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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.

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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: langegu@umdnj.eduAccepted 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.

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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

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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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