Research Analysis - Qualitative Questions
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Long-term_cognitive_and_emotio.pdf
Long-term cognitive and emotional consequences of mild traumatic brain injury
C. Konrad1,2*#, A. J. Geburek2,3#, F. Rist3, H. Blumenroth4, B. Fischer5, I. Husstedt6, V. Arolt2,
H. Schiffbauer4,7$ and H. Lohmann6$
1 Department of Psychiatry and Psychotherapy, Philipps-University of Marburg, Germany 2 Department of Psychiatry, University of Münster, Germany 3 Department of Psychology, University of Münster, Germany 4 Department of Clinical Radiology, University of Münster, Germany 5 Department of Neurosurgery, University of Münster, Germany 6 Department of Neurology, University of Münster, Germany 7 Department of Radiology, University of Bonn, Germany
Background. The objective of this study was to investigate long-term cognitive and emotional sequelae of mild
traumatic brain injury (mTBI), as previous research has remained inconclusive with respect to their prevalence and
extent.
Method. Thirty-three individuals who had sustained mTBI on average 6 years prior to the study and 33 healthy
control subjects were matched according to age, gender and education. Structural brain damage at time of testing
was excluded by magnetic resonance imaging (MRI). A comprehensive neuropsychological test battery was
conducted to assess learning, recall, working memory, attention and executive function. Psychiatric symptoms were
assessed by the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) and the Beck Depression
Inventory (BDI). Possible negative response bias was ruled out by implementing the Word Memory Test (WMT).
Results. The mTBI individuals had significant impairments in all cognitive domains compared to the healthy control
subjects. Effect sizes of cognitive deficits were medium to large, and could not be accounted for by self-perceived
deficits, depression, compensation claims or negative response bias. BDI scores were significantly higher in the
patient group, and three patients fulfilled DSM-IV criteria for a mild episode of major depression.
Conclusions. Primarily, well-recovered individuals who had sustained a minor trauma more than half a decade ago
continue to have long-term cognitive and emotional sequelae relevant for everyday social and professional life. mTBI
may lead to a lasting disruption of neurofunctional circuits not detectable by standard structural MRI and needs to
be taken seriously in clinical and forensic evaluations.
Received 13 April 2010; Revised 30 July 2010; Accepted 4 August 2010; First published online 22 September 2010
Key words : Brain injury, cognition, depression.
Introduction
Mild traumatic brain injury (mTBI) is a frequent
medical condition with an incidence of about 100 to
300 per 100 000. mTBI is often used interchangeably
with related terms such as concussion, cerebral con-
cussion or mild head injury (Anderson et al. 2006).
Various definitions of mTBI or concussion exist,
mainly including an induction by biomechanical
forces, a rapid onset of neurological functional
impairments, and grossly normal neuroimaging
studies (mTBI Committee, 1993; Aubry et al. 2002;
Carroll et al. 2004; Cantu et al. 2006; Ruff, 2009). mTBI
may be caused by relatively minor traumata, such as
sport injuries, household accidents, whiplash injuries
or falls (Rickels et al. 2006). Possible acute symptoms
of mTBI comprise short-time unconsciousness, head-
ache, dizziness, irritability, anxiety and impaired
neuropsychological functions such as reduced atten-
tion, concentration or memory problems (Evans, 1992;
Hall et al. 2005). Remission frequently occurs within
hours up to a 1 or 2 months (Jacobson, 1995; Binder
et al. 1997; Schretlen & Shapiro, 2003; Frencham et al.
2005), but may take up to 1 year (Dikmen et al. 1986,
1995; Alexander, 1995). However, some patients suffer
from physical, cognitive or psychological impairments
* Address for correspondence: Dr C. Konrad, Department of
Psychiatry and Psychotherapy, Philipps-University Marburg,
Rudolf-Bultmann-Strasse 8, 35039 Marburg, Germany.
(Email: [email protected])
# These authors contributed equally as first authors.
$ These authors contributed equally as senior authors.
Psychological Medicine (2011), 41, 1197–1211. f Cambridge University Press 2010 doi:10.1017/S0033291710001728
ORIGINAL ARTICLE
even years after the trauma, which may hamper their
reintegration into social, familial and professional life
(Barth et al. 1996; Gasquoine, 1997; McAllister &
Arciniegas, 2002; Ponsford & Schönberger, 2010).
Long-lasting symptoms are often referred to as
‘post-concussion syndrome’ and include somatic
symptoms such as chronic headaches, chronic
pain syndromes, dizziness and visual disturbances.
Frequently encountered cognitive symptoms include
attentional deficits, slowed information processing,
reduced verbal and working memory, and impaired
executive functions. Psychiatric symptoms such as
depressed mood, anxiety, irritability, agitation, poor
motivation, social withdrawal and interpersonal diffi-
culties are also reported frequently (Binder, 1986;
Ashman et al. 2004). The reported prevalence rates for
long-lasting post-concussion symptoms that occur
after mTBI vary from 7–8% (Binder, 1986) to 10–20%
(Alexander, 1995), up to 33% (Rimel et al. 1981).
Patients with post-concussion symptoms repeatedly
consult health-care services, constituting a therapeutic
challenge for neurologists, psychiatrists and psycho-
logists. As these patients often present with symptoms
several years after mTBI, in the absence of visible
brain damage according to standard clinical neuro-
imaging methods, they often arouse the suspicion of
malingering and stir up a debate about the necessity
of treatment and the fair forensic evaluation of
patients who sustained mTBI earlier in life (Green et al.
1999; Paniak et al. 2002; Flaro et al. 2007; Ruff et al.
2009).
Despite their social and scientific relevance, con-
vincing studies on long-term sequelae of mTBI are
rare, and as a recent review pointed out, there is in-
sufficient evidence to determine whether mTBI is
associated with cognitive deficits 6 months or longer
post-injury (Dikmen et al. 2009). The few studies
covering a time period of several years differ with re-
spect to methods and reveal heterogeneous and
sometimes conflicting results (Table 1). Segalowitz
et al. (2001) investigated students who, on average,
suffered from mTBI 6.4 years ago and did not report
any subjective impairment at the time of investigation.
Nevertheless, a comprehensive neuropsychological
assessment revealed attention and information pro-
cessing deficits. Similarly, Vanderploeg et al. (2005,
2007) found impairments in partial aspects of complex
attention and working memory, on average 8 years
post-injury. By contrast, several studies did not find
evidence of cognitive or psychological deficits several
years after the trauma. For example, Ettenhofer &
Abeles (2009) reported that mTBI does not result in
cognitive impairment or psychiatric dysfunction;
however, follow-up testing was performed 2.9 years
after injury.
Diverging methodological approaches, such as
differences in study design or in the assessment of
confounding variables, constitute a crucial issue
(Gasquoine, 1997; Mathias & Coats, 1999). The lack of
a consistent definition of mTBI is one of several
methodological problems. Many authors refer exclus-
ively to the initial Glasgow Coma Scale (Teasdale &
Jennett, 1974) to assess the degree of trauma, whereas
others base their diagnosis on additional criteria, such
as those suggested by the Mild Traumatic Brain Injury
Committee of the American Congress of Rehabili-
tation Medicine (ACRM) (mTBI Committee, 1993;
Carroll et al. 2004; Lezak et al. 2004). Most investiga-
tions rely on retrospective self-reports, that is diag-
nosis and classification are based on patients’ reports
years after the trauma. The selection of the study
sample constitutes another difficulty in mTBI research.
Many studies were unable to exclude false-positive
findings influenced by secondary reinforcers such as
compensation claims (Paniak et al. 2002; Flaro et al.
2007), an issue of paramount importance in evaluating
mTBI (Arciniegas et al. 2005; Merten et al. 2005).
Furthermore, there is the possibility that investigators
overestimate the consequences and subjective mean-
ing of mTBI in the life of the patients by selecting their
study sample from a clinical population still receiving
medical care at the time of assessment. This issue
was confirmed by the meta-analysis of Belanger et al.
(2005), who reported that cognitive impairments after
mTBI in clinical populations yielded effect sizes of
d=0.74, compared to unselected prospective samples with effect sizes of d=0.04. This underlines the importance of the recruitment procedure for this
kind of study. It is essential to include subjects based
on objective criteria (e.g. time of injury) rather than
selecting them according to subjective criteria such as
the presence of self-reported complaints.
Given that the long-term consequences of mTBI re-
main inconclusive, we conducted an investigation of
patients who had sustained mTBI on average 6 years
ago, but with a methodological improvement. Patients
who fulfilled the criteria of the Mild Traumatic Brain
Injury Committee of the ACRM were selected from
the initial clinical charts and included irrespective of
current symptoms. State-of-the-art magnetic reson-
ance imaging (MRI) was conducted to exclude any
structural brain damage at time of testing. We in-
vestigated a broad range of cognitive domains, while
controlling for psychiatric conditions and malinger-
ing, using established psychometric methods. We
hypothesized that mTBI leads to cognitive impair-
ments that are still detectable 6 years after trauma and
relevant for daily living. We further hypothesized that
emotional disturbances are also more frequent after
having sustained mTBI.
1198 C. Konrad et al.
Table 1. Studies investigating long-term cognitive and emotional consequences after a minimum of 6 years after mild traumatic brain injury (mTBI)
Study
Mean interval
after TBI (years) Sample size (n)
Severity of
TBI Main results
First-named
author (year)
Bernstein
(2002)
8 13 mTBI, 10 controls Milda Reduced P300 amplitude in a set of attention tasks, poorer performance in demanding cognitive tasks
Segalowitz
(2001)
6.4 10 TBI, 12 controls Milda Normal functioning on standard neuropsychological measures, but drop in attentional performance
in a demanding context (oddball task), paralleled by electrophysiological changes
Sterr (2006) 6.8 38 TBI, 38 controls Mildb Higher error rate in patients with unaffected reaction times indicate that cognitive loads exceed a
certain threshold in TBI patients earlier than in controls. Subjectively experienced symptoms and
difficulties are related to objectively measurable parameters in neurocognitive function
Vanderploeg
(2005)
8 254 TBI, 539 motor vehicle accident
controls
3214 healthy controls
Milda No group differences in a standard neuropsychological test battery, but in subtle aspects of complex
attention and working memory
Vanderploeg
(2007)
8 254 TBI, 539 motor vehicle accident
controls
3214 healthy controls
Milda Increased likelihood of depression and post-concussion syndrome, visual imperceptions and tandem
gait. Poorer psychosocial outcomes, for example self-reported disability, underemployment, low
income and marital problems
Draper (2007) 10.56 53 TBI Mild to very
severeb Psychosocial functioning lowest in occupational activity domain, highest in the living skills domains;
poor performance on some cognitive tests associated with functional outcome; anxiety and
depression were strongest predictors for outcome
Hetherington
(1996)
5 v. 10 10 TBI 5 years after TBI, 10 TBI 10
years after TBI, 10 controls
Mild to
severeb No significant group differences in mean reaction time; in TBI group, response latency was related to
age and to task demands; no correlations between any dependent measure and severity of injury
Himanen
(2006)
31 61 TBI, 31 controls Mild to very
severeb Mild cognitive decline during follow-up, associated with male gender and age at injury; by contrast,
semantic memory showed improvement
Klein (1996) 25 TBI, mean age=26.4 years, 25 TBI, mean age=35.7 years, 50 controls
Mild to
moderatea Inferior performance of TBI patients to controls in memory parameters, both consolidation and
retrieval; generalized reduced rate of information processing; evidence for accelerated cognitive
aging
Ponsford
(2008)
10.58 60 TBI, 43 controls Mild to
severeb Overall good functional outcome after TBI; post-traumatic amnesia and lower pre-injury education
strongest predictors of outcome; patients with poorer outcome performed worse on information
processing speed, attention, memory and executive function; anxiety strongly correlated with
outcome
Draper (2009) 10.61 54 TBI, 54 close others Mild to
severeb Reports of TBI patients and close others showed high agreement. There was no strong correlation of
subjective reports with test performance. Relationship of test performance with Hospital Anxiety
and Depression Scale (HADS) anxiety and depression scores was much high
a Self-reported TBI. b TBI defined by diagnostic criteria.
The first five studies included patients with mild TBI only. The inclusion was based on self-report in four cases or defined diagnostic criteria in one case, but not on magnetic resonance imaging
(MRI)-based exclusion of brain lesions at the time of testing. The next six studies included patients with mild to moderate or very severe TBI; thus their results may be influenced by the higher degree
of severity.
L on g -term
con sequ
en ces
of m T B I
1 1 9 9
Method
Ethical guidelines
All procedures were approved by the Institutional
Ethical Review Board. The ethical standards of the
Declaration of Helsinki were met and all participants
provided written informed consent.
Subjects
Patients with the clinical diagnosis of mTBI treated
at the University of Muenster in the years 2001 to 2003
were identified by systematic screening of patients’
charts. Inclusion criteria were documentation of the
clinical diagnosis, age at time of testing between
18 and 65 years, and conformance to the research di-
agnostic criteria of the ACRM (mTBI Committee,
1993). These criteria include any period of loss of
consciousness for a maximum of 30 min and/or post-
traumatic amnesia for a maximum of 24 h and/or any
alteration in mental state at the time of the accident
and/or focal neurological deficit(s) that may or may
not be transient. Furthermore, an initial Glasgow
Coma Scale score (if available) of 13–15 measured
30 min post-injury was required. As language-based
neuropsychological tests were used, only native
German-speaking patients were included. An initial
telephone screening was performed to exclude in-
dividuals with head injuries additional to the index
mTBI, psychopharmacological medication, neurologi-
cal diseases, or MRI contra-indications. According to
the charts, 233 patients suffered from mTBI. Of these,
136 could not be contacted because of missing or in-
accurate contact information. Of the remaining 97
patients who could be contacted, 53 did not give
written informed consent. In the remaining 44, two
patients suffered from claustrophobia and terminated
the MRI scan prematurely and three others did not
attend for neuropsychological testing. Three more
patients completed the neuropsychological testing
but denied participation in the MRI. In two out of
36 patients (5.6%) and one out of 36 controls (2.8%),
the MRI scan showed structural lesions. These patients
and the associated control subjects were excluded
from further analysis, thus 33 matched pairs entered
the final analysis.
Healthy volunteers were recruited by advertise-
ment and matched individually to the patients ac-
cording to gender (same gender), age (¡2 years)
and education level (defined as highest graduation
level). As in patients, an initial telephone screening
was performed to exclude prior head injury, any
medical or neurological diseases, or MRI contra-
indications.
Inclusion into final analysis using additional
neuroimaging criteria
Thirty-six patients and 36 matched healthy controls
met the inclusion criteria. As a unique step for quality
assurance distinguishing this study from other neu-
ropsychological investigations and as part of a larger
investigation, a structural MRI was performed at the
time of testing to screen for previously undetected
brain lesions. MRI data were acquired on a 3-T whole-
body scanner (Gyroscan Intera T30, Philips Medical
Systems, The Netherlands). The imaging protocol
comprised the following sequences:
(1) Axial T2-weighted turbo-spin-echo [echo time
(TE)/repetition time (TR) 80/3000 ms; flip angle
90x; 36 contiguous slices; slice thickness 3.6 mm;
field of view (FOV) 240 mm; matrix 400r512; scan duration 5:15 min].
(2) Axial T2*-weighted fast-field-echo sequence
(TE/TR 16 ms/shortest; flip angle 18x; 36 contigu-
ous slices; slice thickness 3.6 mm; FOV 230 mm;
matrix 256r512; scan duration 4:09 min). (3) Sagittally acquired 3D T1-weighted turbo-field-
echo (TE/TR 3.4/7.4 ms; flip angle 9x; 320 slices;
FOV 256 mmr205 mmr160 mm; matrix 512r 410r320 resulting in isotropic voxels with an edge length of 0.5 mm; scan duration 11:09 min).
All scans were evaluated by a radiologist experienced
in neurosurgery (H.S.) who was blinded to subjects
status (patient or control). For two out of 36 patients
(5.6%) and one out of 36 controls (2.8%), the MRI scan
showed structural lesions. These patients and the as-
sociated control subjects were excluded from further
analysis, thus 33 matched pairs entered the final
analysis.
Characteristics
The group demographic characteristics of the remain-
ing 66 participants are displayed in Table 2. None of
the characteristics differed significantly between
groups. In the final cohort, 18 patients had sustained
mTBI due to a traffic accident, six due to a sports in-
jury, and nine due to a fall or a collision. The mean
time elapsed between injury and testing was 6.02 years
(range 4.75–7.25 years).
Materials and procedures
A neuropsychological and psychiatric test battery
containing the following standardized instruments
was performed:
(1) Auditory Verbal Learning Test (AVLT), German
version: Verbaler Lern- und Merkfähigkeitstest
1200 C. Konrad et al.
(Rey, 1964; Helmstaedter et al. 1996). Subjects
learn, reproduce and recognize a list of 15 common
nouns presented over five trials.
(2) Tests for Attentional Performance (TAP),
German version: Testbatterie zur Aufmerksam-
keitsprüfung, versions 1.02c and 1.7, computer-
based (Zimmermann & Fimm, 1992). Attentional
performance was tested using the working-
memory, divided attention and go/nogo subtests
of the TAP. In the working-memory test, subjects
perform a two-back task based on digits, in the
divided attention test subjects have to attend
to and react to visual and auditory stimuli pres-
ented simultaneously, and in the go/nogo subtest
subjects differentiate between critical and non-
critical visual stimuli and prevent inadequate
reactions.
(3) Trail Making Test Parts A and B (TMT-A and
TMT-B; Reitan, 1958; Spreen & Strauss, 1998).
Subjects connect numbered only circles, or both
numbered and lettered circles.
(4) Word fluency tasks (Regensburger Wort-
flüssigkeits-Test, RWT). Subjects name as many
words as possible for the categories ‘initial
letter S’, ‘animals’ and ‘alteration sports/fruit’
(Aschenbrenner et al. 2000).
(5) Digit span of the Wechsler Memory Scale, Revised,
German adaptation (WMS-R). Subjects repeat
progressively longer strings of digits in the same
or in reverse order respectively (Härting et al.
2000).
(6) Beck Depression Inventory (BDI, German adap-
tation) to assess subjective symptoms of de-
pressed mood (Beck et al. 1961; Hautzinger et al.
1995).
(7) To measure patients’ impairment in daily life, we
constructed a 25-item questionnaire (Q-25), com-
parable with the Rivermead Post Concussion
Symptoms Questionnaire (RPQ). Subjects rated
subjectively perceived performance changes that
occurred since their injury, taking into account
different domains of daily living and cognitive
functioning (King et al. 1995).
(8) A standardized Structured Clinical Interview for
DSM-IV Axis I Disorders (SCID-I) was conducted
with all participants (Wittchen et al. 1997).
(9) A German adaptation of the Word Memory Test
(WMT) was performed. This computer-based ver-
bal learning test provides information on possible
negative response bias during test taking, and
measures immediate recognition (IR), delayed
recognition (DR) and consistency (CNS) below
82.5% (Green, 2005).
The complete testing and clinical interview session was
conducted individually for each participant and lasted
Table 2. Characteristics of the study population
mTBI patients Controls Statistics
Number of subjects 33 33
Gender (frequencies) x2(1)=0.0, p=1.0 Female 16 16
Male 17 17
Age at time of testing (years), mean ¡ S.D. 36.7¡12.4 37.0¡12.0 T(64)=0.10, p=0.92 School education level (frequencies)a x2(2)=1.44, p=0.49
Hauptschul-degree 5 2
Realschul-degree 10 11
Abitur 18 20
Further training after school education (frequencies) x2(3)=1.03, p=0.79 In training 6 6
Apprenticeship completed 17 18
University studies completed 9 9
No further training 1 0
Employment x2(1)=0.16, p=0.69 Unemployed 4 3
Employed 29 30
mTBI, Mild traumatic brain injury; S.D., standard deviation. a German terms for school education are not translated into English, as the education systems are fundamentally different. The
‘Hauptschul-degree’ requires 9 years of education at a basic school, the ‘Realschul-degree’ requires 10 years at a higher level of
education, and the ‘Abitur’ 12–13 years at the highest level of school education.
Long-term consequences of mTBI 1201
about 2–3 h. Test scores were categorized into five
cognitive domains: (1) episodic memory: acquisition
and consolidation, (2) episodic memory: retention and
recognition, (3) working memory, (4) attention, and
(5) executive functions. To control for mood effects, we
also assessed impairment in daily life and depression
(see Table 3) .
For descriptive analysis, means and standard de-
viations (S.D.) were calculated. For statistical analysis,
for each domain the effect of group (patient or control)
on test scores was assessed using multivariate analysis
of variance (MANOVA). Calculations were performed
using SPSS version 15.0. The results of the SCID were
analyzed descriptively.
Results
Group comparisons of neuropsychological and
behavioral data
All seven MANOVAs revealed significant differences
in cognitive performance between mTBI patients
and control subjects. Table 4 shows means, standard
deviations and univariate effects for the 21 neuro-
psychological, two mood and three suboptimal effort
Table 3. List of (neuropsychological) test scores categorized into five cognitive domains, one mood domain and one suboptimal effort
domain
Test scores Description
1. Episodic memory: acquisition and consolidation
AVLT-Sum Trial 1 to 5 Cumulative learning
WMT-Multiple-Choice Delayed cued recognition after 30 min
WMT-Paired-Associations Delayed cued reproduction after 30 min
2. Episodic memory: retention and recognition
AVLT-Trial 6 Recall after interference
AVLT-Trial 7 Delayed recall, 20 min
WMT-Free Recall Delayed free recall after 30 min
WMT-Long Delay Free Recall Long delayed free recall, 50 min
AVLT-Trial 5 minus 6 Loss after interference
AVLT-Trial 5 minus 7 Loss after delay
AVLT-Trial 8 Corrected recognition: hits minus false-positives
3. Working memory
AVLT-Trial 1 Supraspan for verbal material
TAP-Working Memory Working memory performance, reaction time
Digit Span Forwards Supraspan for numerical material
Digit Span Backwards Working memory for numerical material
4. Attention
TAP-Divided Attention Divided attention, reaction time
TAP-Go/Nogo Reaction inhibition, reaction time
TMT-A Information processing
TMT-B Cognitive flexibility
5. Executive functions (word fluency)
Word Fluency-S Lexical word fluency
Word Fluency-Animals Semantic word fluency
Word Fluency-Sports/Fruits Semantic category-alteration
6. Impairment in daily life and depression
BDI Self-rating of depressive symptoms
Q-25 Self-rating of impairment in daily life
SCID-I Rating of psychiatric disorders
7. Negative response bias
WMT-IR Suboptimal effort: score <82.5% WMT-DR Suboptimal effort: score <82.5% WMT-CNS Suboptimal effort: score <82.5%
AVLT, Auditory Verbal Learning Test; WMT, Word Memory Test; TAP, Tests for Attentional Performance; TMT, Trail
Making Test; BDI, Beck Depression Inventory; Q-25, 25-item questionnaire; SCID-I, Structured Clinical Interview for DSM-IV
Axis I Disorders; IR, immediate recognition; DR, delayed recognition; CNS, consistency of immediate and delayed recognition
responses.
1202 C. Konrad et al.
measures across both groups. Fig. 1 displays devia-
tions in cognitive performance of mTBI patients.
(1) Episodic memory: acquisition and consolidation.
Group differences were highly significant [Wilks’
l=0.742, F(3.62)=7.18, p<0.001, partial e2=0.26]. Between-group effects were significant for the par-
ameters WMT-Paired-Associations and AVLT-Sum
Trial 1 to 5. (2) Episodic memory: retention and recog-
nition. The overall effect was highly significant
[Wilks’ l=0.753, F(6.59)=3.23, p<0.01, partial e2= 0.25]. Between-group effects were significant for all
measures except for AVLT-Trial 5 minus 7. (3) Working
memory. Group differences were highly significant in
multivariate analysis [Wilks’ l=0.654, F(4.61)=8.07, p<0.001, partial e2=0.35]. Univariate statistics were significant for three out of four outcomes. (4) Attention.
The main effect was highly significant for this analy-
sis [Wilks’ l=0.785, F(4.61)=4.17, p<0.01, partial e2=0.22]. Group differences were significant in the Trail Making Subtests. (5) Executive functions (word
fluency). For this cognitive function, multivariate
analysis was highly significant [Wilks’ l=0.700, F(3.61)=8.73, p<0.001, partial e2=0.30]. Group dif- ferences were significant for semantic and lexical flu-
ency. (6) Impairment in daily life and Depression. This
analysis showed a highly significant overall analysis
[Wilks’ l=0.718, F(2.63)=12.39, p<0.001, partial e2=0.29]. Both the BDI and the Q-25 resulted in significant group differences. Three patients, but
no controls, had a BDI sum score o18. (7) Response bias. No subject fulfilled criteria for underachieve-
ment, defined as a score in the effort measures of the
WMT <82.5%. There were no significant group dif- ferences in the effort measures of the WMT [Wilks’
l=0.931, F(3.62)=1.532, p=0.215, partial e2=0.07]. None of the patients were involved in compensation
claims due to cognitive and emotional consequences
of mTBI.
To determine whether the above-reported group
differences between mTBI patients and control sub-
jects were modulated by self-reported impairment
in daily life or by actual depressive symptoms, we
performed an additional MANCOVA for each of the
five cognitive domains; including BDI and Q-25 as
covariates affected the reported results only mini-
mally, and all main group differences remained sig-
nificant.
Estimation of the prevalence of manifest neu-
ropsychological impairment in mTBI patients was
based on deteriorated performance with at least 1.5 S.D.
below the mean of the controls in two or more cogni-
tive domains. This resulted in 42.4% of the patients
AV LT
_6
AV LT
_1 to
5
AV LT
_1
TA P_
W M
DS _F
DS _B
W M
T_ M
C
W M
T_ PA
AV LT
_7
W M
T_ FR
W M
T_ LD
FR
AV LT
_5 m
in us
6
AV LT
_5 m
in us
7
AV LT
_8
TA P_
DA
TA P_
Go /N
og o
TM T_
A
TM T_
B W
F_ S
W F_
AN
W F_
SF
Retention and recognitionAcquisition and consolidation
Working memory
3.5 2.5 1.5 0.5
–0.5 –1.5 –2.5 –3.5
3.5 2.5 1.5 0.5
–0.5 –1.5 –2.5 –3.5
3.5 2.5 1.5 0.5
–0.5 –1.5 –2.5 –3.5
3.5 2.5 1.5 0.5
–0.5 –1.5 –2.5 –3.5
Attention and executive functions
M ea
n d
ev ia
ti o
n f
ro m
av
er ag
e (c
o n
tr o
ls )
(z s
co re
) M
ea n
d ev
ia ti
o n
f ro
m
av er
ag e
(c o
n tr
o ls
) (z
s co
re )
Fig. 1. Mean deviation from average of the controls (z scores). AVLT, Auditory Verbal Learning Test; WMT, Word Memory
Test; MC, Multiple Choice; PA, Paired Associations; FR, Free Recall; LDFR, Long Delay Free Recall; TAP, Tests for Attentional
Performance; WM, Working Memory; DS_F, Digit Span Forwards; DS_B, Digit Span Backwards; DA, Divided Attention; TMT,
Trail Making Test, WF_S, Word Fluency – S; AN, Animals; S, Sports/Fruits.
Long-term consequences of mTBI 1203
(14 out of 33) presenting with manifest neuro-
psychological impairment.
Results of the SCID diagnostic assessment
Healthy controls did not reveal any Axis I psychiatric
disorders as assessed by SCID. Three patients had a
mild episode of major depression at time of testing,
two of these as a symptom of recurrent depression.
One of these had already experienced two depressive
episodes before mTBI. Another patient reported one
mild episode of major depression in the time between
mTBI and testing, but was remitted at the time of
current assessment.
Discussion
In this study we investigated a broad range of cogni-
tive domains in patients who sustained mTBI on av-
erage 6 years prior to the study, while controlling for
psychiatric conditions and malingering. We could
confirm our initial hypothesis that considerable cog-
nitive deficits are present in a broad range of cognitive
domains even 6 years after mTBI. Differences between
Table 4. Results
Variables
mTBI (n=33) Controls (n=33) MANOVAs
dMean (S.D.) Mean (S.D.) df F p Partial e2
1. Episodic memory: Acquisition and consolidation [Wilks’ l=0.742, F(3.62)=7.18, p<0.001, partial e2=0.26] AVLT-Sum Trial 1 to 5 58.67 (8.70) 64.58 (5.70) 1 10.65 <0.01** 0.14 0.8 WMT-Multiple-Choice 93.03 (11.72) 95.00 (6.85) 1 0.70 0.408 0.01 0.2
WMT-Paired-Associations 91.82 (13.28) 96.85 (5.21) 1 4.11 <0.05* 0.06 0.5 2. Episodic memory: Retention and recognition [Wilks’ l=0.753, F(6.59)=3.23, p<0.01, partial e2=0.25]
AVLT-Trial 6 12.21 (2.62) 13.85 (1.60) 1 9.37 <0.01** 0.13 0.8 AVLT-Trial 7 12.55 (2.73) 13.85 (1.52) 1 5.74 <0.05* 0.08 0.6 WMT-Free Recall 64.64 (15.67) 78.67 (11.40) 1 17.26 <0.001*** 0.21 1.0 WMT-Long Delay Free Recall 68.06 (16.43) 80.79 (8.94) 1 15.28 <0.001*** 0.19 1.0 AVLT-Trial 5 minus 6 1.58 (1.72) 0.73 (1.13) 1 5.65 <0.05* 0.08 0.6 AVLT-Trial 5 minus 7 1.24 (2.02) 0.73 (1.02) 1 1.68 0.199 0.03 0.3
AVLT-Trial 8 13.52 (2.28) 14.73 (0.52) 1 8.88 <0.01** 0.12 0.7 3. Working memory [Wilks’ l=0.654, F(4.61)=8.07, p<0.001, partial e2=0.35]
LMT-Trial 1 7.88 (1.80) 9.67 (1.60) 1 18.26 <0.001*** 0.22 1.1 TAP-Working Memory 546.78 (152.39) 497.47 (118.89) 1 2.15 0.148 0.03 0.4
Digit Span Forwards 8.33 (1.93) 10.33 (1.51) 1 21.92 <0.001*** 0.26 1.2 Digit Span Backwards 6.85 (2.24) 9.21 (1.73) 1 23.07 <0.001*** 0.27 1.2
4. Attention [Wilks’ l=0.785, F(4.61)=4.17, p<0.01, partial e2=0.22] TAP-Divided Attention 635.95 (62.03) 624.71 (59.36) 1 0.57 0.455 0.01 0.2
TAP-Go/Nogo 495.73 (86.31) 467.12 (61.17) 1 2.42 0.125 0.04 0.4
TMT-A 24.73 (7.77) 19.48 (5.26) 1 10.30 <0.01** 0.12 0.8 TMT-B 59.97 (17.26) 46.48 (14.75) 1 11.64 <0.001*** 0.15 0.8
5. Executive functions (word fluency) [Wilks’ l=0.700, F(3.61)=8.73, p<0.001, partial e2=0.30] Word Fluency-S 25.28 (7.98) 35.33 (7.93) 1 25.96 <0.001*** 0.29 1.3 Word Fluency-Animals 42.03 (11.48) 49.58 (8.80) 1 8.87 <0.01** 0.12 0.7 Word Fluency-Sports/Fruit 25.19 (4.77 27.09 (3.99) 1 3.06 0.085 0.05 0.4
6. Impairment in daily life and depression [Wilks’ l=0.718, F(2.63)=12.39, p<0.001, partial e2=0.29] BDI 6.52 (6.05) 3.85 (4.00) 1 4.46 <0.05* 0.07 0.5 Q-25 49.27 (15.73) 34.48 (7.49) 1 23.79 <0.001*** 0.27 1.2
7. Negative response bias [Wilks’ l=0.931, F(3.62)=1.532, p=0.215, partial e2=0.07] WMT-IR 97.33 (4.30) 98.94 (2.36) 1 3.54 0.064 0.05 0.5
WMT-DR 97.97 (4.85) 99.45 (1.54) 1 2.81 0.099 0.04 0.4
WMT-CNS 96.12 (6.17) 98.67 (2.79) 1 4.66 0.055 0.07 0.5
mTBI, Mild traumatic brain injury; AVLT, Auditory Verbal Learning Test; WMT, Word Memory Test; TAP, Tests for
Attentional Performance; TMT, Trail Making Test; BDI, Beck Depression Inventory; Q-25, 25-item questionnaire; IR, immediate
recognition; DR, delayed recognition; CNS, consistency of immediate and delayed recognition responses; df, degrees of
freedom; S.D., standard deviation.
Significant group difference at: * p<0.05, ** p<0.01, *** p<0.001.
1204 C. Konrad et al.
mTBI patients and controls amounted to medium to
large effect sizes in learning and long-term memory,
working memory, attention, and executive functions.
Previous research on long-lasting consequences of
mTBI yielded ambiguous results. Some investigators
reported no or only subtle differences between control
groups and patients several years after mTBI (Dikmen
et al. 1986, 1995; Frencham et al. 2005; Vanderploeg
et al. 2005). In a comparison of mild to moderate TBI
within 2 months of trauma, Goldstein et al. (2001)
identified no cognitive deficits in the mTBI group.
By contrast, other researchers found significant cog-
nitive impairments even many years after mTBI
(Leininger et al. 1990; Bernstein, 2002; Sterr et al. 2006).
Thus, the debate about long-term deficits of mTBI
remains unresolved. A recent review concluded that,
to date, there is insufficient evidence to determine
whether mTBI is associated with cognitive deficits
6 months or longer post-injury (Dikmen et al. 2009).
It is possible that factors such as depression or
negative response bias influence test performance; we
therefore assessed these variables in the current study
(Bessell et al. 2008). Furthermore, methodological dif-
ferences between studies are large and complicate
comparisons. Some of these investigations suffer from
low sample size, diagnosis relying on self-reports in-
stead of standardized diagnostic assessment at time of
injury, inclusion of various degrees of severity, vari-
able duration between injury and testing, and finally a
large variety of neuropsychological assessment meth-
ods. In addition, the results of previous investigations
may be influenced by the presence of undetected brain
lesions. For our investigation, patients were selected
from the initial clinical charts, the presence of estab-
lished diagnostic criteria for mTBI in the initial clinical
charts was assured, and patients were contacted ir-
respective of current treatment status. Absence of
structural brain damage at the time of investigation
was secured by performing a structural MRI scan
specifically sensitive to TBI. In two out of the initial 36
patients and in one of the initial 36 controls, structural
damage was detected and led to exclusion. This find-
ing is in line with other investigations; for example,
Bruns & Jagoda (2009) reported that about 15% of
patients with clinically diagnosed mTBI present with
acute intracranial lesions detected by cerebral com-
puted tomography. Using 3-T MRI, as we did in this
investigation, the rate of parenchymal lesions was re-
ported to be even higher (Lee et al. 2008). The highest
incidence rate was reported by a group who found
structural lesions in 11 out of 20 mTBI patients (Datta
et al. 2009). Our finding underlines the significance of
initial brain imaging in TBI patients (Stein et al. 2006).
In our investigation, we identified significant defi-
cits in working memory and attention about 6 years
after mTBI. Short-term memory and attention are
known to be affected by mTBI shortly after injury
(Malojcic et al. 2008), but long-term consequences are
less evident. Vanderploeg et al. (2005) investigated
patients with mTBI about 8 years after trauma. Using
non-traditional analysis methods, focusing on the
continuation rate of the Paced Auditory Serial
Addition Test and pro-active interference in the
California Verbal Learning Test, they found subtle
deficits in working memory and attention. Investigat-
ing 38 patients 6.8 years after mTBI, Sterr et al. (2006)
also found deficits of working memory and attention.
As mainly error rates, but not reaction times, were af-
fected, they concluded that the threshold for inefficient
simultaneous management of response accuracy and
speed may be lowered even years after mTBI. In con-
trast to our investigation, the digit span forward and
backward tests did not indicate working memory
deficits in the sample of mTBI subjects; however, the
validity of this observation is limited by the small
sample size of 10 subjects (Segalowitz et al. 2001).
Nevertheless, the authors corroborated deficits of at-
tention by electrophysiological correlates in the P300
component of an oddball task (Segalowitz et al. 2001).
Our findings on working memory are in line with a
recent electroencephalographic (EEG) study in mTBI.
mTBI patients showed impaired verbal and visuospa-
tial attention span, and EEG coherence measures in-
dicated impaired functional connectivity 2.13 months
after mTBI (Kumar et al. 2009b). Thus, previous work
on working memory and attention supports our
observations of deficits even 6 years after mTBI.
In our investigation episodic memory as assessed
by the AVLT and the memory measures of the WMT
was significantly worse in patients compared to con-
trols. This finding is of interest because there is still
considerable debate about whether mTBI might cause
lasting deficits in long-term memory, for example in
encoding or retrieval. Most previous reports of mem-
ory deficits in mTBI are contaminated by the inclusion
of more severe forms of TBI. Klein et al. (1996) ident-
ified impaired memory performance both for consoli-
dating material into memory and for passive retrieval
in 45 patients 3 years after mild or moderate TBI, even
though subjects had no subjective complaints. Draper
et al. (2007) and Ponsford et al. (2008) reported that
memory performance correlated with functional out-
come about 10 years after mild to severe TBI.
Compromised memory functions were also found in
one quarter of TBI patients with relatively preserved
intellectual capacities (Levin et al. 1988). Gupta & Ghai
(1991) reported poorer immediate and delayed free
recall after TBI, whereas Hall & Bornstein (1991) con-
cluded that poorer recall is a lasting feature of memory
function after brain injury. By contrast, Himanen et al.
Long-term consequences of mTBI 1205
(2006) reported good recovery of semantic memory
during a 30-year follow-up in patients with mild
to severe TBI. For isolated mTBI, evidence is sparse.
A recent investigation in high-school athletes showed
that memory deficits persisted for about 7 days, but
resolved by day 10 (Sim et al. 2008). However, Nolin
(2006) reported poor performance in free recall as
assessed by the California Verbal Memory Test in
patients after mTBI, whereas cued recall remained
unimpaired, pointing towards a selective dysfunction
of registration and retrieval processes rather than a
general storage problem. Divergent results may be
explained by other influencing factors, such as atten-
tional load. Recall performances of individuals with
mTBI was similar to controls when words were en-
coded under full attention, whereas they performed
worse when encoding in a divided attention condition
(Blanchet et al. 2009). Our findings indicate that mem-
ory encoding and recall deficits are not confined to
higher degrees of TBI severity, but may be detected
several years after mTBI if a set of sophisticated
neuropsychological tests is used.
In the domain of executive functions, word fluency
tasks tap complex cognitive processes, involving the
perception of a target word, online-maintenance in
working memory, retrieval of its meaning, activation
of related concepts and instruction-dependent active
search for concepts with equivalent meaning (Konrad
et al. 2008). Word fluency tasks have proven to be very
sensitive for the characterization of patients after head
trauma, and impaired performance in word fluency
was observed in patients after TBI (Aschenbrenner
et al. 2000). Word fluency tasks also have proven sen-
sitivity in long-term follow-up of patients after TBI
(Mathias & Coats 1999; Belanger et al. 2005; McHugh
et al. 2006). We also found that word fluency was im-
paired in patients after mTBI. This is in line with the
impairments of working and semantic memory re-
ported above, and with the findings of Draper et al.
(2007) and Ponsford et al. (2008), who reported that
performance in the Controlled Oral Word Association
Test (COWAT) correlated with functional outcome
after mild to severe TBI.
Impairments in daily life were also assessed in
our investigation and differed significantly between
groups. Thus, subtle cognitive impairments indeed
have consequences for daily living. Our finding is in
line with Draper et al. (2007), who found impairments
in self-assessed psychosocial outcome after mild to
severe TBI, that is occupational activity, interpersonal
relationships and independent living skills. By con-
trast, Ettenhofer & Abeles (2009) reported that single-
incident mTBI is of little clinical significance to
long-term cognitive and symptom outcome. Temkin
et al. (2009) reported a dose–response relationship
between severity of injury and social outcomes, but
insufficient evidence for mTBI. Comparisons between
studies are complicated by divergent definitions and
assessment methods of impairments in daily life
functioning. Furthermore, the interval between injury
and testing differs between studies. Notably, self-
assessed psychosocial impairments do not explain the
cognitive impairments measured in this study, as the
effect sizes remained stable after correction for Q-25.
The assessment of emotional consequences 6 years
after mTBI represents another major point of our
study. In daily clinical practice, complaints of de-
pressive mood after mTBI are a frequent clinical and
forensic problem. In studies investigating the occur-
rence of major depression in mTBI, in general about
10–20% of the patients meet diagnostic criteria for
major depression (Deb et al. 1999; Rapoport et al. 2003,
2006). Long-term assessments are often hampered be-
cause patients with different degrees of TBI severity
are included. For example, Draper et al. (2007) re-
ported that 46% of patients with mild or moderate TBI
met criteria for clinical depression, whereas Koponen
et al. (2002) found that 26.7% experienced major de-
pression in the time interval between mild to very se-
vere TBI and the assessment but only 10% showed
depression at the time of the interview about 30 years
after TBI. Depression rates decreased from 31% after
1 month to 17% after 3–5 years in a sample including
patients with mild to severe TBI (Dikmen et al. 2004).
A decreasing depression rate with time after injury
was also supported by Ashman et al. (2004). However,
Whelan-Goodinson et al. (2009), who retrospectively
established pre- and post-traumatic frequencies of
psychiatric disorders (DSM-IV, Axis I), reported a
dramatic increase of major depressive disorder from
17% before to 45% after head trauma, and anxiety
from 13% before to 38% after head trauma. So far, in-
vestigations do not directly support a link between
severity of TBI and occurrence of depression; that is,
more severe trauma is not related to more frequent or
severe depression (Hibbard et al. 1998). This is sup-
ported by our observation indicating an increased rate
of depression even after mTBI.
In our investigation, three out of 33 (9%) patients
fulfilled diagnostic criteria (SCID) of a mild episode of
major depression about 6 years after mTBI. [Even if the
patient who had recurrent episodes before the trauma
is excluded, two out of 33 (6%) still meet diagnostic
criteria.] At first sight, this rate seems low. However,
bearing in mind that we rigorously excluded patients
after moderate or severe TBI and that the interval be-
tween injury and assessment was 6 years on average,
our observation is in line with the rates reported in the
literature. Depressive symptoms were further as-
sessed using BDI self-rating, as depressive symptoms
1206 C. Konrad et al.
are often remarked by the patients themselves even
when third-party raters evaluate normal depression
ratings (Schöning et al. 2009). In line with the SCID
diagnosis, patients scored significantly worse than
healthy patients [mean=6.52 (S.D.=6.05) compared to mean=3.85 (S.D.=4.00), p<0.05]. BDI scores did not interact with cognitive performance measures, as
demonstrated in a MANCOVA model, thus neuro-
psychological impairments cannot be explained by
depression.
Malingering is another frequent concern in the as-
sessment of neurocognitive function in patients after
TBI (Bordini et al. 2002). The rate of negative response
bias in adults after mTBI is much higher than in
second-grade or disabled children (Green et al. 2009).
This is particularly evident when monetary compen-
sation claims come into play, but may also be triggered
by other conscious or unconscious motives (Boone &
Lu, 2003). Although in our investigation no patients
were involved in compensation claims, we tested
putative symptoms fabrication using the WMT, a
state-of-the-art measure for non-credible cognitive
performance (Iverson et al. 1999; Green, 2005). We
were thus able to rule out any negative response bias
in our mTBI group and could ascertain the validity of
our findings.
In summary, our investigation demonstrates sig-
nificant cognitive and emotional impairments on
average 6 years after mTBI. In this study we do not
examine the causes of these impairments, thus we can
only raise some hypotheses. Most frequently, deficits
after TBI are explained by disruption of neuronal
connections by the shearing and stretching forces of
the incident (Graham et al. 2000; Smith et al. 2003). TBI
might cause disruption of neurofunctional circuits,
decreasing cerebral processing speed and interacting
with cerebral functions. External forces seem to be
transmitted mainly to certain predeliction sites that
are more affected than other regions, such as the cor-
pus callosum. Using diffusion tensor imaging (DTI),
reduced fractional anisotropy (FA) as a marker of re-
duced fiber integrity has been observed in the corpus
callosum of patients with moderate TBI, and this
finding was associated with poor neuropsychological
outcome (Kumar et al. 2009a). mTBI patients also
showed reduced FA in some brain regions (Kraus et al.
2007), although findings in the corpus callosum seem
to depend on the time after trauma. Patients with mild
TBI investigated <3 months post-trauma had reduced FA in the genu, whereas patients with mild TBI in-
vestigated o3 months post-trauma showed no sig- nificant differences (Rutgers et al. 2008). Altered EEG
coherence demonstrates that these pathophysiological
processes might indeed occur after mTBI (Kumar et al.
2009b). The emotional disturbances observed after
mTBI may represent an indirect psychological reaction
to the trauma, itself representing a major life event that
is frequently associated with changes in psychosocial
conditions. Emotional changes may also be a direct
consequence of damage to the emotion regulation
system (Draper et al. 2007); for example, left dorso-
frontal brain lesions may increase the probability of
developing depression after TBI (Fedoroff et al. 1992).
A possible explanation for our observations on im-
paired cognitive and emotional function in mTBI may
thus be explained by disruption of important neuro-
functional circuits. Although not assessed by the
T1-, T2- and T2*-weighted imaging sequences used
routinely in the clinical context and applied in this
study, such disruptions might still be present in the
investigated population. DTI might be a useful
imaging modality for assessing more subtle disrup-
tions of structural brain connectivity.
Some limitations of our study need to be acknowl-
edged. Although subjects were matched carefully for
gender, age and education, we cannot fully exclude
systematic differences between groups in other as-
pects. For example, it is possible that a subset of
patients were more interested in participating than
others, although the systematic screening of patients’
charts and the systematic contact of all available
patients independent from actual symptoms was per-
formed to reduce selection bias. The broad age range
(19–64 years) and the balanced gender distribution
(16 females, 17 males) in each group do not favor
this hypothesis; however, the high proportion of in-
dividuals with higher school education in both groups
might indicate a stronger interest in scientific research.
As education levels were matched across groups, this
should not influence our results. Furthermore, our
study cannot answer the question of cause and conse-
quence. It is theoretically possible that subjects in the
mTBI group sustained TBI because their pre-morbid
cognitive or emotional function was already impaired
before mTBI. However, this explanation seems rather
far-fetched, and the fact that no differences existed
between groups concerning age, gender, school and
further education level makes it unlikely that system-
atic differences existed before the brain injury oc-
curred. As a strength of this study, pre-injury and
lifetime psychiatric diagnosis were excluded by the
SCID. Using healthy subjects as the control sample, the
effects we describe may not be specific to mTBI, but
may instead reflect general changes due to traumatic
events. As specificity was not the aim of our study,
further research differentiating various traumatic
events is needed.
In conclusion, our investigation contradicts claims
that mTBI does not result in long-term cognitive or
emotional impairments. By contrast, our investigation
Long-term consequences of mTBI 1207
demonstrates that patients, even 6 years after mTBI,
still show major impairments in a broad range of cog-
nitive domains that can be revealed by thorough
neuropsychological testing. In contrast to many other
studies, we can exclude a significant influence of major
confounding factors, such as depression, malingering
or undetected structural brain damage. Effect sizes of
cognitive deficits were medium to large in a variety of
cognitive domains (partial e2=0.22–0.35, d=0.2–1.3). According to our findings, the notion of complete re-
covery after mTBI is not supported. We suggest that
long-term cognitive and emotional deficits in mTBI
need to be taken seriously when evaluating or treating
patients after mTBI.
Acknowledgments
This study was supported by an IMF grant from
the Medical Faculty of the Westfälische Wilhelms-
University Münster, Germany (KO 210710).
Declaration of Interest
None.
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