# Abstract

 Learned irrelevance (LIrr) refers to a reduction in associative learning after pre-exposure of the conditioned and unconditioned stimulus in a non-contingent fashion. This paradigm might serve as a translational model for (pre)attentive information processing deficits in schizophrenia. This is the first study to investigate the event-related potentials (ERPs) of a within-subject LIrr paradigm in humans. Furthermore, the effects of the muscarinic M1 antagonist biperiden on LIrr were assessed. As expected, LIrr was found to be intact in young healthy volunteers after placebo. Furthermore, in the placebo condition P3b latency was decreased for target stimuli, which were pre-cued. This suggests that the predictability of the occurrence of these stimuli is mainly reflected by this ERP component. Biperiden had no effect on the behavioural LIrr measures, although prolonged reaction times were evident. Biperiden increased the N1 amplitude of the pre-exposed predictor letters, suggesting an effect of this drug on early perceptual processing. In conclusion, the within-subject paradigm used in the current study in combination with electroencephalography can reveal brain mechanisms involved in LIrr. M1 antagonism did not affect LIrr performance but seemed to influence early information processing. # Results One participant did not meet the requirement of at least 80% target hits and was therefore excluded from behavioural and ERP analysis. Part of the behavioural data was missing for another subject; this person was also not included, leaving a total of 15 participants. 

## Behavioural data: LIrr effects [Figure 2](#) shows the effects of the LIrr conditions on RT to the target letters. In the analysis of the RT data, there was a main effect of LIrr condition on RT \[*F*(2, 28)=21.73, *p*\<0.001\]. *Post-hoc* analysis showed that RTs to the target letters were faster for the NPE compared with the RAN (*p*\<0.001) and PE condition (*p*\<0.001). <figure> <p><img src="" /></p> <figcaption>Effects of the learned irrelevance (LIrr) conditions and biperiden on reaction time (RT) to the target letters (means+<span class="smallcaps">s.e.m</span>., \*\* <em>p</em>\<0.01; \*\*\* <em>p</em>\<0.001). In the placebo condition, intact LIrr is present, reflected by larger RTs for pre-exposed (PE)- than for non-pre-exposed (NPE)-cued target letters. Biperiden prolonged RT compared to placebo, but did not affect LIrr. RAN, random.</figcaption> </figure> 

## ERP data: LIrr effects on predictor and target letters In the placebo analyses of the predictor letters, there were no relevant task effects on N1 amplitude and latency (*F*'s\<1.69, n.s.) or P3a amplitude and latency (*F*'s\<2.50, n.s.). In the placebo analyses of the target letters, there were no relevant task effects on N1 amplitude and latency (*F*'s\<1.58, n.s.) or on P3b amplitude (*F*'s\<1.17, n.s.). The effect of LIrr condition on P3b latency did not vary per level of electrode \[no LIrr condition×electrode interaction effects: *F*(10 130)=0.44, n.s.\], yet P3b latency was found to differ between LIrr conditions \[main effect of LIrr condition: *F*(2, 26)=11.99, *p*\<0.001\]; *post-hoc* analysis showed that the P3b latency of NPE-cued targets occurred earlier compared with the P3b latency of RAN-cued (*p*\<0.001) and PE-cued targets (*p*\<0.05). [Figure 3](#) shows the effects of the LIrr conditions on the P3b component of the target letters in the placebo condition. <figure> <p><img src="" /></p> <figcaption>Effects of the learned irrelevance (LIrr) conditions on the P3b component of the target letters in the placebo condition (Pz electrode channel). P3b latency is shortest in the non-pre-exposed (NPE) condition, intermediate for pre-exposed (PE)-cued targets and longest for targets belonging to the random (RAN) condition (\*\*\* <em>p</em>\<0.001).</figcaption> </figure> 

## Behavioural data: effect of biperiden [Figures 2](#) and [4](#) show the effects of biperiden on RT for the target letters and the LIrr index, respectively. The effect of drug did not vary per level of LIrr condition \[no drug×LIrr condition interaction effect: *F*(2, 28)=2.46, n.s.\]. RTs were increased after biperiden treatment \[main effect of drug: *F*(1, 14)=12.43, *p*\<0.01\]. Biperiden had no effect on the LIrr index \[no main effect of drug: *F*(1, 14)=0.06, n.s.\]. <figure> <p><img src="" /></p> <figcaption>Effects of biperiden on the learned irrelevance (LIrr) index (means+<span class="smallcaps">s.e.m</span>.). In the placebo condition, intact LIrr is present, reflected by a LIrr index larger than zero. The same holds for the biperiden condition; in other words, biperiden failed to affect LIrr.</figcaption> </figure> 

## ERP data: effects of biperiden on predictor and target letters [Figure 5](#) shows the effects of biperiden on the N1 component of the PE predictor letters. The analysis of the amplitude of the N1 peak showed that the effect of biperiden varied per level of electrode \[treatment×electrode interaction effect: *F*(2, 26)=7.54, *p*\<0.01\] and per level of LIrr condition \[treatment×LIrr condition interaction effect: *F*(2, 26)=3.94, *p*\<0.05\]. Therefore, we decided to do separate repeated measures ANOVAs per LIrr condition. In the analyses of RAN and NPE predictors, there were no interaction or main effects of biperiden on N1 amplitude (*F*'s\<1.98, n.s.). For the PE predictors, the effect of treatment on N1 amplitude varied per electrode \[treatment×electrode interaction effect: *F*(2, 26)=7.42, *p*\<0.01\]; therefore we performed separate repeated measures ANOVAs per electrode. Biperiden was found to increase the N1 amplitude at Fz and FCz (*F*'s>5.77, *p*\<0.05). There were no relevant interaction effects or main effects of biperiden on N1 latency (*F*'s\<2.40, n.s.), or on P3a amplitude or latency (*F*'s\<2.25, n.s.) of the predictor letters. Furthermore, for the targets there were no effects of biperiden on N1 amplitude and latency (*F*'s\<3.25, n.s.), or on P3b amplitude and latency (*F*'s\<4.18, n.s.). <figure> <p><img src="" /></p> <figcaption>Effects of biperiden on the N1 component of the pre-exposed predictor letters (Fz electrode channel). Biperiden increased N1 amplitude compared to placebo (\* <em>p</em>\<0.05).</figcaption> </figure> 

## Questionnaire data There were no effects of biperiden on the subscales of the self-report questionnaire (*t*'s>−1.87, n.s.), the POMS (*t*'s>−0.92, n.s.) or the Bond & Lader (*t*'s>−1.52, n.s.).


Extracted trial result:
Outcome: Learned irrelevance index (continuous)
Intervention: Biperiden
Comparator: Placebo
Intervention group size: 15
Comparator group size: 15
Notes: numerical data in figure.