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Central Mechanisms of Fatigue What do we learn from exercise studies ?

Central Mechanisms of Fatigue What do we learn from exercise studies ?. R. Meeusen PhD Vrije Universiteit Brussel Human Physiology & Sports Medicine. Fatigue & the Brain. Exercise & Brain Neurotransmission Neurotransmitters & Central Fatigue Brain neurotransmitter manipulations

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Central Mechanisms of Fatigue What do we learn from exercise studies ?

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  1. Central Mechanisms of FatigueWhat do we learn from exercise studies ? R. Meeusen PhD Vrije Universiteit Brussel Human Physiology & Sports Medicine

  2. Fatigue & the Brain • Exercise & Brain Neurotransmission • Neurotransmitters & Central Fatigue • Brain neurotransmitter manipulations • Thermoregulation  Mechanisms

  3. The Central Fatigue Hypothesis During prolonged exercise athletes not only get fatigued because of a decrease in substrates, but there is also fatigue induced by brain mechanisms

  4. Central mechanisms • Mental factors can affect performance • Inadequate CNS drive to the working muscles • Motivation, mood, pain tolerance • Neuromuscular aspects • Neurotransmitters (NT) • Neuromodulators • Thermoregulation • …

  5. The Central Fatigue ‘Hypothesis’ Is based on the increase in brain Serotonin[5-HT] during exercise. Newsholme and colleagues (1987) assumed that during prolonged exercise increased brain serotonergic activity may augment : lethargy and loss of drive resulting in a reduction in motor unit recruitment, affecting physical and mental efficiency of athletes.

  6. TRP Serotonin (5-HT) Tryptophan (TRP) ß 5-Hydroxytryptophan(5-HTP) ß 5-Hydroxytryptamine (5-HT) An amino acid becomes an important signal transducer in the human brain !! Can this small molecule be reponsible for fatigue ??

  7. Manipulation of Brain Neurotransmitter systems Several Animal & Human experiments have been performed, … But do we really know what happens in the brain ?

  8. Experiment Microdialysis in hippocampus Food-deprived rats L-TRP (50mg/kg) or saline Exercise (60 min 12m/min)

  9. Hippocampal 5-HT release Meeusen et al Brain Research(1996) Combination L-TRP + Exc 5-HT No Sign of early fatigue

  10.  involvement of DopamineDavis, Bailey and co-workers Intracranial self stimulationVentral Tegmental Area Burgess et al (1991) *

  11. “Central Fatigue” and neurotransmitters Several possible candidates Neurotransmitters are involved, but …. There might be other possible influencing factors

  12. Manipulation of Brain Neurotransmitter systems

  13. Reuptake inhibition & Performance

  14. Performance (90 min Time Trial) Meeusen et al 2001; Piacentini et al 2002, Piacentini et al 2003, 2004

  15. Re-uptake inhibition in humans  • No influence on time trial performance • Hormonal disturbances indicate the “central effect” • Serotonergic & Catecholaminergic actions differ per hormonal output • Animal research to confirm “central” action* *Piacentini et al 2003 J Appl Physiol Piacentini et al 2003 Life Sci

  16. Central Fatigue: It’s All in the Brain ? Both peripheral and central regulatory mechanisms will be stressed Disturbance of Cerebral Homeostasis that eventually can lead to Central Fatigue • Neurotransmitters are involved • But although brain disturbances occur, fatigue mechanisms seem to need other stressors

  17. How hot is the Brain?

  18. Exercise time to exhaustion during cycling at 70% peak VO2 in 40°C (HT), 20°C (NT), and 3°C (CT).Parkin et al 1999 3°C 20°C 40°C

  19. How could high core temperature cause fatigue? - Peripheral factors - Change brain function? - Change ”motivation”? Gonzales_alonzo et al 1998

  20. Hyperthermia As core temperature increases • RPE increases Effort ‘feels’ harder  Perception  brain B. Nielsen & L. Nybo

  21. Which Neurotransmitters control fatigue mechanisms in extreme conditions ?  thermoregulation Hiroshi Hasegawa– MF Piacentini – Bart Roelands – Sophie Sarre – Maaike Goekint - Phil Watson, …

  22. Central Fatigue in the heat • Which neurotransmitters are involved ? • Can performance in the heat be manipulated ?  Studies in the heat with the TT protocol  Animal studies : Brain measurements

  23. Materials & MethodsWatson,et al J Physiol 2005 • well trained cyclists • age (yrs) = 23 + 1.7 • weight (kg) = 73.5 + 8.5 • height (cm) = 182 + 5.8 • VO2max= 73.5 + 6.4 ml/kg/min 60 min à 55% Wattmax • 30 min Time trial à 75% Wattmax

  24. TT performance Watson, Meeusen et al J Physiol 2005 3.4’ 39.8 36.4 30.6 30.6

  25. Percent change in TT performance Watson, Meeusen et al J Physiol 2005 Clear improvement of 9% 30°C 18°C

  26. 17.3 16.9 * * 17.1 16.7 * ** ** * RPE Core Temperature

  27. DOPAMINERGIC MANIPULATION Ritalin – methylphenidate(Humans) 7.3min * Roelands, et al MSSE 40(5); 2008

  28. Rilatin – methylphenidateHumans Roelands, Meeusen et al 2008

  29. 18°C: NS 30°C: NS Citalopram SSRI Roelands et al submitted Reboxetine NARI Roelands et al JAP 2008 18°C: p=0,018 30°C: p=0,007 *= p<0,05 * * Roelands et al JAP 2008

  30. Time Trial in 30°C  % difference compared to placebo

  31. What did we learn from this ?   Dopaminergic pathways are involved in postponing fatigue. Noradrenergic & Serotonergic manipulations will influence performance negatively ??? NT interactions (inhibiting and stimulating pathways – receptors, …) In the BUP & MPH manipulations, subjects attained core temperatures equal to, or greater than,40°C. This difference occurredwithoutany apparent change in the subjects’perceived exertionorthermal sensation.  Safety Brake ??

  32. The Dopaminergic system could ‘stimulate’ the subjects. They were capable of pushing into a ‘danger zone’ close to critical core temperature without any negative feedback from the central nervous system  Disinhibiting ‘Central control mechanisms’

  33. Which neurotransmitters are involved ? Animal studies Serotonin – Dopamine – Noradrenaline, …

  34. AMPH + Exc  DA release in striatum

  35. Modifications of thermoregulatory functions Microdialysis in hypothalamus (PO/AH) Exercise TTX injection  block neurotransmission Temp. Registration BrainT, Core T,TailT Hasegawa, Meeusen et al JAP 2005

  36. MODIFICATION OF THERMOREGULATORY FUNCTION BY TTX INTO THE PO/AH OF EXERCISING RATS Hasegawa, Meeusen et al JAP 2005 Tail skin temperature (Heat loss) Body core temperature 1. TCore ↑ in the first 20 min Ttail = due to activation of heat loss system. 2. TTX (5µM) → TCore ↑ ↑ and Ttail ↓  Both impairment of heat loss and enhancement of heat production mechanisms during exercise. 3. PO/AH is a crucial brain region involved in thermoregulation, especially heat loss during exercise 4. Specific neurotransmitter ??

  37. Noradrenaline/Dopamine BUPROPION (NA/DA reuptake inhibitor) • increased Ture in Humans Which of both NT is important ??

  38. Acute dopamine/ noradrenaline reuptake inhibition in rats Microdialysis probe inserted in the PO/AH Injection of 17 mg/kg of BUP Body core temperature (Tcore) Brain (Tbrain) and Tail skin temperature (Ttail)  an index of heat loss response Hasegawa, Meeusen et al JAP 2005

  39. Acute dopamine/ noradrenaline reuptake inhibition affects brain and core temperature in rats Brain T NA Core T DA 5-HT Tail T Hasegawa, Meeusen et al 2005

  40. Exercise to exhaustion  cold & Heat + BUP (rat study) Male Wistar rats (n=9-11) Microdialysis probe inserted in the PO/AH Exercise Injection of 17 mg/kg of BUP Body core temperature (Tcore) Brain (Tbrain) and Tail skin temperature (Ttail)  an index of heat loss response (Hasegawa, Meeusen et al J Physiol 2008)

  41. Exc + BUP (rats)Temperature (Hasegawa, Meeusen et al J Physiol 2008)

  42. Exc + BUP (rats)Neurotransmitters NA Piacentini, Meeusen et al JAP 2003 5-HT DA (Hasegawa, Meeusen et al J Physiol 2008)

  43. What did we learn ? • Central fatigue has a brain component • Serotonin and other NT will increase during exc, but is this an explanation for fatigue ? • Neurotransmitters are involved, … • Each transmitter system has several specific features • Several brain area’s, several receptors • …

  44. What happens when things go wrong ? Motivational Controls(Reward, Wanting) Hypothalamus, Accumbens, VTA Motor Controls Striatum, Brainstem, Cerebellum, Spinal cord

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