figure 13). The temperature difference from the area above the upper kneecap showed a side difference of 1.2°C, indicating poor metabolic activity of the lower

The incidence of tendon ruptures has increased in recreational sport activities, with the highest incidence in older age groups (Clayton et al., 2008). However, Rettig et al. (2005) stated that the potential risk of re-rupture is highest in athletes younger than 30 years of age. The infrared images below were taken of a 26-year old triathlete, 6 months following a complete rupture and direct operation of his right Achilles tendon (Figure 14). When the images were taken, he was reffered with mild pain that was exercise dependent and a feeling of numbness in the outer toes. The ongoing healing process did not seem to be sufficiently complete. The temperature difference of an area from the upper Achilles tendon

**4.1.2 Traumatic injuries**

sport too quickly. ALPINE SKIING

TRIATHLON

quadriceps muscle under resting conditions.

Fig. 13. Infrared image from the anterior view of the knees

## SWIMMING

A study, by Sein and co-workers in 2008, investigated shoulder pain in elite swimmers and found that 91% of the swimmers reported shoulder pain; moreover, 84% of the athletes demonstrated a positive impingement sign. The following thermal image was taken of a 27 year-old elite female swimmer under resting conditions (Figure 11). Following a highvolume swimming program, she reported pain and stiffness in both shoulders. With her right arm, she had difficulty reaching behind her back. The clinical examination confirmed overloading of the supraspinatus tendon and general stiffness of the shoulder muscles on both sides. The thermal image shows a hot area above the right deltoid muscle and a hot spot on both shoulders in the region of the humeral head, near the insertion of the supraspinatus muscle. Based on healthy baseline thermal images, MIT should be used to further monitor pathophysiological thermal changes during high-volume swim training prior to the onset of symptoms.

 **a.** right shoulder **b.** left shoulder

#### YOUTH SPORTS

A common problem, predominantly in young, male athletes is the occurrence of enthesopathy of the ligamentum patellae (Gholve et al., 2007). This insertion tendinitis, caused by repetitive mechanical strain of the patella tendon, is characterized by pain, swelling and tenderness above the tibial tuberosity (Brukner & Khan, 2006). Thermal images clearly show a hyperthermic area above the tibial tuberosity (Figure 12). Long term evaluation of affected athletes from alpine skiing (n= 7), football (n=3), running (n=2) and tennis (n=1), who showed acute symptoms in one leg, revealed a side-to-side temperature difference of 1.1°C (± 0.71 °C). The technique provides a quick screening tool and should be used as a first-line detection tool prior to ultrasound or conventional X-rays.

Fig. 12. Infrared images from athletes with enthesopathy of the ligamentum patellae

## **4.1.2 Traumatic injuries**

266 An International Perspective on Topics in Sports Medicine and Sports Injury

A study, by Sein and co-workers in 2008, investigated shoulder pain in elite swimmers and found that 91% of the swimmers reported shoulder pain; moreover, 84% of the athletes demonstrated a positive impingement sign. The following thermal image was taken of a 27 year-old elite female swimmer under resting conditions (Figure 11). Following a highvolume swimming program, she reported pain and stiffness in both shoulders. With her right arm, she had difficulty reaching behind her back. The clinical examination confirmed overloading of the supraspinatus tendon and general stiffness of the shoulder muscles on both sides. The thermal image shows a hot area above the right deltoid muscle and a hot spot on both shoulders in the region of the humeral head, near the insertion of the supraspinatus muscle. Based on healthy baseline thermal images, MIT should be used to further monitor pathophysiological thermal changes during high-volume swim training

A common problem, predominantly in young, male athletes is the occurrence of enthesopathy of the ligamentum patellae (Gholve et al., 2007). This insertion tendinitis, caused by repetitive mechanical strain of the patella tendon, is characterized by pain, swelling and tenderness above the tibial tuberosity (Brukner & Khan, 2006). Thermal images clearly show a hyperthermic area above the tibial tuberosity (Figure 12). Long term evaluation of affected athletes from alpine skiing (n= 7), football (n=3), running (n=2) and tennis (n=1), who showed acute symptoms in one leg, revealed a side-to-side temperature difference of 1.1°C (± 0.71 °C). The technique provides a quick screening tool and should be

used as a first-line detection tool prior to ultrasound or conventional X-rays.

**affected knee**

**affected knee**

Fig. 12. Infrared images from athletes with enthesopathy of the ligamentum patellae

SWIMMING

prior to the onset of symptoms.

YOUTH SPORTS

 **a.** right shoulder **b.** left shoulder Fig. 11. Infrared image from the lateral view of the shoulder

> **affected knee**

Traumatic injuries usually involve a long, costly rehabilitation period, and they are challenging for the athlete. An injured athlete is under pressure to return to competition as soon as possible. High-quality treatment can reduce the duration and negative impact of the rehabilitation period. It is well known that richly vascularized areas heal faster compared to poorly vascularized areas (Singer et al., 1999). MIT may give information about the state of vascularization and the on-going healing process to ensure the most effective treatment and provide recovery information to decrease the likelihood of re-injury by returning to the sport too quickly.

#### ALPINE SKIING

Knee injuries, especially ruptures of the anterior cruciate ligament (ACL), represent a significant problem in professional alpine skiing (Flørenes et al., 2009) as illustrated by the case of a 21-year-old skier. At 16 years the skier ruptured his left anterior cruciate ligament, medial collateral ligament and the medial meniscus. Since that time, he has suffered from periodic pain, predominantly around the patellae. At age 20 years he was diagnosed with articular cartilage, damage grade three. According to the International Cartilage Repair Society, grade three indicates that the lesion affects more than 50% of the cartilage layer. The average temperature difference of the left patellae was found to be 1.6°C lower compared to the right side (Figure 13). The temperature difference from the area above the upper kneecap showed a side difference of 1.2°C, indicating poor metabolic activity of the lower quadriceps muscle under resting conditions.

Fig. 13. Infrared image from the anterior view of the knees

### TRIATHLON

The incidence of tendon ruptures has increased in recreational sport activities, with the highest incidence in older age groups (Clayton et al., 2008). However, Rettig et al. (2005) stated that the potential risk of re-rupture is highest in athletes younger than 30 years of age. The infrared images below were taken of a 26-year old triathlete, 6 months following a complete rupture and direct operation of his right Achilles tendon (Figure 14). When the images were taken, he was reffered with mild pain that was exercise dependent and a feeling of numbness in the outer toes. The ongoing healing process did not seem to be sufficiently complete. The temperature difference of an area from the upper Achilles tendon

The Application of Medical Infrared Thermography in Sports Medicine 269

However, during the season, he reported a feeling of load-dependent, diffuse knee pain in his left leg. The medical examination confirmed a low threshold for pressure on the medial aspect of the knee. No clear diagnosis could be confirmed, indicating a local overuse

Physical exercise and repetitive strain is a challenge to thermal homeostasis. During exercise, the thermoregulatory control of blood flow in the skin is important to maintain normal body temperature and leads to changes in hemodynamics, and, therefore, thermal signals (Kenney & Johnson, 1991). Using state-of-the art infrared sensor technology, cutaneous temperature changes during exercise can be evaluated. Skin blood flow is predominantly regulated by neural regulation (Thomas & Segal, 2004). By taking timesequential images of exercise, the immediate response of the sympathetic nervous system via the somatocutaneous reflex can be visualized. The investigation of infrared images taken before and after sport-specific exercise may further determine the applicability of MIT to investigate the physiology of biological tissue. Furthermore systemic cutaneous blood flow

reaction. Excessive stress should be administered with caution.

**a.** pre-exercise **b.** post-exercise

**4.2 Thermal stimuli- time sequential images following different exercise**

regulation can be monitored as a function of exercise type, duration and intensity.

The mechanism of homeostasis during exercise is guaranteed through multiple functions, such as cardiac processes, peripheral circulatory control, blood pressure regulation and temperature control (Berne & Levy, 2000). A better understanding of the cutaneous circulation, and, therefore, the control of blood flow during exercise is a challenge in integrative physiology (Kellog & Pérgola, 2000). We investigated thermal characteristics of aerobic and anaerobic bicycle exercise to predict evidence of altered perfusion. Twelve athletic males (mean age 26.0 ± 2.7 years, height 177.2cm ± 4.3 cm, mass 71.1 ± 8.4 kg) performed both, anaerobic exercise (5 minutes, 80rpm, 90%HRmax) and aerobic exercise (45

Images were taken prior to (Figure 17a) and immediately following aerobic (Figure 17b) and anaerobic exercise (Figure 17c). The ROI was defined above the middle portion of the M. quadriceps. The temperature above the exercising muscle increased following aerobic

Fig. 16. Infrared image of the anterior view of the legs

AEROBIC VERSUS ANAEROBIC EXERCISE

minutes, 80rpm, 60%HRmax) under thermo-neutral conditions.

to the muscle belly of the musculus triceps surae was found to be 1.6°C, suggesting delayed healing with impaired circulation. In particular the cooler area of the musculotendinous junction should be considered further within physiotherapeutic treatment.

Fig. 14. Infrared image posterior view of lower leg

The area of numbness becomes visible through a clear hypothermia on the affected toes and must be a target of further rehabilitation (Figure 15a,b). Future research will determine if tissue remodeling is still on-going after symptoms disappear.

 **a.** left foot **b.** right foot

Fig. 15. Infrared image of the lateral view of the foot

## **4.1.3 Static versus dynamic measurements**

Baseline recordings, following a sport-specific strain, should be conducted to visualize thermal regulatory processes. Regarding infrared images of overuse injuries, repeated measurements following sport-specific exercise will clarify if symptom-free asymmetrical temperature distributions are predictive for presymptomatic identification of initiating overuse reactions. The following example of an 18-year old football player indicates a presymptomatic thermal abnormality during pre-season measurement. The thermogram at rest demonstrated symmetrical patterns (Figure 16a). Following sport-specific exercise, local side differences on the knee were visible (Figure 16b). The athlete reported no pain at that time.

However, during the season, he reported a feeling of load-dependent, diffuse knee pain in his left leg. The medical examination confirmed a low threshold for pressure on the medial aspect of the knee. No clear diagnosis could be confirmed, indicating a local overuse reaction. Excessive stress should be administered with caution.

268 An International Perspective on Topics in Sports Medicine and Sports Injury

to the muscle belly of the musculus triceps surae was found to be 1.6°C, suggesting delayed healing with impaired circulation. In particular the cooler area of the musculotendinous

The area of numbness becomes visible through a clear hypothermia on the affected toes and must be a target of further rehabilitation (Figure 15a,b). Future research will determine if

Baseline recordings, following a sport-specific strain, should be conducted to visualize thermal regulatory processes. Regarding infrared images of overuse injuries, repeated measurements following sport-specific exercise will clarify if symptom-free asymmetrical temperature distributions are predictive for presymptomatic identification of initiating overuse reactions. The following example of an 18-year old football player indicates a presymptomatic thermal abnormality during pre-season measurement. The thermogram at rest demonstrated symmetrical patterns (Figure 16a). Following sport-specific exercise, local side differences on the knee were visible (Figure 16b). The athlete reported no pain at that

junction should be considered further within physiotherapeutic treatment.

Fig. 14. Infrared image posterior view of lower leg

tissue remodeling is still on-going after symptoms disappear.

 **a.** left foot **b.** right foot

Fig. 15. Infrared image of the lateral view of the foot

**4.1.3 Static versus dynamic measurements**

time.

**a.** pre-exercise **b.** post-exercise

## **4.2 Thermal stimuli- time sequential images following different exercise**

Physical exercise and repetitive strain is a challenge to thermal homeostasis. During exercise, the thermoregulatory control of blood flow in the skin is important to maintain normal body temperature and leads to changes in hemodynamics, and, therefore, thermal signals (Kenney & Johnson, 1991). Using state-of-the art infrared sensor technology, cutaneous temperature changes during exercise can be evaluated. Skin blood flow is predominantly regulated by neural regulation (Thomas & Segal, 2004). By taking timesequential images of exercise, the immediate response of the sympathetic nervous system via the somatocutaneous reflex can be visualized. The investigation of infrared images taken before and after sport-specific exercise may further determine the applicability of MIT to investigate the physiology of biological tissue. Furthermore systemic cutaneous blood flow regulation can be monitored as a function of exercise type, duration and intensity.

AEROBIC VERSUS ANAEROBIC EXERCISE

The mechanism of homeostasis during exercise is guaranteed through multiple functions, such as cardiac processes, peripheral circulatory control, blood pressure regulation and temperature control (Berne & Levy, 2000). A better understanding of the cutaneous circulation, and, therefore, the control of blood flow during exercise is a challenge in integrative physiology (Kellog & Pérgola, 2000). We investigated thermal characteristics of aerobic and anaerobic bicycle exercise to predict evidence of altered perfusion. Twelve athletic males (mean age 26.0 ± 2.7 years, height 177.2cm ± 4.3 cm, mass 71.1 ± 8.4 kg) performed both, anaerobic exercise (5 minutes, 80rpm, 90%HRmax) and aerobic exercise (45 minutes, 80rpm, 60%HRmax) under thermo-neutral conditions.

Images were taken prior to (Figure 17a) and immediately following aerobic (Figure 17b) and anaerobic exercise (Figure 17c). The ROI was defined above the middle portion of the M. quadriceps. The temperature above the exercising muscle increased following aerobic

The Application of Medical Infrared Thermography in Sports Medicine 271

in the tissues. A main challenge is to combine the anatomical and physiological information demonstrated by the thermal pattern of the skin. The biological nature of thermal signals and consistent thermal alterations of different sport-specific injuries should be further addressed. Thermal screening of injured and non-injured athletes is the first step to create a sport-specific database with individual thermograms. Repeated follow-up measurements during the sport season will further clarify the link between asymmetrical temperature distributions, pathophysiological changes on the skin surface and the extent of injury. The long-term aim is to create a knowledge-based database of thermograms of overuse and traumatic injuries. However, it should be considered that within a certain time span, different pathologies could alter their patterns of temperature. A deeper understanding of the different time courses of injuries is important to clarify the benefit of MIT in injury management and to define whether a thermogram is "normal" or not. In terms of quantification of side-to side differences within a defined ROI, it is important to use the medical analysis function of image fusion. The main advantage of MIT is its safety, however, the disadvantage of MIT results from its physical limitations. The non-radiating, two-dimensional technique provides information about surface structures. A conclusion of processes in deeper tissues needs to be further investigated by combining different medical imaging modalities. In addition, it must be clearly stated that the aim of MIT use in sports medicine is not to be a substitute for clinical examination, but to enhance and support it. It can be concluded that MIT is a reliable, low-cost detection tool that should be applied for

Ammer, K. (2006). Diagnosis of Raynaud´s phenomen by thermography. *Skin Research and*

Ammer, K. (2008). The Glamorgan Protocol for recording and evaluation of thermal images

Ammer, K. (2008). The sensitivity of infrared imaging for diagnosing Raynaud´s

Arora, N.; Martins, D.; Ruggerio, D.; Tousimis, E.; Swistel, A.J.; Osborne, M.P.& Simmons,

Berne, R.M. & Levy, M.N. (2000). *Principles of Physiology*. Third Edition, Mosby, ISBN 84-

Bharara, M. (2006). Thermography and Thermometry in the Assessment of Diabetic

Blatteis, C.M. (1998). *Physiology and pathophysiology of temperature regulation*. First edition,

World scientific printers, ISBN 981-02-3172-5, Singapore

of the human body. *Thermology International*, Vol.18, No.4, pp. 125-144, ISSN1560-

phenomenon or Thoracic Outlet Syndrome is dependent on the method of temperature extraction from thermal images. *Thermology International*, Vol.18, No. 3,

R.M. (2008). Effectiveness of a noninvasive digital infrared thermal imaging system in the detection of breast cancer. *The American Journal of Surgery,* Vol.196, No.4, pp.

Neuropathic Foot: A Case for furthering the role of thermal techniques. *The International Journal of Lower Extremity Wounds*, Vol.5, No.4, pp. 250-260, ISSN 1534-

*Technology*, Vol.2, No.4, pp. 182-185, ISSN 0909-752X

pre-scanning athletes.

604X

7346

pp.81-88, ISSN1560-604X

523-526, ISSN 0002- 9610

8174-550-2, St. Louis

**6. References**

exercise (0.7°C, p=0.215) and decreased following anaerobic exercise (-1.5°C, p=0.094). In addition hot colored dots over the thigh occurred after aerobic exercise. To meet the increased metabolic demand of active muscles, short- term, intense exercise leads to a redistribution of blood flow away from inactive tissues such as the skin, to exercising muscles through the vasoconstrictor system (Kenney & Johnson, 1991). This process explained the marginal skin temperature decrease following anaerobic exercise. From a clinical point of view, this observation becomes interesting for patients with compromised cardiac function. As previously reported, these patients showed a higher magnitude of vasoconstriction compared to a healthy group, suggesting that the initial reflex vasoconstriction may be linked to cardiovascular functional capacity (Zelis et al., 1969). With continuing exercise, the body core temperature begins to rise. When internal temperature increases toward a threshold, a regulating system starts to stimulate thermo- sensitive neurons in the central nervous system. This triggering of cutaneous vasodilation ensures the transfer of metabolic heat from the core to the skin (Charkoudian, 2003). The present study showed that the competing system of thermoregulatory drive for cutaneous vasodilation and the non-thermoregulatory drive for cutaneous vasoconstriction could be visualized by using MIT. As previously reported, the interactive control system, as a normal function of dynamic muscular exercise, seems to dependent upon the intensity and duration. The multiple hot spots seen on the thigh (Figure 17b) illustrate the so-called perforating blood vessels that originate in deeper lying tissue. The vasoconstrictor mechanism at the beginning of the exercise is mainly in the skin blood vessels, whereas the perforator vessels are less affected. As exercise duration increases, they contribute to the rewarming of the skin (Merla et al., 2010). The identification of a skin thermographic map of perforator vessels that includes their perfusion area can be important to define individual anatomy of certain tissues (Salmon et al., 1988). Further research should examine the time-course of thermal changes by taking multiple images during and following an exercise. In addition, the relationship between thermal changes, aerobic capacity and performance may further determine different functional states of the body dependent on intensity and duration.

 **a.** pre-exercise **b.** post aerobic exercise **c.** post anaerobic exercise

Fig. 17. Infrared images of the anterior aspect of lower legs

#### **5. Conclusion**

High-quality scientific work with modern 21st-century technology coupled with a better understanding of the regulation of skin blood flow has improved the capability of MIT in medical use. Our research findings suggest that the most beneficial output of MIT seems to be in the screening of athletes for overuse injuries. We suggest combining baseline images with images taken following sport-specific exercise to provoke sufficient thermal alterations in the tissues. A main challenge is to combine the anatomical and physiological information demonstrated by the thermal pattern of the skin. The biological nature of thermal signals and consistent thermal alterations of different sport-specific injuries should be further addressed. Thermal screening of injured and non-injured athletes is the first step to create a sport-specific database with individual thermograms. Repeated follow-up measurements during the sport season will further clarify the link between asymmetrical temperature distributions, pathophysiological changes on the skin surface and the extent of injury. The long-term aim is to create a knowledge-based database of thermograms of overuse and traumatic injuries. However, it should be considered that within a certain time span, different pathologies could alter their patterns of temperature. A deeper understanding of the different time courses of injuries is important to clarify the benefit of MIT in injury management and to define whether a thermogram is "normal" or not. In terms of quantification of side-to side differences within a defined ROI, it is important to use the medical analysis function of image fusion. The main advantage of MIT is its safety, however, the disadvantage of MIT results from its physical limitations. The non-radiating, two-dimensional technique provides information about surface structures. A conclusion of processes in deeper tissues needs to be further investigated by combining different medical imaging modalities. In addition, it must be clearly stated that the aim of MIT use in sports medicine is not to be a substitute for clinical examination, but to enhance and support it. It can be concluded that MIT is a reliable, low-cost detection tool that should be applied for pre-scanning athletes.

#### **6. References**

270 An International Perspective on Topics in Sports Medicine and Sports Injury

exercise (0.7°C, p=0.215) and decreased following anaerobic exercise (-1.5°C, p=0.094). In addition hot colored dots over the thigh occurred after aerobic exercise. To meet the increased metabolic demand of active muscles, short- term, intense exercise leads to a redistribution of blood flow away from inactive tissues such as the skin, to exercising muscles through the vasoconstrictor system (Kenney & Johnson, 1991). This process explained the marginal skin temperature decrease following anaerobic exercise. From a clinical point of view, this observation becomes interesting for patients with compromised cardiac function. As previously reported, these patients showed a higher magnitude of vasoconstriction compared to a healthy group, suggesting that the initial reflex vasoconstriction may be linked to cardiovascular functional capacity (Zelis et al., 1969). With continuing exercise, the body core temperature begins to rise. When internal temperature increases toward a threshold, a regulating system starts to stimulate thermo- sensitive neurons in the central nervous system. This triggering of cutaneous vasodilation ensures the transfer of metabolic heat from the core to the skin (Charkoudian, 2003). The present study showed that the competing system of thermoregulatory drive for cutaneous vasodilation and the non-thermoregulatory drive for cutaneous vasoconstriction could be visualized by using MIT. As previously reported, the interactive control system, as a normal function of dynamic muscular exercise, seems to dependent upon the intensity and duration. The multiple hot spots seen on the thigh (Figure 17b) illustrate the so-called perforating blood vessels that originate in deeper lying tissue. The vasoconstrictor mechanism at the beginning of the exercise is mainly in the skin blood vessels, whereas the perforator vessels are less affected. As exercise duration increases, they contribute to the rewarming of the skin (Merla et al., 2010). The identification of a skin thermographic map of perforator vessels that includes their perfusion area can be important to define individual anatomy of certain tissues (Salmon et al., 1988). Further research should examine the time-course of thermal changes by taking multiple images during and following an exercise. In addition, the relationship between thermal changes, aerobic capacity and performance may further determine different functional states of the body dependent on intensity and duration.

 **a.** pre-exercise **b.** post aerobic exercise **c.** post anaerobic exercise

High-quality scientific work with modern 21st-century technology coupled with a better understanding of the regulation of skin blood flow has improved the capability of MIT in medical use. Our research findings suggest that the most beneficial output of MIT seems to be in the screening of athletes for overuse injuries. We suggest combining baseline images with images taken following sport-specific exercise to provoke sufficient thermal alterations

Fig. 17. Infrared images of the anterior aspect of lower legs

**5. Conclusion**

The Application of Medical Infrared Thermography in Sports Medicine 273

Jiang, L.J.; Ng, E.Y.K.; Yeo, A.C.B.; Wu, S.; Pan, F.; Yau, W.Y.; Chen, J.H. & Yang, Y. (2005). A

Kellog D. L. & Pérgola P. (2000). Skin Response to exercise and training. In: *Exercise and*

Kenney W.L. & Johnson J.M. (1992). Control of skin blood flow during exercise. *Medicine and Science in Sports and Exercise*, Vol. 24, No.3, pp. 303-312, ISSN 1530-0315 Kontos, M.; Wilson, R. & Fentiman, I. (2011). Digital infrared thermal imaging (DITI) of

Merla, A.; DiRomualdo, S.; DiDonato, L.; Proietti, M.; Salsano, F. & Romani, G.L. (2007).

Merla, A; Mattei, P.A.; di Donato, L. & Romani, G.L. (2010). Thermal Imaging of Cutaneous

Ng, E.Y.K. (2009). A review of thermography as promising non-invasive detection modality

Niehof, S.P.; Huygen, F.; van der Weerd, R.; Westra, M. & Zijlstra, F.J. (2006). Thermography

Park, J.Y.; Hyun, J.K. & Seo, J.B. (2007). The effectiveness of digital infrared thermographic

Plassmann,P. & Murawski, P. (2003). CTHERM for standardized thermography, *Proceedings*

Plassman, P.; Ring, E.F.J. & Jones, C.D. (2006). Quality assurance of thermal imaging systems in medicine. *Thermology International*, Vol.16, No.1, pp.10-15, ISSN 1560-604X Rettig, A.C.; Liotta, F.J.; Klootwyk, T.E.; Porter, D.A. & Mieling, P. (2005). Potential Risk of

Ring, E.F.J. & Ammer, K. (2000). The technique of infrared imaging in medicine. *Thermology*

Ring E.F.J. (2007). The Historical development of temperature measurement in medicine. *Infrared Physics and Technology,* Vol.49, No.3, pp. 297- 301, ISSN 1350-4495 Romano, C.L.; Logoluso, N.; Dellóro, F.; Elia, A. & Drago, L. (2011) Telethermographic

Salmon, M.; Taylor, G.I. & Tempest, M.N. (1988). Arteries of the skin, Churchill Livingstone,

*Technology*, Vol.29, No.6, pp. 257-267, ISSN 0309-1902

&Wilkins, pp. 239-250, ISBN 0-683-03421-9, Philadelphia

*Clinical Radiology,* Vol. 66, No.6, pp. 536-539, ISSN 0033-8419

*Biomedical Engineering*, Vol.38, No.1, pp.158-163, ISSN 1573-9686

*Elbow Surgery*, Vol.16, No.5, pp. 548-554, ISSN 1058-2746

*Today,* Vol.1, No.2, pp.108-109, ISSN N/A

of print, ISSN 0968-0160

ISBN<PHONE_NUMBER>, London

*international*, Vol.10, No1, pp. 7-14, ISSN 1560-604X

*of Abstracts the 9th congress of Thermology*, ISBN N/A, Poland

*Society,* pp. 2630-2633, ISSN 1557-170X

ISSN 1290-0729

925X

perspective on medical infrared imaging. *Journal of Medical Engineering and*

*Sports Science,* Garrett, W.E.; Kirkendall, D.T. published by Lippincott Williams

breast lesions: sensitivity and specificity of detection of primary breast cancers.

Combined thermal and laser Doppler imaging in the assessment of cutaneous tissue perfusion. *Conference Proceedings of the IEEE Engineering Medicine and Biology*

Temperature Modifications in Runners During Graded Exercise*. Annals of*

for breast tumor. *International Journal of Thermal Science*, Vol.48, No.5, pp. 849-859,

imaging during static and controlled thermoregulation in complex regional pain syndrome type 1. *Biomedical Engineering OnLine,* Vol.5, No.30, pp. 1-13, ISSN 1475-

imaging in patients with shoulder impingement syndrome. *Journal of Shoulder and*

Rerupture in Primary Achilles Tendon Repair in Athletes Younger Than 30 Years of Age. *American Journal of Sports Medicine*, Vol.33, No.1, pp.119-123, ISSN 0363-5465 Ring, E.F.J. & Ammer, K. (1998). Thermal imaging in sports medicine. *Sport and Medicine*

findings after uncomplicated and septic total knee replacement. *Knee,* Epub ahead

Bruckner, P. & Khan, K. (2006). Fundamental principals, In: *Clinical Sports Medicine*. Third

Bruehl, S.; Lubenow, T.; Nath, H. & Ivankovich, O. (1996). Validation of Thermography in

Charkoudian, N. (2003). Skin blood flow in adult human thermoregulation: how it works,

Clayton, R.A.E. & Court-Brown, C.M. (2008). The epidemiology of musculoskeletal

Cochrane, D.J.; Sanard, S.R.; Firth, E.C. & Rittweger, J. (2010). Comparing Muscle

Denoble, A.E.; Hall, N.; Pieper, C.F. & Kraus, V.P. (2010). Patellar skin surface temperature

Diakides, N.A. & Bronzino J.D. (2008). *Medical Infrared Imaging*, First Edition, CRC Press,

de Weerd, L.; Mercer J. & Setså, L. (2006). Intraoperative Dynamic Infrared Thermography

Eddy, A.L.; Van Hoogmoed, L.M. & Snyder, J.R. (2001). The role of Thermography in the

Elliot, R.L. & Head, J.F. (1999). Medical infrared imaging in the twenty-first century.

Flørenes, T.W.; Bere, T.; Nordsletten, L. Heir, S. & Bahr, R. (2009). Injuries among male and

Gholve, P.; Scher, D.; Khakharia, S.; Widmann, R. & Green, D. (2007). Osgood Schlatter syndrome. *Current Opinion in Pediatrics*, Vol.19, No.1, pp. 44-50, ISSN 1531-698X Hardaker, N.J.; Moss, A.D.; Richards, J.; Jarvis, S.; McEwan, C. & Selfe, J. (2007). The

Hildebrandt, C.; Ammer, K. & Raschner, C. (2010). An Overview of Recent Application of

Hreljac, A. (2005). Etiology, prevention and early intervention of overuse injuries in runners:

*musculoskeletal disorders*, Vol.3, No.1, pp. 69-75, ISSN 11795441

*Thermology International,* Vol.9., No.4, pp. 111, ISSN 1560-604X

*International*, Vol.17, No.2; pp. 45-50, ISSN 1560-604X

*America,* Vol.16, No.3, pp. 651-667, ISSN 1047-9651

No.5, pp. 4700-4715, ISSN 1424-8220

ISBN<PHONE_NUMBER>, Canada

ISBN<PHONE_NUMBER>, Broken

181, ISSN 1090-0233

973-978, ISSN 0306-3674

0025-6196

1475-0961

01487043

1383

No.4, pp. 316-325, ISSN 07498047

edition. Bruckner, P; Khan, K pp. 3-7, McGraw-Hill Medical Publishing Division,

the Diagnosis of Reflex Sympathetic Dystrophy. *Clinical Journal of Pain,* Vol.12,

when it does not and why. *Mayo Clinic Proceedings,* Vol*.*78, No.5, pp. 603-612, ISSN

tendinous and ligamentous injuries. *Injury*, Vol.39, No.12, pp.1338-1344, ISSN 0020-

Temperature during static and dynamic Squatting with and without Whole- Body Vibration. *Clinical Physiology and Functional Imaging*, Vol.30, No.4, pp. 223-229, ISSN

by thermography reflects knee osteoarthritis. *Clinical medicine insights. Arthritis and*

and Free-Flap Surgery. *Annals of Plastic Surgery,* Vol.57, No.3, pp. 279-284, ISSN

Management of Equine Lameness. *The Veterinary Journal,* Vol.162, No.3, pp. 172-

female world cup alpine skiers. *British Journal of Sports Medicine,* Vol.43, No.13, pp.

relationship between skin surface temperature measured via non-contact thermal imaging and intra-muscular temperature of the rectus femoris muscle. *Thermology*

Medical Infrared Thermography in Sports Medicine in Austria. *Sensors*, Vol.10,

a biomechanical perspective. *Physical medicine and rehabilitation clinics of North*

**15**

*Brazil*

**The Involvement of Brain**

**Monoamines in the Onset of**

**Hyperthermic Central Fatigue**

Cândido C. Coimbra1, Danusa D. Soares2 and Laura H. R. Leite3 *1Federal University of Minas Gerais, Department of Physiology and Biophysics,*

The fatigue that results from physical exercise is a multifactorial phenomenon that is comprised of complex interactions between physiological and psychological factors. Fatigue is assumed to be an inability to maintain the required force or power or an increasing difficulty to continue the work rate at a given exercise intensity. Taking into account that homeostasis disturbances may be harmful, fatigue should be considered a defense mechanism that prevents tissue damage by reducing the intensity of or even interrupting

Fatigue is known to have peripheral and/or central origins. Although most studies focus peripheral factors, which include circulatory, metabolic, muscular, nutritional and thermoregulatory disorders, exercise-induced cerebral metabolism and neurohumoral or neurotransmitter turnover are also implicated in fatigue genesis. "Central fatigue" refers to these central nervous system alterations that may prevent muscular and neural damage by

Most authors consider central fatigue during prolonged exercise to be a consequence of the accumulation or depletion of neurotransmitters, serotonin in particular. Although the role of serotonergic neural trafficking on exercise performance has been well documented, dopamine and noradrenaline neurotransmissions also contribute to central fatigue. In addition to having their activity modified by exercise, all of these brain monoamines exhibit relevant thermoregulatory effects. These amines play an important role in the function of thermoregulatory centers, such as the preoptic area and the anterior hypothalamus, and it is hypothesized that changes in their turnover are associated with the development of fatigue

The brain is especially endangered by hyperthermia. For this reason, the exacerbation of exercise-induced hyperthermia appears to diminish the central nervous system drive to the working muscles; this protects the brain from thermal damage while causing a detriment to physical endurance. This effect is more pronounced when hyperthermia occurs simultaneously with inhibitory signals from the central nervous system, as in the case of altered neurotransmitter metabolisms. Even though it has been stated that central fatigue

**1. Introduction**

physical activity.

failing to drive the muscles appropriately.

as a consequence of heat imbalances.

*2Federal University of Minas Gerais, Department of Physical Education,*

*3Federal University of Juiz de Fora, Department of Physiology,*

## **The Involvement of Brain Monoamines in the Onset of Hyperthermic Central Fatigue**

Cândido C. Coimbra1, Danusa D. Soares2 and Laura H. R. Leite3 *1Federal University of Minas Gerais, Department of Physiology and Biophysics, 2Federal University of Minas Gerais, Department of Physical Education, 3Federal University of Juiz de Fora, Department of Physiology, Brazil*

### **1. Introduction**

274 An International Perspective on Topics in Sports Medicine and Sports Injury

Sein, M.L.; Walton, J.; Linklater, J.; Appleyard, R.; Kirkbride, B.; Kuah, D. & Murrell G.A.C.

Selfe, J.; Whitaker, J. & Hardaker, N. (2008). A narrative literature review identifying the

Singer, A.J. & Clark, R.A.F. (1999). Cutaneous wound healing. *The New England Journal of*

Steketee, J. (1973). Spectral emissivity of skin and pericardium. *Physics in Medicine and*

Thomas, *G.D.* & Segal, S.S. (2004). *Neural control of muscle flow during exercise. Journal of*

Turner, T.A. (2000). Diagnostic thermography. *Veterinary Clinics of North America-Equine*

Vardasca, R. (2008). Symmetry of temperature distribution in the upper and lower extremities. *Thermology International, Vol.*18, No.4, pp. 154-155, ISSN 1560-604X Wallin, B.G. (1990). Neural control of human skin blood flow. *Journal of the autonomic nervous*

Wild, W.; Schütte, S.R.; Pau, H.W.; Kramp, B. & Just, T. (2003). Infrared thermography as a

Woods, C.; Hawkins, R.; Hulse, M. & Hodson A. (2002). The Football Association Medical

Zaprodina, N.; Ming, Z. & Hänninen, O.P. (2006). Plantar infrared thermography

Zelis, R.; Mason, D.T. & Braunwald, D. (1969). Partition of blood flow to the cutaneous and

*Congress,* June 22-27, 2003, ISBN 0-7803-8493-8, Dubrovnik Croatia

non invasive application for medical diagnostic. *Proceedings XVII IMEKO World*

Research Programme: an audit of injuries in professional football—analysis of preseason injuries. *British Journal of Sports Medicine*, Vol.36, No.6, pp. 436–441, ISSN

measurements and low back pain intensity. *Journal of Manipulative Physiological*

muscular beds of the forearm at rest and during leg exercise in normal subjects and in patients with heart failure. *Circulation Research*, Vol.24, No.6, pp.799-806, ISSN

knee. *Thermology International*, Vol.18, No.2, 41-44, ISSN 1560-604X

*Medicine,* Vol. 341, No.10, pp. 738-746, ISSN 0028-4793

*Applied Physiology, Vol.97, No.2, pp. 731-738, ISSN 8750-7587*

*Biology.* Vol. 18, No. 5, pp. 686-694, ISSN 0031-9155

*Practice*, Vol.17, No.1, pp. 95-113, ISSN 0749-0739

*system*, Vol. 30, No.S1, pp.185-190, ISSN 1529-8027

*Therapeutics*, Vol.29, No.3, pp.219-223, ISSN 0161-4754

113, ISSN 0306-3674

0306-3674

0009-7330

(2010). Shoulder pain in elite swimmers: primarily due to swim-volume-induced supraspinatus tendinopathy. *British Journal of Sports Medicine*, Vol.44, No.2, pp.105-

minimum clinically important difference for skin temperature asymmetry at the

The fatigue that results from physical exercise is a multifactorial phenomenon that is comprised of complex interactions between physiological and psychological factors. Fatigue is assumed to be an inability to maintain the required force or power or an increasing difficulty to continue the work rate at a given exercise intensity. Taking into account that homeostasis disturbances may be harmful, fatigue should be considered a defense mechanism that prevents tissue damage by reducing the intensity of or even interrupting physical activity.

Fatigue is known to have peripheral and/or central origins. Although most studies focus peripheral factors, which include circulatory, metabolic, muscular, nutritional and thermoregulatory disorders, exercise-induced cerebral metabolism and neurohumoral or neurotransmitter turnover are also implicated in fatigue genesis. "Central fatigue" refers to these central nervous system alterations that may prevent muscular and neural damage by failing to drive the muscles appropriately.

Most authors consider central fatigue during prolonged exercise to be a consequence of the accumulation or depletion of neurotransmitters, serotonin in particular. Although the role of serotonergic neural trafficking on exercise performance has been well documented, dopamine and noradrenaline neurotransmissions also contribute to central fatigue. In addition to having their activity modified by exercise, all of these brain monoamines exhibit relevant thermoregulatory effects. These amines play an important role in the function of thermoregulatory centers, such as the preoptic area and the anterior hypothalamus, and it is hypothesized that changes in their turnover are associated with the development of fatigue as a consequence of heat imbalances.

The brain is especially endangered by hyperthermia. For this reason, the exacerbation of exercise-induced hyperthermia appears to diminish the central nervous system drive to the working muscles; this protects the brain from thermal damage while causing a detriment to physical endurance. This effect is more pronounced when hyperthermia occurs simultaneously with inhibitory signals from the central nervous system, as in the case of altered neurotransmitter metabolisms. Even though it has been stated that central fatigue

The Involvement of Brain Monoamines in the Onset of Hyperthermic Central Fatigue 277

Peripheral information, such as substrate depletion and waste product accumulation, would act as a modulator of the cerebral control process in a dynamic, non-linear and integrated manner; this would cause an oscillatory behavior of the physiological responses and power output during exercise. This integrative model of fatigue proposes that a continuous interrelated control of feed-forward and feed-back mechanisms would exist and would be responsible for a secure system of homeostasis control during exercise (Noakes et al., 2005; Tucker, 2009; Tucker et al., 2006). This integration could be consciously and verbally manifested through the perception of effort, as measured by Borg's scale (1982) (St Clair Gibson et al., 2006; Tucker, 2009). Moreover, the teleoanticipatory central nervous system would be molded by previous exercise experiences and training (Noakes et al., 2005). Thus, fatigue may provide the cognitive system with a signal that encourages the organism to lower present goals and/or seek lower effort alternative strategies (Perrey et al., 2010). In spite of being accepted by some research groups (Marino, 2010; Baron et al., 2009; Flouris & Cheung, 2009; Castle et al., 2006), this model has been criticized by others (Ament & Verkerke, 2009; Shephard, 2009). As discussed later in this chapter, our group has been working with a conception of fatigue that goes in this direction. We have shown that before any harm can occur, afferent information from different physiological systems must be centrally integrated, and exercise must be voluntarily interrupted (Balthazar et al., 2009,

Leite et al., 2010; A. G. Rodrigues et al., 2004, 2009; Soares et al., 2004, 2007).

Although most studies have focused on the peripheral factors of fatigue, including circulatory, metabolic, muscular, nutritional, and thermoregulatory disorders (Bassett & Howley, 2000; Coyle et al., 1986; Coyle & González-Alonso, 2001; Febbraio, 2000; Hargreaves & Febbraio, 1998; Kreider et al., 1993; Noakes, 2000), exercise-induced cerebral metabolism and neurohumoral or neurotransmitter alterations are also implicated in the genesis of fatigue (Foley & Fleshner, 2008; Nybo & Secher, 2004; Roelands & Meeusen, 2010). This participation of central nervous system factors in the reduction of the voluntary activation of skeletal muscles during physical effort has been termed "central fatigue" (Foley & Fleshner, 2008; Gandevia, 2001). In this section, a focused discussion on the possible role of serotonin neurotransmission on exercise-induced central fatigue will be presented. As first suggested by Newsholme et al. (1992), fatigue during prolonged exercise may be influenced by the activity of the brain serotonergic system; this has been commonly referred to as the ''central fatigue hypothesis.'' Its major premise is that elevated central tryptophan availability increases serotonin activity during prolonged exercise, which may cause fatigue by increasing lethargy and loss of central drive/motivation (Newsholme et al., 1992). During resting periods, most tryptophan, the amino acid precursor of serotonin, circulates in the blood bound to albumin, the same transporter of free fatty acids. During prolonged exercise and as a response to metabolic demands, there is an increase in the plasma concentration of free fatty acids. This displaces tryptophan from the biding sites on albumin and causes an elevation in the free portion of this amino acid. As a consequence, tryptophan is readily available to cross the blood-brain barrier. Concomitantly, during prolonged exercise, the plasma concentrations of branched-chain amino acids either fall or do not change. Because these amino acids and tryptophan in its free form share the same transporter across the blood-brain barrier, a reduction in plasma concentrations of branched-chain amino acids during exercise could increase the uptake of tryptophan into

**3. Central fatigue hypothesis**

coincides with critical high core body and brain temperatures, as well as increased heat storage, evidence indicates that complex and dynamic mechanisms are reliable regulators of exercise performance. In this way, the heat storage and the body heating rates associated with changes in neurotransmitter content in thermoregulatory centers emerge as important factors in determining fatigue.

The main focus of this section is to link serotonin, dopamine and noradrenaline brain levels and exercise-induced hyperthermia with the onset of central fatigue. It is improbable that central fatigue is caused by a unique pathway; therefore the interaction between these systems may play an important role in establishing hyperthermia-induced central fatigue. From a health perspective, fatigue should be considered a warning sign that prevents the organism from the harmful consequences of sports activities.

## **2. Fatigue as a defense mechanism during exercise**

Fatigue can disturb performance in many occupations, including firefighting, the military, construction and laboring, and it can limit participation in most recreational activities and sports (McKenna & Hargreaves, 2008). Understanding fatigue has implications far from those circumscribed to sports performance. In ill patients, fatigue and, thus, exercise limitations can drastically restrict daily activities and lead to a poor quality of life. Therefore, it is not surprising that exercise-induced fatigue has gained so much attention among researchers in the fields of exercise science and medicine.

Exercise-induced fatigue has been traditionally defined as an elevation in the perception of effort to develop a desired force or power and also as an eventual inability to produce this force (Davis & Bailey, 1997; Enoka & Stuart, 1992). Many different models have been proposed in an attempt to understand the underlying mechanisms of fatigue. Since the early works by Fletcher and Hopkins (1907) and Hill et al. (1924), lactic acid production, cardiovascular system inefficiency, metabolic substrate depletion and waste product accumulation have been recognized as the main signs of fatigue. Until recently, most studies have dealt with exercise-induced fatigue under a failure perspective, which means that any limitation arising from exercising muscles would lead to an interruption in the motor task. In such an approach, the failure to maintain force depends on "peripheral" fatigue that occurs distal to the point of nerve stimulation and on "central" fatigue that results from a failure to voluntarily activate the muscle (Gandevia, 2001). However, it is important to emphasize that fatigue during exercise can occur without any signs of muscle dysfunction, substrate inadequacy within the exercised muscles or cardiovascular system overload; it may thus be under the influence of psychological factors such as arousal, mood and external motivation (Foley & Fleshner, 2008).

A more recent approach differs from the failure perspective and points to a more integrative scenario where fatigue should be seen as a defense mechanism. Thus, exercise is ended or its intensity is turned down to protect the individual from tissue damage (Marino, 2004). In 1996, Ulmer proposed the concept of teleoanticipation, where a feedback control system would exist for the optimal adjustment of the metabolic rate during exercise and would include a programmer that would take a finishing point into consideration. In this way, a marathon runner would consciously choose to run at a pace that would not pose a threat to himself. This assumption was further developed as the "Central Governor Model" that considers fatigue to be a sensation that results from a complex neural integration between afferent information and the brain (Noakes et al., 2005; Noakes & St Clair Gibson, 2004). Peripheral information, such as substrate depletion and waste product accumulation, would act as a modulator of the cerebral control process in a dynamic, non-linear and integrated manner; this would cause an oscillatory behavior of the physiological responses and power output during exercise. This integrative model of fatigue proposes that a continuous interrelated control of feed-forward and feed-back mechanisms would exist and would be responsible for a secure system of homeostasis control during exercise (Noakes et al., 2005; Tucker, 2009; Tucker et al., 2006). This integration could be consciously and verbally manifested through the perception of effort, as measured by Borg's scale (1982) (St Clair Gibson et al., 2006; Tucker, 2009). Moreover, the teleoanticipatory central nervous system would be molded by previous exercise experiences and training (Noakes et al., 2005). Thus, fatigue may provide the cognitive system with a signal that encourages the organism to lower present goals and/or seek lower effort alternative strategies (Perrey et al., 2010).

In spite of being accepted by some research groups (Marino, 2010; Baron et al., 2009; Flouris & Cheung, 2009; Castle et al., 2006), this model has been criticized by others (Ament & Verkerke, 2009; Shephard, 2009). As discussed later in this chapter, our group has been working with a conception of fatigue that goes in this direction. We have shown that before any harm can occur, afferent information from different physiological systems must be centrally integrated, and exercise must be voluntarily interrupted (Balthazar et al., 2009, Leite et al., 2010; A. G. Rodrigues et al., 2004, 2009; Soares et al., 2004, 2007).

## **3. Central fatigue hypothesis**

276 An International Perspective on Topics in Sports Medicine and Sports Injury

coincides with critical high core body and brain temperatures, as well as increased heat storage, evidence indicates that complex and dynamic mechanisms are reliable regulators of exercise performance. In this way, the heat storage and the body heating rates associated with changes in neurotransmitter content in thermoregulatory centers emerge as important

The main focus of this section is to link serotonin, dopamine and noradrenaline brain levels and exercise-induced hyperthermia with the onset of central fatigue. It is improbable that central fatigue is caused by a unique pathway; therefore the interaction between these systems may play an important role in establishing hyperthermia-induced central fatigue. From a health perspective, fatigue should be considered a warning sign that prevents the

Fatigue can disturb performance in many occupations, including firefighting, the military, construction and laboring, and it can limit participation in most recreational activities and sports (McKenna & Hargreaves, 2008). Understanding fatigue has implications far from those circumscribed to sports performance. In ill patients, fatigue and, thus, exercise limitations can drastically restrict daily activities and lead to a poor quality of life. Therefore, it is not surprising that exercise-induced fatigue has gained so much attention among

Exercise-induced fatigue has been traditionally defined as an elevation in the perception of effort to develop a desired force or power and also as an eventual inability to produce this force (Davis & Bailey, 1997; Enoka & Stuart, 1992). Many different models have been proposed in an attempt to understand the underlying mechanisms of fatigue. Since the early works by Fletcher and Hopkins (1907) and Hill et al. (1924), lactic acid production, cardiovascular system inefficiency, metabolic substrate depletion and waste product accumulation have been recognized as the main signs of fatigue. Until recently, most studies have dealt with exercise-induced fatigue under a failure perspective, which means that any limitation arising from exercising muscles would lead to an interruption in the motor task. In such an approach, the failure to maintain force depends on "peripheral" fatigue that occurs distal to the point of nerve stimulation and on "central" fatigue that results from a failure to voluntarily activate the muscle (Gandevia, 2001). However, it is important to emphasize that fatigue during exercise can occur without any signs of muscle dysfunction, substrate inadequacy within the exercised muscles or cardiovascular system overload; it may thus be under the influence of psychological factors such as arousal, mood and external

A more recent approach differs from the failure perspective and points to a more integrative scenario where fatigue should be seen as a defense mechanism. Thus, exercise is ended or its intensity is turned down to protect the individual from tissue damage (Marino, 2004). In 1996, Ulmer proposed the concept of teleoanticipation, where a feedback control system would exist for the optimal adjustment of the metabolic rate during exercise and would include a programmer that would take a finishing point into consideration. In this way, a marathon runner would consciously choose to run at a pace that would not pose a threat to himself. This assumption was further developed as the "Central Governor Model" that considers fatigue to be a sensation that results from a complex neural integration between afferent information and the brain (Noakes et al., 2005; Noakes & St Clair Gibson, 2004).

factors in determining fatigue.

organism from the harmful consequences of sports activities.

**2. Fatigue as a defense mechanism during exercise**

researchers in the fields of exercise science and medicine.

motivation (Foley & Fleshner, 2008).

Although most studies have focused on the peripheral factors of fatigue, including circulatory, metabolic, muscular, nutritional, and thermoregulatory disorders (Bassett & Howley, 2000; Coyle et al., 1986; Coyle & González-Alonso, 2001; Febbraio, 2000; Hargreaves & Febbraio, 1998; Kreider et al., 1993; Noakes, 2000), exercise-induced cerebral metabolism and neurohumoral or neurotransmitter alterations are also implicated in the genesis of fatigue (Foley & Fleshner, 2008; Nybo & Secher, 2004; Roelands & Meeusen, 2010). This participation of central nervous system factors in the reduction of the voluntary activation of skeletal muscles during physical effort has been termed "central fatigue" (Foley & Fleshner, 2008; Gandevia, 2001). In this section, a focused discussion on the possible role of serotonin neurotransmission on exercise-induced central fatigue will be presented.

As first suggested by Newsholme et al. (1992), fatigue during prolonged exercise may be influenced by the activity of the brain serotonergic system; this has been commonly referred to as the ''central fatigue hypothesis.'' Its major premise is that elevated central tryptophan availability increases serotonin activity during prolonged exercise, which may cause fatigue by increasing lethargy and loss of central drive/motivation (Newsholme et al., 1992). During resting periods, most tryptophan, the amino acid precursor of serotonin, circulates in the blood bound to albumin, the same transporter of free fatty acids. During prolonged exercise and as a response to metabolic demands, there is an increase in the plasma concentration of free fatty acids. This displaces tryptophan from the biding sites on albumin and causes an elevation in the free portion of this amino acid. As a consequence, tryptophan is readily available to cross the blood-brain barrier. Concomitantly, during prolonged exercise, the plasma concentrations of branched-chain amino acids either fall or do not change. Because these amino acids and tryptophan in its free form share the same transporter across the blood-brain barrier, a reduction in plasma concentrations of branched-chain amino acids during exercise could increase the uptake of tryptophan into

The Involvement of Brain Monoamines in the Onset of Hyperthermic Central Fatigue 279

Fatigue should be seen as a multifaceted phenomenon influenced by both central and peripheral factors (Meeusen et al., 2006; Nybo & Secher, 2004). There is no doubt that alterations within the muscle contribute to exercise-induced fatigue; however, it is unlikely that alterations in muscle function are the sole mechanism of fatigue. In fact, the contribution of either central factors or factors upstream of the neuromuscular junction has

At least three factors have been proposed to contribute to the delay in establishing the role of "central" factors in human muscle fatigue. First, it has simply been more convenient to assume that the muscle limits to produce force that have been established in reduced preparations of muscle that are devoid of effective neural input also apply to a conscious human subject. Second, the existing methods to gauge the central drive to muscles have not always been technically rigorous, and findings obtained with these methods have been easily criticized or ignored. Third, although changes in the central nervous system during exercise can be measured, it has been more demanding to show that they cause a deficit in

Because muscle contractions are under the control of the central nervous system, it is likely that any significant alteration in the brain or the spinal cord would alter the neural drive to the neuromuscular junction, thus initiating fatigue (Taylor & Gandevia, 2008). In order to identify the adjustments that occur within the nervous system during fatiguing contractions, most studies have investigated the influence of afferent feedback, descending inputs, and spinal circuitry on the output of the motor neuron pool (Hunter et al., 2004). For example, the metabolites that accumulate in muscles during a prolonged exercise excite afferent fibers; these fibers enhance the central drive to maintain muscle perfusion by increasing the mean arterial pressure and modulating the motor neuron discharge rate (Gandevia, 2001). Such observations indicate that the decrement in force during a fatiguing contraction

During maximal voluntary isometric tasks, voluntary activation usually diminishes, and motor unit firing rates decline (Gandevia, 2001). However, it is not possible to clearly specify all of the putative sites within the central nervous system at which contributions to voluntary activation, central fatigue, and supraspinal fatigue occur. The traditional model indicates that there is a "chain", from higher levels within the central nervous system to the motoneuron via descending paths, and then through motor axons to the neuromuscular junction, the sarcolemma, T tubules, and, ultimately, to actin and myosin (Taylor & Gandevia, 2008). Thus, central fatigue can be considered to be an impaired muscular performance that arises from decreased efferent signaling from the central nervous system. There are two general ways to study central fatigue. The first one seems to be a fairly direct way, and consists of using a technique where "added force" is determined. This occurs by overlaying a supramaximal electrical stimulus of a muscle onto a maximal voluntary contraction for that muscle. Any "added force" that may be generated that is in addition to that produced by the maximal voluntary contraction is indicative of an impairment from the central nervous system down to the level proximal to the neuromuscular junction. The second way to study central fatigue is to use an exogenous substance that is believed to induce central fatigue, and observe its effects on exercise capacity. However, unlike the first alternative, this method is indirect, because it cannot be exactly known if the substance had peripheral

been, for the most part, ignored in the literature (Foley & Fleshner, 2008).

usually involves multiple neural mechanisms (Hunter et al., 2004).

and/or central effects (Evans & Lambert, 2007).

**4. Proposed central mechanisms of fatigue**

force production (Gandevia, 2001).

the central nervous system and lead to an increase in serotonin synthesis during exercise. Thus, these two interrelated mechanisms underlie the "central fatigue hypothesis". Tryptophan increases induced by exercise have been described as occurring simultaneously with a significant rise in the concentration of 5-hydroxyindoleacetic acid, which is the main serotonin metabolite; these data indicate that exercise increases serotonin synthesis and turnover. Tryptophan alters serotonin within the brain, and there is a positive relationship between endogenous serotonin content and the activity of tryptophan transport mechanisms in hypothalamic brain slices or synaptosomal preparations. Electrolytic lesions of raphe nuclei or intracerebroventricular injections of 5,7-dihydroxytryptamine lead to a decrease in synaptosomal tryptophan accumulation with reduced nerve terminals (Denizeau & Sourkes,1977). In addition, both spontaneous and electrically evoked serotonin release from hypothalamic slices have been shown to be dependent on precursor availability, which causes parallel changes in brain serotonin levels and serotonin release (Schaechter & Wurtman, 1990).

Central serotonin activity can affect many physiological responses, such as pain tolerance (Prieto-Gomez et al., 1989), motor activity (Gerin & Privat, 1998), thermoregulation (Imeri et al., 2000; Lin et al., 1998; Myers, 1981, Soares et al., 2007) and hypothalamo–pituitary– adrenal axis activity (Chaouloff, 2000; Korte et al., 1991). Thus, alterations in one or more of the physiological responses mediated by the serotonergic system may decrease work capacity during exercise.

It has been shown that an increased availability of tryptophan, in the central nervous system reduces the mechanical efficiency and running time to fatigue, which are both related to serotonin content in the preoptic area (Soares et al., 2003, 2007). Moreover, serotonin content in the preoptic area is also associated with increased heat production and storage during exercise (Soares et al., 2007). Recently, it has been shown that alterations in the serotonin levels in the preoptic area and in the hypothalamus are also modulated by central angiotensinergic and cholinergic pathways (Leite et al., 2010; A. G. Rodrigues et al., 2009). For more details see section 7.

Serotonergic neurons have many important functions in the central nervous system, including motor activity control. However, the role of serotonin in the regulation of motor control is complex. There is widespread evidence that serotonin in the hippocampus is involved in locomotion (Meeusen et al., 1996; Takahashi et al., 2000). According to Soares et al. (2007), at fatigue, the hippocampal serotonin content was directly correlated with the exercise time of rats but not correlated with the heat storage rate. Data from A. G. Rodrigues et al. (2009) also showed that, at fatigue, the hippocampal serotonin content was not directly correlated with heat storage. Together, these results suggest that hippocampal serotonergic activity might also participate in fatigue during exercise through a mechanism other than thermoregulation. This is in agreement with reports that serotonergic neurons in the median raphe nuclei that project to the hippocampus are related to motor activity (Hillegaart & Hjorth, 1989; Jacobs et al., 1975).

Although the involvement of serotonin in central fatigue has been well documented, it has become evident that other neurotransmitters participate in the mechanisms of exerciseinduced fatigue (Lacerda et al., 2006; A. G. Rodrigues et al., 2009). These data indicate that central fatigue is a more complex phenomenon than previously thought and that it involves the balance of at least two central aminergic neurotransmitter systems, as indicated by the serotonin/dopamine ratio (Balthazar et al., 2010; Foley & Fleshner 2008; Meeusen, 2006).

## **4. Proposed central mechanisms of fatigue**

278 An International Perspective on Topics in Sports Medicine and Sports Injury

the central nervous system and lead to an increase in serotonin synthesis during exercise. Thus, these two interrelated mechanisms underlie the "central fatigue hypothesis". Tryptophan increases induced by exercise have been described as occurring simultaneously with a significant rise in the concentration of 5-hydroxyindoleacetic acid, which is the main serotonin metabolite; these data indicate that exercise increases serotonin synthesis and turnover. Tryptophan alters serotonin within the brain, and there is a positive relationship between endogenous serotonin content and the activity of tryptophan transport mechanisms in hypothalamic brain slices or synaptosomal preparations. Electrolytic lesions of raphe nuclei or intracerebroventricular injections of 5,7-dihydroxytryptamine lead to a decrease in synaptosomal tryptophan accumulation with reduced nerve terminals (Denizeau & Sourkes,1977). In addition, both spontaneous and electrically evoked serotonin release from hypothalamic slices have been shown to be dependent on precursor availability, which causes parallel changes in brain serotonin levels and serotonin release

Central serotonin activity can affect many physiological responses, such as pain tolerance (Prieto-Gomez et al., 1989), motor activity (Gerin & Privat, 1998), thermoregulation (Imeri et al., 2000; Lin et al., 1998; Myers, 1981, Soares et al., 2007) and hypothalamo–pituitary– adrenal axis activity (Chaouloff, 2000; Korte et al., 1991). Thus, alterations in one or more of the physiological responses mediated by the serotonergic system may decrease work

It has been shown that an increased availability of tryptophan, in the central nervous system reduces the mechanical efficiency and running time to fatigue, which are both related to serotonin content in the preoptic area (Soares et al., 2003, 2007). Moreover, serotonin content in the preoptic area is also associated with increased heat production and storage during exercise (Soares et al., 2007). Recently, it has been shown that alterations in the serotonin levels in the preoptic area and in the hypothalamus are also modulated by central angiotensinergic and cholinergic pathways (Leite et al., 2010; A. G. Rodrigues et al., 2009).

Serotonergic neurons have many important functions in the central nervous system, including motor activity control. However, the role of serotonin in the regulation of motor control is complex. There is widespread evidence that serotonin in the hippocampus is involved in locomotion (Meeusen et al., 1996; Takahashi et al., 2000). According to Soares et al. (2007), at fatigue, the hippocampal serotonin content was directly correlated with the exercise time of rats but not correlated with the heat storage rate. Data from A. G. Rodrigues et al. (2009) also showed that, at fatigue, the hippocampal serotonin content was not directly correlated with heat storage. Together, these results suggest that hippocampal serotonergic activity might also participate in fatigue during exercise through a mechanism other than thermoregulation. This is in agreement with reports that serotonergic neurons in the median raphe nuclei that project to the hippocampus are related to motor activity (Hillegaart &

Although the involvement of serotonin in central fatigue has been well documented, it has become evident that other neurotransmitters participate in the mechanisms of exerciseinduced fatigue (Lacerda et al., 2006; A. G. Rodrigues et al., 2009). These data indicate that central fatigue is a more complex phenomenon than previously thought and that it involves the balance of at least two central aminergic neurotransmitter systems, as indicated by the serotonin/dopamine ratio (Balthazar et al., 2010; Foley & Fleshner 2008; Meeusen, 2006).

(Schaechter & Wurtman, 1990).

capacity during exercise.

For more details see section 7.

Hjorth, 1989; Jacobs et al., 1975).

Fatigue should be seen as a multifaceted phenomenon influenced by both central and peripheral factors (Meeusen et al., 2006; Nybo & Secher, 2004). There is no doubt that alterations within the muscle contribute to exercise-induced fatigue; however, it is unlikely that alterations in muscle function are the sole mechanism of fatigue. In fact, the contribution of either central factors or factors upstream of the neuromuscular junction has been, for the most part, ignored in the literature (Foley & Fleshner, 2008).

At least three factors have been proposed to contribute to the delay in establishing the role of "central" factors in human muscle fatigue. First, it has simply been more convenient to assume that the muscle limits to produce force that have been established in reduced preparations of muscle that are devoid of effective neural input also apply to a conscious human subject. Second, the existing methods to gauge the central drive to muscles have not always been technically rigorous, and findings obtained with these methods have been easily criticized or ignored. Third, although changes in the central nervous system during exercise can be measured, it has been more demanding to show that they cause a deficit in force production (Gandevia, 2001).

Because muscle contractions are under the control of the central nervous system, it is likely that any significant alteration in the brain or the spinal cord would alter the neural drive to the neuromuscular junction, thus initiating fatigue (Taylor & Gandevia, 2008). In order to identify the adjustments that occur within the nervous system during fatiguing contractions, most studies have investigated the influence of afferent feedback, descending inputs, and spinal circuitry on the output of the motor neuron pool (Hunter et al., 2004). For example, the metabolites that accumulate in muscles during a prolonged exercise excite afferent fibers; these fibers enhance the central drive to maintain muscle perfusion by increasing the mean arterial pressure and modulating the motor neuron discharge rate (Gandevia, 2001). Such observations indicate that the decrement in force during a fatiguing contraction usually involves multiple neural mechanisms (Hunter et al., 2004).

During maximal voluntary isometric tasks, voluntary activation usually diminishes, and motor unit firing rates decline (Gandevia, 2001). However, it is not possible to clearly specify all of the putative sites within the central nervous system at which contributions to voluntary activation, central fatigue, and supraspinal fatigue occur. The traditional model indicates that there is a "chain", from higher levels within the central nervous system to the motoneuron via descending paths, and then through motor axons to the neuromuscular junction, the sarcolemma, T tubules, and, ultimately, to actin and myosin (Taylor & Gandevia, 2008).

Thus, central fatigue can be considered to be an impaired muscular performance that arises from decreased efferent signaling from the central nervous system. There are two general ways to study central fatigue. The first one seems to be a fairly direct way, and consists of using a technique where "added force" is determined. This occurs by overlaying a supramaximal electrical stimulus of a muscle onto a maximal voluntary contraction for that muscle. Any "added force" that may be generated that is in addition to that produced by the maximal voluntary contraction is indicative of an impairment from the central nervous system down to the level proximal to the neuromuscular junction. The second way to study central fatigue is to use an exogenous substance that is believed to induce central fatigue, and observe its effects on exercise capacity. However, unlike the first alternative, this method is indirect, because it cannot be exactly known if the substance had peripheral and/or central effects (Evans & Lambert, 2007).

The Involvement of Brain Monoamines in the Onset of Hyperthermic Central Fatigue 281

sublethal threshold by establishing a safety level against heat stroke, thus protecting the brain, among other tissues, from thermal damage (Caputa et al., 1986; Marino,2004). The reduction in exercise performance as a consequence of hyperthermic stress has been described in isometric tasks (Nybo & Nielsen, 2001; Thomas et al., 2006; Todd et al., 2005), in dynamic exercises with fixed intensity, i.e., a constant workload (Nybo & Nielsen, 2001), and in self-paced prolonged exercises (Ely et al., 2010; Tatterson, 2000). Recently, from an evolutionary perspective, it has been suggested that physiological and (or) psychological safeguards should protect individuals by voluntarily reducing exercise and metabolic heat production before catastrophic hyperthermia (Cheung, 2007). In fact, various animals will cease exercise when their core temperatures exceed safe limits, and there must be a similar behavioral response in humans to reduce metabolic heat production and ultimately to

Humans possess efficient physiological and behavioral mechanisms for maintaining their internal temperature within narrow limits; these mechanisms allow survival even in diversified thermal environments such as tropical forests, deserts and very cold regions. Our body temperatures are carefully regulated at 37°C ± 1°C. However, our thermal physiology is "asymmetrical", which means that body temperature is placed very closely, within just a few degrees Celsius, to the upper existence limit (possibly related to the denaturation of regulatory proteins) but somewhat far, a few tens of degrees, from the lower survival limit

The lowest values for body temperature occur in the morning, between 04:00 and 06:00 a.m., and the highest are observed between 17:00 and 20:00 h (Waterhouse et al., 2005). It should be noted that the temperature is not the same throughout the human body. There is a temperature gradient between the core (visceral) and body surface (cutaneous). With an elevation in body temperature to values over 42°C, there is an eminent risk of protein denaturating with subsequent cellular death. However, despite being more tolerant to hypothermia than to hyperthermia (see above) when the former is severe, i.e., when body temperature falls below 32°C, there are critical risks for life maintenance that include the loss of motor coordination, cardiac arrhythmias and even death by cardiac arrest (Kanosue, 2010). Body temperature is the net result of the heat produced by metabolic actions and the heat dissipated to the environment. If the heat dissipation is smaller than heat production,

Metabolism generates heat from exergonic oxidative reactions that use adenosine triphosphate (ATP) as fuel. Basal metabolism is around 50% efficient, and the remaining energy is lost as heat. Exercising muscles are even less efficient, at no more than 25%. For example, given that the mean value for the specific heat of body tissue is 0.83 kcal.kg-1.º C-1, a male adult weighting 70 kg with a body temperature of 37°C has around 2,150 Kcal of total

The basal metabolism produces 1 Kcal. kg-1.h-1, even in a thermoneutral environment, where temperature regulation is achieved only by means of sensible heat loss, i.e., without regulatory changes in metabolic heat production or evaporative heat loss. Because human tissues only need 0.83 kcal.kg-1 to increase the internal (core) temperature by 1°C, core temperatures would be elevated by 1°C.h-1, even during rest periods, if no heat loss mechanisms are activated. Thus, losing heat to the environment is essential for survival. If there were no effective means

by which body could lose heat, hyperthermia would be achieved very rapidly.

(probably defined by the freezing temperature of water) (Romanovsky,2007).

protect the physiological integrity (Cheung & Sleivert, 2004).

excessive heat is stored and body temperature increases.

heat stored in his body.

**5.1 Body temperature and thermoregulation**

## **4.1 Central nervous system biochemical changes and central fatigue**

Given that intense exercise challenges the cardiovascular, respiratory, endocrine, and peripheral and central motor systems, changes in many central nervous system transmitter systems would be expected to accompany exercise and task failure or fatigue (Gandevia, 2001). All types of physical or psychological constraints lead to the activation of noradrenergic, dopaminergic and serotonergic systems at the brainstem level. These systems are particularly important for the global regulation of behavior, and they participate in the formulation of an adapted response of the central nervous system to an external stimulus (Sesboue & Guincestre, 2006).

The widespread central actions of many of these systems make it unlikely that any one is uniquely responsible for central fatigue. For example, there are serotonergic projections from the brain stem raphe nuclei to the cortex, hippocampus, hypothalamus, medulla, and spinal cord. There are noradrenergic projections from the locus coeruleus. Arousal, motivation, attention, tolerance to discomfort, and sensitivity to stress can all alter voluntary drive, at least subjectively, which suggests that many neural systems can modify central fatigue (Gandevia, 2001).

There is evidence of the roles of these neuromodulators on fatigue that will be minutely covered later in this chapter. However, it is important to first elucidate some aspects of the interrelatedness of central neuromodulators and fatigue. We have already discussed some aspects of serotonergic neurotransmission and its implication on the central fatigue during exercise.

Central noradrenergic neurons modulate humor and motivation, and when their activity is low, motivation decreases. This decrease leads to a diminishment of motor cortex activation and a subsequent decline in the stimulation of the descending path chain to the motoneurons (Sesboue & Guincestre, 2006). On the other hand, the response of cerebral dopamine to, for example, a physical constraint is biphasic. It has been shown that there is a small elevation in the levels of this neurotransmitter at the beginning of muscle work, which is followed by a reduction in its concentration as the intensity and duration of the effort increases; this reduction is most prominent at fatigue (Foley & Fleshner, 2008).

There are several other transmitters and their subtypes that need to be examined for their role in central fatigue. For example, it is already known that brain gamma-aminobutyricacid (GABA) levels diminish with exercise (Gandevia, 2001) and that baclofen, a GABAergic agonist that acts on GABA B receptors, can postpone fatigue (Abdelmalki et al., 1997). Other humoral signals that must be considered to be involved in central fatigue are glutamine and ammonia, which are diminished and increased, respectively, after exercise (Gandevia, 2001). Another important proposed mechanism of central fatigue is related to hyperthermia during exercise. It is well known that hyperthermia reduces the central nervous system drive for exercise performance (Nielsen et al., 1993; Walters et al., 2000) and precipitates feelings of fatigue during exercise. However, this essential aspect of central fatigue will be discussed in detail in the next section.

## **5. Fatigue induced by exercise hyperthermia**

It has been shown that hyperthermia reduces physical performance in many mammalian species (Bruck & Olschewski, 1987; Fuller et al., 1998; González-Alonso et al., 1999; Nielsen et al., 1993; Walters et al., 2000), reduces central nervous system drive for exercise performance (Nielsen et al., 1993; Walters et al., 2000) and precipitates feelings of fatigue at a sublethal threshold by establishing a safety level against heat stroke, thus protecting the brain, among other tissues, from thermal damage (Caputa et al., 1986; Marino,2004). The reduction in exercise performance as a consequence of hyperthermic stress has been described in isometric tasks (Nybo & Nielsen, 2001; Thomas et al., 2006; Todd et al., 2005), in dynamic exercises with fixed intensity, i.e., a constant workload (Nybo & Nielsen, 2001), and in self-paced prolonged exercises (Ely et al., 2010; Tatterson, 2000). Recently, from an evolutionary perspective, it has been suggested that physiological and (or) psychological safeguards should protect individuals by voluntarily reducing exercise and metabolic heat production before catastrophic hyperthermia (Cheung, 2007). In fact, various animals will cease exercise when their core temperatures exceed safe limits, and there must be a similar behavioral response in humans to reduce metabolic heat production and ultimately to protect the physiological integrity (Cheung & Sleivert, 2004).

#### **5.1 Body temperature and thermoregulation**

280 An International Perspective on Topics in Sports Medicine and Sports Injury

Given that intense exercise challenges the cardiovascular, respiratory, endocrine, and peripheral and central motor systems, changes in many central nervous system transmitter systems would be expected to accompany exercise and task failure or fatigue (Gandevia, 2001). All types of physical or psychological constraints lead to the activation of noradrenergic, dopaminergic and serotonergic systems at the brainstem level. These systems are particularly important for the global regulation of behavior, and they participate in the formulation of an adapted response of the central nervous system to an external stimulus

The widespread central actions of many of these systems make it unlikely that any one is uniquely responsible for central fatigue. For example, there are serotonergic projections from the brain stem raphe nuclei to the cortex, hippocampus, hypothalamus, medulla, and spinal cord. There are noradrenergic projections from the locus coeruleus. Arousal, motivation, attention, tolerance to discomfort, and sensitivity to stress can all alter voluntary drive, at least subjectively, which suggests that many neural systems can modify central

There is evidence of the roles of these neuromodulators on fatigue that will be minutely covered later in this chapter. However, it is important to first elucidate some aspects of the interrelatedness of central neuromodulators and fatigue. We have already discussed some aspects of serotonergic neurotransmission and its implication on the central fatigue during

Central noradrenergic neurons modulate humor and motivation, and when their activity is low, motivation decreases. This decrease leads to a diminishment of motor cortex activation and a subsequent decline in the stimulation of the descending path chain to the motoneurons (Sesboue & Guincestre, 2006). On the other hand, the response of cerebral dopamine to, for example, a physical constraint is biphasic. It has been shown that there is a small elevation in the levels of this neurotransmitter at the beginning of muscle work, which is followed by a reduction in its concentration as the intensity and duration of the effort

There are several other transmitters and their subtypes that need to be examined for their role in central fatigue. For example, it is already known that brain gamma-aminobutyricacid (GABA) levels diminish with exercise (Gandevia, 2001) and that baclofen, a GABAergic agonist that acts on GABA B receptors, can postpone fatigue (Abdelmalki et al., 1997). Other humoral signals that must be considered to be involved in central fatigue are glutamine and ammonia, which are diminished and increased, respectively, after exercise (Gandevia, 2001). Another important proposed mechanism of central fatigue is related to hyperthermia during exercise. It is well known that hyperthermia reduces the central nervous system drive for exercise performance (Nielsen et al., 1993; Walters et al., 2000) and precipitates feelings of fatigue during exercise. However, this essential aspect of central fatigue will be discussed in

It has been shown that hyperthermia reduces physical performance in many mammalian species (Bruck & Olschewski, 1987; Fuller et al., 1998; González-Alonso et al., 1999; Nielsen et al., 1993; Walters et al., 2000), reduces central nervous system drive for exercise performance (Nielsen et al., 1993; Walters et al., 2000) and precipitates feelings of fatigue at a

increases; this reduction is most prominent at fatigue (Foley & Fleshner, 2008).

**4.1 Central nervous system biochemical changes and central fatigue**

(Sesboue & Guincestre, 2006).

fatigue (Gandevia, 2001).

detail in the next section.

**5. Fatigue induced by exercise hyperthermia**

exercise.

Humans possess efficient physiological and behavioral mechanisms for maintaining their internal temperature within narrow limits; these mechanisms allow survival even in diversified thermal environments such as tropical forests, deserts and very cold regions. Our body temperatures are carefully regulated at 37°C ± 1°C. However, our thermal physiology is "asymmetrical", which means that body temperature is placed very closely, within just a few degrees Celsius, to the upper existence limit (possibly related to the denaturation of regulatory proteins) but somewhat far, a few tens of degrees, from the lower survival limit (probably defined by the freezing temperature of water) (Romanovsky,2007).

The lowest values for body temperature occur in the morning, between 04:00 and 06:00 a.m., and the highest are observed between 17:00 and 20:00 h (Waterhouse et al., 2005). It should be noted that the temperature is not the same throughout the human body. There is a temperature gradient between the core (visceral) and body surface (cutaneous). With an elevation in body temperature to values over 42°C, there is an eminent risk of protein denaturating with subsequent cellular death. However, despite being more tolerant to hypothermia than to hyperthermia (see above) when the former is severe, i.e., when body temperature falls below 32°C, there are critical risks for life maintenance that include the loss of motor coordination, cardiac arrhythmias and even death by cardiac arrest (Kanosue, 2010).

Body temperature is the net result of the heat produced by metabolic actions and the heat dissipated to the environment. If the heat dissipation is smaller than heat production, excessive heat is stored and body temperature increases.

Metabolism generates heat from exergonic oxidative reactions that use adenosine triphosphate (ATP) as fuel. Basal metabolism is around 50% efficient, and the remaining energy is lost as heat. Exercising muscles are even less efficient, at no more than 25%. For example, given that the mean value for the specific heat of body tissue is 0.83 kcal.kg-1.º C-1, a male adult weighting 70 kg with a body temperature of 37°C has around 2,150 Kcal of total heat stored in his body.

The basal metabolism produces 1 Kcal. kg-1.h-1, even in a thermoneutral environment, where temperature regulation is achieved only by means of sensible heat loss, i.e., without regulatory changes in metabolic heat production or evaporative heat loss. Because human tissues only need 0.83 kcal.kg-1 to increase the internal (core) temperature by 1°C, core temperatures would be elevated by 1°C.h-1, even during rest periods, if no heat loss mechanisms are activated. Thus, losing heat to the environment is essential for survival. If there were no effective means by which body could lose heat, hyperthermia would be achieved very rapidly.

The Involvement of Brain Monoamines in the Onset of Hyperthermic Central Fatigue 283

that both the heat storage rate and the internal body temperature seem to be the important determinants of fatigue during exercise (Balthazar et al., 2010; Coelho et al., 2010; Garcia et al., 2006; Lacerda et al., 2005; Leite et al., 2006; Magalhães et al., 2010; Nassif et al., 2008; A. G. Rodrigues et al., 2008; Soares et al., 2004, 2007). Thus, dissipation of heat from the body is thought to be more important than the control of heat production in the regulation of body

Temperature regulation during exercise can be divided into two phases. During the first minutes of exercise, in what has been called the dynamic phase, there is a imbalance between heat production, which depends mainly on exercise intensity, and heat dissipation; this imbalance results in an abrupt increase in body (internal) temperature. Rapid peripheral vasoconstriction, mediated by the noradrenergic sympathetic system and observed at this earlier phase, impairs heat dissipation during this stage of exercise and leads to hyperthermia. Venous blood that drains exercising muscles brings excessive heat to the body core. Hypothalamic thermosensors detect the increase in blood temperature, and the thermal integrative center of the hypothalamus activates efferent heat loss mechanisms. The second phase of exercise, known as the steady phase of thermal balance, begins as thermal thresholds for heat dissipation mechanisms (vasodilation and sweating) are attained (Lacerda et al., 2006). From this point on, there is an increase in skin blood flow, mediated by the vasodilator cholinergic sympathetic system, which parallels the increase in the sweating rate. These autonomic actions increase the body heat dissipation and minimize the body temperature elevation. When heat storage reaches a critical limit, protective fatigue occurs independently of body energy stores. This excessive stored heat reduces the

motivation for voluntary exercise before the individual integrity is compromised.

2004). The reduction in central drive may also result from both of these possibilities.

effort to be higher during hyperthermic condition (Nielsen et al., 2001).

Neuromuscular control and hyperthermia have been widely investigated, and it has been consistently shown that hyperthermia diminishes neuromuscular activation (Morrison et al., 2004; Nybo & Nielsen, 2001; Todd et al., 2005). A model has been proposed that suggests that this impairment causes systemic failures in order to protect the organism from severe heat injuries (Cheung, 2007). A reduction in the central drive to the motor neuron pool during hyperthermia is thought to result from at least two possibilities. One considers that there is a reduction in the descending message from the higher brain impulses to the motor neurons. The other indicates that inhibition occurs subcortically, at the site of the motor neurons, where afferent feedback may decrease the excitability of those motor neurons (Cheung & Sleivert,

Brain function may also be altered during hyperthermia. Changes in behavior seen with overheating, such as confusion, a loss of coordination, syncope, and, in extreme hyperthermia, a loss of consciousness or seizures, have been consistently observed (Fuller et al., 1998; Schlader et al., 2010; Walters et al., 2000). These data indirectly suggest a change in central nervous system function with hyperthermia (Cheung & Sleivert, 2004; Nybo, 2008). Brain activity, specifically the ratio of low frequency (α: 8 –13 Hz) and high frequency (β: 13–30 Hz) brainwaves, is an indicator of arousal during hyperthermia. Exercise has been investigated in subjects cycling at 60% aerobic power in both a hot ( 40°C) and cool (19°C) environment (Nielsen et al., 2001). There was a reduction in β waves in the hot exercise condition such that the ratio of α to β waves increased, which indicates a reduced state of arousal in hyperthermic subjects. Moreover, the magnitude of the increase in the α to β wave ratio was correlated to elevated core temperatures. In the same study, subjects continually rated their perception of

temperature during exercise (Cheung & Sleivert, 2004).

Thermoregulation is a typical example of an integrative hypothalamic function that generates autonomic, endocrine, motor and behavioral patterns as a response to an external challenge. Thermoregulation systems are composed of multiple independent neural pathways that have both feedback and feedforward mechanisms; these mechanism are activated by afferent information from peripheral temperature sensors and modulate the relationship between ambient and skin temperatures (Mekjavic & Eiken, 2006; Webb, 1995).

The endothermic/homoeothermic animals are relatively independent from environmental conditions because they are able to regulate their body temperature through an association of autonomic and behavioral mechanisms (Mekjavic & Eiken, 2006; Schlader et al., 2009, 2010). The autonomic processes consist of involuntary thermoeffector responses, either to heat or cold, which modify heat production and dissipation rates, and include sweating, shivering and vasomotor alterations at the body surface (IUPS, 2001). However, as pointed out by some authors (Schalader et al, 2010; Romanovsky, 2007), those autonomic responses have a limited capacity to regulate body temperature. In contrast, behavioral mechanisms of thermoregulation are intended to establish a thermal environment that represents a preferred condition for heat exchange (heat gain, heat loss, or heat balance) between the organism and its environment. The responses involved in such regulation include moves to a different thermal ambiance, changes in posture, wetting of body surfaces, changes in microclimate by nest building, parental behavior (huddling), and, in humans, voluntary exercise and cultural achievements (e.g. clothing, housing, and air-conditioning) (IUPS, 2001).The association of behavioral and autonomic responses allows humans to survive in different and extreme environments (Mekjavi & Eiken, 2006).

Vasomotion and evaporation are the main mechanisms of heat defense. However, sweating (or panting) usually starts at a higher threshold temperature than skin vasodilation. Thus, sweating functions as a second line of defense for situations where an increase in skin blood flow alone is not sufficient to prevent a serious increase in body temperature. Cold defense processes operate in a parallel manner such that non-shivering thermogenesis is activated before shivering (Kanosue et al., 2010).

#### **5.2 Exercise hyperthermia and fatigue**

Because the mechanical efficiency of active muscles is around 25%, most of the remaining energy produced during exercise should be dissipated to the environment; otherwise, exercise may impose thermal stress to the organism. This dissipation can be hard if exercise takes place in a warm environment where heat dissipation mechanisms, such as conduction and radiation, are impaired. Dissipation can be even worse if it is associated with high humidity because heat lost by sweat evaporation would be severely compromised. In these environmental conditions, keeping up the same intensity effort during physical exercise could lead to a harmful situation in which the heat dissipation would be insufficient to compensate for the heat production. As a result, the body temperature would continuously increase, and a thermal equilibrium would not be reached.

To avoid serious injuries induced by excessive body heat storage and subsequent hyperthermia, it is imperative that the related activation of both the autonomic and behavioral responses, along with the different physiological systems, results in a decrease of exercise intensity or even in a termination of the activity (Cheung, 2007).

An elevation in internal body temperature and an increase in heat storage have been proposed as limiting factors to physical performance. Recent data support the hypothesis

Thermoregulation is a typical example of an integrative hypothalamic function that generates autonomic, endocrine, motor and behavioral patterns as a response to an external challenge. Thermoregulation systems are composed of multiple independent neural pathways that have both feedback and feedforward mechanisms; these mechanism are activated by afferent information from peripheral temperature sensors and modulate the relationship between ambient and skin temperatures (Mekjavic & Eiken, 2006; Webb, 1995). The endothermic/homoeothermic animals are relatively independent from environmental conditions because they are able to regulate their body temperature through an association of autonomic and behavioral mechanisms (Mekjavic & Eiken, 2006; Schlader et al., 2009, 2010). The autonomic processes consist of involuntary thermoeffector responses, either to heat or cold, which modify heat production and dissipation rates, and include sweating, shivering and vasomotor alterations at the body surface (IUPS, 2001). However, as pointed out by some authors (Schalader et al, 2010; Romanovsky, 2007), those autonomic responses have a limited capacity to regulate body temperature. In contrast, behavioral mechanisms of thermoregulation are intended to establish a thermal environment that represents a preferred condition for heat exchange (heat gain, heat loss, or heat balance) between the organism and its environment. The responses involved in such regulation include moves to a different thermal ambiance, changes in posture, wetting of body surfaces, changes in microclimate by nest building, parental behavior (huddling), and, in humans, voluntary exercise and cultural achievements (e.g. clothing, housing, and air-conditioning) (IUPS, 2001).The association of behavioral and autonomic responses allows humans to survive in

Vasomotion and evaporation are the main mechanisms of heat defense. However, sweating (or panting) usually starts at a higher threshold temperature than skin vasodilation. Thus, sweating functions as a second line of defense for situations where an increase in skin blood flow alone is not sufficient to prevent a serious increase in body temperature. Cold defense processes operate in a parallel manner such that non-shivering thermogenesis is activated

Because the mechanical efficiency of active muscles is around 25%, most of the remaining energy produced during exercise should be dissipated to the environment; otherwise, exercise may impose thermal stress to the organism. This dissipation can be hard if exercise takes place in a warm environment where heat dissipation mechanisms, such as conduction and radiation, are impaired. Dissipation can be even worse if it is associated with high humidity because heat lost by sweat evaporation would be severely compromised. In these environmental conditions, keeping up the same intensity effort during physical exercise could lead to a harmful situation in which the heat dissipation would be insufficient to compensate for the heat production. As a result, the body temperature would continuously

To avoid serious injuries induced by excessive body heat storage and subsequent hyperthermia, it is imperative that the related activation of both the autonomic and behavioral responses, along with the different physiological systems, results in a decrease of

An elevation in internal body temperature and an increase in heat storage have been proposed as limiting factors to physical performance. Recent data support the hypothesis

different and extreme environments (Mekjavi & Eiken, 2006).

increase, and a thermal equilibrium would not be reached.

exercise intensity or even in a termination of the activity (Cheung, 2007).

before shivering (Kanosue et al., 2010).

**5.2 Exercise hyperthermia and fatigue**

that both the heat storage rate and the internal body temperature seem to be the important determinants of fatigue during exercise (Balthazar et al., 2010; Coelho et al., 2010; Garcia et al., 2006; Lacerda et al., 2005; Leite et al., 2006; Magalhães et al., 2010; Nassif et al., 2008; A. G. Rodrigues et al., 2008; Soares et al., 2004, 2007). Thus, dissipation of heat from the body is thought to be more important than the control of heat production in the regulation of body temperature during exercise (Cheung & Sleivert, 2004).

Temperature regulation during exercise can be divided into two phases. During the first minutes of exercise, in what has been called the dynamic phase, there is a imbalance between heat production, which depends mainly on exercise intensity, and heat dissipation; this imbalance results in an abrupt increase in body (internal) temperature. Rapid peripheral vasoconstriction, mediated by the noradrenergic sympathetic system and observed at this earlier phase, impairs heat dissipation during this stage of exercise and leads to hyperthermia. Venous blood that drains exercising muscles brings excessive heat to the body core. Hypothalamic thermosensors detect the increase in blood temperature, and the thermal integrative center of the hypothalamus activates efferent heat loss mechanisms. The second phase of exercise, known as the steady phase of thermal balance, begins as thermal thresholds for heat dissipation mechanisms (vasodilation and sweating) are attained (Lacerda et al., 2006). From this point on, there is an increase in skin blood flow, mediated by the vasodilator cholinergic sympathetic system, which parallels the increase in the sweating rate. These autonomic actions increase the body heat dissipation and minimize the body temperature elevation. When heat storage reaches a critical limit, protective fatigue occurs independently of body energy stores. This excessive stored heat reduces the motivation for voluntary exercise before the individual integrity is compromised.

Neuromuscular control and hyperthermia have been widely investigated, and it has been consistently shown that hyperthermia diminishes neuromuscular activation (Morrison et al., 2004; Nybo & Nielsen, 2001; Todd et al., 2005). A model has been proposed that suggests that this impairment causes systemic failures in order to protect the organism from severe heat injuries (Cheung, 2007). A reduction in the central drive to the motor neuron pool during hyperthermia is thought to result from at least two possibilities. One considers that there is a reduction in the descending message from the higher brain impulses to the motor neurons. The other indicates that inhibition occurs subcortically, at the site of the motor neurons, where afferent feedback may decrease the excitability of those motor neurons (Cheung & Sleivert, 2004). The reduction in central drive may also result from both of these possibilities.

Brain function may also be altered during hyperthermia. Changes in behavior seen with overheating, such as confusion, a loss of coordination, syncope, and, in extreme hyperthermia, a loss of consciousness or seizures, have been consistently observed (Fuller et al., 1998; Schlader et al., 2010; Walters et al., 2000). These data indirectly suggest a change in central nervous system function with hyperthermia (Cheung & Sleivert, 2004; Nybo, 2008). Brain activity, specifically the ratio of low frequency (α: 8 –13 Hz) and high frequency (β: 13–30 Hz) brainwaves, is an indicator of arousal during hyperthermia. Exercise has been investigated in subjects cycling at 60% aerobic power in both a hot ( 40°C) and cool (19°C) environment (Nielsen et al., 2001). There was a reduction in β waves in the hot exercise condition such that the ratio of α to β waves increased, which indicates a reduced state of arousal in hyperthermic subjects. Moreover, the magnitude of the increase in the α to β wave ratio was correlated to elevated core temperatures. In the same study, subjects continually rated their perception of effort to be higher during hyperthermic condition (Nielsen et al., 2001).

The Involvement of Brain Monoamines in the Onset of Hyperthermic Central Fatigue 285

Although the role of serotonergic neural traffic on exercise performance has been welldocumented, evidence demonstrates that dopaminergic and noradrenergic neurotransmissions contribute to central fatigue as well (Foley & Fleshner, 2008; Hasegawa et al., 2008; Nybo & Secher, 2004; Roelands & Meeusen, 2010). Interestingly, all of these brain monoamines, in addition to having their activity modified by exercise, exhibit relevant thermoregulatory effects (Balthazar et al., 2009; Foley & Fleshner, 2008; Hasegawa et al., 2008; Roelands & Meeusen, 2010; Soares et al., 2004, 2007). It has been proposed that shifts in the turnover of these amines, which play an important role in the centers responsible for body temperature control, like the preoptic area and the anterior hypothalamus, may be

Many authors have provided convincing evidence of the involvement of serotonin on the development of central fatigue (Blomstrand et al., 1989; Chaouloff, 1997; Fernstrom & Fernstrom, 2006; Gomez-Merino et al., 2001, Soares et al., 2007). The major premise is that increased brain serotonergic activity contributes to the onset of fatigue, possibly through its influence on many behavioral functions, such as elevated feelings of lethargy, tiredness and a loss of drive (Blomstrand, 2006; Meeusen et al., 2006; Roelands & Meeusen, 2010; Soares et al 2004, 2007). In contrast, low serotonin brain levels would favor improved exercise

One the first studies that associated physical activity with elevated levels of serotonin in the central nervous system is Barchas & Freedman (1963), who reported high brain serotonin activity in rats who swam until exhaustion. Since then, many findings have confirmed that serotonin levels in the central nervous system increase during exercise and peak at the fatigue point (Blomstrand et al., 1989; Chaouloff, 1997; Fernstrom & Fernstrom, 2006; Gomez-Merino et al., 2001, Soares et al., 2007). Exercising until fatigue has been shown to cause an increase in the levels of both serotonin and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the brain stem and hypothalamus and an additional increase in the level of 5-HIAA in the hippocampus and striatum. The authors concluded that because there was an increase in the turnover of serotonin in some parts of the brain, these may play a role in physical performance (Blomstrand et al., 1989). Gomez-Merino et al. (2001) examined the impact of acute intensive treadmill running on serotonin levels in the hippocampus and the frontal cortex and observed high levels of the monoamine in both regions after 90 minutes of exercise. In these same regions, as well as in the hippocampus, Soares et al. (2007) and A. G. Rodrigues et al. (2009) reported elevated concentrations of serotonin after running until fatigue. More recently, Caperuto et al. (2009) reported that although swimming training induced similar hypothalamic serotonin concentrations as sedentarism, its concentration in this brain region increased after an exhaustive training program with an insufficient recovery period. The data led to the hypothesis that elevated serotonin content may

associated with the development of fatigue coupled with heat imbalance.

performance through the maintenance of motivation and arousal.

contribute to poor exercise performance during periods of excessive training.

A special focus has been given to the pharmacological manipulations used to elucidate the relationship between increased serotonergic activity and the early onset of fatigue (Bailey et al., 1993; Roelands et al., 2009). A study by Bailey et al. (1993) demonstrated that exercise performance benefitted from the use of a serotonin antagonist, while treatment with a serotonin agonist led to a detriment in exercise performance. Similarly, increased brain serotonin availability during exercise results in poor physical performance (Soares et al.,

**6.1 Serotonin**

Another important aspect regarding fatigue induced by exercise hyperthermia is cardiovascular function. It has been suggested that cardiovascular strain accompanying hyperthermia could indeed be one of the main factors underlying fatigue (Cheung & Sleivert, 2004). When heat production during exercise surpasses the capacity for heat dissipation to the environment and hyperthermia consequently develops, the ability to maintain cardiac output is jeopardized because stroke volume declines as the core temperature increases (Nybo, 2008). The competition between metabolic and thermoregulatory demands for blood flow during exercise may also accelerate the onset of fatigue through localized ischemia in specific tissues such as the brain or the gastrointestinal tract. Reduced blood flow to the gastrointestinal tract during exercise in heat may compromise the integrity of the intestinal walls (Sakurada & Hales 1998). As a result, the eventual leakage of lipopolysaccharides (endotoxins) into the circulation, a welldocumented response to severe exercise-induced hyperthermia, can occur. It is important to point out that an occurrence of endotoxemia can trigger a cascade of detrimental physiological responses mediated by cytokines, which can induce a fever-like situation and can accelerate heat storage and heat stroke.

Neurohumoral factors, primarily disturbances in cerebral neurotransmitter levels, are part of the diverse mechanisms underlying fatigue induced by exercise hyperthermia. It is clear that several neurotransmitter systems are activated during exercise and that several of these systems affect the preoptic area and the anterior hypothalamus, which is of major importance for thermoregulation (Nybo, 2008). Therefore, it is important to highlight studies that correlate high heat storage and heating rates with elevated levels of serotonin in centers essential for thermoregulation (Leite et al., 2010; A. G. Rodrigues et al., 2009; Soares et al., 2007). However, there are only a few that have examined whether hyperthermia alters monoamines and other neurotransmitter levels in the brain during exercise. Although this subject will be discussed in detail in subsequent topics in this chapter, it is essential to first call attention to some aspects.

Among the monoamines, serotonin is of particular interest because it influences arousal levels. If serotonin levels increase, this could contribute to an increase in perceived effort and a reduction in work rate, actions that have often been observed during hyperthermia (Cheung & Sleivert, 2004). In contrast, because dopamine and noradrenaline have been associated with arousal, motivation, reinforcement and reward, control of motor behavior and mechanisms of addiction, some authors have investigated the role of these neurotransmitters on fatigue induced by exercise hyperthermia (Meeusen et al., 2006). Recently, it has been demonstrated that an alteration in dopamine transmission induced by the central blockade of dopamine D1 and D2 receptors impaired running performance in rats by decreasing the tolerance to heat storage. Furthermore, this blockade also impaired both the dissipation of exercise-induced heat and the recovery of the metabolic rate during the post-exercise period. These data provide evidence that the central activation of either dopamine D1 or D2 receptors may be essential for heat balance and exercise performance (Balthazar et al., 2010).

## **6. Ergogenic and ergolytic amines**

Most theories consider central fatigue during prolonged exercise to be a consequence of changes in neurotransmitter turnover, particularly in the serotonergic system (Foley & Fleshner, 2008; Hasegawa et al., 2008; Nybo & Secher, 2004; Roelands & Meeusen, 2010). Although the role of serotonergic neural traffic on exercise performance has been welldocumented, evidence demonstrates that dopaminergic and noradrenergic neurotransmissions contribute to central fatigue as well (Foley & Fleshner, 2008; Hasegawa et al., 2008; Nybo & Secher, 2004; Roelands & Meeusen, 2010). Interestingly, all of these brain monoamines, in addition to having their activity modified by exercise, exhibit relevant thermoregulatory effects (Balthazar et al., 2009; Foley & Fleshner, 2008; Hasegawa et al., 2008; Roelands & Meeusen, 2010; Soares et al., 2004, 2007). It has been proposed that shifts in the turnover of these amines, which play an important role in the centers responsible for body temperature control, like the preoptic area and the anterior hypothalamus, may be associated with the development of fatigue coupled with heat imbalance.

#### **6.1 Serotonin**

284 An International Perspective on Topics in Sports Medicine and Sports Injury

Another important aspect regarding fatigue induced by exercise hyperthermia is cardiovascular function. It has been suggested that cardiovascular strain accompanying hyperthermia could indeed be one of the main factors underlying fatigue (Cheung & Sleivert, 2004). When heat production during exercise surpasses the capacity for heat dissipation to the environment and hyperthermia consequently develops, the ability to maintain cardiac output is jeopardized because stroke volume declines as the core temperature increases (Nybo, 2008). The competition between metabolic and thermoregulatory demands for blood flow during exercise may also accelerate the onset of fatigue through localized ischemia in specific tissues such as the brain or the gastrointestinal tract. Reduced blood flow to the gastrointestinal tract during exercise in heat may compromise the integrity of the intestinal walls (Sakurada & Hales 1998). As a result, the eventual leakage of lipopolysaccharides (endotoxins) into the circulation, a welldocumented response to severe exercise-induced hyperthermia, can occur. It is important to point out that an occurrence of endotoxemia can trigger a cascade of detrimental physiological responses mediated by cytokines, which can induce a fever-like situation and

Neurohumoral factors, primarily disturbances in cerebral neurotransmitter levels, are part of the diverse mechanisms underlying fatigue induced by exercise hyperthermia. It is clear that several neurotransmitter systems are activated during exercise and that several of these systems affect the preoptic area and the anterior hypothalamus, which is of major importance for thermoregulation (Nybo, 2008). Therefore, it is important to highlight studies that correlate high heat storage and heating rates with elevated levels of serotonin in centers essential for thermoregulation (Leite et al., 2010; A. G. Rodrigues et al., 2009; Soares et al., 2007). However, there are only a few that have examined whether hyperthermia alters monoamines and other neurotransmitter levels in the brain during exercise. Although this subject will be discussed in detail in subsequent topics in this chapter, it is essential to first

Among the monoamines, serotonin is of particular interest because it influences arousal levels. If serotonin levels increase, this could contribute to an increase in perceived effort and a reduction in work rate, actions that have often been observed during hyperthermia (Cheung & Sleivert, 2004). In contrast, because dopamine and noradrenaline have been associated with arousal, motivation, reinforcement and reward, control of motor behavior and mechanisms of addiction, some authors have investigated the role of these neurotransmitters on fatigue induced by exercise hyperthermia (Meeusen et al., 2006). Recently, it has been demonstrated that an alteration in dopamine transmission induced by the central blockade of dopamine D1 and D2 receptors impaired running performance in rats by decreasing the tolerance to heat storage. Furthermore, this blockade also impaired both the dissipation of exercise-induced heat and the recovery of the metabolic rate during the post-exercise period. These data provide evidence that the central activation of either dopamine D1 or D2 receptors may be essential for heat balance and exercise performance

Most theories consider central fatigue during prolonged exercise to be a consequence of changes in neurotransmitter turnover, particularly in the serotonergic system (Foley & Fleshner, 2008; Hasegawa et al., 2008; Nybo & Secher, 2004; Roelands & Meeusen, 2010).

can accelerate heat storage and heat stroke.

call attention to some aspects.

(Balthazar et al., 2010).

**6. Ergogenic and ergolytic amines**

Many authors have provided convincing evidence of the involvement of serotonin on the development of central fatigue (Blomstrand et al., 1989; Chaouloff, 1997; Fernstrom & Fernstrom, 2006; Gomez-Merino et al., 2001, Soares et al., 2007). The major premise is that increased brain serotonergic activity contributes to the onset of fatigue, possibly through its influence on many behavioral functions, such as elevated feelings of lethargy, tiredness and a loss of drive (Blomstrand, 2006; Meeusen et al., 2006; Roelands & Meeusen, 2010; Soares et al 2004, 2007). In contrast, low serotonin brain levels would favor improved exercise performance through the maintenance of motivation and arousal.

One the first studies that associated physical activity with elevated levels of serotonin in the central nervous system is Barchas & Freedman (1963), who reported high brain serotonin activity in rats who swam until exhaustion. Since then, many findings have confirmed that serotonin levels in the central nervous system increase during exercise and peak at the fatigue point (Blomstrand et al., 1989; Chaouloff, 1997; Fernstrom & Fernstrom, 2006; Gomez-Merino et al., 2001, Soares et al., 2007). Exercising until fatigue has been shown to cause an increase in the levels of both serotonin and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the brain stem and hypothalamus and an additional increase in the level of 5-HIAA in the hippocampus and striatum. The authors concluded that because there was an increase in the turnover of serotonin in some parts of the brain, these may play a role in physical performance (Blomstrand et al., 1989). Gomez-Merino et al. (2001) examined the impact of acute intensive treadmill running on serotonin levels in the hippocampus and the frontal cortex and observed high levels of the monoamine in both regions after 90 minutes of exercise. In these same regions, as well as in the hippocampus, Soares et al. (2007) and A. G. Rodrigues et al. (2009) reported elevated concentrations of serotonin after running until fatigue. More recently, Caperuto et al. (2009) reported that although swimming training induced similar hypothalamic serotonin concentrations as sedentarism, its concentration in this brain region increased after an exhaustive training program with an insufficient recovery period. The data led to the hypothesis that elevated serotonin content may contribute to poor exercise performance during periods of excessive training.

A special focus has been given to the pharmacological manipulations used to elucidate the relationship between increased serotonergic activity and the early onset of fatigue (Bailey et al., 1993; Roelands et al., 2009). A study by Bailey et al. (1993) demonstrated that exercise performance benefitted from the use of a serotonin antagonist, while treatment with a serotonin agonist led to a detriment in exercise performance. Similarly, increased brain serotonin availability during exercise results in poor physical performance (Soares et al.,

The Involvement of Brain Monoamines in the Onset of Hyperthermic Central Fatigue 287

Central dopamine metabolism has been shown to increase in several brain regions during exercise (Balthazar et al., 2009; Foley & Fleshner, 2008; Hasegawa et al., 2008; Meeusen et al., 2007). Meeusen et al. (1997) showed that 60 min of exercise significantly increased dopamine content in the striatum. The same increase in dopamine concentration was seen in the midbrain, hypothalamus and hippocampus during exercise (Balthazar et al., 2009, 2010; Chaouloff et al., 1987). On the other hand, Bailey et al. (1993) reported reduced cerebral dopamine levels after prolonged running, which indicates that low dopamine levels during intense exercise may contribute to the reduction in physical capacity through an interference with motivation, arousal and the motor drive. It is important to point out that recent studies reveal that the variation in the brain dopamine content during exercise exhibits a dynamic profile; the levels increase between exercises and return to basal levels at the point of fatigue, which is the same time that serotonin content is at its peak (Bailey et al., 2003; Balthazar et al., 2009; Foley & Fleshner, 2008; Struder & Weicker, 2001a,b). Therefore, it seems that exercise continuation is favored by the increase in dopamine brain levels in between exercises, while central fatigue is a consequence of the reduced central dopamine concentrations along with