It’s not only our muscles that get tired during intense exercise; our brains also experience fatigue. Fatigue is also a common and often debilitating symptom in many diseases. Join researcher Guillaume Millet for this webinar to hear key insights from his studies on both exercise-related and chronic fatigue. Learn about the factors that contribute to fatigue and how strategies like regular exercise can actually help alleviate it.

1. Our Brains and Fatigue
Guillaume Millet
Professor, Faculty of Kinesiology
October 4, 2016

2. Welcome
 Webinar series by University of Calgary scholars
 Information presented is a summary of the
scholars’ research
 Please submit questions throughout the duration of
the webinar
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3. Welcome
 Professor at the University of Calgary’s Faculty of
Kinesiology
 Head of the Neuromuscular Fatigue Lab within the
faculty’s Human Performance Laboratory
 Research interests are in the areas of exercise
physiology, neuromuscular function and fatigue
Guillaume Millet

4. Physiological, neurophysiological and biomechanical
factors associated with fatigue in both:
 Patients (neuromuscular diseases, cancer)
 Extreme exercise
www.ucalgary.ca/nmfl
Neuromuscular Fatigue
Laboratory

5.  Origin of acute fatigue: central vs peripheral
 Central fatigue in ultramarathon and at altitude
 Limits of current tools to measure fatigue
 Acute fatigue resistance: does it play a role in
subjective chronic cancer-related fatigue?
Outline

6. …leading to an increase of psychological/energy cost
to perform an exercise
and/or to a decrease of maximal strength/power
Changes in (physical, mental) capabilities…
…whether or not the task can be sustained.
Definition of fatigue

7. Intensity
Maximal
strength
Time
100
75
50
25
0
target
Neuromuscular Fatigue Laboratory
Fatigue vs exhaustion

8. Intensity
Maximal
strength
Time
100
75
50
25
0
target
Neuromuscular Fatigue Laboratory
Fatigue vs exhaustion

9. Duration
Intensity
Mode of contraction
Temperature
Muscle typology
Continuous vs
intermittent
Fitness
level
Local vs
global
Sex
Age
Nutrition
Altitude
Task dependency
Etc.
Neuromuscular Fatigue Laboratory

10. Definition of fatigue
Time
Functionalcapacity
Workload Fatigue
Neuromuscular Fatigue Laboratory

11. Etiology of neuromuscular
fatigue: central vs peripheral
Neuromuscular Fatigue Laboratory

12. Central
fatigue
Motor planning
Motor output
Motoneuron pool output
Motor axon conduction
Neuromuscular junction
Peripheral
fatigue
Muscle
Feedback
Interaction central/peripheral

13. Tools to evaluate NM
function
Adapted from Millet et al. Eur J Appl Physiol 2011
Sensory Ia
afferent axone
a-Mn
axoneEMG
Force/Movement
Motor Cortex
Spinal level
Muscle
Transcranial Magnetic Stimulation
Peripheral Nerve
Stimulation
Muscle
Stimulation
Cervicomedullary
Stimulation
Central
Peripheral
Neuromuscular Fatigue Laboratory

14. Different types of central fatigue
Fatigue =  maximal strength
Cognitive
Function
Subjective
Fatigue (RPE)
Intermuscular
Coordination
Decrease of %VA

15. force
stimulus
MVC
Merton J Physiol 1954
superimposed
twitch
resting
twitch
Maximal voluntary activation
(nerve stimulation)
From Janet Taylor, Neuroscience Research Australia

16. force
stimulus
MVC
Merton J Physiol 1954
superimposed
twitch
resting
twitch
Maximal voluntary activation
(nerve stimulation)
From Janet Taylor, Neuroscience Research Australia
resting
twitch

17. Transcranial Magnetic
Stimulation (TMS)

18. Exercise duration and central
fatigue
Duration
Intensity
Mode of contraction
Temperature
Muscle typology
Continuous vs
intermittent
Fitness
level
Local vs
global
Gender
Age
Nutrition
Altitude
Neuromuscular Fatigue Laboratory

19. Central fatigue in
ultra-marathon
165 km
D+/-: 9000m

20. Central fatigue in
ultra-marathon

21. Change in voluntary
activation?
PRE

22. Change in voluntary
activation?
PRE
POST

23. Origin of fatigue
peripheral
fatigue
(muscular)
central
fatigue
(neural)
Not as simple as that…
Neuromuscular Fatigue Laboratory

24. Causes of central fatigue
Adapted from Janet Taylor, Neuroscience Research Australia
3. Afferent
input
1. Corticospinal
drive
(Supraspinal
fatigue)
muscle spindles
excitation
tendon organs
inhibition
recurrent
inhibitiongroup III & IV
fatigue-sensitive
muscle afferents

25. Altitude (hypoxia)
Duration
Intensity
Mode of contraction
Temperature
Muscle typology
Continuous vs
intermittent
Fitness
level
Local vs
global
Gender
Age
Nutrition
Altitude
Neuromuscular Fatigue Laboratory

26. Vergès et al. 2012
Am J Physiol Regul Integr Comp Physiol
Altitude (hypoxia)

27. 4 simulated
altitudes
oxygenation
Cuff
(total ischemia)
Direct effect of hypoxia on
central drive

28. 50
55
60
65
70
Bef
cuff
1
min
2
min
3
min
4
min
5
min
#1 #2 #3 #4 #5 #6 #7 #8 #9 #10 #11 Last
cerebralTOI(%)
30% 21% 14% 9%
Cerebral
oxygenation
Millet et al. J Appl Physiol, 2012
Direct effect of hypoxia on
central drive

29. 0
10
20
30
40
50
60
70
Bef
cuff
1
min
2
min
3
min
4
min
5
min
#1 #2 #3 #4 #5 #6 #7 #8 #9 #10 #11 Last
muscleTOI(%)
30% 21% 14% 9%
Muscle
oxygenation
Millet et al. J Appl Physiol, 2012
Direct effect of hypoxia on
central drive

30. 10
12
14
16
18
20
*
#Repetitions
Millet et al. J Appl Physiol, 2012
Direct effect of hypoxia on
central drive

31. 10
12
14
16
18
20
*
#Repetitions
Millet et al. J Appl Physiol, 2012
Direct effect of hypoxia on
central drive

32. Neuromuscular
function during
exercise
Typical
exercise
ProblemsAdvantages
Single joint, isometric
contraction
• Measurements during exercise
• Mostly upper body and/or single-limb
exercise
• Isometric
• Does not represent exercise performed
in sports/rehabilitation.
Fatigue assessment

33. Fatigue induced by 45 s sustained
MVC of adductor pollicis
Sheean et al. Brain, 1997, 120: 299-315
Voluntaryactivation(%)

34. Move the
subject
from the
bike to
the
testing
chair
Other option

35. Neuromuscular
function during
exercise
Neuromuscular
function before
and after exercise
Typical
exercise
ProblemsAdvantages
Single joint, isometric
contraction
Human locomotion :
walking, cycling
• Measurements during exercise • Ecological situation
• Represents the reality of daily
life/rehabilitation in patients.
• Mostly upper body and/or single-limb
exercise
• Isometric
• Does not represent exercise performed
in sports/rehabilitation.
• Installation time required to test
subjects
• Depending on the type of exercise,
determining factors of fatigue and
exhaustion (exercise cessation) might be
completely misinterpreted.
Fatigue assessment

36. Problem
of
recovery
(delay)
Other option

37. Effect of short recovery on
muscle fatigue
3
8
PRE 20 40 60 80 100 1 2 4 8
% fatiguing exercise Recovery (min)
100
90
80
70
60
50
40
30
Torque(%initialvalue)
High frequency tetanus
High frequency doublet
Single twitch
Froyd et al. J Physiol 2013

38. Testing NMF during and immediately
after whole-body exercise
Neuromuscular
function during
exercise
Neuromuscular
function before
and after exercise
Fatigue assessment

39. Innovative ergometer
VO2
TMS
FNES
CMEP
EMG

40. Innovative
ergometer

41. Chronic fatigue
Chronic Fatigue: even more complicated
e.g. Cancer-Related Fatigue
 Severe, unrelenting feeling of fatigue, that is not
improved by rest or sleep
 CRF affects 70-100% of individuals with cancer
 Last up to months/years post cancer (up to 30% of
survivors)

42. Cancer-related fatigue
Physical activity is important in fatigue
management
Cramp & Daniel, 2008, Cochrane Reviews
VICIOUS CYCLE
OF FATIGUE
Fatigue is the #1 reported side
effect by cancer patients and has
been found to be the most
distressing treatment-related
symptom.
• 94% of oncologists treat pain,
only 5% treat fatigue
-National Cancer Institute, 2007
From Nicole Culos-Reed

44. Acute neuromuscular fatigue and
chronic fatigue in cancer?
Andrews et al. Fatigue in Cancer 2004
Anemia – cachexia –
reduction of specific force
Cancer
and cancer
treatment
Altered
muscle
metabolism
Peripheral
(muscular)
mechanisms
Central
(brain)
mechanisms
 physical
performance
and 
fatigue

45. Definition of fatigue
Time
Functionalcapacity
Workload Fatigue
Neuromuscular Fatigue Laboratory

46. Effect of workload on
fatigue
Time
Workload
Fatigue and recovery light exercise
Heavy exercise
Neuromuscular Fatigue Laboratory
Functionalcapacity

47. Deteriorated fatigue
resistance
Time
Functionalcapacity
Workload
Normal fatigue resistance
Deteriorated fatigue resistance
Neuromuscular Fatigue Laboratory

48. Time
Functionalcapacity
Fatigue
accumulation
Daily workloads Normal fatigue resistance Deteriorated fatigue resistance
Chronic vs acute fatigue
Neuromuscular Fatigue Laboratory

49. Chronic fatigue
Chronic Fatigue: even more complicated
e.g. Cancer-Related Fatigue
 Severe, unrelenting feeling of fatigue, that is not
improved by rest or sleep
 CRF affects 70-100% of individuals with cancer
 Last up to months/years post cancer (up to 30% of
survivors)
Subjective

50. PNS
CNS
Muscle
1. Sensory pathway
from periphery
2. Copy of efferent
signal to sensory
cortex
May contribute to
chronic fatigue
Neuromuscular vs subjective
fatigue?

51. Hypothesized mechanisms
Direct
Physiologic
• Voluntary activation
• Muscle strength
• Muscle endurance
• Cardiopulmonary fitness
• Body composition
• Fatiguability
• Muscle efficiency
Biologic/hematologic
• Inflammatory response
• Muscle damage
• Metabolic function
(insulin resistance)
• Endocrine function
• Immune function
• Anemia (brain and
muscle oxygenation)
Indirect
Psychological
• Anxiety
• Depression
• Distress
• Cognition
Social
• Social
interaction
• Positive
• reinforcement
Behavioral
• Sleep quantity and quality
• Appetite
Adapted from
McNeely et al. 2010
Cancer-related fatigue

52. Hypothesized mechanisms
Direct
Physiologic
• Voluntary activation
• Muscle strength
• Muscle endurance
• Cardiopulmonary fitness
• Body composition
• Fatiguability
• Muscle efficiency
Biologic/hematologic
• Inflammatory response
• Muscle damage
• Metabolic function
(insulin resistance)
• Endocrine function
• Immune function
• Anemia (brain and
muscle oxygenation)
Indirect
Psychological
• Anxiety
• Depression
• Distress
• Cognition
Social
• Social
interaction
• Positive
• reinforcement
Behavioral
• Sleep quantity and quality
• Appetite
Adapted from
McNeely et al. 2010
Cancer-related fatigue

53. Makes no sense if not considering… the Big Picture
Anemia
Pain
Activity
Level
Mal-
nutrition
Sleep
Disorders
Co-
Morbidities
Neuro-
muscular
Function
Cachexia
Inflamm. &
oxidative
stress
Psycho-social
environment
Low acute fatigue resistance cannot fully explain directly chronic
fatigue… but can contribute (provided it is appropriately measured)
Cancer-related fatigue

54. Tailoring training to fatigue
causes
Testing Intervention

55. Tailoring training to fatigue
causes
Testing Intervention

56. Examples
• Social interaction
• Sleep quality and quality
• Inflammatory response
• Muscle damage
• Metabolic function
• Immune function
• Voluntary activation
• Cardiopulmonary fitness
Outdoor endurance
training late afternoon
Strength training high
volume
Electromyostimulation
• Cachexia
Strength training low
volume
Supervised group
training
Low intensity
endurance training
High intensity
endurance training

57. Take home message
Goal: better understand Chronic Fatigue
(e.g. CRF) to better treat it!
Tailor training interventions
Testing tools Training tools
Tested on athletes
 Ultimately enhance the quality of life of patients

58. Acknowledgements

59. gmillet@ucalgary.ca
www.ucalgary.ca/nmfl
Merci
Guillaume Millet

60. Upcoming webinars
 No Pain No Gain? The Sociology of Sports, October
6, 12-1 p.m. MST
 The Race to Prevent Running Injuries, October 11,
12-1 p.m. MST
 Inside the Mind of an Olympian, October 13, 12-1
p.m. MST
 Knocking Out Concussions in Sports, October 20,
10-11 a.m. MST

61. Thank you
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