Dawn Schiehser, PhD

Neuropsychologist 

Research Service 

VA San Diego Healthcare System 

Assistant Professor

Department of Psychiatry

University of California, San Diego

June 24, 2014
Disclaimer 

 Dawn Schiehser, Ph.D., has no relevant relationship to 

disclose with any entity associated with this presentation.

 Her research is supported by the Veterans Administration 

CDA grant program

 Her opinions and assertions provided in this presentation 

are her own and do not necessarily reflect the opinion of 

the Veterans Administration or the University of California.
Poll Question #1

 What is your primary role in the VA?

 Student, Trainee, or Fellow

 Clinician

 Researcher 

 Manager or Policy-maker

 Other
Presentation Overview

 Overview of Traumatic Brain Injury (TBI) and 

Postconcussive Symptoms (PCS) 

 Defining Fatigue in TBI

 Epidemiology and Correlates of Post-TBI Fatigue

 Assessment and Diagnosis of Fatigue in TBI

 Mechanism of Post-TBI Fatigue

 Management and Treatment of Fatigue in TBI
Traumatic Brain Injury (TBI)

 VA/DoD Clinical Practice Guideline for Management of 

Concussion/Mild Traumatic Brain Injury (2009): 

 A traumatically induced structural injury and/or 

physiologic disruption of brain function as a result of an 

external force that is indicated by new onset or 

worsening of at least one of the following:

 (1) any period of loss of consciousness (LOC)

 (2)any loss of memory for events immediately before or after 

the accident (Post-traumatic amnesia; PTA)

 (3) any alteration in mental state at the time of the accident 

(Alteration of Consciousness; AOC)

 (4) neurological deficits that may or may not be transient
Traumatic Brain Injury (TBI)

VA/DoD TBI Severity Stratification Criteria
TBI Severity

80%

10% 

10% 

Mild

Moderate

Severe
Postconcussive Symptoms (PCS)

 Physical

 Fatigue, Headaches, Nausea, Dizziness, Vision 

problems, Sleep disturbance, Noise/Light Sensitivity, 

Balance problems

 Cognitive

 Problems in Attention/Concentration, Memory, 

Processing Speed, Executive function

 Behavioral/Emotional

 Depression, Anxiety, Agitation, Irritability, Impulsivity, 

Aggression 
Postconcussive Symptoms (PCS)

 Approximately 85-90% of individuals experience 

resolution in symptoms within weeks to 3 months 

following mild TBI 

 For 10-15%, symptoms become chronic (persisting 

longer than 3 months*)

 *Definitions of chronic vary from 4 weeks to 6 months 

or longer
Postconcussional Disorder: DSM-IV-TR

A. A history of head trauma that has caused significant cerebral 

concussion. 

B. Evidence from neuropsychological testing or quantified 

cognitive assessment of difficulty in attention or memory.

C. Three (or more) of the following occur shortly after the trauma and last at least 3 months*:

 Becoming fatigued easily

 Disordered sleep

 Headache

 Vertigo or dizziness

 Irritability or aggression with little or no provocation

 Anxiety, depression, or affective lability

 Changes in personality (eg, social or sexual inappropriateness)

 Apathy or lack of spontaneity

*Onset following head trauma; significant impairment in function
Postconcussional Syndrome: ICD-10 

 History of head trauma with loss of consciousness preceding 

the onset of symptoms by a period of up to four weeks

 At least three of the following:

 Complaints of unpleasant sensations and pains, such as 

headache, dizziness, general malaise and excessive fatigue or 

noise intolerance

 Emotional changes

 Subjective complaints of difficulty in concentration and in 

performing mental tasks, and of memory complaints, without 

clear objective evidence (e.g., psychological tests)

 Insomnia

 Reduced tolerance to alcohol

 Preoccupation with above symptoms and fear of brain damage 

with hypochondriacal over-valued ideas / adoption of sick role
Defining Fatigue in TBI 
What is Fatigue? 

 There is no universally accepted definition of fatigue

 Surprisingly, little is known about fatigue...

 What exactly is it?

 What is its function?

 What causes it? 

 Terminology overlap

 tiredness, exhaustion, lethargy, listlessness, “worn out”, 

“petered out”, lack of energy, sleepy...

 What fatigue is not: 

 Sleepiness: feeling of being tired, needing or desiring 

sleep, and which is alleviated by sleep
Defining Fatigue: Primary vs. Secondary 

 Primary: caused by a disease or disorder

 Secondary: results from or exacerbated by a secondary cause (e.g., pain, sleep disturbance, psychological distress)

Pain

• Chaudhuri & Behan, 2000; Ponsford et al., 2012

TBI Fatigue Structural Damage; 

Diffuse Axonal Injury

Fatigue

Metabolic

Sleep 

Disturbance

Cognitive 

Problems Environmental 

Stress

Anxiety/PTSD

Depression Medications
Defining Fatigue: Peripheral vs. Central 

 Peripheral

 Physical, metabolic or muscular 

origin

 Central

 Cognitive/Mental 

 Arises from Central Nervous System 

(CNS)

 “The failure to initiate and/or sustain 

attentional (cognitive/mental) tasks 

and physical activities requiring selfmotivation” (Chaudhuri & Behan, 2000)
Defining Fatigue: Subtypes 

 Central Fatigue Subtypes

 Mental/Cognitive

 Physical

 Others: Emotional/Psychological, Psychosocial 

 State vs. Trait

 State: situational; at a particular point in time

 Trait: over time; more stable symptom

 Acute vs. Chronic

 Acute: transient, immediately following injury 

 Chronic: persisting, longer-term post-injury
Defining Fatigue in TBI 

 Post-traumatic Fatigue (PTF) / Post-TBI Fatigue 

(PTBIF) 

 Central/Cognitive Fatigue 

 Primary 

 Acute (days or weeks) / Chronic (>3 months)

 Definitions vary, making epidemiology difficult to 

describe
Epidemiology and Correlates of Post-TBI 

Fatigue 
Post-TBI Fatigue: Epidemiology

 Fatigue is ubiquitous

 Problematic fatigue occurs in 10-20% of the general 

population

 For those with TBI, fatigue is significantly higher (21%-

77%)

 One of the most common symptoms in TBI

 While post-TBI fatigue may improve, some studies 

suggest that fatigue remains problematic or becomes 

worse over time
Post-TBI Fatigue: Epidemiology

 Veterans a positive or negative VA TBI screen (Scholten et al., 2012)
Post-TBI Fatigue: Epidemiology

 Mixed TBI sample at 2 years (n=254) and 5 years (n= 103) post-injury 

(Olver et al., 1996)
Post-TBI Fatigue and PCS Associations

 PTF not typically associated with age, gender, 

education, TBI severity, or years since injury

 PTF is associated with other PCS (depression, sleep 

disturbance, anxiety, pain) 

 Is fatigue the chicken or the egg?

Model adapted from 

Ponsford et al., 2014
Post-TBI Fatigue and Quality of Life

 Fatigue is one of the most critical PCS (out of 22) associated with 

decreased QoL in Veterans with chronic mild TBI (Schiehser et al., 

2014).
Assessment and Diagnosis of Fatigue in 

TBI 
Assessment/Diagnosis of Fatigue

 No “gold standard” measure of fatigue

 Subjective Assessment

 Interview

 Self-reports 

 Objective Assessment

 Performance decline over time

 Physiological measures

 Imaging 
Assessment of Fatigue: Interview

 Questions to ask during the Interview:

 When did the symptoms of post-TBI fatigue start?

 Did the onset of fatigue symptoms correlate with any other 

event such as starting a new medicine or getting depressed?

 What helps make the fatigue go away, or decrease?

 What aggravates it?

 What triggers it?

 In what ways are you fatigued physically, and when?

 In what ways are you fatigued mentally, and when?

 How is your sleep?

 How is your mood?

 Do you suffer from significant chronic pain? • Dr. Nathan Zasler, www.brainline.org
Assessment of Post-TBI Fatigue: Rule-Outs 

 Rule-outs for PTF

 Seizure-related fatigue

 Hormonal abnormalities, 

like hypothyroidism

 Nutritional deficiencies 

such as low B12, anemia, or 

blood cancers (i.e., 

leukemia)

 Renal failure

 Hepatitis

 Substance use/abuse

 Medications that can cause 

fatigue

 Muscle relaxers

 Pain medication

 Blood pressure 

medications

 Benzodiazepines (Xanax, 

Valium)

 Antihistamines

 Antidepressants

 Antibiotics
Assessment of Fatigue: Self-Report Measures

 A fatigue measure by any other name... is not the same

 State (Situational) vs. Trait (Chronic)

 State: At that specific point in time

 Visual Analogue Scale-Fatigue (VAS-F): “...how you are feeling 

RIGHT NOW.”

 Trait: Longer term (over weeks or months)

 Modified Fatigue Impact Scale (MFIS): “how often fatigue has 

affected you...during the past four weeks.”

 Unidimensional vs. Multidimensional

 Unidimensional: general or overall fatigue

 Fatigue Severity Scale (FSS): Total score derived from 9 items

 Multidimensional: Cognitive/Mental, Physical, other Subtypes 

 MFIS: Cognitive & Physical subscales
Assessment of Fatigue: Self-Report Measures

 Fatigue impact vs. “fatigue” quantification

 Fatigue Impact (e.g., MFIS)

 Fatigue Quantification (e.g., Multidimensional Fatigue 

Symptom Inventory-Short Form; MFSI-SF)
Assessment of Fatigue: Self-Report cont.

 Psychometric properties and use of cut-off scores

 Is it valid and reliable in TBI?

 MFIS validated in mild-moderate TBI (Schiehser et al., 2014)

 Advantages of self-report measures

 Assessment of subjective fatigue as an internal state

 Limitations of self-report measures

 Measurement overlap (depression, sleep disturbance)

 Biases 
Poll Question #2

 Do you use self-report measures of fatigue with your 

patients or research subjects?

 Yes

 No
Assessment of Fatigue: Objective Measurement

 Decline of (cognitive) performance over time

Mental 

Fatigue

 Accuracy & Reaction Time

 Objective is not always associated with subjective fatigue 

 Fatigued individuals may achieve adequate performance

CANTAB accuracy scores at double baseline (T1 & T2) and 

after 2 hours of questionnaires (T3) – Ashman et al., 2008
Assessment of Fatigue: Objective Measurement

 Compensation: The role of effort

 Effort to maintain adequate performance = fatigue

 Measuring Effort as a proxy for fatigue

 Physiological measures (blood pressure)

 TBI and controls performed task adequately, while TBI had 

increased blood pressure (greater effort), which was 

associated with subjective fatigue (Ziino & Ponsford, 2006)

 Neuroimaging (fMRI) 

 Cortical activation = effort = fatigue 
Mechanism of Post-TBI Fatigue
Mechanism of Post-TBI Fatigue

 Theoretical Model of Cognitive Fatigue in TBI

 “Coping Hypothesis” (van Zomeren et al., 1984)

 Cognitive fatigue is due to the constant (mental) effort

individuals with TBI need to exert to compensate for 

cognitive impairments (attentional problems and slowed 

processing) in order to maintain adequate task 

performance. 

TBI Cognitive 

Impairment

Cognitive 

Fatigue

Increased 

Mental Effort

(Adequate) 

Performance
Mechanism of Central Fatigue

 Chaudhuri & Behan (2000, 2004) theoretical mechanistic 

model of fatigue

 Striatal-thalamic-frontal cortical system (“loop”) disruption

 Basal Ganglia and prefrontal cortex-thalamus connection

Prototypical frontal cortico-striatal circuit. Bidirectional arrows: pathways with both afferent and efferent connections. Dotted lines: notional connections. Solid lines: literal connections. Th: 

Thalamus. SN: Substantia nigra. GP: Globus pallidus. Striatum: caudate nucleus and putamen . Model adapted from Hayhow et al., 2013

Anterior Internal Capsule

Glutamate 

(Hansson & Ronnback, 2004)

Basal Ganglia

Dopamine

Chaudhuri & Behan, 2000)
Mechanism of Post-TBI (Central) Fatigue

Study Overview

- 11 moderate to severe TBI v. 11 HC

-fMRI attentional task (mSDMT) 

-No differences in performance 

between TBI and HC

Anterior Cingulate Middle Frontal 

Gyrus

Left Basal 

Ganglia 
Mechanism of Post-TBI Fatigue

 Research is still needed

 Neural correlates of subjective & objective cognitive 

fatigue

 Mild TBI

 Correlates with injury (blast v. blunt) and comorbid 

symptoms (sleep, depression)

 What we’re doing ...

 Neural correlates of cognitive fatigue in OEF/OIF 

Veterans 

 Functional MRI (fMRI), Diffusion Tensor Imaging (DTI) 
Mechanism of Fatigue in mTBI: DTI

 38 Veterans with mild TBI

 Measure of Fatigue: MFIS (Total, Cognitive, Physical)

 Measure of white matter integrity: Diffusion Tensor 

Imaging (DTI) / FA • Schiehser et al., in preparation

Demographics Mean (SD)

Age (years) 32.9 (7.1)

Gender (m:f) 34:4

Education (years) 14.4 (1.6)

Number of TBIs 2.3 (1.1)

% Reporting any LOC 68%

“Worst” TBI LOC duration in minutes 4.68 (9.47)

Months Since Last TBI 59.28 (33.96)
Posterior 

Internal Capsule

Anterior Internal Capsule (AIC)

Posterior

Anterior

Mechanism of Fatigue in mTBI: DTI

 Fatigue (cognitive, but not physical) was associated with 

decreased white matter integrity (FA) in the AIC

 AIC has connections through the caudate and thalamus

 Results support the role of the striatal-thalamic-frontal 

system in fatigue • Schiehser et al., in preparation
Management and Treatment of Fatigue in 

TBI 
Poll Question #3

 Do you treat patients with fatigue?

 Yes, it is a primary symptom I treat

 Yes, but it is a secondary symptom of other 

disorders/diseases that I treat (e.g., depression, sleep 

problems) 

 No, I do not treat fatigue in my patients

 No, I am not involved in treatment work
Management and Treatment of Fatigue

 To treat or not to treat?

 Adaptive theory: Fatigue as a warning signal

 Rest

 Dysfunctional fatigue

 Interferes with activities of daily living

 No empirically supported treatments for PTF

 Two main approaches:

 Pharmacological 

 Behavioral 
Pharmacological Treatment of Fatigue

 What should you treat first?

 Primary vs. Secondary Fatigue?

 Depression 

 Antidepressants: Prozac, Wellbutrin, Effexor, Tricyclics

(Vivactil) 

 Sleep Disorder

 Medication effects (e.g., for pain)
Pharmacological Treatment of Fatigue cont.

 Primary (TBI) Fatigue

 Little research support for medications to treat PTF

 Commonly (off-label) used medications

 Neurostimulants (Ritalin, Dexedrine, Cylert) 

 Dopaminergic medications (Symmetrel) 

 Herbal (St. John’s Wart, Ginko biloba, Ginseng); Caffeine

 Modafinil: 2 double blind, placebo-controlled studies in 

TBI (Jha et al., 2008; Kaiser et al., 2010): No clinical benefits 

over placebo for fatigue

 Ritalin: double blind, cross-over study: decreased 

mental fatigue in 29 mild TBI subjects (Johansson et al., 

2014)
Behavioral Treatment of Fatigue

 Psychoeducation 

 sleep hygiene, nutrition, self pacing (breaks, rest)

 Cognitive Behavioral Therapy (CBT)

 CBT improves fatigue in other populations (MS, CFS)

 8 weeks of CBT for post-TBI insomnia improved fatigue in 11 (mild-severe) TBI patients (Oullet & Morin, 2007)

 Mindfulness-based Stress Reduction (MBSR) 

 Randomized controlled trial of 8 weeks of MBSR in 

TBI/stroke patients; fatigue improved (Johansson et al., 2012)

 Physical Exercise

 Shown to reduce fatigue in other populations (e.g., MS)

 12-weeks (30 minutes; 3x/week) of aerobic exercise on 

treadmill reduced subjective fatigue (FSS) in 10 TBI (50% 

mild) patients (Chin et al., 2014)
Summary and Conclusions

 Fatigue is one of the most common and persistent symptoms of 

TBI and is associated with poor QoL. 

 Post-TBI fatigue is most often defined as central/ cognitive/ 

mental fatigue.

 There is no gold standard measure of PTF; however, it can be 

assessed with self-reports, interviews and objective-based 

methods. 

 PTF appears to involve a disruption in the striatal-thalamicfrontal cortical system. 

 There are no empirically-supported treatments for PTF; however, 

behavioral (CBT, MBSR, Exercise) and some pharmacological 

(Ritalin) treatments appear promising.

 More research is needed to better ascertain the mechanisms, 

trajectory, treatment, and management of Post-TBI fatigue.
References 

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 Department of Veterans Affairs and Department of Defense. VA/DoD Clinical Practice Guideline for 

Management of Concussion/Mild Traumatic Brain Injury (mTBI). April 2009. 

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Rehabil 2008;23(1):52-63.

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Quality of Life in Veterans With Mild to Moderate Traumatic Brain Injury. J Head Trauma Rehabil

2014. Jun 11. [Epub ahead of print].

 Schiehser DM, Delano-Wood L, Jak AJ, et al. Validation of the Modified Fatigue Impact Scale in Mild 

to Moderate Traumatic Brain Injury. J Head Trauma Rehabil 2014. Jan 9. [Epub ahead of print].

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 van Zomeren A, Brouwer W, Deelman B, eds. The riddles of selectivity, speed, and alertness. Oxford: 

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Acknowledgements / Collaborators

 Department of Veterans Affairs, CSR&D

 VA San Diego Healthcare System

 University of California, San Diego

 VA Center of Excellence for Stress and Mental Health

 Collaborators: 

 Vince Filoteo, PhD

 Amy Jak, PhD

 Ariel Lang, PhD

 Alan Simmons, PhD

 Elizabeth Twamley, PhD

 Lab Members:

 Lisa Delano-Wood, PhD

 Scott Sorg, PhD

 Alexandra Clark

 Norman Luc

 Russell Kim
Questions/Contact Information

Dawn Schiehser, PhD 

Neuropsychologist, VA San Diego

Assistant Professor, UCSD

Email: dschiehser@ucsd.edu

Thank you