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Cognitive Functioning in Gulf WarIllnessG. Lange , L.A. Tiersky , J. DeLuca , J.B. Scharer , T. Policastro ,N. Fiedler , J.E. Morgan & B.H. NatelsonPublished online: 09 Aug 2010.
To cite this article: G. Lange , L.A. Tiersky , J. DeLuca , J.B. Scharer , T. Policastro , N. Fiedler ,J.E. Morgan & B.H. Natelson (2001) Cognitive Functioning in Gulf War Illness, Journal of Clinicaland Experimental Neuropsychology, 23:2, 240-249
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Journal of Clinical and Experimental Neuropsychology 1380-3395/01/2302-240$16.002001, Vol. 23, No. 2, pp. 240±249 # Swets & Zeitlinger
Cognitive Functioning in Gulf War Illness
G. Lange1,3,4, L.A. Tiersky7, J. DeLuca1,2,5,6, J.B. Scharer1, T. Policastro1,
N. Fiedler1, J.E. Morgan1,2, and B.H. Natelson1,2
1Center for Environmental Hazards Research, DVA NJ Health Care System, East Orange, NJ,UMDNJ-New Jersey Medical School, Newark, NJ, 2Department Neuroscience,
3Psychiatry, 4Radiology, and 5Physical Medicine and Rehabilitation,6Kessler Medical Rehabilitation Research and Education Corporation,
West Orange, NJ, and 7Fairleigh Dickinson University, Teaneck, NJ, USA
ABSTRACT
A comprehensive neuropsychological battery was administered to 48 veterans with Gulf War Illness (GWI)characterized by severe fatigue (GV-F) and 39 healthy veterans (GV-H). Subjects were matched onintelligence and did not differ on age, gender, race, and alcohol consumption. Compared to GVs-H, GVs-Fwere signi®cantly impaired on four tasks: three attention, concentration, information processing tasks andone measure of abstraction and conceptualization. After considering the presence of post-war Axis Ipsychopathology, GWI remained a signi®cant predictor of cognitive performance on one of the attention,concentration, and information processing tasks and one abstraction and conceptualization measure.Performance on the remaining two attention, concentration, and information processing tasks was onlysigni®cantly predicted by Axis I psychopathology with post-war onset. The results suggest that Gulf WarIllness is associated with some aspects of cognitive dysfunction in Gulf Veterans, over and above thecontribution of psychopathology.
Following their participation in the Gulf War,
many returning soldiers developed a series of
complaints centering on severe fatigue, muscle
aches, and cognitive dif®culties. This symptom
complex has come to be known as Gulf War
Illness (GWI) (Fukuda et al., 1998; Haley et al.,
1997). It is important for research to determine
whether cognitive dif®culties in Gulf Veterans can
be documented objectively via neuropsychologi-
cal testing. Studies designed to evaluate cognitive
dysfunction by objective neuropsychological
assessment in GVs have yielded con¯icting
results. While some investigators did not ®nd
evidence of cognitive impairment (Axelrod &
Milner, 1997), others found abnormalities across
a broad spectrum of cognitive domains (i.e.,
Gardiner, 1997; Hom et al., 1997; Vasterling
et al., 1998). Some of the reasons for a lack of
consensus may be due to methodological differ-
ences such as absence of a control group (Axelrod
& Milner, 1997) or selection of different neurop-
sychological assessment instruments used to
assess similar cognitive constructs (Sillanpaa
et al., 1997; Sutker et al., 1995). Also, since GWI
is a heterogeneous disorder by de®nition, differ-
ent study entry criteria for Gulf Veterans could
affect neuropsychological performance (Axelrod
& Milner, 1997; Gardiner, 1997; Hom et al.,
1997).
In the present study, we attempted to reduce
the heterogeneity inherent in the multi-system
complaints of the symptomatic Gulf Veteran
population. Recent data indicate (Fukuda et al.,
1998) that fatiguing illness is a common consti-
* Address correspondence to: G. Lange, Department of Psychiatry, ADMC 14, New Jersey Medical School, 30Bergen Street, Newark, NJ 07107 USA. Tel. (973) 972-6838. Fax: (973) 972-8305. E-mail: [email protected] for publication: September 26, 2000.
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tuent of GWI and that over 50% of the most
symptomatic Gulf Veterans ful®ll case de®nitions
for Chronic Fatigue Syndrome (CFS). Thus, we
studied only those Gulf Veterans who ful®lled
published case de®nitions for medically unex-
plained fatiguing illnesses, particularly CFS
(Holmes et al., 1988; Fukuda et al., 1994) and/
or Multiple Chemical Sensitivity (MCS; Cullen
et al., 1987), which is often comorbid with CFS
(Fiedler et al., 1996; Pollet et al., 1998). Com-
monly, self-reported cognitive dysfunction is a
hallmark symptom in civilians with fatiguing ill-
ness and has been investigated widely with objec-
tive neuropsychological measures (DeLuca et al.,
1993,1995, 1997). The most robust ®nding is a
subtle impairment in ef®cient information proces-
sing, most notably in CFS subjects without psy-
chiatric comorbidity (DeLuca et al., 1997). We
adopted the strategy proven successful in civilians
with fatiguing illness and compared neuropsycho-
logical performance, across a variety of cognitive
domains, between Gulf Veterans with and without
GWI (i.e., fatiguing illness). Gulf Veterans were
administered neuropsychological assessment
instruments that have been consistently sensitive
to differences between civilians with fatiguing
illness and healthy controls. In keeping with
these previous reports, we expect to ®nd differ-
ences between Gulf Veterans with GWI and the
control group of healthy Gulf Veterans speci®-
cally on tasks requiring ef®cient information
processing.
Based on reports in the literature, GWI is
highly associated with the presence of psycho-
pathology, most notably Post Traumatic Stress
Disorder (PTSD; Baker et al., 1997) and Major
Depressive Disorder (MDD; Sutker et al., 1993;
1995). Individuals suffering from PTSD have
been found to suffer from a variety of cognitive
dif®culties including alterations in speed and
accuracy of information processing (Wolfe &
Schlesinger, 1997). Similarly, MDD is often
accompanied by inef®cient information proces-
sing (Zakzanis et al., 1998). Thus, we were parti-
cularly interested to examine whether presence
of GWI would still be signi®cantly associated
with neuropsychological performance of Gulf
Veterans when the presence of diagnosed post-
war psychiatric illness had been accounted for.
METHODS
SubjectsThe subjects were 87 Gulf Veterans on the Gulf WarRegistry (for characteristics of Registry participants,see Gray et al., 1998) forming two groups. Onegroup was comprised of 39 healthy veterans withoutcomplaints of fatiguing illness (GV-H) and anotherof 48 veterans with fatiguing illness (i.e., GWI),including prominent complaints of severe fatigue(GV-F). Exclusion criteria were: age greater than 57,history of loss of consciousness for longer than 30minutes, presence of a medical cause for thefatiguing illness, alcohol abuse/dependence withinthe two years prior to study intake, the presence ofany of the following lifetime psychiatric diagnoses:mania, schizophrenia, or eating disorder. As shownin Table 1, no signi®cant differences were foundbetween GV-H and GV-F in age, gender, race,
Table 1. Demographic Variable for GV-H and GV-F Before and After Strati®cation on Presence of Postwar Axis IPsychopathology.
N�87 N�87GV-H w/o GV-H with GV-F w/o GV-F w Axis
GV-H GV-F Axis I Dx Axis I Dx Axis I Dx I DxN�39 N�48 N�34 N�5 N�16 N�32
M (SD) M (SD) M (SD) M (SD) M (SD) M (SD)
Age 34.3 (7.7) 35.5 (8.5) 34.6 (8.1) 32.2 (8.1) 36.4 (9.4) 35.0 (8.1)Gender (Male) 72% 71% 68% 100% 69% 72%Race (Caucasian) 72% 75% 74% 60% 88% 69%Premorbid 10 (2.3) 9 (2.6) 10 (2.1) 8 (2.8) 10 (2.5) 9 (2.7)Estimated IQ(SS)
COGNITIVE FUNCTIONING IN GULF WAR ILLNESS 241
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and premorbid estimated intellectual functioning[derived from WAIS-RVocabulary subtest raw scoresfrequently used for this purpose (Lezak, 1995)].
General ProcedureAfter obtaining informed consent, all subjects weremedically evaluated by an internist according topublished procedures (Schluederberg et al., 1992) torule out medical and/or neurological causes of thefatiguing illness and re-af®rm subject categorization.GV-F ful®lled case de®nitions for the followingfatiguing illnesses: either CFS (n � 27), CFS andMCS (n � 17), or MCS alone (n � 4; see Polletet al., 1998). Generally, to be diagnosed with CFS,Gulf veterans had to report severe fatigue of at least6 months duration, at least a 50% decrease in activityfrom prior levels and at least 7 of 11 symptoms fromthe 1988 case de®nition symptom list (Holmes et al.,1988). In order to receive a diagnosis of MCS(Cullen et al., 1987), Gulf Veterans had to besensitive to 5 of 8 listed chemicals or report unusualsensitivity to everyday chemicals in addition toendorsing 2 of 4 possible life style changes due tochemical sensitivity (Fiedler et al., 1996). Next, a2 1
2hr neuropsychological test battery was adminis-
tered by a trained masters or doctoral levelpsychologist/neuropsychologist blind to groupmembership. Following the neuro-psychologicaltesting, Gulf Veterans underwent a computerizedstandardized psychiatric interview (Q-DIS-III-R;Marcus et al., 1990) administered by trained staffto determine the psychiatric status of the veteransince return from the Gulf War. Finally, a detailedself-report of drug and alcohol history was taken,assessing both the quantity and frequency of drug/alcohol use.
Based on the psychiatric interview, 5 of 39 GV-Hand 32 of 48 GV-F were found to have a post-warpsychiatric diagnosis (see Table 2). Compared toGV-H, GV-F ful®lled diagnoses for MDD, AnxietyDisorders (Simple Phobia, Generalized AnxietyDisorder, Social Phobia, Panic Disorder, Agorapho-bia), and PTSD signi®cantly more often. The
number of alcohol abuse/dependence diagnoseshaving occurred more than 2 years prior to intakewas not signi®cantly different between groups.
Age, gender, race, and premorbid intellectualfunctioning (as estimated by the WAIS-R Vocabu-lary subtest, Standard Score) were not signi®cantlydifferent between groups.
Alcohol and Drug UseAlthough we excluded subjects with DSM-III-Rdiagnoses of alcohol/drug abuse/dependency in the 2years prior to intake, we wanted to evaluate thepossibility that prior alcohol use could have affectedcognitive status. For this purpose, we used thealcohol and drug use questionnaire from theNational Institute of Drug Abuse (NIDA) supportedRutgers Health and Human Development Project(Bates & Tracy, 1990). Both groups reported druguse much more infrequently than alcohol use. Of theparticipating 87 veterans, only 6 admitted tocannabis use prior to their deployment. Therefore,only the amount and frequency of alcohol use wascompared between GV-H and GV-F. As shown inTable 3, no signi®cant differences were foundbetween GV-H and GV-F for the age that drinkingbegan, the total number of years of drinking, theaverage amount of drinks consumed over the pastyear or the total average amount of drinks consumedover lifetime. Comparisons were also not signi®cantwhen veteran groups were strati®ed on absence andpresence of post-war psychopathology.
Neuropsychological BatteryThe neuropsychological test battery consisted of 15cognitive measures assessing ®ve major domains ofcognition (see Table 3): Attention, Concentrationand Information Processing, Verbal and VisualMemory, Abstraction and Conceptualization,Visual-perceptual and perceptual-motor functions,and Fine Motor Function.
1. Attention, Concentration and Information Pro-cessing Measures in this domain assess
Table 2. Frequency Distribution of Post-war DSM-III-R Diagnoses in GV-H and GV-F.
GV-H (n�5) GV-F (n�32) P*
M (SD) M (SD) (S)
Major Depressive Disorder (MDD) 1 (3%) 20 (42%) < .001Anxiety Disorders 2 (5%) 14 (29%) .005Post Traumatic Stress Disorder (PTSD) 1 (3%) 10 (21%) .02Alcohol abuse/dependence > 2 years prior to intake 3 (8%) 6 (12%) .72
*Fisher's Exact Test, 2-tailed.
242 G. LANGE ET AL.
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simple and complex reaction time, ef®ciencyof information processing and mental tracking.Included are the mean scores on the NESsimple and complex reaction time tests, thetotal score on the Paced Auditory Serial Addi-tion Test (PASAT), and the total scores on theWAIS-R Digit Span Forward and Backwardsubtests.
2. Verbal and Visual Memory Measures in thisdomain assess short and long delay verbal andvisual free memory recall. Included are the rawscores on the short and long delay free recallcomponents of the California Verbal LearningTest (CVLT) and the raw scores on the im-mediate and delayed recall conditions on theRey-Osterrieth Complex Figure Test (ROCF).
3. Abstraction and Conceptualization Mea-sures in this domain assess the ability to formabstract concepts and planning ability andinclude the difference score (secs.) between theTrail Making Tests A and B. We calculated thedifference score in order to subtract out themotor component of the task (drawing lineswith a pencil to connect the symbols) as well asthe basic visual attention aspect of the task(scanning for the next symbol to be connectedby a line). Thus, the score that remains isthought to re¯ect the time it takes to plan andconceptualize the task. Another measure in thisdomain was the total number of errors on thecomputerized version of the Category Test.
4. Visual-perceptual and perceptual-motor func-tions One measure in this domain assessesbasic visual perceptual function using the totalscore on the Judgment of Line Orientation Test
(JOL). Another measure, the total score on theWAIS-R Block Design subtest, evaluatesperceptual-motor function.
5. Fine Motor Function The measure in thisdomain assesses ®ne motor speed using totaltime to complete the Grooved Pegboard Testfor each hand separately.
Variations of this test battery have been usedrepeatedly with civilians diagnosed with fatiguingillness and have proven to be a reliable indicator forareas of cognitive strengths and weaknesses in thispopulation (DeLuca et al., 1993, 1995, 1997). Alltests were administered and scored in accordancewith standard published procedures.
Data AnalysisThe data analysis was organized to answer twoquestions:
1. Does cognitive function differ between GulfVeterans with and without GWI? To addressthis question, data comparing the GV-F andGV-H groups were analyzed with MultivariateAnalysis of Variance (MANOVA). A separateMANOVA was conducted for each of the ®vecognitive domains, including Attention, Con-centration and Information Processing, Verbaland Visual Memory, Abstraction and Concep-tualization, Visual-Perceptual and Perceptual-Motor Function, as well as Fine MotorFunction. If domain-wise MANOVA resultswere signi®cant, separate t-tests, adjusted formultiple comparisons (Bonferroni), were runon the variables within each domain.
Table 3. Alcohol Variables for GV-H and GV-F Before and After Strati®cation on Presence of Axis IPsychopathology.
N�87 N�87
GV-H w/o GV-H with GV-F w/o GV-F w
GV-H GV-F Axis I Dx Axis I Dx Axis I Dx Axis I Dx
N�39 N�48 N�34 N�5 N�16 N�32
M (SD) M (SD) M (SD) M (SD) M (SD) M (SD)
Youngest Age 21 (18.5) 26 (25.3) 21 (20.0) 17 (1.3) 27 (28.1) 26 (24.3)
Drinking Began
Total # Years of 13 (18.8) 9 (23.0) 13 (20.1) 15 (4.1) 9 (25.4) 9 (23.7)
Drinking
Average Amount of 92 (230.0) 100 (133.1) 103 (139.5) 77.6 (82.8) 46 (59.5) 115 (278.5)
Drinks Consumed
Over Past Year
Total Average 7559 (19100.4) 3793 (4451.2) 3224 (3948.4) 7665 (6172.0) 8125 (24575.0) 7277 (16144.7)
Amount of Drinks
over Lifetime
COGNITIVE FUNCTIONING IN GULF WAR ILLNESS 243
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2. For each cognitive measure that was signi®-cant in analysis 1, does GWI still contribute todifferences in cognitive performance after ac-counting for post-war psychopathology (MDD,Anxiety Disorders, PTSD)? To answer thesecond question, we used a two step approach.First, a multiple regression model was ®ttedwith the psychopathology variables, MDD,Anxiety Disorders, and PTSD as independentvariables (dichotomous variables) and thecognitive measure as the dependent variable.A conventional statistical selection model(stepwise) was used to obtain a subset ofpredictors (psychopathology variables) thatbest explained the linear association with thedependent variable (cognitive measure; SPSS,1990). To be allowed for entry into the secondstep of the analysis, a psychopathology vari-able had to be signi®cant at the p < :10 level inthe ®rst step. Second, a multiple regressionmodel was ®tted with the selected psycho-pathology variables from the ®rst step andGWI as predictors and the cognitive measureas the response variable.
RESULTS
Does Cognitive Function Differ Between GulfVeterans With and Without GWI?The GV-F group scored signi®cantly below the
GV-H group across two domains: Attention, Con-
centration, and Information Processing [Wilk's
Lambda, F � 4.53 (5,78), p < :001] and Abstrac-
tion and Conceptualization [Wilks' Lambda,
F � 4.06 (2,83), p < :02], as described in detail
below. The overall MANOVA results for each of
the remaining three domains (Verbal and Visual
Memory, Visual-Perceptual and Perceptual-
Motor Function, Fine Motor Function) were not
signi®cant. Presented in Table 4 are the results of
the separate t-tests for the Attention, Concentra-
tion, and Information Processing as well as
Abstraction and Conceptualization domains after
being adjusted for domain-wise multiple pairwise
comparisons.
Attention, Concentration, and Information
Processing
Comparing the group means, performance of
GV-F was signi®cantly impaired on three out of
the ®ve measures in this category. Speci®cally,
GV-F's simple and complex reaction times were
slower and the total score on a complex working
memory task (PASAT) was lower. Groups did not
differ in their performances on the WAIS-R Digit
Span forward and backward tasks.
Abstraction and Conceptualization
Compared to the group of GV-H, GV-F made a
signi®cantly greater number of errors on the
Category test. The difference score on the Trail
Making Test was not signi®cantly different
between groups.
For each Cognitive Measure that wasSigni®cant in Analysis 1, does GWI StillContribute to Differences in CognitivePerformance after Accounting forPsychopathology with Post-War Onset(MDD, Anxiety Disorders, PTSD)?The group of GVs with GWI examined in this
study, showed evidence of high psychiatric co-
morbidityÐ2/3 of GV-Fs carried either single or
multiple post-war psychiatric diagnoses (see
Table 1). Therefore, it is possible that group
differences attributed to GWI (as shown in
Table 4) could be primarily due to the presence
of MDD, Anxiety Disorders, or PTSD, the post-
war psychiatric diagnoses most frequently occur-
ring in veterans participating in this study. Results
of the second analysis are shown in Table 5 and
described below:
Attention, Concentration, and Information
Processing
The ®rst step of the regression analysis showed
that among the psychopathology variables only
MDD was a statistically signi®cant predictor
(< .10) of performance on the NES simple and
complex reaction time tests. For the PASAT,
MDD and Anxiety disorders were both found to
be signi®cant predictors (<.10). PTSD was not
signi®cantly associated with any of the cognitive
variables examined in this domain.
After accounting for post-war psychopathol-
ogy in the second step of the analysis, GWI was
still found to be signi®cantly associated with
performance on the NES simple reaction time
test ( p < :03). The ®tted regression shows that,
on average, after factoring out MDD, simple
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reaction time of GV-F was still 45 seconds slower
than that of GV-Hs. In contrast, after accounting
for post-war psychopathology, GWI was no longer
signi®cantly associated with performance on the
NES complex reaction time test and the PASAT.
Abstraction and Conceptualization
The ®rst step of the regression analysis showed
that none of the psychopathology variables satis-
®ed the predetermined inclusion criterion and
thus were not signi®cantly associated with per-
formance on the Category Test. Therefore, only
GWI was included as a predictor in the regression
model and remained signi®cant (p < :02), as
already shown in analysis 1. The ®tted regression
model shows that, on average, a veteran with GWI
made 13 more errors on the Category test than a
veteran without GWI.
DISCUSSION
The results of the present study show that Veter-
ans suffering from Gulf War Illness, de®ned by a
diagnosis of severe fatiguing illness (CFS and/or
MCS), have signi®cant dif®culties on tasks requi-
ring attention, concentration, information proces-
sing, and the use of abstract concepts. Even after
accounting for the contributions of post-war psy-
chopathology GWI remained as a signi®cant pre-
dictor of poor performance on some cognitive
tasks.
The ®rst goal of this study was to examine
whether, compared to a control group of Gulf
Veterans without GWI (GV-H), Gulf Veterans
with GWI (GV-F) were objectively impaired on
a variety of neuropsychological tasks tapping into
®ve distinct cognitive domains (see Table 4).
Analyses of the data showed that both groups
performed similarly on cognitive measures com-
prising the domains of visual-perceptual, ®ne
motor, and visual and verbal memory functions.
In contrast, GVs-F task performance was signi®-
cantly impaired on tasks comprising the remain-
ing two cognitive domains that address attention,
concentration, and information processing, as
well as abstraction and conceptualization.
Among the ®ve cognitive measures assessing
attention, concentration, and information proces-
sing, GV-F performed signi®cantly poorer than
GV-H on three tasks Ð two reaction time mea-
sures (NES simple and complex reaction time
tests) and an auditory working memory task
(PASAT). Generally, on these three tasks, GV-F
had signi®cantly more dif®culties than GV-H to
process and respond swiftly to task demands. As a
result, GV-F reaction times on the NES simple
and complex reaction time tests were signi®cantly
delayed and the number of incorrect or omitted
responses on the PASAT was greater. GV-F also
Table 4. Results of Students' t-test for Group Comparisons for the Attention, Concentration, and InformationProcessing and Abstraction and Conceptualization Domains.
Cognitive Domain
Attention, Concentration, and Information GV-H (N�39) GV-F (N�48)Processing M (SEM) M (SEM) t p
NES Simple Reaction Time Test (secs.) 263.77 (8.9) 329.25 (14.8) ÿ3.79 <.001*
NES Complex Reaction Time Test (secs.) 384.44 (6.9) 426.36 (13.0) ÿ2.85 .006*
WAIS-R Digit Span Forward (Raw Score) 8.62 (0.4) 8.23 (.34) .76 .45WAIS-R Digit Span Backward (Raw Score) 7.77 (0.5) 6.42 (0.3) 2.42 .02PASAT - Total Score 138.05 (5.7) 117.09 (4.5) 2.94 .004*
Abstraction and Conceptualization
Trail Making Test(Difference Score Trails B- Trails A) 29.52 (1.8) 4.33 (6.1) ÿ1.97 .05Category Test (Total Number of Errors) 38.64 (3.6) 51.38 (3.6) ÿ2.49 .02**
**At a p-level of < .05 the Bonferroni adjusted signi®cance level corresponds to < .01.**At a p-level of < .05 the Bonferroni adjusted signi®cance level corresponds to <.025.
COGNITIVE FUNCTIONING IN GULF WAR ILLNESS 245
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showed evidence of impaired performance on one
of the two tasks included in the abstraction and
conceptualization domain±the computerized ver-
sion of the Category Test. They made signi®-
cantly more errors than GV-H when required to
apply abstract concepts to solve problems on this
complex visual reasoning task. This ®nding was
not due to visual perceptual problems, since basic
perceptual skills were intact in both veteran
groups. Thus, decrements on the Category Test
can be attributed to impairments in higher cogni-
tive functioning, such as ef®cient switching of
response sets. Taken together, the data suggest
that poor neuropsychological performance may
re¯ect an inability to encode, manipulate, process
and apply information quickly, smoothly, and
ef®ciently.
The initial ®nding of the present report sup-
ports results of a recent population-based study,
identifying a subgroup of Gulf veterans with
`̀ PG[Persian Gulf] symptoms'' as `̀ slow cases''
(Anger et al., 1999). Gulf Veterans in that study
had to ful®l inclusion criteria similar to those
employed in this study. However, group differ-
ences between veterans with symptoms and
asymptomatic controls on a number of cognitive
tasks could be attributed primarily to a particular
group of veterans who had signi®cantly delayed
response times (i.e., `̀ slow cases'') and not to the
remaining group of participating veterans (i.e.
`̀ other cases''). Compared to `̀ other cases'', the
subgroup of `̀ slow cases'' had signi®cant pro-
blems on measures involving working memory
and attention. In their report, Anger et al. (1999)
suggested that the de®cits observed in this slow
responding group of symptomatic Gulf veterans
could be associated with either environmental
(neurotoxic) exposure or psychological distress
incurred as a consequence of participating in the
Gulf War.
We also recognized the possibility that differ-
ences in cognitive function between GV-H and
GV-F might be a function of co-morbid psychia-
tric illness with post-war onset. Thus, in a second
set of analyses, we examined whether illness state
remained predictive of poor cognitive perfor-
mance after the contribution of co-morbid psy-
chopathology of post-war onset (i.e. MDD,
Anxiety Disorders) was considered. While the
presence of post-war major depressive disorder
was signi®cantly associated with performance on
the NES simple reaction time task, a diagnosis of
GWI signi®cantly added to the explanation of
delayed responses on this task, above and beyond
Table 5. Multiple Regression Model Predicting Cognitive Performance as a Function of GWI After AccountingFor Post-war Psychopathology.
Parameter (B)Cognitive Domain R2 pr2 M (SEM) p
Attention, Concentration, Information ProcessingNES Simple Reaction Time Test (secs.) .18
(Intercept � 262.45, SEM � 13.3)MDD .05 51.60 (23.4) .03GWI .06 45.30 (20.1) .03
NES Complex Reaction Time Test (secs.) .12(Intercept � 383.37, SEM � 11.3)
MDD .05 41.46 (20.1) .04GWI .03 26.23 (17.1) .13
PASAT-Total Score .19(Intercept � 139.01, SEM � 5.1)
MDD .02 ÿ10.91 (9.0) .23Anxiety Disorders .08 ÿ25.54 (9.6) .009GWI .02 ÿ9.91 (7.9) .22
Abstraction and ConceptualizationCategory Test (Total Number of Errors) .07
(Intercept � 38.64, SEM � 3.8).07 12.73 (5.1) .02
246 G. LANGE ET AL.
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its association with MDD. This was not the case
for GV-F performance on the NES complex reac-
tion time test and the PASAT. A diagnosis of major
depressive disorder with post-war onset was sig-
ni®cantly related to the slowed reaction time
responses on the NES complex reaction time
test, while a post-war diagnosis of an Anxiety
Disorder, not MDD, accounted for the greater
number of errors on the PASAT. Gulf War Illness
alone was signi®cantly associated with veteran's
performance on the Category Test. Overall, the
data suggest that GWI is signi®cantly associated
with aspects of cognition related to response
speed and mental ¯exibility, above and beyond
the contribution of post-war psychopathology.
However, since MDD or Anxiety Disorders can
affect cognitive function a thorough psychiatric
assessment is important when evaluating Gulf
Veterans neuropsychologically.
There are two competing hypotheses often
used to explain the etiology of GWI and the
symptom complex accompanying it, including
cognitive dysfunction. One hypothesis is that
GWI is a consequence of the `̀ emotional dis-
tress'' brought about by stress associated with
war. This wartime stress often manifests itself in
the form of an Axis I diagnosis. Thus, much
attention has been devoted to examine cognitive
functioning in Gulf veterans with PTSD (Deahl
et al., 1994; Sutker et al., 1995a, 1995b; Vasterl-
ing et al., 1998) or those with indices of high
psychological disturbance (Sillanpaa et al., 1997).
Findings of these studies report impairments in
concentration, attention, mental tracking, infor-
mation processing, motor coordination, and
executive functioning (Sillanpaa et al. 1997; Sut-
ker et al., 1995; Vasterling et al., 1998). The
results of the present investigation show that
factors other than psychiatric illness can be asso-
ciated with cognitive dysfunction.
An alternative hypothesis to explain GWI is
related to environmental exposure to toxic agents
during the Gulf War (Anger et al., 1999; Haley
et al., 1997). Such exposure could lead to cogni-
tive dysfunction (Hom et al., 1997). Data from
civilians repeatedly exposed to organophosphates
over a long period of time show a pattern of
impairment in sustained attention, speed of pro-
cessing (Stephens et al., 1995), concentration as
well as memory (Gunderson et al., 1992; for re-
view see Steenland, 1996; Stephens et al., 1995).
Our data indicate that GV-F had poor response
speed and dif®culty with ef®cient set switching.
This outcome may result from neurotoxic expo-
sure that affects both of these aspects of cognition
simultaneously.
One limitation of the present study is the
generalizability of the present ®ndings. Since
our sample was drawn from Gulf Veterans on
the Gulf War registry, the present study accessed a
sample of health-care seeking individuals. It
would be useful for future studies to employ a
sample of deployed non-registry veterans to
address this concern.
In conclusion, the present study shows that
registry veterans with GWI, who ful®ll clinical
criteria for severe medically unexplained fati-
guing illness, demonstrated reduced performance
on tasks assessing the ability to encode, process,
manipulate and integrate information smoothly
and respond ef®ciently. These de®cits do not seem
to be due to impairments in basic motor or per-
ceptual function. While psychiatric factors play a
signi®cant role in cognitive performance speci®-
cally in the area of attention, concentration, and
information processing, the present study shows
that GWI signi®cantly contributes to impairments
in this domain, over and above those associated
with post-war psychopathology. Thus, while evi-
dence is strong that GWI symptoms, including
severe fatigue and cognitive dif®culties may be
due to emotional distress experienced as a con-
sequence of war, GWI as a consequence of
environmental exposure cannot be ruled out.
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