Central Mechanisms of FatigueWhat do we learn from exercise studies ?

R. Meeusen PhD

Vrije Universiteit Brussel

Human Physiology & Sports Medicine

Fatigue & the BrainExercise & Brain Neurotransmission Neurotransmitters & Central Fatigue Brain neurotransmitter manipulations

Thermoregulation

Mechanisms

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

Central mechanisms

Mental factors can affect performance Inadequate CNS drive to the working musclesMotivation, mood, pain toleranceNeuromuscular aspectsNeurotransmitters (NT)NeuromodulatorsThermoregulation…

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.

TRP Serotonin (5-HT)

Tryptophan (TRP) 

5-Hydroxytryptophan (5-HTP) 

 

5-Hydroxytryptamine (5-HT)

An amino acid becomes an important signal transducer in the human brain !!

Can this small molecule be reponsible for fatigue ??

Manipulation of Brain Neurotransmitter systems

Several Animal & Human experiments have been performed, …

But do we really know what happens in the brain ?

Experiment

Microdialysis in hippocampus

Food-deprived rats

L-TRP (50mg/kg) or saline

Exercise (60 min 12m/min)

Hippocampal 5-HT release

Combination L-TRP + Exc

5-HT No Sign of

early fatigue

5-HT

0

50

100

150

200

250

-60 -40 -20 20 40 60 80 100 120 140 160 180 200 220 240

L-TRP

Saline

Injection

Exercise

Time (min)

% increase

*#*#

*#*# *# *#

*# *#*# *#

*#

** *

*

Meeusen et al Brain Research(1996)

involvement of DopamineDavis, Bailey and co-workers

Intracranial self stimulationVentral Tegmental Area Burgess et al (1991)

TTE (min)

0

20

40

60

80

Exc-Sham Exc-Stim

*

“Central Fatigue” and neurotransmitters

Several possible candidates

Neurotransmitters are involved, but ….

There might be other possible influencing factors

Manipulation of Brain Neurotransmitter systems

Reuptake inhibition

& Performance

Ref Drug Performance

Wilson & Maughan ’92 Paroxetine

Struder et al ’98 Paroxetine

Strachan et al ‘04 Paroxetine (30°C)

=

Meeusen et al ’01 Fluoxetine =

Pannier et al ’95 Pizotifen =

Meeusen et al ’97 L-DOPA =

Meeusen et al ’97 Ritanserin =

Piacentini et al ’02 Venlafaxine =

Piacentini et al ’02 Reboxetine =

Piacentini et al ’04 Bupropion =

Watson et al ’05 Bupropion (30°C)

Performance (90 min Time Trial)

88,9 88,8 93,1 89,498,3

0

20

40

60

80

100

120

Placebo fluoxetine 5-HT venlafaxine 5-HT/NA

reboxetine NA bupropionNA/DA

Per

form

ance

(m

in)

Meeusen et al 2001; Piacentini et al 2002, Piacentini et al 2003, 2004

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

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 involvedBut although brain disturbances occur,

fatigue mechanisms seem to need other stressors

How hot is the Brain?

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°C20°C

40°C

How could high core temperature cause fatigue?

- Peripheral factors - Change brain function?

- Change ”motivation”?

Gonzales_alonzo et al 1998

Hyperthermia

As core temperature increases RPE increases

Effort ‘feels’ harder

Perception brain

*

*R

ati

ng

of

Pe

rce

ive

d E

xe

rtio

n

8

10

12

14

16

18

20ControlHyperthermia

Exercise time (min)

0 10 20 30 40 50 60 70

Es

op

ha

ge

al t

em

pe

ratu

re (

oC

)

36.5

37.0

37.5

38.0

38.5

39.0

39.5

40.0

B. Nielsen & L. Nybo

Which Neurotransmitters control fatigue mechanisms in extreme

conditions ? thermoregulation

Hiroshi Hasegawa– MF Piacentini – Bart Roelands – Sophie Sarre – Maaike Goekint - Phil Watson, …

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

Materials & Methods Watson,et al J Physiol 2005

well trained cyclistsage (yrs) = 23 + 1.7weight (kg) = 73.5 + 8.5height (cm) = 182 + 5.8VO2max = 73.5 + 6.4 ml/kg/min

60 min à 55% Wattmax

30 min Time trial à 75% Wattmax

TT performance

20

25

30

35

40

45

pla18 bup18 pla30 bup30

Trial

TT

tim

e (

min

ute

s)

30.6 30.6

39.836.4

3.4’

Watson, Meeusen et al J Physiol 2005

Percent change in TT performance

-15

-10

-5

0

5

10

15

20

25

30

pla18 bup18

% C

ha

ng

e in

Ex

erc

ise

Ca

pa

cit

y

Mean

-15

-10

-5

0

5

10

15

20

25

30

pla30 bup30

% C

han

ge

in E

xerc

ise

Cap

acit

y

Clear improvement

of 9%

18°C 30°C

Watson, Meeusen et al J Physiol 2005

36,5

37,0

37,5

38,0

38,5

39,0

39,5

40,0

40,5pla18

bup18

36,5

37,0

37,5

38,0

38,5

39,0

39,5

40,0

40,5

-10

0 10 20 30 40 50 60 TT

10

TT

20

End

rec10

Time (minutes)

pla30

bup30*

***

***

*

Core Temperature

10

12

14

16

18

20

15 30 45 60 TT10 TT20 End

Time (minutes)

RP

E

pla30

bup30

10

12

14

16

18

20

RP

E

pla18

bup18

RPE

17.316.9

17.116.7

DOPAMINERGIC MANIPULATION Ritalin – methylphenidate

(Humans)

Time Trial Time

15

20

25

30

35

40

45

50

55

Fam Pla18 Rit18 Pla30 Rit30

Trial

TT

Tim

e (m

in)

7.3min

Roelands, et al MSSE 40(5); 2008

*

Rilatin – methylphenidateHumans

Core Temperature

36,5

37

37,5

38

38,5

39

39,5

40

40,5

-10

0 10 20 30 40 50 60 TT

10

TT

20

TT

30

End

rec10

Time (min)

Tco

re (°

C)

Pla18 Rit18

§§

Core Temperature

36,5

37

37,5

38

38,5

39

39,5

40

40,5

41

-10

0 10 20 30 40 50 60 TT

10

TT

20

TT

30

End

rec10

Time (min)

Tco

re (

°C)

Pla30 Rit30

* * *

* *

* **

* * *

* **

*

RPE

8

10

12

14

16

18

20

15 30 45 60 TT10 TT20 TT30 TT40 End

Time (min)

RP

E

Pla18 Rit18

RPE

8

10

12

14

16

18

20

15 30 45 60 TT10 TT20 TT30 TT40 End

Time (min)

RP

E

Pla30 Rit30

*

Roelands, Meeusen et al 2008

Citalopram

SSRI

Roelands et al submitted

32,8 32,0 37,7 40,0

20

30

40

50

pla18 cital18 pla30 cital30

Trial

TT

Tim

e (m

in)

25

30

35

40

45

50

55

60

65

70

Fam Pla18 Rebox18 Pla30 Rebox30Trial

TT

Tim

e (m

in)

18°C: p=0,018

30°C: p=0,007 **

18°C: NS

30°C: NS

Reboxetine

NARI

Roelands et al JAP 2008

-15 -9 6 20-25

-15

-5

5

15

25

35

MPH (DA) BUP (NA/DA) CITAL (5-HT) REBOX (NA)

Time Trial in 30°C % difference compared to placebo

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 ??

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’

Which neurotransmitters are involved ?

Animal studies

Serotonin – Dopamine – Noradrenaline, …

0

50

100

150

200

250

20 40 60 80 100 120 140 160 180 200 220 240

Exc

AMPH+exc

ExerciseAMPH

**

**

***

***

*

*$*$

*$*$

*$ *$

* *

*$

$ $

DA

AMPH + Exc DA release in striatum

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

MODIFICATION OF THERMOREGULATORY FUNCTION BY TTX INTO THE PO/AH OF EXERCISING RATS

Hasegawa, Meeusen et al JAP 2005Body core temperature

36.5

37.0

37.5

38.0

38.5

39.0

39.5

40.0

Cor

e te

mer

atur

e (℃

）

-180 -120 -60 0 60 120 180 240 300

TIME (min)

TTX (n=12)

Control (n=12) *

Exercise(10m/min)

TTX

Tail skin temperature(Heat loss)

22

24

26

28

30

32

34

Tta

il s

kin

tem

pera

ture

(℃）

-60 -30 0 30 60 90 120 150 180

TIME (min)

TTX (n=12)

Control (n=12)

Exercise(10m/min)

TTX

*

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 ??

Noradrenaline/Dopamine

BUPROPION

(NA/DA reuptake inhibitor)increased Ture in Humans

Which of both NT is important ??

20

25

30

35

40

45

pla18 bup18 pla30 bup30

Trial

TT

tim

e (

min

ute

s)

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

Acute dopamine/ noradrenaline reuptake inhibition affects brain and core temperature in rats

0

100

200

300

400

500

600

Cha

nges

in

NA

(%

)

0

100

200

300

400

500

600

Cha

nges

in

5-H

T (

%)

-40 -20 0 20 40 60 80 100 120

Time (minutes)

0

100

200

300

400

500

600

Cha

nges

in

DA

(%

)

*

*

*

*

**

#

#

#

## #

#

##

##

^

A

B

C

-0.4

-0.2

0

0.2

0.4

0.6

0.8

1

Cha

nges

in

brai

n te

mpe

ratu

re (

C

)

-0.6

-0.4

-0.2

0

0.2

0.4

0.6

0.8

Cha

nges

in

core

tem

pera

ture

(

C)

-4

-3

-2

-1

0

1

2

Cha

nges

in

tail

tem

pera

ture

(

C)

-40 -20 0 20 40 60 80 100 120

A * ** *

*

* *

**

* *

**

##

#

# #

##

B

C

Time (minutes)

Brain T

Core T

Tail T

NA

DA

5-HT

Hasegawa, Meeusen et al 2005

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)

Exc + BUP (rats)Temperature

36

37

38

39

40

41

42

43

-120

-100 -80

-60

-40

-20 0 20 40 60 80 100

120

140

160

180

EN

D

200

220

240

260

280

300

Time (min)

Bra

in te

mpe

ratu

re (

°C)

Cool Warm BUP+Warm

18

20

22

24

26

28

30

32

34

36

38

0 20 40 60 80 100 120 140 160 180 END

Time (min)

Tai

l sk

in t

emper

ature

(°C

)

Cool Warm BUP+Warm

(Hasegawa, Meeusen et al J Physiol 2008)

36

37

38

39

40

41

42

43

-120

-100 -80

-60

-40

-20 0 20 40 60 80 100

120

140

160

180

EN

D

200

220

240

260

280

300

Time (min)

Abd

omin

al te

mpe

ratu

re (

°C)

Cool Warm BUP+Warm

20

25

30

35

40

45

pla18 bup18 pla30 bup30

Trial

TT

tim

e (

min

ute

s)

Exc + BUP (rats)Neurotransmitters

0

100

200

300

400

500

600

Res

t3

Res

t4

Res

t5

Res

t6

EX

1

EX

2

EX

3

EX

4

EX

5

EX

6

EX

7

EX

8

RE

C1

RE

C2

RE

C3

RE

C4

RE

C5

RE

C6

Time (minutes)

NA

(%

of

base

line)

Cool Warm BUP+Warm

0

100

200

300

400

500

600

700

-60

-40

-20 0 20 40 60 80 100

120

140

160

180

200

220

240

280

300

Time (minutes)

DA

(%

of

base

line)

Cool Warm BUP+Warm

0

20

40

60

80

100

120

140

160

180

200

-60

-40

-20 0 20 40 60 80 100

120

140

160

180

200

220

240

280

300

Time (minutes)

5-H

T (

% o

f ba

selin

e)

Cool Warm BUP+Warm

(Hasegawa, Meeusen et al J Physiol 2008)

0

100

200

300

400

500

% in

crea

se

NA DA

Piacentini, Meeusen et al JAP 2003

NA

DA5-HT

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

• …

What happens when things go wrong ?

Cognitive ControlHippocampus, Cortex

Executive ControlsPrefrontal & cingular cortex

Emotional controlsAmygdala, Prefrontal cortex

Motivational Controls (Reward, Wanting)Hypothalamus, Accumbens, VTA

Motor ControlsStriatum, Brainstem, Cerebellum, Spinal cord