cognitive fatigue in multiple sclerosis: facts and hypotheses€¦ · medical nosology as a disease...
TRANSCRIPT
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Our greatest weariness comes from work not done – Eric Hoffer
John DeLuca, Ph.D.
Senior Vice President for Research
Kessler Foundation
Professor
Physical Medicine and Rehabilitation
Neurology
Rutgers -New Jersey Medical School
Cognitive Fatigue in
Multiple Sclerosis:
Facts and Hypotheses
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Overview
• History of Fatigue
• What is Fatigue
• Fatigue in General population
• Fatigue in Clinical Populations
• Measurement of Fatigue
• Pathophysiology of Fatigue
• Treatment of Fatigue
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History of Fatigue
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History of Fatigue
• Before 1800’s, fatigue was a non-symptom
– Perhaps known among families
– Not generally reported to physicians
– Not mentioned in medical dictionaries in Europe until
1840’s or 1850’s
• Gained prominence with Industrialization
– Fatigue became a limitation of “man the machine”
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History of Fatigue
• Neurasthenia – George Beard “discovered” fatigue
• Symptoms:
– general malaise
– debility of all function
– poor appetite
– fugitive neuralgic pains
– Hysteria
– Insomnia
– Hypochondriases
– disinclination for consecutive mental labor
– severe and weakening attacks of headaches
(Macmillan, 1976)
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History of Fatigue
• Neurasthenia quickly became accepted in
medical nosology as a disease of its own, NOT a
symptom
• Viewed as a disease of the nervous system
resulting from nervous exhaustion due to
overwork
– “overexertion of the brain”
• By 1900, laboratories for the study of fatigue
were established in most European countries
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History of Fatigue
• But causes of Neurasthenia proved vague. Used synonymously for:
– General nervousness and mild depression
– Fatigue in those not depressed
– Male versions of “Hysteria”
• Difficult to differentiate “exhaustion” due to
– Perceptions
– objective muscle dysfunction
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History of Fatigue
• As a result, the view of Neurasthenia began to
change at the turn into the 20th century
– No longer considered a neurologic ailment
– Became associated with anxiety and depression
• Nonetheless, by 1900, neurasthenia had
become the single most common diagnosis in
the domain of neuropathology and
psychopathology
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History of Fatigue
• With the shift from being physiological to
psychological in origin, the term Neurasthenia
was used less frequently because of the
stigma of psychiatric labels.
• Neurasthenia as a disorder began to be less
frequently noted in neurological textbooks
• It became further subdivided into various
“neuroses”, including obsessive-compulsive
disorders, anxiety neuroses, and hysteria
(Wessely, 1991)
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History of Fatigue
• At this same time, Psychiatry was involved in
its own movements and changes
• Moving away from DISEASE concepts of Kraepelin
• Endorsing SYMPTOMS (European movement)
• Fatigue became a symptom rather than a
disease
• This school of thought narrowed Fatigue to a
synonym for “tiredness”
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History of Fatigue
• Fatigue has been conceptualized as an: – “illness”
– “symptom”
• Plagues our understanding of fatigue to this day
• Can anyone think of another construct which is both an illness and a symptom? – Depression
– Anxiety
– sleep
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History of Fatigue
• Coincidentally, unexplained fatigue was also
observed in illnesses other than Neurasthenia
– Irritable Heart - Crimean and US Civil wars
– Effort syndrome - World War I
– Neurocirculatory asthenia – World War I
– Gulf War Syndrome
– PTSD?
• Initially thought to be cardiac in nature, but soon
doomed to the psychiatric realm like
Neurasthenia
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History of Fatigue
• 20th century also saw several outbreaks of
fatigue illnesses with unknown etiologies
• Given various names including:
– myalgic encephalomyelitis
– epidemic neuromysathenia
– Iceland disease
– atypical poliomyelitis.
• No etiology could be determined
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History of Fatigue
• By the early to mid 1900s, the once great
interest in fatigue syndromes had dwindled
from mainstream medicine and
psychology.
• With the publication of DSM-III in 1980,
fatigue as a disease vanished altogether in
Psychiatry and American Medicine.
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History of Fatigue
• Ironically, while fatigue disorders were “eliminated” from psychiatry in America in 1980, there became renewed interest in fatigue as a disease
• Chronic Fatigue Syndrome was formally recognized in America in 1988
• Great Britain already recognized myalgic encephalomyelitis
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History of Fatigue
• Today Chronic Fatigue Syndrome is coded
under “Diseases of the Nervous System”
• ICD-10-CM G93.3
• Post Viral Fatigue Syndrome
• Used to code CFS
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Historical Landmarks in Fatigue
1869 Beard establishes concept of neurasthenia
1884 Mosso invents “ergograph” to measure muscle fatigue
1890 Fatigue laboratories established
1914 World War 1
1918 Sir Thomas Lewis describes “effort syndrome” in soldiers
1921 Muscio recommends term fatigue be “abandoned”
1939 World War 2
1943 Fatigue laboratories closed
1947 Bartley & Chute distinguish between aspects of fatigue
1988 Chronic Fatigue Syndrome defined
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History of Fatigue
• In 100 years, we have come full circle
• But is our understanding of fatigue
better today than it was 100 years
ago?
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What is Fatigue?
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Defining Fatigue
• Concept we all know, but difficult to define – Meaning often vague, elusive, difficult to operationalize
• After over 100 years of inquiry, its definition remains elusive – Some have suggested the term be abandoned (e.g., Muscio, 1921)
• “The word fatigue has been defined so inconsistently and applied so loosely …that its
meaning is now obscure” (Balkin & Wesensten, 2011)
• The multidimensional nature of fatigue has been known for over 100 years
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Defining Fatigue: Mosso (1904)
• Mosso published “Fatigue” in 1904, which
was the focus of the “science of fatigue”
• Conducted series of studies measuring
performance decrements with repetition of
a simple task
– Using the “ergograpgh”
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Mosso’ s Ergograph
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Mosso’s Findings (1904)
• Work (BEHAVIOR based on ergograph) shows evidence of decline over time
• Poor correlation between FEELING of fatigue and fatigue BEHAVIOR
• Must be a MECHANISM of fatigue, which he conceived as a substance produced by work
• Fatigue could be affected by CONTEXTUAL factors – Stress in one’s life
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Mosso’s Findings (1904)
• Four components to Fatigue:
– BEHAVIOR (decrement in performance)
– FEELING STATE
– MECHANISM
– CONTEXT (e.g., stress in one’s life; cultural issues)
• 100 years ago we see the beginning of the separation of the global fatigue concept into measurable components
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Mosso’s 4 Components of Fatigue
• Fatigue as Behavior
– Physical performance decrement • Ability to maintain physical work
– Mental performance decrement • Operating sophisticated machines in WW 1 & II
• Decision-making and performance over long periods
• Such work still a major focus today
• But is acute fatigue studied in healthy subjects the same as chronic fatigue?
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Mosso’s 4 Components of Fatigue
• Fatigue as a Feeling State
– Based on self-report
– This is what clinicians have decided to use
in the study and evaluation of fatigue
– Generally, little to no correlation with
objective measurements (behavior)
– What is actually assessed?
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Synonyms of Fatigue
• Tired, worn out, or run down
• Feelings of weakness
• Exhaustion
• Sleepiness
• Lack of energy
• Malaise
• Effort – in relation to a task
• Lack of motivation
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Synonyms of Fatigue
• Are these synonyms all measuring the
same construct?
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Differing prevalence for synonyms of
Fatigue
• In community surveys, Fatigue found
to be:
– Twice as common as exhaustion
– 10 times more common than feeling
“generally run down”
– Up to 10 times more common than
weakness
Wessely et al., 1998, p19
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Weakness and Fatigue Synonyms?
Fatigue (%) Weakness (%)
David et al 1990 males 40 24
David et al 1990 females 54 26
Epidemiology Catchment
program 24 11
Hannay 1978 23 2
Kellner & Sheffield 1973 45 12
Reienberg & Lowenthal
1968 37 3
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Severity of Fatigue is Continuously
Distributed
• Pawlckowsta et al (1994)
– Surveyed patients of general
practitioners in London
– 9-item scale to measure fatigue severity
– Assumed more items endorsed, greater
fatigue severity
Wessely et al., 1998
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Dimensions of Fatigue in a population sample
Pawlikowska et al (1994)
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Mosso’s Four Components of
Fatigue
• Fatigue and Context
– Cultural influences
– Social environment
• Social support
• Life stressors or events
– Physical environment
• Ambient temperature
• Noise
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Mosso’s Four Components of
Fatigue
• Fatigue Mechanism
– Will discuss below under Pathophysiology
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Central vs Peripheral fatigue
• Dates back to at least turn of 19th
century
• Concept of peripheral fatigue
achieves its primary meaning when
an end organ (e.g., muscle) is being
studied.
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Central vs Peripheral fatigue
• Central fatigue can be defined as
– “the failure to initiate and/or sustain attentional
tasks (‘mental fatigue’) and physical activities
(‘physical fatigue’) requiring self motivation
(as opposed to external stimulation)”
(Chaudhuri & Behan, 2000, p35)
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Central vs Peripheral fatigue
• How clear is the distinction?
– motor fatigue can be due to fatigue in either the muscle itself, (i.e., peripheral state) or due to brain control over the muscle(s) (central state).
– is cognitive fatigue due to central processes • requiring more cerebral effort to sustain
performance
• or due to the deconditioning (general physical state of the body)
• or both?
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Defining Fatigue?
“The awareness of a decreased capacity
for physical and/or mental activity due to an
imbalance in the availability, utilization, and/or
restoration of resources needed to perform
activity.” (p46)
“fatigue is the decline in performance that
occurs in any prolonged or repeated task…”
(Fischler, 1999)
(Aronson et al, (1999) Image J Nrs Sch)
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What is Fatigue?
“Under fatiguing conditions, performance sometimes
declines, sometimes remains unchanged, or sometimes
even increases as time on task increases.” (Ackerman, 2011, p.3)
• Decades of research have replicated this.
– We and others show that cognitive performance can
improve
– Acute exercise improves cognition (Chang et al, 2012)
• Even as intensity and duration increases
• Lack of relationship between objective & subjective
fatigue most consistent finding over 100 years
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What is Fatigue?
• “[there are two] conditions of experimentation with the
purpose of finding a fatigue test:
– That we know what we mean by fatigue;
– That we have some method [test] … that different degrees of
fatigue are present at certain different times.
• That the first of these conditions is necessary is self-
evident
• It is obviously absurd to set about finding a test of an
undefined entity.”
Muscio (1921), “Is a Fatigue Test Possible,”
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What is Fatigue?
• “Before a concept can be measured, it
must be defined, and before a definition
can be agreed, there must exist an
instrument for assessing phenomenology.
There is unfortunately no ‘gold standard’
for fatigue, nor is there ever likely to be”
Dittner, Wessely, & Brown, 2004, p.166
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Time on Task and Cognitive Fatigue
• 239 college students - 3 SAT’s duration
– 3.5 hrs, 4.5hrs (standard), 5.5 hrs
• RESULT: Subjective fatigue increased with TOT
• Performance IMPROVED with longer test length
• Personality/motivation/interest had greater
predictive power on subjective fatigue than TOT
– Neuroticism, anxiety, worry correlated with
subjective fatigue
Ackerman & Kanfer, 2009
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Acute exercise has a small but
Significant positive effect on
Cognition
Effect is stronger with greater:
duration
intensity
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What is Fatigue?
• “Fatigue is so common as to be almost normal” (Wessely et al., 1998, p25)
• Poor correlation between FEELING of fatigue and fatigue BEHAVIOR (Mosso 1904;
DeLuca 2005)
• What is NOT fatigue?
– Depression
– Sleepiness
– Cognitive fatigue is not equal to cognitive impairment
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Definition of Fatigue in MS
• MS Council for Clinical Practice
Guidelines (1998) defines fatigue as:
– “A subjective lack of physical and/or mental
energy that is perceived by the individual or
caregiver to interfere with usual and desired
activities”
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MS Council for Clinical Practice
Definition of Fatigue in MS
• Differentiates chronic from acute fatigue
• Chronic Fatigue
– fatigue present for any amount of time on 50% of days for more than six weeks, which limits functional activities or quality of life
• Acute Fatigue
– new or significant increase in feelings of fatigue in the previous six weeks, which limits functional activities or quality of life
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Chronic Fatigue Syndrome
CDC/NIH Revised Definition (Fukuda, 1994)
• New onset of unexplained, persistent or
relapsing fatigue for at least 6 months
– not result of ongoing exertion
– not substantially alleviated by rest
– substantial reduction in level of functioning
• 4 or more minor criteria
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Questions
• Why should subjective fatigue be the gold standard?
• Why should objective and subjective fatigue correlate? – They don’t
• Must behavioral changes be a decrease?
• Lets face it, subjective fatigue correlates with other subjective ratings
– Depression, pain, subjective sleep, deconditioning, medication effects, hormonal changes, cognitive complaints, stress
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Overview
• History of Fatigue
• What is Fatigue
• Fatigue in General population • Fatigue in Clinical Populations
• Measurement of Fatigue
• Pathophysiology of Fatigue
• Treatment of Fatigue
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Prevalence of Fatigue in the
Community
• “Fatigue is so common as to be
almost normal” (Wessely et al., 1998, p25)
– Only 14% of community sample reported NO
symptoms (Ridsdale, 1989)
– 81% of a US college sample experienced at
least 1 somatic symptom during last 3 days
(Reidenberg & Lowenthal, 1968)
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Some Community Studies of Fatigue
Prevalence*
0%10%20%30%40%50%60%70%80%90%
100%
Gener
al fatig
ue
Fatigue
Tired all t
ime
Tired la
st wee
k
Fatigue 3
days
Fatigue 7
days
Tiredness
>2 wks
*Adapted from Lewis and Wessley, 1992
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Some studies of prevalence of fatigue
> six months
20.8% 17.5%4.3% 4.9% 4.2%0%
10%
20%
30%
40%
50%
60%
70%
Buchwald 1995
Raphael (u
npublished
)
Steele
1998
Reyes 2003
Jason 1999
Last 3 studies used “severe” in wording
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Prevalence of Fatigue in the
Community by Age
• Little variation with age
• Exception is that fatigue is uncommon
before adolescence
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Fatigue Prevalence by Age: Health and
Life Survey (From Wessely et al., 1998)
Age % Male (n=3905)
% Female (n=5098)
18-24 21.7 34.6
25-34 19.1 33.0
35-49 18.7 30.8
50-64 18.8 26.3
65+ 17.6 26.1
Total 19.0 29.8
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Prevalence of Fatigue in the
Community by Gender
• Most studies show that fatigue is more
common in woman
• Health and Lifestyle Survey (Cox et al, 1987)
– 29.8% in woman (n=5098)
– 19.0% in men (n=3905)
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Prevalence of Fatigue in the
Community by Social Class
• Often thought that fatigue is associated with
higher social status or social class, perhaps from
the assumptions among the fatigue syndromes
(CFS)
• Populations studies reveal the opposite
• Fatigue is more common in lower SES groups
– Studies from USA, Scotland, France and Australia
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Fatigue and Social Class Health and Lifestyle Survey (Cox et al, 1987)
SES gradient Males (%) Females (%)
Professional 17.9 27.0
Other non-manual 17.8 29.1
Skilled manual 18.6 29.2
Semi and unskilled
manual 22.0 33.8
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Prevalence summary
• Prevalence rates of fatigue vary dramatically, based upon definition
• Fatigue is on a continuum, not a categorical state
• Approximately 20% of community residents probably have chronic (> 6 months) fatigue, but only about 4-5% have severe chronic fatigue.
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Fatigue in Primary
Care and Hospital
Populations
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Prevalence of Fatigue in Primary Care
• Survey studies of all patients attending
primary care (various terms used to assess fatigue)
– 21-24 % in 2 USA studies
– 21% in Australian study
– 32% Israeli study
– 29% Senegal
Wessely et al, 1998
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Prevalence of Fatigue in Primary Care
• Patients consulting primary care with a specific complaint of fatigue
• 1985 American survey found 0.9% of primary care visits
• This makes fatigue more common than: – “cold”
– Rash
– Headache
– Chest pain
Wessely et al., 1998
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Fatigue in Hospital Care
• Standard Neurology text states:
– “more than half of all patients attending a
general hospital, register a direct complaint of
fatigability or admit it when questioned”
» Adams & Victor, 3rd edition
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Fatigue in Hospital Care
Kroenke & Mangelsdorff, 1989
Reviewed records from 1000 patients from
general medical outpatients in an
American hospital. Fatigue presenting
symptom in 8% of cases
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What Causes
Fatigue?
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Some Causes of Fatigue?
Physiological Psychosocial Increased exertion Depression
Inadequate rest Anxiety disorders
Sedentary lifestyle Stress reaction
Sleep disorders
Pregnancy
Renal disease (e.g., chronic renal failure)
Hepatic disease
Cardiovascular disease
Hematological problems (e.g., anemia)
Respiratory disorders (e.g., COPD)
Infectious disease (e.g., HIV, Lyme, tuberculosis, mononucleosis)
Endocrine disorders (e.g., Cushings syndrome, hypothyroidism, diabetes)
Metabolic disorders
Autoimmune disease (e.g., MS, LUPUS, RA, myasthenia gravis)
CNS disorders (e.g., stroke, TBI)
Komaroff & Fagioli, 1996
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Fatigue and
Depression
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Fatigue and Depression
• Like Fatigue, depression is both a
– symptom
– syndrome
• Long history of association between
fatigue and depressive disorder
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Fatigue and Depression: Community
Samples
• Over 80% of college students scoring
above depression cut-off on CES-D felt
that “everything is an effort”
• In Switzerland, “exhaustion” is 3x more
likely in those with depression than not
• Association between depression and
fatigue is found throughout adult life, into
old age
Wessely et al., 1998
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Pawlikowska et al (1994)
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Fatigue and Depression: Community
Samples
• High GHQ associated with depression and
anxiety
– “The relationship between feeling tired and
the probability of having an emotional disorder
is clear – The more of one, the more of the
other” (Wessely et al., 1998, p83)
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Fatigue and Depression: Primary and
Secondary Care
• Most common cause of fatigue among all
patients who seek medical care is
depression (Komaroff, 1993, 1996)
• Most persons presenting with complaint of
fatigue to primary care receive psychiatric
diagnosis
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Fatigue and Pain
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02
46
81
0
Fatig
ue
0 .5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 6.5 7 7.5 8 8.5 9 9.5 10
Pain scaleexcludes outside values
Relationship between pain and fatigue
Wolfe, 2005: n=over12,000 with Rheumatic illness
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Cognition and
Fatigue?
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Don’t be fooled!
• Claims of instruments to assess mental vs.
physical fatigue (e.g., MFI)
– I have been forgetful
– I have been less alert
– I have difficulty paying attention for long
periods of time
– I have trouble concentrating
– My thinking has been slowed down
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• Typically asses fatigue without defining it
• The questions included may have little of
nothing to do with fatigue at all
• For example: not clear that patients can
truly differentiate fatigue from:
– motor impairment (e.g., weakness vs fatigue)
– cognitive impairment
– Sleepiness
– depression
Self Report Instruments
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Chalder Fatigue Scale
• Physical symptoms – Do you have a problem with tiredness?
– Do you need rest more?
– Do you feel sleepy or drowsy?
– Do you have problems starting things?
– Do you start things without difficulty but get weak as
you go?
– Are you lacking in energy?
– Do you have less strength in your muscles?
– Do you feel weak?
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Chalder Fatigue Scale
• Mental symptoms
– Do you have difficulty concentrating?
– Do you have problems thinking clearly?
– Do you make slips of the tongue when
speaking?
– Do you find it more difficult to find the correct
word?
– How is your memory?
– Have you lost interest in things you used to do?
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Neuropsychological Rehabilitation (2018), 28:1, 57-116
Fatigue thought to affect cognition after stroke
Systematic review following databases:
EMBASE, Psychinfo,CINAHAL, MEDLINE, Ethos, DART
11 of 413 papers met inclusion criteria
Results:
4 found significant correlation between fatigue & cognition
7 did not
most studies had quality limitations
“There was insufficient evidence to support or refute a
Relationship between fatigue and cognition post-stroke”
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Fatigue and Sleep
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Sleepiness and Fatigue
• Sleepiness and fatigue often used interchangeably
• Thus, sleep findings often extended to fatigue – e.g., disturbed sleep leads to cognitive dysfunction
• Increasing evidence that sleepiness and fatigue arise from distinct neural mechanisms
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Sleepiness and Fatigue
• Excessive sleepiness is defined as:
“drowsiness or sleep onset that occurs at
inappropriate or undesirable times”
• Excessive sleepiness can lead to fatigue, but are
not synonymous
– Excessive sleepiness usual restored with rest
– Fatigue is not necessarily restored with rest
(Duntley, 2005)
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Sleepiness and Fatigue
• General medicine and mental health rely
on accurate distinctions between
sometimes overlapping symptoms
• This is important because sleepiness and
fatigue may involve different treatments
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Sleepiness and Fatigue
• “While sleepiness and fatigue both result from
insufficient sleep and tend to overlap in clinical
syndromes, they are clearly distinct phenomenon that
can occur independently”
(Duntley, 2005, p221)
– Can be differentially affected by manipulation of the
sleep-wake cycle
– Fatigue, rather than sleepiness, is correlated with the
experience of insomnia (Chambers & Keller, 1993)
– Higher doses of Modafinil improves sleepiness but
not fatigue (Rammohan et al., 2002)
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Excessive daytime sleepiness (EDS) and fatigue common after TBI
RCT of 20 TBI with EDS or fatigue or both
Baseline: Epworth Sleepiness Scale
Fatigue Severity Scale
Modafinil 100-200mg mornings for 6 weeks
Placebo
Results:
Modafinil significantly improved:
EDS
ability to stay awake (maintenance of wakefulness scale)
Modafinil had no impact on fatigue
Modafinil improves posttraumatic EDS but not fatigue
Class I evidence
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RCT 53 TBI
Modafinil vs placebo
FSS
Epworth Sleepiness scale
No effect Modafinil on fatigue
Minor effect on sleepiness
effect at 4 weeks
none at 10 weeks
Modafinil side effect
increased fatigue
increased insomnia
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SLEEPINESS FATIGUE
Biological Role Clear Vague
Definition Objective,
Measurable
Vague,
Subjective
Resolves With
Rest Yes
Not typically in
clinical
populations
Measurement Objective Subjective
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PURPOSE: Construct 2 scales that represent unconfounded measures of
sleepiness & fatigue
SUBJECTS: (Developmental sample)
19 CFS; 14 narcolepsy; 11 healthy controls
SUBJECTS: (Validation sample)
128 older community-based volunteers METHOD: 4 questionnaires
Sleepiness Stanford Sleepiness Scale (SSS) Epworth Sleepiness Scale (ESS)
Fatigue Fatigue Severity Scale (FSS) Chalder Fatigue Scale (CFS)
Battery measuring Objective sleep Psychological and health functioning
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Results
• 4 questionnaires (SSS, ESS,FSS,CFM)
correlated highly among each other,
showing how the constructs are
confounded
• Correlation analysis left only 9 items not
correlated between fatigue and sleepiness
– Empirical Sleepiness Scale (ESS) - 6 items
– Empirical Fatigue Scale (EFS) - 3 items
Bailes et al (2006)
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Empirical Sleepiness Scale Items
1. How likely are you to doze off or fall asleep in the following situations, in contrast to just feeling tired?
– Sitting and reading.
– Watching TV.
– Sitting inactive in a public place (e.g., theatre, meeting).
– As a passenger in a car for an hour when circumstances permit.
– Sitting and talking to someone.
– Sitting quietly after lunch without alcohol.
Bailes et al (2006)
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Empirical Fatigue Scale Items
• Exercise brings on my fatigue.
• I start things without difficulty but get weak as I go on.
• I lack energy.
Bailes et al (2006)
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ITEMS ESS EFS Empirical Sleepiness Scale Items
1. .79 * .06
2. .79 * .08
3. .84 * .10
4. .73 * .13
5. .56 * .14
6. .69 * .01
Empirical Fatigue Scale Items
1. .01 .67 *
2. .01 .75 *
3. .04 .78 *
ESS and EFS item/total correlations for both
samples at all testing times
Validation sample (n=128), retrospective
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ESS EFS
Validation Validation
sample (n=128) sample (n=128)
SF-36 Physical functioning -.06 -.38***
SF-36 Role physical -.03 -.43***
SF-36 Bodily pain -.04 -.22
SF-36 General health .00 -.37***
SF-36 Vitality -.04 -.58***
SF-36 Social functioning .01 -.35***
SF-36 Role emotional -.08 -.22
SF-36 Mental health -.10 -.25**
Empirical Sleepiness & Fatigue Scale correlations with sleep,
psychological, and health functioning (validation sample)
*p<.05 = NS; ** p<.01; ***p<.001
Retrospective
Questionnaire
Battery
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ESS EFS
Validation Validation
sample (n=128) sample (n=128)
Do you have any illnesses? .09 .05
Do you have insomnia? -.07 .10
I do not feel refresh in the morning -.04 .26**
What is the quality of your sleep? -.15 -.13
How satisfied are you with your sleep? -.15 -.05
How refreshed you feel in the morning? -.01 -.34***
How tired do you feel during the day? .06 .47***
Beck Depression Inventory total .03 .41***
Retrospective
Questionnaire
Battery
Empirical Sleepiness & Fatigue Scale correlations with sleep,
psychological, and health functioning (validation sample)
*p<.05 = NS; ** p<.01; ***p<.001
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Conclusions
• Existing scales confound sleepiness and fatigue
• ESE and EFS selectively measure sleep and fatigue respectively
• ESE related to: – Falling asleep during the daytime
• EFE related to wider range of variable: – perceived poor physical and psychological
adjustment
– Physical tiredness
• Specific treatment for sleepiness and fatigue are available
Bailes et al (2006)
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Overview
• History of Fatigue
• What is Fatigue
• Fatigue in General population
• Fatigue in Clinical Populations
• Measurement of Fatigue • Pathophysiology of Fatigue
• Treatment of Fatigue
• A Conceptual model for the Future
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Measurement of Fatigue
• Challenge compounded by fundamental
lack of understanding of the precise
mechanism of fatigue
• Two Basic Measurement Approaches
– Patient’s perceived level of fatigue
– Performance-based measures
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Patients perceived level of fatigue
• Two general category of fatigue scales
– Stand alone Fatigue Scales • Fatigue Severity Scale (FSS)
• Modified Fatigue Impact Scale (MFIS)
• Multidimensional Fatigue Inventory (MFI)
• Visual Analog Scale (VAS)
• Chalder Fatigue Scale (CFS)
– Broader Instruments with Fatigue subscales • SF-36
• POMS – Profile of Mood States
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Patients perceived level of fatigue
• Some scales provide global level measure
• Others attempt to assess various
dimensions • Physical
• Mental
• However, construct validity of these
various dimensions are not well
established
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Fatigue Questionnaires:
Any Differences?
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Variable MAF Total
BFI Total
SF-36 Vitality
VAS Fatigue
Fatigue Scores
MAF Total 1.00 0.86 0.79 0.80
BFI Total 0.86 1.00 0.75 0.76
Vitality 0.79 0.75 1.00 0.71
VAS Fatigue 0.80 0.76 0.71 1.00
Clinical Variables
HAQ 0.50 0.55 0.52 0.54
SF36 physical function 0.51 0.56 0.55 0.52
PCS 0.53 0.55 0.59 0.55
Pain 0.55 0.57 0.50 0.62
Patient global 0.57 0.60 0.57 0.61
Satisfaction 0.56 0.58 0.61 0.54
QOL 0.63 0.68 0.62 0.64
RADAI 0.62 0.63 0.57 0.65
Correlations of Fatigue Scales & Clinical Variables in Rheumatic Disease (N = 7,760)
MAF: Multi-dimensional Assessment of Fatigue. BFI: Brief Fatigue Inventory. Vitality: SF-36 vitality scale. VAS Fatigue:
Fatigue as measured by a single item visual analog scale. HAQ: Health Assessment Questionnaire. SF-36: Medical
outcome study short form 36. PCS: SF-36 Physical component scale. QOL: Quality of life. RADAI: Rheumatoid Arthritis
Disease Activity Index.
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Fatigue Scale Conclusions (Data from Rheumatoid Arthritis study)
• All scales have similar distributions
• Standardized scores are similar
• Scales are highly correlated
• Scales are correlated similarly with clinical
variables
• VAS performs as well or better than
complex, longer scales
Wolfe, personal communication
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Is Fatigue, Fatigue? And can we measure it (them)?
• Measuring subjective fatigue:
– State: “Online” measure of fatigue
(during task performance)
– Trait: “Offline” measure of fatigue
(e.g., over last 1-4 weeks)
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• Trait Fatigue
– FSS (over the last week)
– MFIS (over last 4 weeks)
• State Fatigue
– VAS (right now: 0-100)
• Correlations:
– FSS and MFIS: r = 0.46
– FSS and VAS: ns
– MFIS and VAS: ns
Fatigue may not be fatigue!
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Measuring Motor
Fatigue
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Measurement of Fatigue
• Performance-based measures of fatigue
– Physical (e.g., motor, muscle firing)
– Mental (e.g., cognitive)
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Measuring physical (motor) fatigue
• Schwid et al (1999) in MS examined:
– Motor fatigue – loss of maximal capacity to
generate force during exercise
– Muscle weakness (strength) – ability to
maintain motor output during
• Sustained muscle contractions
• Repetitive muscle contractions
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Measuring physical (motor) fatigue
Results
• MS group showed both motor fatigue and
motor weakness compared to controls
• No significant correlation between Motor
fatigue and Weakness (strength) in any
muscles tested
• Suggest that motor fatigue and weakness
are distinct features of motor dysfunction
Schwid et al (1999)
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Measuring physical (motor) fatigue
• Do chronic TBI subjects who complain of
subjective fatigue have less muscle strength and
endurance than TBI subjects who do NOT
complain of subjective fatigue?
• 21 male TBI subjects
– 13 fatigued
– 9 no-fatigue
• 10 Age and gender matched controls
Walker et al., 1991
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Measuring physical (motor) fatigue
• Methods:
– Subjective ratings of fatigue
– Isokinetic/isometric testing of knee extension
and contraction using dynamometer
– Depression - Zung self-rated depression
– Anxiety - Zung self-rated anxiety
– Health status - Sickness Impact Profile
Walker et al., 1991
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Measuring physical (motor) fatigue
• Results:
– Subjective fatigue higher in TBI than HC
– Subjective fatigue correlated with
depression, anxiety and health status
– Isokinetic/isometric scores did not differ
across the 3 groups
– Subjective fatigue was not correlated with
objective measures of strength and
endurance
Walker et al., 1991
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Measuring physical (motor) fatigue
• Brain injured S’s and examined:
– Motor fatigue – continuous thumb pressing
• Four trials of 40 second thumb pressing of a microswitch
– Subjective fatigue
• FSS
• FIS
• VAS
– 30 brain injury (24 TBI, 4 stroke, 2 other)
– 30 gender and age matched students
Lachapelle & Finlayson (1998)
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Results
• No group differences in objective fatigue
performance (thumb pressing)
• Both TBI and controls showed decreased
frequency of thumb presses across trials
• TBI significantly higher subjective fatigue
than HC
• No support for correlation between
subjective and objective fatigue
Lachapelle & Finlayson (1998)
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85
90
95
100
105
110
115
1 2 3 4
Healthy
TBI
Frequency Thumb press Subjective Fatigue Scores
Lachapelle & Finlayson (1998)
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Examined subjective fatigue, undemanding finger-motor task, MRI
MFIS: fatigue in the previous month (not task related)
DV: temporal accuracy: ability to keep up with metronome rhythm
Results
greater fatigue better temporal accuracy!
temporal accuracy correlated with MRI activation in:
right cerebellum
Authors speculate: “fatigue seems to represent the experiential
correlate of the increased resource demand for motor activities,
potentially acting as an adaptive fail-safe mechanism to avoid
exhaustive states”
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Pardini et al, (2001) Scientific Reports
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What Does Self-reported Fatigue Predict?
• Stroke
– Predicts death at 1 year (Stulemeijer et al, 2005)
– reduced long-term survival (Mead et al, 2011).
– increased risk of “suicidality” (Tang et al, 2011)
– independently associated with pre-stroke • depression
• white matter changes
• diabetes mellitus
• Pain
• sleeping disturbances (Naess et al, 2012)
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What Does Self-reported Fatigue Predict?
• Coronary heart disease
– Independently predict the development of: • coronary heart disease
• risk of future cardiac events
• survival following myocardial infarction
– These relationships remain even after controlling for the traditional risk factors
• elevated cholesterol
• Hypertension
• Smoking
• age, etc.
Siegel & Schneiderman, 2005
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What Have We Learned About Fatigue in General?
• Systemic Fatigue may differ from factors which
exacerbate or perpetuate it
– Physical illness (e.g., MS, TBI) may cause initial
symptoms of fatigue
• CNS involvement
– Secondary factors exacerbate the primary symptoms
• De-conditioning
• Sleep disturbance
• Depression
• Medication, etc
• Time to differentiate Primary and
Secondary fatigue
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Primary and Secondary Fatigue
• PRIMARY FATIGUE
– Systemic mechanism(s) responsible for
fatigue
• (i.e., primary neural mechanisms)
• SECONDARY FATIGUE
– Factors which exacerbate its effects
• (e.g., Sleep disturbance, de-conditioning,
depression, medication, etc)
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Models predicting Fatigue in MS
• Strober & Arnett (2005) examined collective role
of important variables in predicting fatigue in MS
– Disease severity
– Sleep disturbance
– Depression
• Four models were examined (based on
research)
• Path analysis used to predict fatigue
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Model 1
Disease
Severity
Sleep
Disturbance
Depression
Fatigue
Model 2
Disease
Severity
Fatigue
Sleep
Disturbance
Depression
Strober and Arnett (2005)
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Model 3
Disease
Severity
Sleep
Disturbance
Model 4
Fatigue Depression
Disease
Severity
Depression
Sleep
Disturbance
Fatigue
Strober and Arnett (2005)
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Results
• Model 3 – best fit in predicting fatigue
– “suggests that depression and sleep
disturbance lead to fatigue independent of
disease severity”
• Models 1,2,4 - poor fit to the data
Strober and Arnett (2005)
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Measuring
Cognitive Fatigue
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TBI patient account of Cognitive
Fatigue Patient 10 years post severe TBI
• “…several individuals with brain
injury have described the similar
feeling of ‘hitting a wall’ followed
by the ‘need to crash’. After brain
injury, the experience of fatigue is
real and persistent.”
Howard (2004). Brain Injury/professional, 1, 28-31.
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• “The more distractions there are, the
more cognitive energy that must be
expended to filter out background
noise, increasing the attentional
demands on my brain to complete
each task. Everything takes more
cognitive energy after serious brain
injury”
Howard (2004). Brain Injury/professional, 1, 28-31.
TBI patient account of Cognitive
Fatigue Patient 10 years post severe TBI
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Some Forms of Fatigue
• Physical or motor fatigue
• Cognitive fatigue
– Feeling mentally drained
– Perceived difficulty in maintaining attention
• Do we know what Cognitive Fatigue is?
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Cognitive Fatigue
and
Neuropsychological
Testing
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Fatigue and Neuropsychological
Performance
• Detrimental effects of fatigue on
neuropsychological performance is
taught in training programs
• But is there data to support these claims
in clinical populations?
Lezak, 1983; p 127
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• “The patient who fatigues easily rarely
performs well and may experience
relatively intact functions as more
impaired as they actually are”
Lezak, 1983; p 127
Fatigue and Neuropsychological
Performance
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• “In arranging [a] test time, the
patient’s daily schedule must be
considered if the effects of fatigue are
to be kept minimal. When necessary,
the examiner may insist that the
patient take a nap before being
tested.”
Lezak, 1983; p 127
Fatigue and Neuropsychological
Performance
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• Lezak (1983) recommends:
– Shortening test sessions
– Giving difficult tests early in a session
– Allowing many rest periods
Lezak, 1983; p 127
Fatigue and Neuropsychological
Performance
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• Assumption is that NP performance is
adversely affected by fatigue as the testing
sessions progresses (prolonged effort
model)
• Unfortunately, little evidence to support the
specific claims in clinical samples that:
– Fatigue affects NP performance
– Recommendations actually reduce any
potential fatigue effects
Fatigue and Neuropsychological
Performance
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Cognitive performance during high vs
low fatigue in MS
• 30 fatigued MS patients
• Cognitive testing during high and low
fatigue (within subjects design)
• Results:
– No differences in objective performance
– Subjectively rated performance as worse
during high fatigue
(Parmenter et al, 2000)
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Central or Cognitive Fatigue
• Central fatigue can be defined as
– “the failure to initiate and/or sustain attentional
tasks (‘mental fatigue’) and physical activities
(‘physical fatigue’) requiring self motivation
(as opposed to external stimulation)”
(Chaudhuri & Behan, 2000, p35)
• Cognitive Fatigue: Fatigue resulting from
performing cognitive tasks
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Objective measurement of cognitive fatigue
• Cognitive Fatigue over an extended time
• Cognitive Fatigue DURING sustained
mental effort
• Cognitive fatigue AFTER challenging
mental exertion
• Cognitive fatigue AFTER challenging
physical exertion
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1. Cognitive Fatigue over an
extended time • Cognitive testing over several hours
• No difference in performance between MS or
TBI and controls – Jennekens-Schinkel et al., 1988
– Johnson et al., 1997
– Paul et al., 1998
– Riese et al, 1999
– Beatty et al., 2003
• In all studies, MS and TBI worse in subjective
fatigue
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Cognitive Fatigue over an extended
time
• “induced” fatigue: giving PASAT 4 times
over 3 hours
• Three fatiguing groups:
– MS
– CFS
– Major Depression
• examined subjective fatigue before and
after each PASAT assessment
Johnson, Lange, DeLuca et al (1997)
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Mean PASAT Performance Across Sessions Johnson, Lange, DeLuca et al (1997)
100
120
140
160
180
200
1 2 3 4
HC
CFS
DEP
MS
PASAT Sessions
# correct
Johnson, Lange, DeLuca et al (1997)
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Results
• Subjective fatigue higher in the 3 fatigue
groups relative to controls
• All 4 groups increased subjective fatigue
across 4 sessions
• No significant relationship between
objective performance (PASAT) and
subjective fatigue
Johnson, Lange, DeLuca et al (1997)
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Fatigue over the work day in MS
• Pre-post work day assessment of:
– 4 NP tests of information processing
– 25 ft timed walk
– Subjective fatigue
• 17 MS
• 12 healthy controls
Beatty et al (2003)
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Fatigue over the work day in MS
• Subjective fatigue did not differ at baseline
but MS subjects reported significantly
more fatigue at the end of the day
Beatty et al (2003)
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Subjective Fatigue Across the
Workday (Beatty et al., 2003)
0
1
2
3
4
5
6
baseline end of day
MS
HC
Mean fatigue
Group by time interaction: p<.01 Beatty et al (2003)
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NP Measures Across the Workday
• No group differences on any NP measure
– List recall
– Letter-number sequence
– SDMT
– PASAT (3 second trial)
• Subjective fatigue did not correlate with
objective NP performance
Beatty et al (2003)
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PASAT Across the Workday in MS
0
10
20
30
40
50
60
Baseline End of Day
MS
HC
Mean Correct
p=NS
Beatty et al (2003)
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Fatigue over the work day in MS
• Authors conclude:
– “…results confirm other reports that patients’
subjective ratings of their fatigue are not valid
indicators of their actual performance on
cognitive tests”
Beatty et al (2003)
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1. Cognitive Fatigue over an
extended time • Conclusions:
• Little to no evidence that prolonged activity
produces cognitive fatigue which results in
decreased objective cognitive
performance
• Subjective fatigue increases over time
• Subjective and objective measures of
fatigue are not correlated
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2. Cognitive Fatigue DURING
sustained mental effort • Decreased performance on second half vs
first half of a sustained cognitive task • Kujala et al (1995)
• Krupp & Elkins (2000)
• Schwid et al (2003)
• Bryant et al (2004)
• Neuman et al (2014)
• Aldughmi et al (2017)
• Conceptually similar to muscle fatigue studies
• Self reported fatigue generally unrelated to objective performance
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2. Cognitive Fatigue DURING
sustained mental effort • Review after 2005
• No evidence between performance & subjective fatigue
• Memory (18 studies)
• Cognitive speed/selective attention (11 studies)
• Language/Visuospatial processing (6 studies)
• Weak evidence in working memory (16 studies)
– Strong evidence on alertness/vigilance (12 studies)
• All required sustained mental effort!
Hanken et al, (2015), MSJ
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Krupp & Elkins, 2000
• 35 MS and 12 HC
• Complex concentration task: A-A task
– Continuous mental arithmetic
• Hypothesized that MS S’s would “fatigue” in second half vs first half of test
• Results:
– RT slower in MS in second half
– Accuracy data not reported
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Bryant, Chiaravolloti & DeLuca 2004
• 56 MS and 39 HC
• PASAT
• Hypothesized that MS S’s would “fatigue”
in second half vs first half of test
• Results:
– MS significant worse in second half
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Perceived fatigue: Neurologic Fatigue Index (NFI-MS)
perceived physical and cognitive fatigue
Fatigability: 6 minute walk (6MWT)
% change in meters from 1st to last minute
Grip strength
15 trials, holdings maximal contractions 5 sec
% change in force from 1st to last trial
Continuous Performance test
press space bar when any letter but “X” displayed
mean response speed variability
State fatigue: Visual analogue scale (0-100)
before and after each trial
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% change in 6MWT and Grip strength NOT
Associated with any NFI-MS scores
CPT RSV showed mild but significant
Correlation with all 3 NFI-MS scores
Aldughmi et al (2017), Intl J MS Care
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State and Trait perceived fatigue
did not correlate, at least for 6MWT
and grip strength
Is perceived fatigue then fatigue?
Aldughmi et al (2017), Intl J MS Care
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Aldughmi et al (2017), Intl J MS Care
Subjective fatigue
associated with
various clinical
factors
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30 MS with cognitive fatigue
15 HC
2.5 hr cognitive testing
Assessed: pre (T1) and post (T2)
& 1 hour recovery (T3)
Journal of the Neurological Sciences 340 (2014) 178–182
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Conclusions:
2. Cognitive Fatigue DURING
sustained mental effort
• Significant evidence for decreased
performance during sustained mental
effort
• Perhaps this is where we should focus
our continued research efforts?
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3. Cognitive fatigue AFTER
challenging mental exertion
• Prior mental challenge decreases
subsequent performance
– Inconsistent evidence
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Ziino & Ponsford, 2006
• 46 TBI and 46 HC
• Cognitive Pre and post Vigilance task
• Design *
– C-SAT Vigilance C-SAT
• Defined difference in C-SAT as objective
measure of fatigue
(* C-SAT – Complex Selective Attention Task)
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C-SAT Reaction Time
0
200
400
600
800
1000
1200
1400
1600
1800
Mean RT 1 Mean RT 2
TBI
HC
No significant group x time interaction
Ziino & Ponsford, 2006
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C-SAT Errors
0
1
2
3
4
5
6
7
Errors T1 Errors T2
TBI
HC
No significant group x time interaction
Ziino & Ponsford, 2006
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Ziino & Ponsford, 2006
• No effect of prolonged mental effort on
performance AFTERWARD
• Subjective fatigue not correlated with
“Objective fatigue”
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Krupp & Elkins, 2000
• 45 MS and 14 HC
• 4 hr session of cognitive testing
• Design
– Initial NP A-A task Follow-up NP
• Hypothesized that MS s’s would fatigue
over time and show a decline in cognitive
performance
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Krupp & Elkins, 2000 – Results Selective Reminding test (sum recall)
42
44
46
48
50
52
54
56
time 1 time 2
MS
HC
Total score
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Krupp & Elkins, 2000 – Results
Tower of Hanoi
0
5
10
15
20
25
time 1 time 2
MS
HC
Total score
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Krupp & Elkins, 2000 Relationship between Subjective and Objective Fatigue
• No relationship observed (with 3 methods)
– When NP test analyzed with FSS as covariate
• No correlation between FSS and NP scores
– Compared MS subgroup with low fatigue
(FSS < 4) vs high fatigue
• No group differences in NP performance
• Supports measurable cognitive fatigue
effect
– Design issues complicate interpretation
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Do long-lasting work demands have after-effects on attention-demanding
tasks
Simulated 2 full “work days” (9:00-20:00 h) in the lab
morning work same for both days (easy work)
afternoon work task-load was manipulated
difficult: changing the pace rate, memory load, lack of reinforces
easy: much easier
pre-post “probe” task each day
s’s presented with 3 letters in memory
4 new letters presented
decide quickly if one was identical to the original 3
95 trials
DV: speed (RT) and accuracy (errors)
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Heart rate variability used as an index of “mental effort”
Urinary adrenaline: used to verify “work-load effort”
higher = more “effort”
Subjective measure:
fatigue: Scale of Experienced Load (SEB)
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Adrenaline levels not different in morning between 2 groups
During Afternoon, effort decreased in both days (less effort)
During the difficult afternoon, adrenaline decreased less (p<.011 interaction)
Physiological “verification”: difficult afternoon was more effortful
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Schellekens et al, (2000) Biological Psych
Performance AFTER long work day: Effect on Errors not Reaction time
Errors increased significantly
across day in the DIFFICULT group
No significant changes
in RT in either group
p<.006 p<.05
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Schellekens et al, (2000) Biological Psych
Fatigue and “effort” across the day in
DIFFUCULT and EASY conditions
Subjective fatigue over time in
both groups (interaction NS)
Significant decline in “mental effort” in
difficult group at end of the day
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Summary
• Fatigue increased across the day in both groups
• Easy day: Fatigue had no effect on post test
errors (tended to get better) and RT
• Difficult day: made more errors, tended to
decrease RT (got faster!), invested less effort at
end of day, felt more fatigued
– Shift toward less-effort, increased “risky” strategies,
related to increased fatigue
– “Prolonged high mental task demands … may result
in feelings of fatigue (where) … S’s were apparently
unwilling (unmotivated) or unable to invest effort and
pay attention to the task” p53.
Schellekens et al, (2000) Biological Psych
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Conclusions
3. Cognitive fatigue AFTER challenging
mental exertion
• May see behavioral changes after mental
exertion
• Not necessarily associated with increased
fatigue
– May result in strategy change of less effort?
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4. Cognitive fatigue AFTER
challenging physical exertion
• Mixed evidence in CFS
• Only preliminary study in in MS
– (Caruso et al., 1991)
– No effect observed
• No conclusions available at this time
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Acute exercise has a small but
Significant positive effect on
Cognition
Effect is stronger with greater:
duration
intensity
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Conclusions on Cognitive Fatigue
• Cognitive fatigue is a complex construct
• Simple subjective questionnaires are not
adequate
• Best evidence is for fatigue DURING
sustained cognitive performance
• Subjective fatigue does NOT correlate with
objective measurements
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Overview
• History of Fatigue
• What is Fatigue
• Fatigue in General population
• Fatigue in Clinical Populations
• Measurement of Fatigue
• Pathophysiology of Fatigue • Treatment of Fatigue
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Pathophysiology of Fatigue
Most of the work is done in MS
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Pathophysiology of Fatigue in MS
• Little is known
• Several physiological mechanisms proposed
– immune system dysregulation
– CNS mechanisms
– impaired nerve conduction
– neuroendocrine/neurotransmitter dysregulation
– autonomic nervous system involvement
• All Likely interact with no pathway sole cause
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Pathophysiology of Fatigue in MS:
Immune System Dysfunction
• Strong evidence of Immune system
dysregulation in MS
• However, its relationship to fatigue is not
clear
– Correlation of fatigue with circulating
cytokines have been inconsistent
– Suggestions of relationship with abnormal
HPA axis, but studies unclear
Krupp, 2005
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Pathophysiology of Fatigue in MS:
Immune System Dysfunction
– immune modulators, the interferon-betas,
produces fatigue as a side effect
– Association between thyroid dysfunction and
fatigue in MS has been suggested
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Hypothalamic-Pituitary-Adrenal (HPA)
Axis and Fatigue in MS
• Strong evidence that MS is an autoimmune disease driven by autoreactive T cells and an imbalance of proinflamatory cytokines
• Because of the interplay of the immune and endocrine systems, there is much interest in studying the HPA-axis in MS
• But data to support HPA hyperactivity as a cause of fatigue is mixed
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HPA-axis and Fatigue in MS
• HPA dysregulation studied with
– combined dexamethasone-corticotropin
releasing hormone (Dex-CRH) suppression
test
• 31 clinically definite RR MS participants
– 15 with fatigue (FSS > 4)
– 16 without fatigue (FSS < 4)
Gottschalk et al 2005
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HPA-axis and Fatigue in MS
• MS with fatigue showed dysegulation of the HPA
axis
– Significantly elevated plasma ACTH relative to no-
fatigue MS group
– However, cortisol levels did not differ
– No relationship of fatigue with EDSS
• Concluded that proinflammatory cytokines may
cause the HPA axis alterations and the strong
feelings of fatigue
Gottschalk et al 2005
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HPA-axis and Fatigue in MS
• Dex-CRH in 40 MS and 11 HC
– Found altered HPA activity in primary and
secondary progressive MS, but not RR MS
– HPA dysregulation
• Not related to fatigue
• Not related to depression
• Was related to
– cognitive processing
– EDSS
Heesen et al 2002
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Cognitive fatigue and autonomic abnormalities common in MS
Hypothesis both share common neural network
aberrant vagus nerve activity from inflammation
Explored using self-report inventories in 95 MS S’s
Fatigue - Fatigue Scale of Motor and Cognitive Functions (FSMC)
Autonomic: Composite Autonomic Symptom Scale-31 (COMPASS-31)
Autonomic functions predicted Cognitive Fatigue (R2=.47 p<.001)
Pupillomotor dysfunction
Orthostatic intolerance
Bladder dysfunction
Supports model that fatigue explained in part by inflammation-induced
vagus nerve abnormality
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Correlation between Cognitive Fatigue and
Autonomic Composite Score Orthostatic Intolerance
Sander et al (2017) Frontiers in Neurology
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Correlation between Cognitive Fatigue and
Pupillomotor Dysfunction Bladder Dysfunction
Sander et al (2017) Frontiers in Neurology
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CNS and Fatigue in MS
• Recent research suggests that fatigue is
centrally-mediated, perhaps related too:
– Nerve demyelination and inflammation
– Axonal impairments
– Altered functional cerebral activity
(Schapiro, 2002; Hillary et al, 2003)
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Basal Ganglia and Fatigue
• Fatigue involves the non-motor functions
of the basal ganglia
• central fatigue result of
– “failure in the integration of limbic input and
motor functions within the basal ganglia
affecting the striatal-thalamic-frontal cortical
system”
Chaudhuri & Behan, 2000
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Consider the Following Model
• Fatigue is likely an interaction between
environmental factors (e.g., stress,
trauma) and complex physiological activity
• Environmental factors can result in flurry of
physiological activity
– including cytokine release
• Pro-inflammatory cytokines operate as a
stimulus for HPA activation and NT activity
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Consider the Following Model
• Well known that basal ganglia vulnerable to various insults such as:
– Hypoxia
– Viruses
– Pro-inflammatory cytokines
– Alterations in neurotransmitter balance
• Thus, basal ganglia may play critical role in fatigue
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Consider the Following Model
• Basal ganglia communicates with:
– Frontal lobes via striato-cortical fibers
• Reduced NT activity are hypothesized to result in
suppression of frontal lobes
– Thalamus via striato-thalamo-cortical loop
• This hypothesized model of the basal
ganglia is best model currently available
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Environmental Factors
Physiological Factors
e.g. Endocrine response
HPA Activation
Neurotransmitter Activity
Activates Basal Ganglia
Frontal Lobes Thalamus
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Conclusions: Pathophysiology of
Fatigue
• Some progress is being made regarding
pathophysiology
• Models are now available for future
research
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Overview
• History of Fatigue
• What is Fatigue
• Fatigue in General population
• Fatigue in Clinical Populations
• Measurement of Fatigue
• Pathophysiology of Fatigue:
–Neuroimaging and Fatigue • Treatment of Fatigue
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Is there a relationship between fatigue
and measures of brain functioning?
• Structural MRI
• Electrophysiological (not discussed here)
• Functional neuroimaging
• Multiple Sclerosis as illustration
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Basal Ganglia and Central Fatigue Chaudhuri & Behan, 2000, 2004
• Fatigue involves the non-motor functions
of the basal ganglia
• central fatigue result of
– “failure in the integration of limbic input and
non-motor functions within the basal ganglia
affecting the striatal-thalamic-frontal cortical
system”
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Brain Mechanisms of Cognitive
Fatigue
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Brain Mechanisms of Cognitive
Fatigue
• These areas have been associated with
cognitive fatigue in:
– Parkinson’s Disease
– Multiple Sclerosis
– Traumatic Brain Injury
– Chronic Fatigue Syndrome
– Gulf War Illness
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Fatigue and Brain Functioning in MS:
Structural MRI
• Not related to fatigue
– brain volume, T2 lesion load, atrophy, BPF, etc
• Marrie et al (2005)
• Tartaglia et al (2004)
• Filippi et al (2002)
• Colombo et al (2000)
• Mainero et al (1999)
• Bakshi et al (1999)
• Van der Werf et al (1998)
• Codella et al (2002a, 2002b) (DTI or magnetic transfer imaging )
• Gobbi et al (2014) (GM, WM atrophy)
• Ricciteli et al (2011) (T2 lesion load)
None of these studies looked at cognitive fatigue!
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Fatigue and Brain Functioning in MS:
Structural MRI
• Yes Relationship with fatigue
• Grey matter and cortical atrophy
– Gomez et al (2013) (VBM: white and grey atrophy)
– Derache et al (2013) (grey matter density)
– Riccitelli et al (2011) (VBM: white and grey atrophy)
– Calabrese et al (2010)
– Pellicano et al (2010)
– Sepulcre et al (2009) (grey and white matter)
– Calabrese et al (2007)
– Audoin et al (2006)
• DTI
– Genova et al (2013) *
– Pardini et al (2010)
*only 1 study that looked at cognitive fatigue!
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20% prevalence of chronic fatigue in healthy population
Hypothesized fatigue in healthy associated with BG and prefrontal cortex
883 young HC: 489 male, 394 female
Aim: examine brain white matter structures of fatigue using DTI
mean diffusivity (MD)
Fatigue: Checklist Individual Strength Questionnaire (CIS)
Results:
CIS and CIS motivation subscore associated with increased MD
right putamen, pallidus and caudate
Fatigue may involve abnormal dopaminergic activity in the
basal ganglia that are associated with motivation and reward
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Significant positive correlation between CIS and MD in right putamen
spanning from the palladium to the caudate (x,y,z=32, -12, 2; p<.001)
Nakagawa et al (2016), Scientific Reports
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334 consecutive acute stroke patients
MRI at admission
PSF at 3 months post (FSS >4)
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Localization of acute infarcts (%)
0
5
10
15
20
25
30
35
40
45
PSF (n=78)
No PSF (n=256)
Tang et al, (2010), J. Neurol.
p<.02 p<.03
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Multivariate model of clinical and radiological
predictors of PSF
p value Odds Ratio
Infarcts in B. Ganglia 0.014 2.1
Sex (female) 0.034 1.9
Depression 0.001 1.4
Number of infarcts NS 1.1
Independent predictors of PSF
Tang et al, (2010), J. Neurol.
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500 consecutive acute stroke patients
MRI at admission
PSF at 3 months post (FSS >4)
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Localization of acute infarcts (%)
0
5
10
15
20
25
PSF (n=125)
No PSF (n=375)
Tang et al, (2013), J. Neurol. Sci.
p<.001 p<.043
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Multivariate model of clinical and radiological
predictors of PSF
p value Odds Ratio
Infarcts in Caudate 0.001 6.4
Sex (female) 0.002 2.0
Depression 0.001 1.2
Infarcts in Putamen NS
Independent predictors of PSF
Tang et al, (2013), J. Neurol. Sci
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152 MS divided into hi and low fatigue (FSS > 4)
F-MS vs NF-MS had atrophy in:
Striatum
Thalamus
superior frontal gyrus
inferior parietal gyrus
Supports BG, fronto-parietal association
Did not look at cognitive fatigue
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MFIS cognitive
domain low Hi
Putamen Volume
Middle Frontal Gyrus
Thickness
Calabrese, M. et al., (2010). Multiple Sclerosis, 16(10), 1220-1228
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Figure 1. Lateral views of the pial surface 3D representation with cortical thickness map: representative individuals
Calabrese, M. et al., (2010). Multiple Sclerosis, 16(10), 1220-1228
RED: Cortical areas thicker than 2.0mm GREEN: Cortical areas thinner that 2.0mm
HC Non-fatigued RRMS Fatigued RRMS
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• Time on task effect – during sustained taxing
cognitive load, performance worsens over time
• Induced TOT effect in the scanner
– 15 HC’s perform psychomotor task for 20m
min in scanner
• Psychomotor vigilance test (PVT)
• Arterial spin labeling perfusion fMRI
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a) RT increased with TOT
c) Subjective fatigue increase
From before to after the PVT
Task
d) No correlation between
objective decline and
self-rated fatigue
Behavioral data
Lim et al., NeuroImage, 49, 2010, 3426-3435.
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Sustained PVT performance activates right fronto-parietal attentional
network and basal ganglia (see above)
Better performance across time was associated with greater activation
in fronto-parietal network (MFG, IPC, ACC)
Self-report fatigue did not correlate with behavioral performance
Relationship between self-report fatigue and brain activation not mentioned
Lim et al., NeuroImage, 49, 2010, 3426-3435
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Fatigue and brain functioning in MS:
Functional neuroimaging
• Positive Relationship
– Engstrom et al (2013), fMRI
– * Genova et al (2013), fMRI
– Specogna et al (2012), fMRI
– White et al (2009), fMRI
– * DeLuca et al (2008), fMRI
– Rocca et al (2009), fMRI
– Tartalglia et al (2004), MRS
– Filippi et al (2002), fMRI
– Roelcke et al (1997), PET
* Only 2 study looked at cognitive fatigue!
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10 mTBI and 10 HC
Sustained mental effort during MRI imaging
20-minute long psychomotor vigilance task (PVT)
bar press when see target of 4 zero’s
change in regional cerebral blood flow (rCBF)
self-reported fatigue
FSS >4
VAS
Fatigability at end of PVT associated with increased rCBF in
R middle temporal gyrus
Self reported fatigue associated with increased rCBF in
L medial frontal and ACC
decreased rCBF – frontal/thalamic network
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Self-reported fatigue: VAS no differences at baseline
Significant increase in mTBI group only post PVT
Moller et al, Frontiers Neurol, (2017)
0
1
2
3
4
5
6
7
FSS
mTBI HC
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RT during PVT: Significant increase in mTBI group only
Did not do 2x5 ANOVA
Moller et al, Frontiers Neurol, (2017)
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RTRSD during PVT and VAS-f POST PVT During Quintile 5 only
Moller et al, Frontiers Neurol, (2017)
VAS associated with
RT during end of
Task only
Change in RT from
start to end not
correlated with
change in VAS
before and after MRI
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Current Approach
• Examine primary fatigue using fMRI
• Subjective Fatigue measured using state
fatigue
• “Induce” cognitive fatigue: multiple runs of
cognitive task during fMRI
• Examine how functional imaging changes
with changes in state fatigue
• Relate to behavioral performance
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• Purpose - objectively assess cognitive fatigue in MS
using fMRI
• Hypothesis - persons with MS would show altered
cerebral activation across trials of behavioral task
compared to controls
• This was interpreted as cognitive fatigue.
DeLuca et al, (2008) J Neurol Sci
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Cognitive Fatigue using fMRI
• 15 HC and 15 MS
• Induced cognitive fatigue during scanning
– 4 trials of mSDMT during fMRI scanning
• Hypothesized interaction effect in BOLD
response across trials
– Increased activation in MS
– Decreased activation in HC
DeLuca et al, (2008) J Neurol Sci
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Hypothesized Fatigue Effect
Run 1 Run 2 Run 3
Cere
bra
l A
cti
vati
on
MS
HC
DeLuca et al, (2008) J Neurol Sci
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Modified Symbol Digit Modality
Test
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Run 1
1st half 2nd half
RT
(m
sec)
1600
1800
2000
2200
2400
2600
2800
3000
Behavioral Data
Run 2
1st half 2nd half
Run 3
1st half 2nd half
Run 4
1st half 2nd half
HC
MS
Response time: within- and across- run fatigue
No group differences in accuracy
MS = 98%
HC = 96%
DeLuca et al, (2008) J Neurol Sci
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Within-run fatigue
[-4 31 -19]
Run/trial half
1st half 2nd half
Perc
en
t sig
na
l ch
an
ge
-0.20
-0.15
-0.10
-0.05
0.00
0.05
0.10
Healthy control
Multiple sclerosis
Cerebral Activity in Orbital Frontal Gyrus
DeLuca et al, (2008) J Neurol Sci
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Across-run Fatigue
[24 -67 45]
Run/Trial
1 2 3 4
Pe
rce
nt
sig
na
l ch
an
ge
0.2
0.4
0.6
0.8
1.0
1.2
1.4
HC
MS
Cerebral activity in parietal cortex
DeLuca et al, (2008) J Neurol Sci
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Across-run Fatigue
[-16 -7 19]
Run/Trial
1 2 3 4
Perc
en
t sig
nal change
-0.05
0.00
0.05
0.10
0.15
0.20
0.25
0.30
HC
MS
Cerebral Activity in Caudate
DeLuca et al, (2008) J Neurol Sci
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• 11 moderate-severe TBI and 11 HC
• Induce fatigue in the scanner
• 3 trials of processing speed task (mSDMT)
• Hypothesized interaction effect BOLD response
across trials
• Increased activation in MS
• Decreased activation in HC
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Behavioral Results
0
500
1000
1500
2000
2500
3000
Re
ac
tio
n T
ime
(m
se
c)
TBI HC
Run 1 Run 2 Run 3
Accuracy was 95% in HC and 96% in TBI
Kohl, et al (2009), Brain Injury
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Left Basal Ganglia (Caudate/Putamen)
-12
-7
-2
3
8
HC
TBI
Beta
Weig
ht
1st Half 2nd Half
-20
-15
-10
-5
0
HC
TBI
Beta
Weig
ht
1st Half 2nd Half
Left Middle Frontal Gyrus
Kohl et al (2009), Brain Injury
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-1
0
1
2
3
4
5
6
7
TBI
HC
Run 1 Run 2 Run 3
Left Anterior Cingulate
-20
-15
-10
-5
0
5
HC TBI
2nd Half 1st Half
Right Superior Parietal Lobule
Be
ta W
eig
ht
Be
ta W
eig
ht
Kohl et al (2009), Brain Injury
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Cognitive Fatigue using fMRI
• Altered fMRI activation on mSDMT in MS
and TBI interpreted as cognitive fatigue
• Found only in brain areas hypothesized to
subserve cognitive fatigue (Chaudhuri & Behan,
2000)
• fMRI activation is associated with fatigue,
suggest an objective measurement
• What about subjective fatigue?
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Genova et al, (2014), PLOS one
State fatigue – VAS 0-100
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Towards an operational definition of fatigue
• Two ways to relate subjective reports of fatigue
to brain activation:
– State: “Online” measure of fatigue
(during task performance)
– Trait: “Offline” measure of fatigue
(e.g., over last 2 weeks)
On a scale of 0-100, how mentally fatigued
do you feel, right now, at this moment?
0 100 VAS-F
Also given for anger, tension, happiness, sadness and pain
Genova et al (2014), PLOS one
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Prediction
• Prediction: MS with higher fatigue ratings
will show increased brain activity in ROIs
thought to subserve fatigue vs individuals
with lower fatigue ratings
• ROIs:
– Caudate
– Parietal (Precuneus)
– Prefrontal
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Cognitive Fatigue: MS vs HC
Genova et al (2014), PLOS one
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Fatigue-related Activity in the Brain
Caudate Tail: Activation increases as
VAS scores increase in MS vs HC
Genova et al (2014), PLOS one
MS group required increased activation in caudate vs HC in response to
increasing “state” fatigue
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Examined association between brain activation & cognitive fatigue
TBI = 22 (mod-severe)
HC = 20
4 blocks of difficult (2-back) & control (0-back) WM task
Also looked at mSDMT on different day
Cognitive fatigue (CF) assessed before and after each block
VAS (0-100)
CF used as covariate to assess fatigue-related brain activation
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Towards an operational definition of fatigue
• Two ways to relate subjective reports of fatigue
to brain activation:
– State: “Online” measure of fatigue
(during task performance)
– Trait: “Offline” measure of fatigue
(e.g., over last 2 weeks)
On a scale of 0-100, how mentally fatigued
do you feel, right now, at this moment?
0 100 VAS-F
Also given for anger, tension, happiness, sadness and pain
Wylie et al, (2017), Scientific Reports
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Wylie et al, (2017), Scientific Reports
VAS Results • TBI > HC
• VAS increased
across block
0
10
20
30
40
TBI HC
20
22
24
26
28
30
32
1 2 3 4 5
No group x block interaction
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Wylie et al, (2017), Scientific Reports
n-back and brain
• As CF increased, activation increased in:
– caudate
– posterior cingulate
– superior temporal gyrus
– frontal regions
• Anterior cingulate
• Insula
– parietal areas
• precuneus
• Inferior parietal
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Wylie et al, (2017), Scientific Reports
n-back and brain
• CF & n-back and caudate in TBI separately
• Increased caudate activation with increased CF
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Conclusions
• Chaudhuri & Behan model is supported
– Caudate appears to play a consistent role
• fMRI can be used to measure “primary”
Fatigue
• State fatigue may be a better measure of
“fatigue” than trait instruments
• Cognitive fatigue should not be defined as
decreased performance
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Overview
• History of Fatigue
• What is Fatigue
• Fatigue in General population
• Fatigue in Clinical Populations
• Measurement of Fatigue
• Pathophysiology of Fatigue
• Treatment of Fatigue
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Exercise for Fatigue in MS - treatment
45 RCT’s with
69 interventions
2250 Ms S’s
Mostly RRMS
Heine et al, 2015
Determine effectiveness and safety
Safety not an issue
Effectiveness (reducing fatigue)for:
Endurance
Mixed
“other”
Most studies: fatigue not inclusion criterion
Therapy did not target fatigue specifically
Validated measure of fatigue not used
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Cochrane Database of Systematic Reviews 2015, Issue 5. Art.
No.: CD006788. DOI: 10.1002/14651858.CD006788.pub3.
Pharmacological treatments
for fatigue associated with
palliative care Martin Mücke1,2, Mochamat1,3, Henning Cuhls1,
Vera Peuckmann-Post4 , Ollie Minton5, Patrick
Stone6, Lukas Radbruch1
“Based on limited evidence from
small studies, the evidence
does not support the use of
a specific drug for the treatment
of fatigue in palliative care.”
45 RCT tx fatigue, 4696 participants
cancer 3223
MS 753
HIV/AIDS 514
post polio 58
end stage renal disease 56
multi-type in hospice 30
ALS 28
end stage lung 15
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Search following databases: Pubmed
Embase
Medline
Google Scholar
Cochrane Library
Search yielded: 7 RCT’s involving 723 MS patients
Target: self-reported fatigue
Meta-analysis Results: Current data limited
Amantadine - evidence to reduce fatigue in MS
Modafinil – no evidence
Further RCT’s with larger sample sizes needed
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Std mean diff = -1.09, p<.00001 Std mean diff = -.11, ns
Yang et al (2017) J Neurol Sci
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Pubmed search RCT’s on patient education TX for fatigue in MS
10 RCT’s met criteria, on 1021 MS patients
Meta-analyses showed positive effects on:
fatigue severity
fatigue frequency
NOT for depression
Patient education divided into 2 types:
CBT vs those that teach patients to manage fatigue
CBT was more effective than non-CBT
Individual tx more effective than group tx
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weighted mean difference
-.60 CBT
-.20 non-CBT
CBT stronger effect in reducing fatigue than non-CBT approaches
-.43 overall effect
Wendenbourg et al (2017) PLOS one
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Individual tx stronger effect in reducing fatigue than group approaches
weighted mean difference
Wendenbourg et al (2017) PLOS one
-.80 individual approach
-.17 group approach
-.42 overall effect
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Aim to provide evidence-based recommendations for Tx of MS fatigue
Systematic review revealing:
17 non-pharmacological tx studies
5 pharmacological tx studies
2 combined
Results:
no pharmacological interventions had strong evidence
limited evidence for Amantadine
some evidence for Modafinil
non-pharma interventions mixed conclusions
supporting evidence for energy conservation, exercise
limited support for CBT and mindfulness
Contrasts with other recent reviews in MS
Wendebourg et al (2017)
Yang et al (2017)
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RCT to examine 4 interventions for fatigue in CFS
Specialist medical care (SMC) n=160
Adaptive pacing therapy (APT) n=160
Graded exercise training (GET) n=160
Cognitive behavioral therapy (CBT) n=160
3 sessions of SMC for all groups
14 sessions of therapy over 23 weeks
booster session at 36 week
Outcome assessed at 52 week
CFQ Chalder Fatigue Questionnaire
SF-36 PF physical function
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White et al (2011) Lancet
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White et al (2011) Lancet
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Fatigue
SF-36 PF
White et al (2011) Lancet
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PACE Trial Conclusions
• CBT and GET plus specialist medical care
(SMC) were more effective than SMC
alone in improving:
– Fatigue
– Physical functioning
• At one year after randomization
• Adaptive Pacing (APT) plus SMS was not
White et al (2011) Lancet
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481 (75%) s’s from PACE trial returned questionnaires
2.5 years later
CFQ
SF-36 PF
Specialist medical care (SMC)
Adaptive pacing therapy (APT)
Graded exercise training (GET)
Cognitive behavioral therapy (CBT)
Improvements in fatigue and physical functioning observed
at 1 year were maintained 2.5 years later
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Sharpe et al (2015), Lancet Psychiatry
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Sharpe et al (2015), Lancet Psychiatry
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CFS patients randomly assigned to:
Specialist medical care (SMC) alone (control group) (n=102)
SMC specialist doctors care but was not standardized
SMC with additional guided graded exercise self-help (GES) (n=97)
GES consisted of a self-help booklet describing a 6-step graded exercise
program, 12 weeks to complete, and up to 4 guidance sessions with a
physiotherapist over 8 weeks
Primary outcomes:
Fatigue: Chalder Fatigue Questionnaire
Physical function: Short Form-36 physical function subscale
Both self-rated by patients at 12 weeks after randomization
Lancet. 2017 Jul 22; 390(10092): 363–373.
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CFS Pre – Post Response to Treatment
15
17
19
21
23
25
27
Pre PostGES Control
44
46
48
50
52
54
56
58
Pre Post
GES Control
Chalder Fatigue Questionnaire SF-36 Physical function
Clark et al (2017), Lancet
p<.0001 p<.006
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0
10
20
30
40
50
60
70
GES Control
0
10
20
30
40
50
60
70
GES Control
Chalder Fatigue Questionnaire SF-36 Physical function
% CFS Subjects Respond to Treatment
Clark et al (2017), Lancet
p<.005 p<.0001
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Three RCT’s to improve fatigue in
MS
Dutch TREFAMS-ACE study
group
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Dutch TREFAMS-ACE study group
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Dutch TREFAMS-ACE study group
• RCT in MS subjects with severe fatigue
• 3 trials comparing an active treatment to control
– Aerobic exercise
– Cognitive behavioral therapy (CBT)
– Energy conservation management (ECM)
– 12 45-minute treatment sessions over 4 months
• Control condition
– 3 45-minute sessions with trained nurse over 4 months
• Pre, post, 6 month (from start) and 1 year
• Primary Outcomes
– Checklist Individual Strengths – fatigue subscale (CIS20R)
– Impact on Participation and Autonomy Questionnaire (IPA)
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No improvement
on fatigue or
Social participation
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No effect of ECM on fatigue
No effect on 4 of 5 IPA indices
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Positive effect post –TX
Gradually wore off
Across time
No effect on social
participation
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All show some effect at 16 weeks
ECM not significant
None significant at 26 weeks
CBT has moderate effect size
None show effect at 1 year
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New Treatments?
Neuroscience approach to new
treatments
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Examined if tDCS (transcranial direct current stimulation) can decrease fatigue
tDCS delivered at home via telerehabilitation
DLPFC let anodal tDCS + playing computer game
self administered with real-time guidance
Study 1:
10 session tDCS tx (1.5mA, n=15)
10 session computer game only
Study 2: RCT, 20 sessions
active (2.0mA, n=15)
sham (n=12)
Fatigue assessed: PROMIS Fatigue short form
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p<.05
NS
PROMIS fatigue score range 8-40. Higher score is worse
Significant Fatigue reduction in Study 2
Charvet et al (2017), MSJ
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Rehabilitation through
motivation (reward)
Dobryakova, E., DeLuca, J., Genova, H.& Wylie, G. (2013).
Neural correlates of cognitive fatigue in clinical populations:
Basal ganglia and cortico-striatal circuitry.
Journal of the International Neuropsychological Society, 19, 1-5.
Ekaterina Dobryakova, PhD
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How do we Treat Fatigue?
• No truly effective treatment
• Medication that increases dopamine reduces fatigue
in:
– Cancer patients
– TBI
– CFS
– PD
• Non-pharmacological methods?
– CBT
– Exercise
Work of Ekaterina Dobryakova, PhD
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Fatigue, Motivation & Reward
• Loss of motivational influence of the striato-thalamic inputs to
the frontal lobe is integral to developing fatigue (Chadhuri & Behan, 2000)
• Evaluation of predicted rewards and energy costs might be
central to cognitive fatigue
• When tasks are prolonged, the amount of energy invested to
perform the task increases to the potential rewards, resulting
in decreased motivation to continue or provide effort
• Dopamine is involved in the control of motivational process
and reward seeking behavior
• Disruption of the dopamine system has been proposed as a
mechanism underlying fatigue
Dobryakova, et al., 2013), JINS
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Hypothesized Neural Mechanism of Fatigue
• Due to non-motor function of the basal
ganglia (Chaudhuri and Behan, 2000)
• The Basal Ganglia
– Not only a motor region
– Involved in
• Decision-making
• Learning
• Language
• Widespread projections to the prefrontal
cortex
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Motivation in the Brain Impairment of the Motivational pathway (Dobryakova, et al., 2013, 2015)
Ventromedial
Prefrontal /
Image from Seger, 2008
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Motivational Loop Function • Involved in learning & outcome anticipation
• Learning of action-outcome contingencies
– Studying for a class
• ‘good’ vs. ‘bad’ grade
• Outcome anticipation
– Gambling
• “Do I win if I bet on red?”
• Dopamine-dependent mechanism
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Motivational Loop in Animals & Healthy
Adults and Reward
• Animal studies
– VMPFC & striatal neurons fire to reward
delivery (Schultz, 1992; Schultz et al., 2011; Padoa-Schioppa & Cai, 2011)
• Human studies
– Greater VMPFC & striatal activation to
reward presentation (Dobryakova & Tricomi, 2013; Delgado et al.,
2000; Jessup & O’Doherty, 2011; Balleine et al., 2011)
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Dopamine and Reward: Human Studies
• Motivational network sensitive to presentation of
rewards and punishments
• Dopamine release during reward presentation
• Dopamine agonists increase reward seeking and
enhance activation of the motivational network
e.g. Delgado et al., 2000
Dobryakova & Tricomi, 2013
e.g. Pessiglione et al., 2006
e.g. Pappata et al., 2002
Weiland et al., 2014
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Can fatigue be reduced through reward
anticipation in individuals reporting fatigue?
• Hypothesis
– Motivation will increase the
activity of the fronto-striatal
network (i.e., motivational loop)
in MS reporting cognitive fatigue
– Motivation will decrease fatigue
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investigate whether stimulation of the fronto-striatal network through goal
attainment (potential monetary gain) leads to fatigue reduction in MS and HC
receive monetary reward during the outcome condition of the task but not during
the no outcome condition.
Fatigue decreased, and greater activation was observed
in the ventral striatum in the outcome condition compared
to the no outcome condition in both groups.
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Participants
• Current sample:
– MS: n=19
• Age: 31-58
• Edu: 14.5
– HC =15
• Age: 24-58
• Edu: 15.8
– All female
Dobryakova et al. (2017), Multiple Sclerosis Journal
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The Task: Card Guessing task
• 2 Conditions: Reward and no reward
– Reward condition: subjects told they win
money (but probability is chance)
– No Reward: control condition
• 2 conditions randomized
• Subjective fatigue assessed after each
condition
Dobryakova et al. (2017), Multiple Sclerosis Journal
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Design: fMRI Procedure • Card Guessing Task (Delgado et al., 2000)
• Stimulates reward anticipation
Reward
Condition
Control
Condition
Reward
Condition
Control
Condition
VAS
Fatigue
VAS
Fatigue
VAS
Fatigue
VAS
Fatigue
Time
Dobryakova et al. (2017), Multiple Sclerosis Journal
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Card Task:
Reward Condition
?
3 sec
7
√
+$1.00
1 sec
4
X
- $0.50
1 sec
1-5 sec
Back of a card
Dobryakova et al. (2017), Multiple Sclerosis Journal
Is the number you will see higher or lower than 5
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Card Task:
Control Condition
7
1-5 sec 7
#
3 sec 1 sec
Dobryakova et al. (2017), Multiple Sclerosis Journal
Is this number higher or lower than 5
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Visual Analogue Scale
• Fatigue Visual Analogue Scale (VAS) after
each block
How Mentally Fatigued are You?
0 1 2 3 4 5 6 7 8 9 10
l
5
Dobryakova et al. (2017), Multiple Sclerosis Journal
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Dobryakova et al. (2017), Multiple Sclerosis Journal
Across time, fatigue decreases in reward condition and
increases in the control condition
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fMRI Results
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VS = ventral Striatum
Dobryakova et al. (2017), Multiple Sclerosis Journal
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Summary
• Less fatigue after reward condition
• Increased Activation of the motivational
network in MS and HC during reward
• Supports the dopamine imbalance
hypothesis
• How to apply in rehabilitation setting? • Can reward decrease fatigue?
• What techniques might work?
• What is rewarding? (not always monetary)
– Praise? Bonus? “good job”, achieving goals?
Dobryakova et al. (2017), Multiple Sclerosis Journal
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Effects of Exercise
Intervention on Fatigue
unpublished pilot data
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Progressive resistive training (PRT) been shown to reduce fatigue in MS
Study PRT on fatigue and RSFC of caudate in MS with severe fatigue
Semi-randomly assigned to 16 week home based exercise
PRT (n=5)
Stretching control (n=5)
PRT based on American College of sports Medicine guidelines, 2009
Akbar et al, submitted
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Both groups reduced fatigue PRT group: post training increases in RSFC of caudate vs controls in:
L inferior parietal area
Bilateral frontal regions
Right insula
RSFC correlated with fatigue reduction (L inferior parietal) (r=.52)
Initial support for potential mechanism of PRT on fatigue
Akbar et al, submitted
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Left Inferior
Parietal
Lobule
Right Inferior
Frontal Gyrus
Left Inferior
Frontal Gyrus
Right
Insula
Caudate increased connectivity vs control post training with:
Akbar et al, submitted
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Summary
• Exciting new behavioral techniques may
reduce fatigue by targeting basal ganglia
activity
• Reward may reduce fatigue
– Dopaminergic system
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Overall Conclusions
• Fatigue is a multidimensional construct
which is difficult to define
– State vs trait fatigue
– Fatigue: not always decreased performance
– Use fMRI to study “primary” fatigue
• Chaudhuri & Behan model supported
• Striatum (caudate) plays a key role
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Overall Conclusions
• Self report does not correlate with objective measures of fatigue
• Cognitive fatigue is not straight forward
• Functional imaging offers a new technique to show: – self-reported fatigue may correlate with brain
activity
– need to correlate self report with objective fatigue may no longer be necessary
• Exciting new behavioral techniques may reduce fatigue by targeting basal ganglia activity
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Acknowledgments Glenn Wylie, D.Phil.
Frank Hillary, Ph.D.
Alex Kohl
Helen Genova, Ph.D.
Nancy Chiaravalloti, Ph.D.
Ekatrina Dobryakova, Ph.D.
Joshua Sandry, Ph.D.
Brian Sandroff, PhD
Nadine Akbar, PhD
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Thank You