Chaire Francqui

Central Fatigue it’s all in the brain

« Central Fatigue » -

05/03/2009: 18-20hr

Exists, but is linked to more than one neurotransmitter system Probably other ‘stressors’ are necessary to disturbe this solid homeostatic mechanism

« Thermoregulation – how hot is the Brain ? » -

12/03/2009: 16-18hr

The dopaminergic system has an important role in the ‘drive’ to continue during prolonged exercise in the heat

« Neurogenesis and Exercise »

17/03/2009: 14-16hr

- Exercise is one of the most important ‘primers’for neurogenesis

Prof Dr Romain MEEUSEN VRIJE UNIVERSITEIT BRUSSEL HUMAN PHYSIOLOGY - BLITS

« The Overtraining Syndrome : facts and fiction » -

24/03/2009: 10-12hr

The hormonal disturbance due to NFO or OTS can be detected using a ‘double exercise protocol’

« Cryotherapy »

26/03/2009: 14-16hr

- Recovery From exercise : should we cool the body ?

Fatigue

Fatigue

A failure to maintain the required or expected force or power output

Is there a link with the Brain ?

Peripheral Fatigue

Central Fatigue

Muscular contraction

Central nervous system

Animal & Human studies using ‘central manipulation’

Peripheral Fatigue
Substrate availability
Accumulation metabolites
Ca2+ distribution (release and

uptake)
Neuromuscular function impairment
...

Exogenous carbohydrate intake is limited At exercise intensities below 50% to 60% of VO2max exogenous CHO oxidation will increase With increasing total CHO oxidation rates, usually above approximately 50% to 60% of VO2max, oxidation rates will not increase further.

1

Carbohydrate ingestion Increases performance Also during long duration training Training period

Central mechanisms

Central Fatigue Fatigue associated with specific alterations in CNS functioning other than muscular dysfunction

What happens in the Brain during exercise ?
Neurotransmitters


Mental factors can affect performance
Perception of effort


Exercise & NT


Inadequate CNS drive to the working muscles


Extracellular space


Motivation, mood, pain tolerance


Exercise & Fatigue


…

Noradrenergic System
Locus coeruleus :

Attention, arousal, sleep-wake cycles, learning & memory, anxiety, pain, mood, depression

Dopaminergic system
Substantia nigra :

initiation voluntary movement, Parkinson’s disease
Ventral Tegmental

area : reward system, addiction, psychiatric disorders

2

Serotonergic System

Exercise and Brain NT concentrations Meeusen & De Meirleir Sports Med 1995

Acute Exercise

Training

NA


 Striatum, Cortex,



DA





~ ()

[5-HT] & [5-HIAA]


Raphe nuclei :

Caudal  spinal cord ! Pain Rostral : arousal, sleepwake, attention, mood, addiction, depression, …

5-HT

Region specific

Exercise and Brain Neurotransmitters First Neurotransmitter studies Whole brain concentrations  Different brain regions  Acute Exercise  Chronic exercise  Tissue preparations

What happens in the specific brain regions during exercise? Extracellular space

Microdialysis

Features of Microdialysis

Microdialysis is a sampling technique for determination of substances from the extracellular space of essentially any tissue of the body A small hollow needle is introduced in a specific brain area to collect neurotransmitters

      

extracellular fluid every organ intact tissue living, awake,freely moving animals sample continuously recovering and/or introducing substances minimal damage

Meeusen et al Sports Med 2001

3

Monoamines : 20 min of moderate exercise - Striatum

Guide implantation DA

Recovery from surgery

NA

5-HT

% increase 250

Probe implantation

*

200

Experiment

150

*

*

*

* *

**

*

100 50 0 Exc

Baseline Neurotransmitter levels in Rat Striatum 6wks of Training

Control

Trained

DA (fmol/20min)

178.4 ± 32.6

57.1 ± 13.1*

NA (fmol/20min)

27.7 ± 6.1

8.3 ± 2.6*

GLU

0.86 ± 0.18

0.28 ± 0.03*

(µ mol/20min) (µ mol/20min)

0.018 ± 0.004 0.019 ± 0.006

60

80

Percent Increase

% increase

Trained **

**

**

DA (fmol/20min)

Control **

**

**

**

**

26-20

12-60

150 100 50 0 -120 -100 -80 -60 -40 -20 Exc Exc Exc 80 100 120 140 160 180

*

* *

Exc

80

100

120

140

160

180

Time (min)

Time (min)

Meeusen et al Acta Physiol Scand (1997)

Exc influences release of neurotransmitters in different brain regions Speed & duration Training : « adaptation »  cfr. peripheral mechanisms

26-60

*

Exc

Exercise & Brain NT

% increase 200 *

Control

200

Exc

12-20

Trained

300 250

**

100

0

Speed - Duration

Absolute Values

350

200

50

Meeusen et al Acta Physiol Scand (1997)

100 120 140 160 180 Time (min)

DA release at rest & during 60 min exercise

150

GABA

40

*

150

100

50 20

40

60

80

100

120

140

160

180

Time (min)

4

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. Eric Newsholme et al (1987)

The ‘Central Fatigue Hypothesis’ Is based on the increase in brain [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.

Tryptophan (TRP)

TRP

One of the 8 essential amino acids found in the human diet.

5-HT

Essential amino acids must be gotten from food or supplements;

5-HIAA

REST

TRP Serotonin (5-HT)

BRAIN

Trp

Tryptophan (TRP)

FFA FFA

Trp

alb

BCAA

Trp

Trp

⇓

BCAA

BLOOD BRAIN

An amino acid becomes an important signal transducer in 5-Hydroxytryptophan (5-HTP) the human brain !!

⇓

BCAA

alb

FFA alb

5-Hydroxytryptamine (5-HT)

Trp

Trp FFA

alb Trp

BLOOD

BCAA

BARRIER

BCAA

Can this small molecule be reponsible for fatigue ??

5-HT

5-HT

5-HT

5

Long duration exercise

Serotonin and its precursor : long duration exercise

FFA

BRAIN

Trp

FFA

BCAA

alb Trp BCAA

FFA

Trp

alb

BCAA

Trp

Trp

5-HT

Trp

alb Trp

5-HT

Trp BCAA

BARRIER

FFA

TRP in periphery bound to albumin FFA more affinity to albumin Long duration exc  more free TRP BCAA & TRP use the same carrier to cross the BBB TRP- hydroxylase not saturated  no rate limiting step !

Trp

BCAA

Trp

BLOOD BRAIN

FFA

5-HT 5-HT 5-HT

BLOOD

5-HT

What about the “Central Fatigue Hypothesis” ? 5-HT

Central Fatigue ??

Central Fatigue

Several Animal & Human experiments have been performed, …


Stockholm marathon
N = 22
2hr45 4hr42

BUT DO WE REALLY KNOW WHAT HAPPENS IN THE BRAIN ?

Blomstrand (1988) - Newsholme et al (1989)



5-HT Depression sleep/wake pain fatigue ...

« We propose a hypothesis to account for central fatigue »

Exercise, 5-HT and Hippocampus

Free TRP conc. before and after a marathon After

Before

6

Exercise and 5-HT

Material & Methods
food-deprived rats


food restriction


L-TRP (50mg/kg) or saline


precursor availability


exercise (60 min 12m/min)
combination


precursor-induced changes in synthesis  release ?


microdialysis in hippocampus

Group 1: L-TRP & Exc Group 2: Saline & Exc Group 3: Exercise Group 4: L-TRP Group 5: Saline

Results Baseline values (n = 30)

Hippocampal 5-HT release

5-HT % increase 200

Combination L-TRP + Exc Sign ↑ %increase No sign early 250 fatigue

Start exercise * *

150

*

*

100

5-HT:

7.0 ±1.2 fmol/20µl

50 0

5-HIAA : 5.5 ± 0.7 pmol/20µ l

-60 -40 -20 Exc Exc Exc 80

100 120 140 160 180

Injection

150

200 injection

*#

*#

*#

*#

*# *#

*# *

*#

*#

*

*

*# *#

*#

*#

*#

*

L-TRP Saline

100 #

50

100 50

0 0

Time (min) -60

-40

-20

20

40

60

80

100


Newsholme et al
Animal & human studies : [5-HT] in brain ↑ ???
Drug induced alterations of [5-HT]
Nutritional manipulations
Other neurotransmitter manipulation

-60 -40 -20 20 40 60 80 100 120 140 160 180 200 220 240 Time (min)

120 140 160

BCAA – 5-HT – central fatigue


…

5-HT Exercise

% increase

150

Sign.≠ Saline-Exc / L-TRPExc

Meeusen et al Brain Research (1996)

200

Time (min)

5-HT

sign.↑ [5-HT] & [5-HIAA]

n=6 n=6 n=6 n=6 n=6

Nutritional Manipulations  Brain ??
Amino Acids  BCAA  TRP  TYR


CHO

7

Long duration exercise – BCAA supplementation FFA

BCAA

alb

BCAA BCAA

FFA FFA

Trp

BCAA

alb

Trp

BCAA

BCAA

Trp

Verger et al (1994) rats

No positive results in well-controlled studies

5-HT

Trp

Trp BCAA

BARRIER

Trp

alb

5-HT

Trp

BCAA

Trp

Van Hall et al (1995) humans

BCAA

Trp

FFA

BLOOD BRAIN

FFA

BCAA administration

BRAIN

Trp

TTE (min)

TTE (min) 250 200

5-HT

150

150 100

100 50

BLOOD

Intermittent Exc & BCAA

**

200

50

0 control

TRP

low BCAA

High BCAA

0 BCAA

Water

Glucose

TYROSINE (TYR)  Dopamine
Several authors failed to show positive effects on exc


CHO and CHO + BCAA drinks improved

performance
 co-ingestion of CHO ! (?)

performance (e.g. Struder et al 1998; Chenevre et al 2002, Sutton et al 2005)


TYR ingestion might improve stress-induced

cognitive and behavioral deficits (working memory, attentional tasks etc.)
 Soccer ?

Other possible factors responsible for ‘Central Fatigue’
Other neurotransmitters (GABA, GLU, …)

Pharmacological studies Agonist : will ‘strengthen’ the effect of the drug


NH3
BBB permeability

Antagonist : will decrease or block the effect


Metabolic, thermodynamic, circulatory and humoral

responses that can lead to a disturbance of cerebral homeostasis

Reuptake Blocker : sits in the reuptake transporter and therefore creates more and longer NT interaction in the synapse

8

5-HT agonism, antagonism (rats) Bailey et al (1992) mCPP (5-HT1C ago)

Central Fatigue & Serotonin

Bailey et al (1993) QD (5-HTago) LY53857 (5-HT antago)


Brain neurotransmitters are influenced by exercise
Several possible transmitter systems might also be

involved
In animal studies it was possible to manipulate

TTE (min)

250

performance, but, …

TTE (min)

*

180

200

150

150

120

100

90

50

60

0

30

0 mg/kg

1 mg/kg

1,375 mg/kg

1,75 mg/kg

*

Untill now no straightforward evidence that 5-HT is the only player in the field

0

2,5 mg/kg


In Humans no effect was found,

vehicle

QD (ago)

LY53857 (antago)

What about Dopamine ?

Dose dependent effects AMPH injection Run to exhaustion


Intracranial self stimulation

Burgess et al (1991) VTA TTE (min)

*

80

Dopaminergic (DA) neurotransmission

60 40

AMPH inj. DA release in Striatum

20 0 Exc-Sham

Exc-Stim

Gerald et al (1978)

Microdialysis: Striatal Dopamine

Manipulation of Brain Neurotransmitter systems

DA

250 Exercise

AMPH

200 *$

150

*$

*$

*$ *

*

*

*$

*$ *

*

*

* *

*

*

*

* *

*

$ $

100



$

50

Exc AMPH+exc

Pharmacological manipulations of brain neurotransmitt er concentrations

0 20

40

60

80 100 120 140 160 180 200 220 240

9

Materials & Methods

Exercise Performance Humans Nutritional manipulations DA agonism & 5-HT antagonism DA manipulation NA manipulation 5-HT reuptake inhibition Combination : -


Young healthy subjects (n= 5-9)
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

5-HT/NA reuptake inhibition NA/DA reuptake inhibition

90 min Time trial à 65% Wattmax

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

Performance (90 min Time Trial) 120

PRL (mIU/L)

Time (min)

*

placebo

fluoxetine- 5-HT

venlafaxine 5-HT/NA

reboxetine NA

bupropion NA/DA

100 1400

80

1200

60 88,9

93,1

88,8

98,2

1000

89,4 PRL mIU/L

40 20 0

800

600

400

Placebo

fluoxetine 5HT

venlafaxine 5-HT/NA

reboxetine NA

bupropion NA/DA

200

0

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

Ref Wilson & Maughan ’92

Drug

Performance

Paroxetine



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

=

Bupropion (30°C)



Struder et al ’98

Watson et al ’05

rest

30

60

90

rec

Re-uptake inhibition in humans Reuptake inhibition & Performance


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

10

Venlafaxine Rats

Catheterisation

(5-HT/NA) Piacentini, Meeusen et al Life Sci 2003

600

* *

5-HT % increase

Clear serotonergic and 150 noradrenergic influence

500

100

200

200

*

*

*

*

*

*

400

Start exercise

*

300

100

50

0

0 -60 -40 -20 Exc Exc Exc 80 100 120 140 160 180

baseline

20

40

60 80 time (min)

Time (min)

600

600

500

500

400

400

300

300

*

*

100

120

140

*

200

200

100

100

0 0

baseline

baseline 20

40

60 80 time (min)

PRL

60

80

100

120

140

time (min)

Piacentini, Meeusen et al JAP 2003 5-HT Sign increase in Cats. 200 No effect on Hippocampal 150 5-HT release 100

DA

100 min

0 -60 -40 -20 Exc Exc Exc 80 100 120 140 160 180

180

60 min Time

160

20 min

140

baseline

*

120

baseline

50

0

*

*

#

#

#

140

50

*

*

120

100

0,5 0,4 0,3 0,2 0,1 0

80

*

200

*

100

*

60

Start exercise

250

40

300

20

% increase

150

time (min)

Time (min)

ACTH 5-HT

0

20 min

60 min

baseline

100 min

20 min

60 min

100 min

180

#

160

# *

100

#

80

60

# *

40

20

nM

*

time (min)

Time

Time

0,5 0,4 0,3 0,2 0,1 0

baseline

50

0

180

100

50

160

100

140

150

120

150

#

80

200

60

250

200

40

250

NA *

0,5 0,4 0,3 0,2 0,1 0 20

300

baseline

350

300

nM

*

350

100

GH

baseline

40

*

350

Auto-inhibition GH cfr Humans ?

20

140

nM

Hormonal influence

120

Bupropion Rats (DA/NA)

Venlafaxine Rats Piacentini, Meeusen et al Life Sci 2003

100

time (min)

Conclusions

Bupropion Rats Piacentini, Meeusen et al JAP 2003

Hormonal values

A

PRL

35 30 25 20

*

15

dopaminergic influence

¤ *

10 5 0 baseline

20 min

60 min

changed levels of substrates, amino acids,  neuromodulators,  or pituitary hormones. 

100 min



B

ACTH

Although the theoretical rationale for the “serotoninfatigue hypothesis” is clear it is mainly supported by results from animal studies or circumstantial evidence

GH

60

3

50

2.5

40

2

30

1.5

20

1

10

0.5

E

0

0 baseline

20 min

60 min

100 min

baseline

20 min

60 min

100 min

11

Conclusions it is likely that the interaction of cerebral metabolic, thermodynamic and hormonal responses during prolonged exercise will determine the delicate communication between the brain and the periphery. Fatigue is therefore likely to be an integrated phenomenon with complex interaction among central and peripheral factors

Central Fatigue: It’s All in the Brain ?

Central Fatigue
Exists
But it is not as simple as the first hypothesis put

forward
The administration of BCAA has no real influence on

endurance performance
Glucose ingestion has indicating the importance of

the peripheral factors

Fatigue ?

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 Thermal stress is a good candidate to explore this

12