1 Central Mechanisms of Fatigue What do we learn from exercise studies ?R. Meeusen PhD Vrije Universiteit Brussel Human Physiology & Sports Medicine
2 Fatigue & the Brain Exercise & Brain NeurotransmissionNeurotransmitters & Central Fatigue Brain neurotransmitter manipulations Thermoregulation Mechanisms
3 The Central Fatigue HypothesisDuring 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 performanceInadequate 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) ß ß 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 systemsSeveral 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 releaseCombination L-TRP + Exc 5-HT No Sign of early fatigue Meeusen et al Brain Research(1996)
10 involvement of Dopamine Davis, Bailey and co-workersIntracranial self stimulation Ventral Tegmental Area Burgess et al (1991) *
11 “Central Fatigue” and neurotransmittersSeveral possible candidates Neurotransmitters are involved, but …. There might be other possible influencing factors
12 Manipulation of Brain Neurotransmitter systems
13 Reuptake inhibition & PerformanceRef Drug Performance Wilson & Maughan ’92 Paroxetine Struder et al ’98 Strachan et al ‘04 Paroxetine (30°C) = Meeusen et al ’01 Fluoxetine Pannier et al ’95 Pizotifen Meeusen et al ’97 L-DOPA Ritanserin Piacentini et al ’02 Venlafaxine Reboxetine Piacentini et al ’04 Bupropion Watson et al ’05 Bupropion (30°C) 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 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 increasesEffort ‘feels’ harder Perception brain B. Nielsen & L. Nybo
21 Which Neurotransmitters control fatigue mechanisms in extreme conditions ? thermoregulationHiroshi Hasegawa– MF Piacentini – Bart Roelands – Sophie Sarre – Maaike Goekint - Phil Watson, …
22 Central Fatigue in the heatWhich neurotransmitters are involved ? Can performance in the heat be manipulated ? Studies in the heat with the TT protocol Animal studies : Brain measurements
23 Materials & Methods Watson,et al J Physiol 2005well trained cyclists age (yrs) = weight (kg) = height (cm) = VO2max = 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 performanceWatson, Meeusen et al J Physiol 2005 Clear improvement of 9% 18°C 30°C
26 17.3 16.9 * * 17.1 16.7 * ** ** * Core Temperature RPE
27 DOPAMINERGIC MANIPULATION Ritalin – methylphenidate (Humans)* Roelands, et al MSSE 40(5); 2008
28 Rilatin – methylphenidate HumansRoelands, Meeusen et al 2008
29 Roelands et al submittedCitalopram SSRI Roelands et al submitted 18°C: NS 30°C: NS Reboxetine NARI Roelands et al JAP 2008 *= p<0,05 18°C: p=0,018 30°C: p=0,007 * * Roelands et al JAP 2008
30 % difference compared to placeboTime Trial in 30°C % difference compared to placebo
31 What did we learn from this ? 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 occurred without any apparent change in the subjects’ perceived exertion or thermal sensation. Safety Brake ??
32 The Dopaminergic system could ‘stimulate’ the subjectsThe 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 studiesSerotonin – Dopamine – Noradrenaline, …
34 AMPH + Exc DA release in striatum
35 Modifications of thermoregulatory functionsMicrodialysis in hypothalamus (PO/AH) Exercise TTX injection block neurotransmission Temp. Registration BrainT, Core T,TailT Hasegawa, Meeusen et al JAP 2005
36 Hasegawa, Meeusen et al JAP 2005MODIFICATION OF THERMOREGULATORY FUNCTION BY TTX INTO THE PO/AH OF EXERCISING RATS Hasegawa, Meeusen et al JAP 2005 Body core temperature Tail skin temperature (Heat loss) 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/DopamineBUPROPION (NA/DA reuptake inhibitor) increased Ture in Humans Which of both NT is important ??
38 Acute dopamine/ noradrenaline reuptake inhibition in ratsMicrodialysis 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 ratsBrain 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) NeurotransmittersNA 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 componentSerotonin 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