Psychoneuroendocrinology (2004) 29, 1109–1118

*Corresponding author. Tel.: +49-391-6718469; fax: +49-391-6711947.

E-mail address: thomas.muente@medizin.uni-magdeburg.de(T.F. Munte).

0306-4530/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.doi:10.1016/j.psyneuen.2003.12.001

www.elsevier.com/locate/psyneuen

Cognitive changes in short-term hypothyroidismassessed with event-related brain potentials

Thomas F. Muntea,*, Christian Lillb, Gundula Ottingc, Georg Brabantd

aDepartment of Neuropsychology, Otto-von-Guericke Universitat Magdeburg, Universitatsplatz 2,Gebaude 24, 39016 Magdeburg, GermanybDepartment of Neurology, Medical School of Hannover, 30623 Hannover, GermanycDepartment of Nuclear Medicine, Medical School of Hannover, 30623 Hannover, GermanydDepartment of Clinical Endocrinology, Medical School of Hannover, 30623 Hannover, Germany

Received 12 February 2003; received in revised form 2 December 2003; accepted 6 December 2003

KEYWORDSHypothyroidism;Radiation therapy;Cognitive deficits;Event-related brainpotentials

Summary Hypothyroidism is a common clinical problem during 131Iodine-therapy ofthyroid cancer. In the present investigation, possible cognitive dysfunction duringhypothyroid state was assessed by means of neuropsychological tests and therecording of event-related brain potentials (ERPs).

Fifteen patients undergoing therapy for thyroid cancer were examined twice: (1)substituted with thyroid hormones, (2) during hypothyroid state immediately priorto treatment. Standard neuropsychological tests were applied during both sessionsand subjects showed a mild-to-moderate impairment in their hypothyroid state. Inaddition, ERPs were recorded from 19 scalp sites while subjects performed two vis-ual search tasks. The serial task required the effortful one-by-one scanning of sev-eral items within a visual array, while the parallel task allowed processing of allstimulus items in parallel and automatically. ERPs showed a marked amplitude dec-rement and delay of the P3 component known to index the speed of stimulus evalu-ation and the amount of available processing resources. This effect was present onlyfor the serial search task, while no changes were seen in the parallel search task.These data show that hypothyroidism during 131Iodine-therapy is associated withclinically relevant cognitive dysfunctions, especially with effortful attentiondemanding tasks.# 2003 Elsevier Ltd. All rights reserved.

1. Introduction

The effects of congenital (Weber et al., 1995;

Mitchell and Klein, 1995; Rovet and Alvarez, 1996)

or acquired hypothyroidism in adulthood on cogni-tive and mental functioning have been the subjectof intensive study (Haggerty et al., 1986, 1990;Osterweil et al., 1992; Leentjens and Kappers,1995; Derksen-Lubsen and Verkerk, 1996; Lubosh-itzky et al., 1996; Baldini et al., 1997; Dugbartey,1998; Hendrick et al., 1998). There is growing evi-dence that even subclinical hypothyroidism maybeassociated with a risk of cognitive decline (e.g.,

T.F. Munte et al.1110

Volpato et al., 2002). Less information is availableon short-term deficiency of thyroid hormones buta recent study by Constant et al. (2001) has showna generalized decrease in regional cerebral bloodflow and in cerebral glucose metabolism in hypo-thyroid vs. euthyroid state in patients that hadundergone thyroidectomy for carcinoma. Thesephysiological changes were accompanied by defi-cits on psychological testing.

Yet, until recombinant human thyrotropin forshort-term use was widely available, hypothyroid-ism presented an important and unavoidable clini-cal problem for the use of radioiodine in testingand treatment of patients with thyroid cancer(Guimaraes and DeGroot, 1996; Ladenson et al.,1997; Reynolds and Robbins, 1997).

Sensitive and ecologically valid methods for afine-grained analysis of cognitive dysfunction inhypothyroidism are, therefore, highly desirable. Inthe present study, we tried to mimic the dailytask of identifying a visual object in a complexenvironment, as is required, for example, whenone has to look for a traffic sign while driving.Two types of laboratory tasks have been designedto assess these visual search processes. The firstone allows the subject to process all items withina stimulus array in parallel, with target detectionbeing a seemingly effortless fast process that doesnot draw heavily on the subject’s processingresources. This can be contrasted with a secondtype of task in which the scanning of the items ofan array is done serially and the target detectionis effortful (Treisman and Gelade, 1980; Luck andHillyard, 1990, 1995). Effortless parallel searchusually occurs when the target item contains anextra feature that is absent from the distractoritems, causing it to pop-out from the stimulusarray. For example, in the stimuli used in thepresent study (Fig. 1A), the triangle with an extrahorizontal line is readily detected in the paralleltask. In contrast, the targets in serial search con-ditions are either characterized by the absence ofa stimulus-feature or require the search for a con-junction of several features. Fig. 1B shows thestimuli used in the serial search experiment of theexperiment described here. The triangle with amissing horizontal line is not easily detected. Infact, every item of the array has to be scanneduntil the subject encounters a target item. Thus,the number of items in an array has a pronouncedeffect on reaction times and error rates underserial (but not parallel) search conditions. Luckand Hillyard (1990, 1995) were the first research-ers to adapt the search task for the recording ofevent-related brain potentials (ERPs) (Munte et al.,2000). These are minute voltage fluctuationswhich can be extracted from the ongoing EEG by

computer averaging. Their peaks and troughs(components) have been shown to vary systemati-cally as a function of cognitive processes. Usingthis technique, Luck and Hillyard (1990) foundthat the amplitude and latency of a specific ERP-component, the P3, was sensitive to the searchmode (parallel vs. serial) and to the number ofdistractor items present in the serial search con-dition. As the latency of the P3 component can beused as an index for the time it takes to evaluatea stimulus (Kutas et al., 1977; McCarthy andDonchin, 1981), ERPs provide useful informationon the chronometry of information processing.Further investigations have shown that the para-digm is sensitive to delays in information proces-sing caused by drugs or neurological disease(Heinze et al., 1992; Munte et al., 1996, 1997).For example, in a group of patients with Hunting-ton’s disease, it was found that the P3 latencywas disproportionately slowed for the visual arrayscontaining more items.

We predicted that the effects of hypothyroidismshould be more pronounced in the serial searchtask and that parallel search should be affectedonly minimally.

Note that in addition to the cognitive effects ofhypothyroidisms, a direct radiation effect on thebrain and consequently also on cognitive functionsis possible. Detrimental effects of irradiation ofthe brain on cognitive functions have been well-documented (e.g., Brown et al., 2003; Torreset al., 2003). However, because radioiodine treat-

Examples for stimuli in the parallel (

Fig. 1. A) andserial (B) search tasks.

1111ERPs in hypothyrodism

ment leads only to a relatively small radiationdose to the brain and, moreover, radiation effectsgenerally take a long time to develop, sucheffects can be excluded in the present study.

2. Materials and methods

All procedures were approved by the local insti-tutional review board.

2.1. Subjects

The study was approved by the local institutionalreview board. Before entering the study, patientssigned an informed consent form. They wereinformed that they were allowed to withdrawfrom the study at any time. Sixteen patients (11women, age range 21–37 years, mean 31 years, 13right-handed) were recruited from the populationtreated at the Department of Nuclear Medicine atHannover Medical School. All patients had beendiagnosed with well-differentiated carcinoma ofthe thyroid, had undergone thyroidectomy and atleast one therapy session with 131Iodine. Onepatient was did not participate in the second ses-sion since recurrence of the tumor necessitatedan operation. Ten of the remaining 15 patientswere women. Mean age was between 22 and 39years (mean 31.5). Thorough examination of thepatients by one of us (G.O.) did not reveal any sig-nificant health problems, especially no neurologi-cal diseases, in addition to their thyroid problem.All had normal or corrected to normal vision.

Patients were recruited during a routine exam-ination at the Department of Nuclear Medicine,carried out to prepare the patients for a routineiodine test following their thyroid cancer diag-nosis. Each participant took part in two 5 h ses-sions that included the recording of ERPs,neuropsychological testing, laboratory investiga-tions and cardio-vascular tests: the first sessiontook place immediately prior to therapy after a 4week interruption of the thyroxine-substitutiontherapy. Thyroid stimulating hormone (TSH) andthyroid hormone levels were measured by com-mercially available assay systems. The second ses-sion was conducted 2–3 months later when thesubjects had thyroxin levels in the upper normalrange. Pertinent laboratory results are given inTable 1.

No formal power analysis was carried out forthe present study to determine the necessarynumber of subjects. However, previous studiesusing the same paradigm in Huntington’s patients(Munte et al., 1997), patients with amyotrophicsclerosis (Munte et al., 1999) or normal subjects

under the influence of benzodiazepines (Munteet al., 1996) have revealed significant ERP andbehavioral effects with group sizes of 10–15 witheffect sizes of up to 3.

2.2. Neuropsychological testing

A set of standardized neuropsychological tests wasadministered to the patients that included mea-sures of visual attention and concentration (d2test; Brickenkamp, 1994), auditory attention span(digit span forward, taken from the German ver-sion of the Wechsler Adult Intelligence Scale;Tewes, 1991), response inhibition and inter-ference (Stroop test; MacLeod, 1991) and memory(Verbal Learning and Memory Test, VLMT, Helm-staedter et al., 2001; similar to California VerbalLearning Test, Elwood, 1995). To aid theinterpretation, all results with the exception ofthe Stroop test were z-transformed using the nor-mative data contained in the cited references.Higher z-values signify better performance. Forthe Stroop test, the time to complete a stimuluscard was scored (seconds). In this case, highervalues denote worse performance.

The ‘‘d2 test’’ by Brickenkamp is a letter can-cellation task which requires visual selective andsustained attention. It consists of rows of the let-ters ‘‘d’’ and ‘‘p’’. The patient is instructed tocross out all letters ‘‘d’’ having two small dashes(either two above, two below, or one above andone below). Letters ‘‘d’’ with no dash, one, threeor four dashes as well as all different versions ofthe letter ‘‘p’’ are to be ignored. The perform-ance is scored for errors and number of targetscrossed out within the allotted time (14 lines; 20 sper line; 4:40 min total time). Published data(e.g., Brickenkamp, 1994) show that the test–ret-est reliability is high and that learning effects playno role, if this test is applied twice within severalmonths.

Table 1 Patient data

Parameter

Euthyroid Hypothyroid p

Body weight (kg)

68.8 (12.2) 72.2 (14.1) <0.05 BMIa (kg/m2) 23.5 (3.6) 24.3 (3.9) <0.05 TT3b (nmol/l) 2.0 (0.45) 0.73 (0.16) <0.001 TT4c (nmol/l) 158.1 (26.9) 17.3 (14.3) <0.001 TSH (mU/l) 0.83 (1.44) 86.3 (75.1) <0.001 TBG (lg/ml) 23.3 (5.9) 28.1 (6.5) <0.001 SHBG (lg/ml) 7.8 (4.9) 5.1 (5.7) <0.01

aBody mass index.bTotal T3.cTotal T4.

T.F. Munte et al.1112

For the Stroop test, a version used by Ruff aspart of the San Diego Neuropsychological Test Bat-tery (see, for example, Niemann et al., 1990) wasused. Norms for German speaking subjects havebeen obtained in the authors’ laboratory. TheStroop test is based on the finding that it takeslonger to name the color of colored patches thanto read words, and even longer to read printedcolor names when the print ink is a color differentthan the name of the color word. Firstly, subjectsmust read color words printed in black ink; sec-ondly, subjects are required to name the color ofthe ink used to print short common Germanwords; thirdly, subjects state the color of the inkused to print the name of a different color. A dis-proportionate slowing for the most difficult con-dition (color words printed in colored ink) can befound in some neurological conditions (MacLeod,1991). Virtually no learning effects are observedin the Stroop test (MacLeod, 1991), which is whyno parallel test version had to be used.

The VLMT is based on the repeated auditorypresentation of 15 German words. After each offive presentations, the subject is required torepeat as many of the 15 words as possible. Thesixth run comprises the presentation of an inter-ference list of 15 words followed by another pres-entation of the original 15 items. This test allowsdelineation of overall performance of the subject,his or her learning curve and his or her suscepti-bility to interference. Two parallel forms wereused in the current study with the order of formscounter-balanced across subjects.

2.3. Stimuli and procedure

2.3.1. Experiment 1: parallel searchThe first experiment addressed the extraction ofan additional feature from the stimuli present inan array containing a number of distractor ele-ments. The array consisted of eight items placedat random locations on the monitor within animaginary rectangle 8.2

�of visual angle wide and

6.5�high. There were two types of items: a tri-

angle with one vertical left side and two obliquesides pointing to the right, and the same trianglewith a horizontal line extending leftward from thevertical line as an additional feature (see Fig. 1A).Standard stimuli, i.e. those that did not require aresponse included eight plain triangles, while thetarget stimuli contained one triangle with theadditional horizontal line and seven plain triangles(see Fig. 1A). The positions of the target and dis-tractor items were randomized from one arraypresentation to the next. The stimulus durationwas 1.5 s, and the interstimulus interval variedrandomly between 3 and 3.5 s. A total of 100standard and 100 target stimuli were presented in

a randomized fashion. The subjects’ task was tosearch the stimulus arrays for a target item and torespond as quickly as possible by pressing a buttonheld in the right hand.

2.3.2. Experiment 2: serial searchThe stimuli of Experiment 2 were very similar tothe ones used in Experiment 1. However, thestimulus arrays were constructed such that theplain triangle was the target item, while the trian-gles with the additional horizontal line weredesignated the distractor items (Fig. 1B). More-over, the set size (i.e. number of items within anarray) randomly varied between 4, 8 and 12(33.3% of the presentations in each condition).Again, 50% of the stimuli contained the targetitem (plain triangle) requiring a speeded buttonpress. A total of 64 targets and 64 standard stim-uli were delivered for each of the three set sizes.All of these stimuli were presented in a rando-mized fashion with the same timing as thatdescribed for Experiment 1. It has been shownthat learning effects in search task take exten-sive, repeated practice sessions to occur (Pashlerand Johnston, 1998). Thus, no learning effectswere expected in the current study. Moreover,previous medication studies of our group usingdouble-blind cross-over designs did not show ordereffects (e.g., Munte et al., 1996).

2.4. Recording

The EEG was recorded from all positions of theInternational 10/20 system (Jasper, 1958) withtin-electrodes mounted in an elastic cap. The ref-erence electrode was located on the right mas-toid. Horizontal eye movements were monitoredwith electrodes located on the outer ocular can-thi, which were referenced to one another, andvertical eye movements were detected through anelectrode located below the right eye, which wasreferenced to the electrode on the right outerocular canthus. All channels were amplified usinga 10-s time constant, filtered with a bandpassbetween 0.01 and 35 Hz (half amplitude low andhigh frequency cut-offs), digitized at a rate of 256Hz, and stored on a hard-disk.

2.5. Data analysis

After artifact rejection for excessive eye move-ments or amplifier blocking, ERPs were averagedseparately offline for correctly detected targetsand correct rejections of non-targets. The ERPwaveforms were quantified by mean amplitudemeasures in several different time windows rela-tive to the prestimulus baseline. As the main com-ponents of interest in the present investigation

1113ERPs in hypothyrodism

(P1, N1, P3) have a posterior distribution, themeasures were carried out only on those electro-des clearly showing experimental effects (C3/C4,P3/4, O1/O2). Behavioral performance was quan-tified by measuring reaction time (RT) and calcu-lating percentages of hit scores to assess thenumber of correctly detected targets.

All ERP and behavioral measures were evaluatedwith repeated measures analyses of variance(ANOVA). The factors for the ERP evaluation werethyroid status (eu- vs. hypothyroidism), stimuluscategory (targets vs. non-targets), electrode site(central, parietal, occipital) and hemisphere (leftvs. right). For the serial task, an additional factorof set size (4, 8, 12 elements) was included. Beha-vioral measures were analyzed with the factorthyroid status and set size (serial task only). Allanalyses were adjusted for non-sphericity with theGreenhouse–Geisser epsilon coefficient.

3. Results

3.1. Neuropsychological tests

The results of the tests are summarized in Table 2.A highly significant detrimental effect of thyroidstatus was found in all four tests. A pronouncedperformance decrement was observed in the d2test indicating a marked influence of the hypo-thyroid state on complex visual attention func-tions. The worse performance in the digitrepetition task indicates an impairment ofimmediate auditory working memory. The VLMTtest results indicate that in the hypothyroid state,subjects have a shallower learning curve, with aperformance decrement of about 0.5 standard

deviations. The results in the Stroop test suggest ageneral cognitive slowing.

3.2. Behavioral effects

The behavioral results of both experiments arepresented in Table 3. For the reaction times, sig-nificant main effects for the factor thyroid statuswere obtained in both experiments reflecting theslower reaction times associated with hypothyr-oidism (parallel: Fð1; 14Þ ¼ 17:16, p< 0:001,serial: Fð1; 14Þ ¼ 6:07, p< 0:02). In addition, ahighly significant main effect of the factor set sizewas obtained in the serial search experiment(Fð2; 28Þ ¼ 77:27, p< 0:0001) reflecting the factthat it took the subject much longer to search forthe target item in displays with more elements.

The accuracy of the subjects, measured as per-cent correct responses, was decreased duringhypothyroidism only in the serial task (parallel:Fð1; 14Þ ¼ 4:06, n.s., serial: Fð1; 14Þ ¼ 10:24,p< 0:007), and the markedly reduced perform-ance for larger set sizes was similarly significant(Fð2; 28Þ ¼ 71:13, p< 0:0001).

3.3. ERP effects

3.3.1. Parallel searchThe grand average ERPs from the parallel searchexperiment are shown in Fig. 2 for the euthyroid-ism session. Up to about 250 ms post-stimulus,standard and target waveforms virtually overlap.Over posterior scalp sites, a small positive compo-nent with a peak latency of about 110 ms (P1) isfollowed by a negativity peaking at 170 ms (N1)and a positivity at about 230 ms (P2). Standardsand targets are differentiated by the more posi-tive going waveform elicited by target stimuli,

Table 2 Results of neuropsychological tests

Test M

easure E uthyroid H ypothyroid E ffect size p

d2 test G

Z-Fa (z) 1 .26 (1.02) 0 .61 (1.04) 0 .63 (d) <0.0001 Card 1 (s) 1 1.5 (1.2) 1 3.1 (2.6)

Stroop C

ard 2 (s) 1 3.9 (2.3) 1 5.5 (2.7) 0 .66 (g2) <0.0001 Card 3 (s) 2 0.7 (5.7) 2 2.2 (6.2)

Digit repetition N

b (z) � 0.01 (0.97) � 0.82 (1.21) 0 .72 <0.0007 Run 1–5 (z) 0 .27 (0.88) � 0.28 (0.83) 0 .64 <0.001

VLMTc I

nterference (z) � 0.41 (0.54) � 0.78 (0.65) 0 .63 n.s. Run 6 (z) 0 .50 (0.70) 0 .08 (0.87) 0 .54 <0.025

aTotal number of letters minus errors.bNumber of digits repeated.cVerbaler Lern- und Merkfahigkeitstest (Verbal Learning and Memory Test).

T.F. Munte et al.1114

which peaked at about 470 ms and constitutes theP3 component.

As illustrated in Fig. 3, which included the mid-line electrodes for each of the sessions, there wasno effect of thyroid status in the parallel task. Inparticular, the size of the standard–target differ-ence was unchanged by the thyroid status.

Statistically, no effects of stimulus category andthyroid status were obtained on the P1 (meanamplitude 90–130 ms) and N1 (mean amplitude150–200 ms) components. However, there was theexpected increase in amplitude of the P3 compo-nent (mean amplitude 400–700 ms) for the targetstimuli, reflected in a main effect of the stimuluscategory factor (Fð1; 14Þ ¼ 29:84, p< 0:0001). Nosignificant effects were attained for the thyroidstatus factor. The slightly more posterior overalldistribution of the ERPs in the hypothyroidismcondition was the source of a thyroid status byelectrode-site interaction (Fð2; 28Þ ¼ 13:58,p< 0:0001).

Finally, the latency of the P3 component (tar-gets only) was measured in the 400–600 ms win-dow (after digitally low-pass filtering the data at 7Hz). Euthyroidism (latency 472 ms, SD 63) andhypothyroidism (475 ms, SD 65) did not differ sig-nificantly on this measure.

3.3.2. Serial searchThe ERPs in the serial search experiment wereradically different from those in the parallel con-dition. The grand average potentials at the par-ietal midline site (Pz) are shown for the differentset sizes in Fig. 4. The targets and standards inthis condition overlap for the first 400 ms or soduring which the P1 and N1 components are dis-cernible. At about 500 ms and thereafter, the

ERPs to the target stimuli become more positivethan those for the standard stimuli. Unlike in theparallel search condition, there is no peak to theP3 component and the amplitude of the P3 isseemingly reduced. This apparent amplitude dec-rement is due to the fact that the componenttends to get smeared out by the variable searchtimes in the serial condition leading to a broaderand smaller appearance (see also, Luck and Hill-yard, 1990, 1995).

The separation between targets and standardsoccurs slightly earlier for the set size 4 arrays.

Table 3 Response characteristics in the search tasks

Reaction times (ms)

Euthyroidism H ypothyroidism Effect size

Parallel

726� 70 7 72� 82 0.60 Serial, set size 4 619� 88 7 02� 79 0.97 Serial, set size 8 851� 78 9 67� 98 1.31 Serial, set size 12 963� 88 1 012� 84 0.56

Hit rate (% correct)

Parallel 91:6� 8:9 8 9:2� 8:4 0.27 Serial, set size 4 90:6� 12:5 8 4:3� 12:2 0.51 Serial, set size 8 71:8� 15:9 6 5:3� 17:1 0.39 Serial, set size 12 68:7� 21:7 5 6:3� 19:2 0.62

In both experiments, slower reaction times were found during hypothyroidism. In the serial search task, reactiontimes increased as a function of set size. The accuracy of the subjects, measured as percent correct responses,was impaired during hypothyroidism only in the serial task. In the serial task, a worse performance was seen withincreasing set sizes. For statistics, see Section 3.2.

. Grand average ERPs for the parallel search

Fig. 2 task(euthyroidism session). The positions of the electrodesites roughly correspond to the locations on the head withthe top indicating more anterior and the bottom moreposterior scalp areas. Up to about 270 ms, ERPs fromstandard and target stimuli virtually overlap. From thenon, targets are characterized by a positive componentknown as the P3. Typical ERP components are labeled inthis figure. Standard stimuli: visual arrays with eight plaintriangles, no response required. Target stimuli: visualarray with seven plain triangles and one triangle withadditional horizontal line, button press required.

1115ERPs in hypothyrodism

Moreover, there is a marked difference in theonset latency and size of the target–standard dif-ference between the euthyroidism and hypothyr-oidism conditions, with the former conditionhaving earlier onsets and larger P3 amplitude dif-ferences.

Statistically, no effects of stimulus category,set size, and thyroid status were observed for theP1 and N1 components. As the P3 component inthe serial search experiment was smeared out andpart of the effect appeared to consist in a delayof the standard–target separation in the hypothyr-oidism condition, the following strategy forquantification was adopted: A set of ANOVAs onadjacent 50 ms mean amplitude measures wasconducted (starting at 400 ms). All time windowsexcept for the first (400–450 ms) showed an inter-action between thyroid status and stimulus cate-gory (all Fð1; 14Þ > 4:3, p< 0:03), indicating thatthe standard–target difference was of greateramplitude in the euthyroidism condition. In thetime windows 450–500, 500–550 and 550–600 ms,a triple order interaction between stimulus cate-gory, set size, and thyroid status suggested a dif-ferential effect of the thyroid condition on theonset of the standard–target difference (allFð2; 28Þ > 5:1, p< 0:015). In order to estimate theonset latency of the standard–target difference,separate ANOVAs were conducted for each setsize and thyroid conditions. The onsets of the ear-liest time windows to show an effect of stimuluscategory were (for set sizes 4/8/12): euthyroidism450/550/550 ms, hypothyroidism 650/650/650 ms.

3.4. Relationship of neuropsychological andelectrophysiological measures

To assess the possible relationship between neu-ropsychological and electrophysiological measuresin the current study, correlational analyses wereperformed. As the focus of the study is on the cog-nitive effects of hypothyroidism, hypothyroidismminus euthyroidism difference scores wereobtained for each of the measures. These weretaken as input for the correlational analysis. Eachof the neuropsychological difference scores (d2,Stroop card 3, digit repetition, VLMT run 1–5) wascorrelated with each of the electrophysiologicaldifference scores (serial search: set size 4, set size8, set size 12). The mean amplitude of the ERP tothe target stimulus in the time window 450–650ms at the Pz electrode served as the basis for thedifference scores. No correlations were performedfor measures of the parallel search task, as noeffects of thyroid status were observed in thattask. Significant correlations were obtained forthe following pairs: d2/set size 4 (r ¼ 0:5245,p< 0:05), d2/set size 8 (r ¼ 0:5377, p< 0:04),digit repetition/set size 4 (r ¼ 0:5701, p< 0:025),digit repetition/set size 8 (r ¼ 0:6236, p< 0:015).All other correlations were non-significant.

omparison of euthyroidism and hyp

Fig. 3. C othyroid-ism sessions for the parallel search task. Shown are themidline electrodes only. No effects of thyroid status areobservable in this simple, automatic task. Standardstimuli: visual arrays with eight plain triangles, noresponse required. Target stimuli: visual array withseven plain triangles and one triangle with additionalhorizontal line, button press required.

erial search task: comparison of E

Fig. 4. S RPs fromthe euthyroidism and hypothyroidism sessions for theparietal midline electrode shows a marked reduction ofthe standard–target difference. Moreover, the onset ofthe standard–target difference is delayed for the hypo-thyroidism session. Standard stimuli: visual arrays witheight triangles with additional horizontal line, noresponse required. Target stimuli: visual array withseven triangles with additional horizontal line and oneplain triangle, button press required.

T.F. Munte et al.1116

4. Discussion

The present data show a pronounced effect oftemporary hypothyroidism on overt behavior andelectrophysiological indices of information proces-sing in two visual search tasks.

A small set of neuropsychological tests showeddecreases in performance in the hypothyroidstate, roughly amounting to about one-half of astandard deviation in attention (d2, digit span)and response inhibition (Stroop test) tasks. Thesetests, however, do not allow speculations as tothe nature of the underlying information proces-sing deficit. The connection between the obtainedneuropsychological measures and their underlyingbrain correlates can be better understood byrecording ERPs during the performance of thesearch tasks used here.

Despite their apparent similarities (see Fig. 1),the two search tasks require radically differentinformation processing routines. The effortlessdiscrimination of a single defining target featurein the parallel task does not tax processing resour-ces. Therefore, the amplitude and latency of theP3 component were not significantly altered bythyroid status. It, thus, appears that automaticaspects of information processing are still intactin moderate hypothyroidism.

A totally different picture emerges when theserial search task is examined. Here, the detec-tion of the target stimulus requires an item byitem scanning of the visual array which, in turn,entails additional attentional processing resources(Treisman and Gelade, 1980; Luck and Hillyard,1990, 1995). Both amplitude and onset latency ofthe P3 component were altered by hypothyroid-ism: the delayed onset latency indicates that thediscrimination between target and standard stim-uli, that is, the time it takes to detect the targetitem in an array, is significantly delayed in theserial search task. Thus, the differences in overallreaction time obtained in the current set of datacan be ascribed to a slowing of stimulus evalu-ation rather than to a slowing of execution of themotor response (Kutas et al., 1977; McCarthy andDonchin, 1981). Moreover, the decrease of P3amplitude in the serial search task suggests areduction in the available processing resources(Hoffman et al., 1985; Schubert et al., 2003) inthe hypothyroid state. This is corroborated by thesignificantly reduced detection rates in the serialtask. The question may arise to what extent theERP differences in the present study are due todifferences in search saccades. Eye-movementpatterns during visual search have been the sub-ject of intense research in recent years (Binello

et al., 1995; Findlay, 1995, 1997; Williams et al.,1997; Motter and Belky, 1998). These studies haveindicated that the first saccade very often is onthe target item in a search array (Findlay, 1995,1997; Gilchrist et al., 1999). This indicates thatthe relevant target information is available beforethe first saccade, which has latencies of about 400ms. We, therefore, argue that present electro-physiological effects are not due to search sac-cades.

Overall, these data indicate marked difficultiesof patients with moderate hypothyroidism due tothyroxin withdrawal prior to radioiodine treat-ment and, thus, replicate and extend previousresults (Osterweil et al., 1992; Weber et al.,1995). These difficulties are especially evidentwhen the information processing system of thepatients is taxed by a resource demanding task.Moreover, the data underscore the utility of elec-trophysiological indices of information processing,especially when paradigms assessing specific cog-nitive functions are used. Using additional ERPparadigms addressing spatial attention (Hillyardand Anllo-Vento, 1998), working memory (Munteet al., 1998) and memory (Donaldson and Rugg,1998), it will be possible to provide a moredetailed picture of the detrimental effects ofhypothyroidism on human information processing.

The practical consequences of resource andspeed reductions of information processing foreveryday activities like driving a car or conductingan attention demanding conversation are quiteobvious and subjectively noticeable for thepatients. These data, therefore, could be taken tosupport the use of recombinant human thyrotropinin testing and treating thyroid carcinoma patientswith radioiodine (Ladenson et al., 1997; Reynoldsand Robbins, 1997; Pellegriti et al., 2001; Robbinset al., 2001; Giovanni et al., 2002), which canprevent hypothyroidism.

Acknowledgements

Supported by grants from the DFG. We thank Ber-dieke Wieringa for her help in collecting the data.

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