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Behavioural Brain Research 180 (2007) 13

Research report

Repeated measurements of learned irrelevance bya novel within-subject paradigm in humans

Ariane Orosz a,b,e,, Joram Feldon a, Gilad Gal c,Andor Simon d, Katja Cattapan-Ludewig b,e

a Laboratory of Behavioral Biology, ETH Zurich, Switzerlandb University Hospital of Psychiatry, Bern, Switzerland

cMental Health Epidemiology and Psychosocial Aspects of Illness, The Gertner Institute for Epidemiology and

Health Policy Research, Sheba Medical Center, Tel Hashomer, Israeld Specialised Outpatient Service for Early Psychosis, Department of Psychiatry, Bruderholz, Switzerland

e MediQ, Psychiatric Services of Aargau Canton AG, Research Department, Brugg, Switzerland

Received 20 September 2006; received in revised form 1 February 2007; accepted 6 February 2007Available online 12 February 2007

Abstract

Learned irrelevance (LIrr) refers to the retardation of classical conditioning following preexposure of the to-be-associated stimuli. Healthy

volunteers have been tested on three occasions with a new LIrr paradigm avoiding methodological problems which afflict traditional paradigms.

A significant LIrr effect was demonstrated on each occasion. Thus, the new paradigm enables repeated measurements of LIrr and might be useful

in evaluating long-term effects of medication in psychiatric disorders exhibiting aberrant LIrr.

2007 Elsevier B.V. All rights reserved.

Keywords: Learned irrelevance; Latent inhibition; Repeated measurements; Within-subject design; Information processing; Attention; Schizophrenia

Learned irrelevance is considered a measure of informa-

tion processing, specifically, the ability of normal individuals to

ignore irrelevant internal and external stimuli in order to protect

themselves from stimulus overload. Learned irrelevance (LIrr)

refers to the retardation of associative learning, such as classical

conditioning - which stands for the formation of an associa-

tion between a conditioned stimulus (CS) and an unconditioned

stimulus (US) - following repeated unpaired presentations of

the CS and the US. LIrr is closely related to the to date more

extensively studied phenomenon of latent inhibition (LI)[9].LI

differs from LIrr in terms of the preexposure stage: in an LI pro-

cedure only the CS is preexposed, while in LIrr both the CS and

the US are presented inconsequentially prior to conditioning.

LIrr has been shown to produce comparable data to LI as both

phenomena were observed to be deficient in acute schizophrenia

patients ([1],for a review see[5]).Therefore, disrupted LI and

Corresponding author at: University Hospital of Psychiatry (UPD),

Department of Psychiatric Neurophysiology, Murtenstr. 21, CH-3010 Bern,

Switzerland. Tel.: +41 31 632 88 92; fax: +41 31 632 89 44.

E-mail address:ariane.orosz@insel.ch(A. Orosz).

LI-like phenomena have become an important tool to character-

ize cognitive and attentional deficits in schizophrenia and might

even be treated as a state marker of it[10].Disrupted or reduced

LI in schizophrenia patients takes the form of faster learning

of the CSUS association compared to normal subjects. This

implies that patients who show a general cognitive performance

deficit actually perform betterin the LI task following preex-

posure than control subjects[1,5].Thus, factors such as general

deficits in intellectual ability, medication side effects or lack of

motivation of schizophrenia patients can be excluded from being

responsible for LI disruption[5,6].

Traditional LI paradigms used to date are unsuitable for

repeated measurements[1,3]. This is due to the fact that tra-

ditional LI paradigms use an instrumental learning task and the

dependent measure is the number of trials needed to learn the

CSUS association[1,4].As these associations are quite sim-

ple, learning retardation by CS preexposure occurs at best only

on one occasion, i.e. no LI effect can be repeatedly observed in

the same subject, as the association has already been learned.

An additional limitation to these traditional LI paradigms is that

they apply a between-subject design. Thus, an LI effect can be

determined only by group comparisons[6].

0166-4328/$ see front matter 2007 Elsevier B.V. All rights reserved.

doi:10.1016/j.bbr.2007.02.008

mailto:ariane.orosz@insel.chhttp://localhost/var/www/apps/conversion/tmp/scratch_7/dx.doi.org/10.1016/j.bbr.2007.02.008http://localhost/var/www/apps/conversion/tmp/scratch_7/dx.doi.org/10.1016/j.bbr.2007.02.008mailto:ariane.orosz@insel.ch

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Some advanced LI paradigms[7,8]and the LIrr paradigm

used in the present study enable a within-subject design as they

involve more complex learning tasks which are not based on

a simple solution. Moreover, they measure the reaction time

(RT) as the dependent variable. It is suggested that by applying

a complex task and measuring RTs repeated measurements of

LIrr can be performed within one individual.

Sixteen healthy volunteers (3f, 13m) with a mean age of 23.4

years (S.D. = 2, range = 2029) were tested on three occasions

with the new LIrr paradigm at monthly intervals. A diagnostic

interview (DIA-X[11])was performed with the subjects prior

to the first test session in order to confirm the absence of a

personal or family history of psychiatric disorders. The study

was carried out at the Psychiatric Services of Aargau Canton,

Switzerland. Subjects were recruited by electronic advertise-

ments and by placards. The study protocol and consent forms

were reviewed and approved by the Ethical Committee of the

Psychiatric Services of Aargau Canton. The LIrr test used in the

present study is a simple computerized visual target-detecting

task of 7.5 min duration. It is an advanced version of the LIrrparadigm developed by Young et al. [12] which was further

modified by Gal et al.[2].The paradigm appeared as a RT task

in which the subjects were instructed to press the space bar of the

computer keyboard as soon as the letter X, which represented

the target, appeared on the screen. In addition to the target letter,

there were 10 different capital Latin letters (vowels: A, E, I, O, U

and five consonants: B, D, T, Y and Z) occurring in the test. All

characters were yellow and were presented on blue background.

The letters were all of the same size and were positioned in the

center of the screen. They appeared continuously one after the

other in a 1 s rate. A test session was composed of 75 targets

and 375 non-target letters, thus a total of 450 letters. As eachletter persisted for 1 s on the screen, the duration of a session was

450 s. The non-target letters were divided into two groups, non-

preexposed (NPE) and preexposed (PE). The five vowels (A,

E, I, O and U) were assigned to be the NPE letters, while five

consonants (B, D, T, Y and Z) constituted the PE letter group.

NPE letters, PE letters and the targets were presented accord-

ing to the schedules of three different conditions: preexposed

(PE), non-preexposed (NPE) and random (R). Each condition

was segmented in five blocks. The total of 15 blocks of the three

different conditions were always presented in the same order,

whereby the first block of a test session was always an R block

and there were never two successive blocks of the same condi-

tion. All blocks contained 30 letters: 5 targets, 5 target predictorletters which are presented immediately before the target, and

20 filler letters. Filler letters consisted of characters of the PE

group (consonants). They served to fill the period between the

predictor letter-target contingencies (e.g. B-X in a PE and O-X

in a NPE block). There were one to eight, on average four, filler

letters between the predictor letter-target contingencies. Filler

letters never predicted the target.

In an NPE condition block, the target was predicted five con-

secutivetimesby the samevowel, e.g. A.Thus, in eachof the five

NPE blocks one of the five NPE letters (vowels) was used as the

target predictor. Consequently, the five vowels were distributed

to the five NPE condition blocks.

It is important to note that a particular vowel is only presented

in the NPE block in which it predicted the target. It does not

appear before and will not be presented later in the test session.

In the PE condition, the PE letters served as target predictors.

Similarly to NPE, in a PE block the target was preceded five

times by the same PE letter, e.g. five times by B. Thus, each

consonantactedas targetpredictor in oneparticular PE condition

block. In the R blocks the five targets appeared once after each of

the five PE letters, i.e. five times by a different consonant (once

after B, once after D, etc.). Hence, preexposure to the PE letters

took place especially in the R blocks as well as during filler

letter presentations, where the subjects learned that a consonant

was not necessarily followed by the target. In contrast, a vowel

reliably predicted a target. Therefore, in the NPE blocks there

was full prediction of the target, while in PE the targetcould only

partly be predicted and in R not at all. Accordingly, the RT to the

target was expected to be the lowest (fastest) in NPE, higher in

PE and the highest (slowest) in R. In case of LIrr, performance

on the RT task is supposed to be significantly faster in the NPE

than in the PE condition.Prior to the test, the subjects were instructed that they were

going to perform a RT task which lasted about 7 min. During

this time they should watch the screen and whenever the letter

X appeared, they had to press the space bar as quickly as they

could. Moreover, they were also told to attentively follow the

non-target letters as they may give a hint to the appearance of

the X. Finally, they were asked to avoid making mistakes.

The RTs, i.e. the time (in ms) between the target onset and the

pressing of the space bar was recorded as the dependent variable.

To be included in the analysis, subjects had to detect at least

60 of the 75 targets in a test session. In the present study, this

criterion has been met by all subjects. RTs were analyzed using335 repeated measures analysis of variance(ANOVA) with

test session (1st, 2nd, 3rd), condition (R, PE, NPE) and block

(15) as within-subject factors.

There was no effect of session, as the performance in the

three different conditions, especially R and PE, remained stable

(similar RTs) over sessions (Fig. 1).The effect of condition was

significant (F(2.30) = 31.91,p < 0.001). This effect was, on the

one hand, due to a difference in performance in the PE compared

with the NPE condition, which was either significant or close to

significant, reflecting an LIrr effect in all three test sessions [post

hoc tests (Tukeys HSD) revealed for baseline:p = 0.09; 2nd test

session:p < 0.001;3rd test session:p < 0.001]. On theotherhand,

the condition effect reflected higher RTs in R compared to bothPE and NPE (baseline-R versus PE: p < 0.05, R versus NPE:

p < 0.001; 2nd test session-R versus PE:p < 0.01, R versus NPE:

p < 0.001; 3rd test session-R versus PE:p < 0.05, R versus NPE:

p < 0.001). As expected, slowest performance was evident in the

R condition. The interaction between session and condition was

significant(F(4.60) = 7.55,p < 0.001). Post hoctestsshowed that

the significant interaction was due to a decreasein RT in the NPE

condition while there were hardly any changes in performance

in R and PE conditions.

LIrr and LI are defined as the reduced associative learning

when preexposed stimuli, i.e. PECS (consonants) are involved.

Disruption of LI, which is the case when the same subject is

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A. Orosz et al. / Behavioural Brain Research 180 (2007 ) 13 3

Fig. 1. The figure depicts the average reaction times in the three different con-

ditions (R, PE and NPE) on three occasions. Independent of the test session, the

slowest performance occurred in R, where subjects showed significantly higher

reaction times compared to PE and NPE. The subjects showed a significant LIrr

effect in all test sessions in terms of significantly (or trend to) slower reaction

times in PE vs. NPE. While performance in R and PE remained stable, reaction

times in NPE decreased over sessions (from 1st to 2nd session: p < 0.001, from

2nd to 3rd session: n.s.). The whiskers represent the standard error of the mean.#p = 0.09 (trend);:p < 0.05; *p < 0.001.

repeatedly tested, is supposed to occur because the subject starts

to learn the PECS-target contingency after a specific number

of trials. In the present study subjects have exhibited similar

RTs in the PE blocks across sessions. Moreover, they showed

reduced learning on the PECS compared to the learning on

the NPECSs in all three test sessions. These results indicate

that a stable LIrr effect could be repeatedly measured on three

occasions.

It is noticeable that the LIrr effect seems to strengthen oversessions. Actually, this improvement in LIrr is caused by the

subjectslearningon theNPECSs.The learning on NPECSs is

facilitated, as the NPE-letters (vowels) always correctly predict

thetarget.Thus, in NPEthereis basicallya classicalconditioning

procedure, in which the subject learns that a vowel (CS) is a

signal for the target (US).

To our knowledge this is the first study examining repeated

measurements with the novel within-subject LIrr test. Further-

more, no comparable study has been reported in the human LI

literature. We were able to show that by applying a complex

task in which the CSUS association can be learned only rudi-

mentarily, a LIrr effect can be elicited several times in the samesubject. The major advantage of such a within-subject LIrr test

which enables repeated measurement of a LIrr effect is its use-

fulness for long-term studies. LIrr disruption is considered as an

indication for dysfunctional attentional information processing

as it is present in acute schizophrenia. Repeated measurements

of LIrr in schizophrenia patients might be helpful in evaluating

the development of attentional dysfunctions over the course of

disease or in observing the long-term effect of new antipsychotic

drugs on attentional information processing deficits.

Acknowledgments

Financialsupport wasprovided by theSarasotaOperaBenefit

through a 2003 NARSAD Young Investigators Award received

by Katja Cattapan-Ludewig. The authors are specially grateful

for the assistance of Pietro Ballinari in statistical matters.

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