Schizophrenia Bulletin vol. 49 no. 2 pp. 339–349, 2023 https://doi.org/10.1093/schbul/sbac163 Advance Access publication December 14, 2022 Speech Illusions in People at Clinical High Risk for Psychosis Linked to Clinical Outcome Emily J. Hird*,1,17, , Noriyuki Ohmuro1,2,3,17, Paul Allen1,4, Peter Moseley5, , Matthew J. Kempton1, Gemma Modinos1, , Gabriele Sachs6, , Mark van der Gaag7,8,9, Lieuwe de Haan10,11, Ary Gadelha12, Rodrigo Bressan12, Neus Barrantes-Vidal13, , Stephan Ruhrmann14, Ana Catalan1,15, , EU-GEI High Risk Study16, and Philip McGuire1 1 Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK; 2 Department of Psychiatry, Tohoku University Hospital, Sendai, Miyagi, Japan; 3Department of Psychiatry, Osaki Citizen Hospital, Osaki, Japan; 4School of Psychology, Whitelands College, University of Roehampton, Holybourne Ave, London, SW15 4JD, UK; 5 Psychology Department, Northumbria University, College Lane, Newcastle-Upon-Tyne, NE1 8ST, UK; 6Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria; 7Faculty of Behavioural and Movement Sciences, Department of Clinical Psychology, VU University, van der Boechorststraat 1, 1081 BT Amsterdam, The Netherlands; 8EMGO Institute for Health and Care Research, VU University, van der Boechorststraat 1, 1081 BT Amsterdam, The Netherlands; 9Department of Psychosis Research, Parnassia Psychiatric Institute, Zoutkeetsingel 40, 2512 HN The Hague, The Netherlands; 10Department Early Psychosis, AMC, Academic Psychiatric Centre, Meibergdreef 5, 1105 AZ Amsterdam, The Netherlands; 11Arkin, Amsterdam, The Netherlands; 12 LiNC - Lab Interdisciplinar Neurociências Clínicas, Depto Psiquiatria, Escola Paulista de Medicina, Universidade Federal de São Paulo – UNIFESP, São Paulo, Brazil; 13Departament de Psicologia Clínica i de la Salut (Universitat Autònoma de Barcelona), Fundació Sanitària Sant Pere Claver (Spain), Spanish Mental Health Research Network (CIBERSAM), Barcelona, Spain; 14Department of Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany; 15Psychiatry Department, Biocruces Bizkaia Health Research Institute, OSI Bilbao-Basurto, Facultad de Medicina y Odontología, University of the Basque Country UPV/EHU, Centro de Investigación en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Plaza de Cruces 12, 48903 Barakaldo, Bizkaia, Spain; 16The EU-GEI group author list is included at the end of the paper * To whom correspondence should be addressed; Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, 16 De Crespigny Park, SE5 8AF, London, UK; e-mail: emily.hird@kcl.ac.uk 17 These authors contributed equally. Background and hypothesis: Around 20% of people at clin- (OR = 7.61, P = .043) and this variable was additionally ical high risk (CHR) for psychosis later develop a psychotic associated with a greater likelihood of transition to psy- disorder, but it is difficult to predict who this will be. We chosis (OR = 5.34, P = .029). Conclusions: In CHR indi- assessed the incidence of hearing speech (termed speech viduals, a tendency to hear speech in noise, and uncertainty illusions [SIs]) in noise in CHR participants and exam- about the affective valence of this speech, is associated with ined whether this was associated with adverse clinical out- adverse outcomes. This task could be used in a battery of comes. Study design: At baseline, 344 CHR participants cognitive markers to stratify CHR participants according and 67 healthy controls were presented with a computer- to subsequent outcomes. ized white noise task and asked whether they heard speech, and whether speech was neutral, affective, or whether they Key words: signal-detection/white noise task/uncertainty/ were uncertain about its valence. After 2 years, we assessed remission/transition whether participants transitioned to psychosis, or remitted from the CHR state, and their functioning. Study re- sults: CHR participants had a lower sensitivity to the task. Introduction Logistic regression revealed that a bias towards hearing Psychosis is often preceded by a clinical high risk (CHR) targets in stimuli was associated with remission status (OR stage, characterized by attenuated psychotic symptoms = 0.21, P = 042). Conversely, hearing SIs with uncertain and a reduction in functioning. Although 40%–50% remit valence at baseline was associated with reduced likelihood from the CHR state within 2 years,1 more than half con- of remission (OR = 7.72. P = .007). When we assessed only tinue to experience symptoms and impairments in func- participants who did not take antipsychotic medication at tioning2,3 and around 20% develop psychosis.4–6 baseline, the association between hearing SIs with uncer- People with hallucinatory experiences are at increased tain valence at baseline and remission likelihood remained risk of developing psychosis.7,8 One way to experimentally © The Author(s) 2022. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com 339 E. J. Hird et al assess proneness to psychotic experiences is to use the multicentre study. Eleven sites contributed and from these white noise task (WNT).9 In this computerized para- sites, HCs were recruited from the general population. digm, participants are presented with white noise, with Inclusion criteria for CHR participants were: Meet or without neutral speech, and asked whether they heard at least 1 criterion in the Comprehensive Assessment of speech and if so, whether speech was neutral, positive, At Risk Mental State (CAARMS4): (1) attenuated psy- negative, or whether they were unsure about the valence chotic symptoms (subthreshold positive psychotic symp- of speech. The incidence of speech illusions (SIs)—speech toms for at least 1 month in the previous year), (2) brief heard on white noise-only trials—is increased in people limited intermittent psychotic symptoms (an episode of who report hearing voices,10 is related to the level of fa- frank psychotic symptoms that resolved in less than 1 milial risk for psychosis,9 and is associated with schizo- week without treatment), and (3) vulnerability (a first-de- typy in some9 but not all11 studies. However, to date, the gree relative with a psychotic disorder or schizotypal per- frequency of SIs in CHR participants has not yet been sonality disorder and a drop in functioning for at least 1 compared to that in healthy controls (HC). month in the previous year). Exclusion criteria for CHR Data from the WNT can be analyzed within a signal participants were: An IQ lower than 60, a current or past detection theory (SDT) framework12 which describes the psychotic disorder, or that symptoms could be explained probabilistic processes of decision-making under condi- by a disease or substance dependency. For CHR partici- tions of uncertainty. According to SDT, on a given trial pants, the CAARMS was used to determine whether in- in which a target stimulus or noise may be presented, dividuals met at least one of CHR criteria: Attenuated participants respond according to the value of an inner Psychosis Group, Vulnerability Group, or Brief Limited decision variable. If this reaches a certain criterion, the Intermittent Psychotic Symptoms Group. Exclusion cri- participant responds that a target is present; otherwise, teria for all participants were: (1) past/present diagnosis the participant responds that it is not. Responses are of psychotic disorder, determined by CAARMS, and categorized into hits (correctly detecting speech), false Structural Clinical Interview for DSM Disorders, (2) rel- alarms (hearing speech when there is none), sensitivity evant symptoms explained by neurological disorder or (dʹ), and a bias towards responding “yes” or “no” (c).13,14 drug/alcohol dependency, (3) contraindications to MRI Healthy participants who report more hallucinatory ex- scanning or unwillingness to provide blood/saliva sample periences experience more false alarms, accompanied by (for the measures collected within the larger EU-GEI a bias towards responding “yes,”15–17 but results are mixed study); and (4) IQ estimate <60. HC participants did not as to whether this is associated with altered sensitivity on meet CHR criteria. Typical age of participants was 18–35 the WNT.12,17 The first aim of this study was to compare years but not restricted due to variation between sites in the incidence of SIs and SDT parameters of performance the age at which persons are accepted by clinical services in a large sample of CHR participants and controls. We (table 1). hypothesized that CHR participants would report SIs more frequently than healthy volunteers and would show reduced sensitivity and greater response bias. Instruments Within CHR participants, impaired performance across a range of different cognitive tasks has been as- Clinical Measures. Clinical measures were assessed at sociated with adverse outcomes, including transition to baseline and follow-up by assessors trained in the use of psychosis,18–21 persistence of CHR symptoms,22 and low the CAARMS and the Global Assessment of Functioning functioning.22 Whilst the perceived length of SI23 has Scale (GAF4,25,26). Participants undertook follow-up as- been linked to transition to psychosis, the incidence of sessments at 24 months. Transition to psychosis was de- SIs, and associated SDT parameters, have not been as- fined as the development of psychotic disorder using the sociated with clinical outcome. The second aim of this CAARMS.4 Available clinical records were used to deter- study was to assess whether within a CHR cohort the in- mine any diagnosis of a psychotic disorder when partici- cidence of SIs or associated SDT parameters at baseline pants did not return for follow-up assessments. In CHR is associated with transition to psychosis, persistence of participants that could not be contacted at follow-up, the symptoms, or decreased functioning, 2 years later. onset of psychosis was defined using information from clinical records. Remission was defined as a participant no longer meeting the criteria for the CHR state at fol- Methods low-up. Those who transitioned at follow-up were classed Sample as non-remitters. Level of functioning was assessed based Data were collected from 344 CHR participants and 67 on the GAF disability score, as in previous research.22 HCs recruited as part of the EU-GEI high-risk study White Noise Task. The WNT was used to assess the (European Network of National Networks studying incidence of SIs heard in white noise9,11,27,28 (figure 1). Gene-Environment Interactions in Schizophrenia) Participants, wearing earphones, sat in a room with a (https://www.eu-gei.eu/),24 a naturalistic prospective trained experimenter and were presented with either: (1) 340 Speech Illusions in Early Psychosis white noise only, (2) white noise plus clearly audible neu- .759 .729 .189 .040 .817 .135 .160 .095 .526 .956 .548 .015 P tral speech, and (3) white noise plus barely audible neu- tral speech. The neutral speech fragments had content Note: HC, healthy controls; CHR, participants at clinical high-risk of psychosis; T, transition; NT, non-transition; NR, non-remission; R, remission; P, significance; SD, 102.60 (14.22) 2 standard deviation; how often use cannabis, 1 = every day, 2 = more than once per week, 3 = a few times per month, 4 = a few times per year, 5=only once or twice; no, 48.81 (12.94) 3 such as: “Sport is good for health,” Speech was adapted 22.83 (4.59) 0 15.37 (2.58) 1 8.65 (6.87) 21 5.97 (8.69) 14 2.97 (1.48) 14 56.89 (8.08) 0 9.50 (3.64) 0 7.69 (3.20) 0 Table 1. Sociodemographic Variables of the Participants Who Completed the White Noise Task, Split By Participant Group, Transition Status, and Remission Status R (N = 52) 1 (2.43) 11 26 (50) 0 to each country’s native language. Each fragment had a Remission Status duration of 4.3 s and sound fragments were binaurally presented through headphones. Participants were pre- sented with 25 trials of each condition, in random order, and were required to verbally endorse one of five possible responses per trial: (1) no speech heard, (2) heard speech 10.23 (10.97) 32 50.45 (14.11) 13 97.59 (14.92) 3 8.38 (10.09) 25 23.39 (5.34) 0 14.89 (3.36) 8 2.55 (1.55) 24 53.74 (9.61) 5 NR (N = 88) 10 (12.82) 10 9.82 (4.11) 0 7.51 (3.10) 1 41 (46.59) 0 saying something neutral, (3) heard speech saying some- thing positive, or (4) heard speech saying something nega- tive, and (5) heard speech, but uncertain if it was positive, negative, or neutral. A response of 2,3,4, or 5 during con- dition 1 (white noise only) was defined as a SI. .959 .655 .306 .470 .414 .281 .416 .020 .253 .374 .169 .085 P IQ. A 15-minute version of the short-form Wechsler number; N/A, not applicable. Significant differences are in bold. Number of missing values for each variable is given in italics. Adult Intelligence Scale, including Digit Symbol Coding, 99.02 (17.60) 17 11.14 (11.94) 94 48.38 (15.65) 54 14.55 (3.04) 20 7.43 (11.76) 81 55.83 (9.87) 21 NT (N = 253) Block Design, Information, and Arithmetic subtests29,30 22.64 (4.92) 0 2.84 (1.56) 73 121 (47.83) 0 9.56 (4.14) 5 6.91 (3.41) 9 14 (6.86) 49 assessed intellectual function. Transition Status Groups for Analysis. Comparisons were made between the entire CHR sample and HC, and between CHR sub- groups defined according to clinical outcomes: transition to psychosis (CHR-T vs CHR-NT) and remission from 96.98 (13.64) 3 8.95 (11.03) 18 52.43 (15.80) 8 22.71 (4.95) 0 14.13 (3.49) 9 2.58 (1.55) 17 2.58 (1.55) 17 10.58 (3.56) 0 53.99 (9.98) 5 the CHR state (CHR-R vs CHR-NR). 7.45 (3.39) 0 24 (43.63) 0 T (N = 55) 9 (19.14) 6 Signal Detection Theory. The WNT was analyzed using a SDT framework.14 Conditions (2) and (3) (white noise with neutral speech) were treated as the target, and condi- tion (1) (“white noise only”) was treated as the nontarget. Three parameters were calculated: <.001 <.001 <.001 N/A N/A N/A N/A .134 1.00 .030 .750 .095 P 1. False alarms (F) (proportion of white-noise-only trials incorrectly identified as targets) (with a log-linear 14.48 (3.12) (29) 10.81 (11.49) 117 98.65 (16.95) 20 49.15 (15.73) 62 CHR (N = 308) transformation to account for extreme values in the 22.66 (4.92) 0 7.7 (11.63) 99 145 (47.08) 0 2.8 (1.56) 90 9.98 (4.05) 5 7.01 (3.41) 9 55.5 (9.9) 26 23 (9.2) 57 data31). Subject Group 2. Sensitivity dʹ as a global measure of performance,31 calculated as the difference between the inverse normal distribution of the hit rate and the inverse normal dis- tribution of the false alarm rate (NORMSINV(H)— 110.25 (17.71) 0 NORMSINV(F) in excel).31 23.35 (3.99) 0 16.35 (2.84) 0 6.69 (8.38) 25 3.26 (1.19) 16 87.14 (9.17) 1 HC (N = 51) 6.21 (7.08) 8 24 (47.05) 0 3. Response bias c, signifying a bias towards detecting a N/A N/A N/A N/A stimulus as a target (a lower value of c indicates a bias towards responding “yes”),31 calculated as the average of the inverse normal distribution of the hit rate and the inverse normal distribution of the false alarm rate Baseline CAARMS negative score, M (SD) Baseline CAARMS positive score, M (SD) No. of alcoholic drinks per week, M (SD) ((NORMSINV(H) + NORMSINV(F))/2 in excel).31 Baseline CAARMS total score, M (SD) Uses antipsychotic medication, no (%) Number of cigarettes per day, M (SD) Baseline GAF average score, M (SD) How often uses cannabis, M (SD) Affective and Uncertain SIs. We assessed whether SIs were affectively salient, ie, when participants perceived speech Years in education, M (SD) as negative or positive, or whether there was uncertainty WAIS IQ, mean (SD) Age in years, M (SD) around SIs, ie, when participants were uncertain if the Female sex, no (%) perceived speech was neutral or had either a negative or positive salience. SI scores were skewed, as expected, be- cause participants expressed a low rate of false alarms. To Measure address this, following previous work,9,27,28 performance was parameterized as 3 dichotomous variables according 341 E. J. Hird et al Fig. 1. The white noise task. Participants were presented with one of three conditions whilst wearing earphones: (1) white noise only, (2) white noise plus clearly audible neutral speech, (3) white noise plus barely audible neutral speech and required to verbally endorse one of five possible responses per trial: (1) no speech heard; (2) heard speech saying something neutral; (3) heard speech saying something positive; (4) heard speech saying something negative; (5) heard speech, but uncertain if it was positive, negative, or neutral. A response of 2,3,4, or 5 during condition 1 (white noise only) was defined as a speech illusion. to responses during the white noise-only condition: Each each variable predicted transition or remission status in participant was rated as 1 or 0 depending on whether they CHR participants. We also applied a linear regression heard at least 2 SIs that they perceived as (1) neutral, (2) model to each of the 3 dichotomous variables to assess positive or negative, or (3) unsure whether they were neu- whether each variable predicted GAF disability score in tral, positive, or negative. We included a threshold of at CHR participants. least 2 SIs per condition, to exclude possible erroneous All models used a significance threshold of P < .05. attributions of SIs.27 All regression models were adjusted for site, age, sex, cannabis and tobacco use, IQ (shortened WAIS), and Group Differences. Group differences between partici- years in education, based on the previous work9,28 and on pant group (CHR vs HC), transition status and remis- which variables showed group differences between HC sion status on the incidence of SIs were assessed using and CHR participants (table 1). Fisher’s exact tests, and on hit rate, false alarms, sensi- tivity (dʹ), and response bias (cʹ), using independent sam- Attrition Analysis. Due to numerous attritions at fol- ples t tests. All tests used a significance threshold of P < low-up, we assessed group differences between parti- .05 (two-tailed). cipants who did or did not drop out at follow-up, to Association With Outcome confirm that attritions were random and did not influ- ence the assessment of association with outcome, using SDT Parameters. We applied a logistic regression model independent samples t tests with a significance threshold to each of the three SDT parameters (false alarm rate, of P < .05 (two-tailed). sensitivity, or response bias) to assess whether each var- iable predicted transition or remission status in CHR Effect of Antipsychotic Medication. We repeated the ana- participants. We also applied a linear regression model lyses to include only CHR participants who were not on to each of the three SDT parameters to assess whether antipsychotic medication at the baseline assessment. each variable predicted GAF disability score in CHR participants. Results Dichotomous Variables. We applied a logistic regression Demographics model to each of the 3 dichotomous variables (heard 2 All sociodemographic, clinical, and medication data cat- or more SIs, heard 2 or more positive/negative SIs, heard egorized by group, transition, and remission status are 2 or more SIs with uncertain valence) to assess whether summarized in table 1. Two years from baseline, 55 CHR 342 Speech Illusions in Early Psychosis participants (18% of the total sample) transitioned to .053 .212 .318 .064 .200 .171 P psychosis (CHR-T) and 252 (82%) did not (CHR-NT), and 88 (63% of the remaining sample) had not remitted Variables “Heard 2 or More SI”, “Heard 2 or More Affective SI”, “Heard 2 or More Uncertain SI”. Significant differences are in bold. SI: Speech Illusion; no, Number Table 2. Participant Group and Outcome Differences on Signal Detection Theory Parameters Hit Rate, False Alarm Rate, d and c, and 3 Dichotomous Speech Illusion −0.23 (0.46) from the CHR state, and 52 (37%) had remitted. At base- 3.39 (0.87) 0.12 (0.16) R (N = 52) 16 (30.7) 2 (3.8) 5 (9.6) line CHR participants had fewer years of education, Remission Status lower IQ, smoked more cigarettes, and had a lower base- line GAF score than HC participants. Fewer CHR par- ticipants who transitioned to psychosis at 2 years were taking antipsychotic medication at baseline, and CHR −0.38 (0.44) NR (N = 88) participants who remitted from the CHR state had a 3.19 (0.89) 0.16 (0.17) 42 (47.7) 15 (17.0) 9 (10.2) higher IQ and a higher GAF average score at baseline. Of CHR participants who heard 2 or more SIs on the WNT, fewer were female, and participants who heard 2 or more affectively salient SIs at baseline had more years in edu- cation (supplementary table 4). .649 .402 .182 .743 .803 .273 P Group Differences on the WNT NT (N = 253) −0.29 (0.53) 3.26 (1.04) 0.14 (0.18) 97 (38.3) 29 (11.5) 18 (7.1) Transition Status Group differences on the WNT are summarized in table 2. HC participants (N = 51, M = 3.58) had a higher sensitivity dʹ than CHR participants (N = 308, M = 3.26) (P = .018). There were no other differences in the SDT parameters or the 3 dichotomous variables −0.27 (0.44) (heard 2 or more SIs, heard 2 or more affectively sa- 3.29 (0.83) 0.12 (0.12) T (N = 55) 23 (41.8) 10 (18.2) 6 (10.9) lient SIs, heard 2 or more SIs with uncertain valence) between HC and CHR participants, CHR-T (N = 55) and CHR-NT (N = 253) participants, or between CHR participants whose symptoms persisted at follow-up (CHR-NR) (N = 88) compared to CHR participants .645 .229 .290 .018 .368 1.0 P whose symptoms had resolved at follow-up (CHR-R) (N = 52) (table 2). CHR (N = 308) -0.28 (0.51) 3.26 (1.01) 0.14 (0.17) 120 (39.0) 39 (12.7) Participant Group 24 (7.8) Performance on the WNT Associated With Outcome All results of the outcome regression models are sum- marized in table 3. In CHR participants, a lower value of c (a higher likelihood of hearing targets in stimuli) (OR = 0.21, P = .042) and hearing 2 or more SIs with uncertain −0.35 (0.39) HC (N = 51) 3.58 (0.84) 0.12 (0.16) valence at baseline (OR = 7.72, P = .007), were associated 18 (35.3) 6 (11.8) 1 (1.9) with non-remission at 2-year follow-up. See figure 2A for a figure summarizing the significant results. There were no other associations between task parameters and out- come measures. Heard SI with uncertain valence, no (%) Attrition Analysis All results of the attrition analysis are summarized in supplementary table 1. CHR participants with fol- False alarm rate mean (SD) Heard affective SI, no (%) low-up data (N = 111) were at baseline older, had more years in education, and had a lower CAARMS posi- tive score and a higher CAARMS negative score and Heard SI, no (%) a low CAARMS positive score than CHR participants dʹ mean (SD) c mean (SD) without follow-up data (N = 197), and fewer CHR par- ticipants with follow-up data were taking antipsychotic Measure medication at baseline than CHR participants without follow-up data. 343 E. J. Hird et al Table 3. Logistic Regression Models Assessing the Association Between Transition Status/Remission Status and Linear Regression Models Assessing the Association Between Functional Outcome, With Signal Detection Theory Parameters Hit Rate, False Alarm Rate, d and c, and 3 Dichotomous Speech Illusion Variables “Heard 2 or More SI”, “Heard 2 or More Affective SI”, “Heard 2 or More Uncertain SI”. Each Row Signifies a Separate Model for Transition Status, Remission Status, and Functional Outcome. Significant Predictors are in Bold. All Models Were Adjusted for Age, Gender, Years in Education, IQ, Cigarettes Smoked Per Day, Site, and Cannabis Use, Replicating Previous Work9,29 and on Variables Showing Significant Differences at Baseline (table 1) Transition Status (N = 145) Remission Status (N = 70) Functional Outcome (N = 61) Measure P OR (95% CI) P OR (95% CI) P B SE B β False alarm rate .237 7.45 (0.27, 207.59) .279 10.59 (0.15, 759.81) .107 −19.84 12.08 −0.23 d' .215 0.71 (0.42, 1.22) .570 0.78 (0.34, 1.81) .122 3.96 2.52 0.21 C .431 0.61 (0.17, 2.09) .042 0.21 (0.05, 0.94) .386 3.94 4.5 0.12 Heard SI .063 3.82 (0.93, 15.73) .320 0.37 (0.05, 2.63) .229 −6.60 5.41 −0.16 Heard affective SI .582 1.72 (0.25, 11.89) .711 0.59 (0.04, 9.67) .251 −9.27 7.97 −0.17 Heard SI with uncertain valence .059 2.87 (0.96, 8.58) .007 7.72 (1.73, 34.49) .099 -−.88 4.09 −0.23 Note: OR, odds ratio. Fig. 2. Associations between performance on the white noise task and outcomes in CHR participants 2 years later, (A) including participants taking antipsychotic medication at baseline, and (B) excluding participants taking antipsychotic medication at baseline. Effect of Antipsychotic Medication all CHR participants (table 3), the association between c All results of the analysis which included only CHR par- and non-remission at 2-year follow-up was not significant ticipants who were not on antipsychotic medication at in CHR participants who were taking antipsychotic med- the baseline assessment are summarized in supplemen- ication (supplementary table 3) (OR = 0.38, P = .277). A tary tables 2 and 3 (N = 46 HC and 228 CHR when ex- new finding was that hearing 2 or more SIs with uncer- cluding participants on antipsychotic medication [and tain valence at baseline was associated with transition to participants whose data about antipsychotic medication psychosis in CHR participants who were taking antipsy- was missing] compared to N = 51 HC and 308 CHR when chotic medication (supplementary table 3) (OR = 7.61, including all participants). As in the analysis of all CHR P = .029). See figure 2B for a figure summarizing the sig- participants (table 2), HC participants (N = 46, M = 3.53) nificant results There were no other associations between had a higher sensitivity dʹ when compared to CHR par- task parameters and outcome measures. ticipants who were taking antipsychotic medication (N = 228, M = 3.24) (P = .048), but there were no other group Discussion differences (supplementary table 2). As with the analysis The main findings of the study were that CHR parti- in all CHR participants (table 3), in CHR participants cipants had lower sensitivity (dʹ), and that CHR parti- who were not taking antipsychotic medication, hearing 2 cipants with a bias towards reporting hearing targets or more SIs with uncertain valence at baseline was asso- in stimuli, or who heard SIs with uncertain valence on ciated with non-remission from the CHR state at 2-year the WNT at presentation, were less likely to be in re- follow-up (OR = 7.61, P = .043). Unlike the analysis in mission at 2-year follow-up. This association between 344 Speech Illusions in Early Psychosis hearing SIs with uncertain valence and non-remission beliefs about volatility are associated with a hippocampal- remained significant when assessing only CHR partici- cerebellar network on a perceptual conditioning task,42 pants who were not taking antipsychotic medication at and remission from the CHR state is associated with baseline. Furthermore, in this cohort, SIs with uncertain normalization in hippocampal perfusion,43 which hints valence were also associated with transition to psychosis at a neural correlate for our behavioral results. Indeed, at follow-up. verbal memory in CHR participants is associated with Cognitive models propose that perception represents hippocampal function,44 and verbal recall performance is a compromise between top-down beliefs and bottom-up also associated with remission in CHR participants.22,45 sensory information,32 and that psychosis symptoms,33 Generally, CHR participants show altered uncertainty including hallucinations34 may result from an imbal- processing as measured by salience tasks39 which are as- ance between these parameters. The finding that CHR sociated with transition to psychosis.46 participants had lower sensitivity on the WNT, and the In CHR participants not taking antipsychotic medi- associations between performance on the task and ad- cation at baseline, we replicated the association between verse outcomes at follow-up, is in line with this account. hearing SIs with uncertain valence and non-remission, Our approach to assessing uncertainty on the WNT and we also observed an association between hearing SIs is in contrast to previous studies using this task, which with uncertain valence and transition to psychosis. This strictly focused on affective salience.9,27,28 We examined latter result is in line with a previous study that reported uncertainty because decision-making under conditions that the perceived length of SIs in multispeaker babble of uncertainty is suboptimal in CHR participants,35–37 was associated with transition to psychosis in CHR and is associated with psychotic-like symptoms.38 From participants,23 but only in medication-free participants. a computational psychiatry perspective, this alteration Similarly, our result was observed only in CHR partici- can be attributed to the suboptimal precision-weighting pants not taking antipsychotic medication at baseline, of beliefs in the context of new information during per- suggesting that antipsychotic use confounded the asso- ception.39 Interestingly, we found that within the CHR ciation between SIs and transition to psychosis. Given sample, SDT measures of performance were associated replication of our results, the propensity to make uncer- with worse clinical outcomes. SDT describes the proba- tain responses on a cognitive task could offer a putative bilistic processes of decision-making under conditions of marker of clinical outcome in early psychosis, particu- uncertainty.14 We are the first to assess an association be- larly in participants not taking antipsychotic medication, tween SDT parameters on the WNT and clinical outcome as would likely be the case at initial presentation. Future in CHR participants. Our analysis revealed that across all studies should investigate the association with outcomes CHR participants, sensitivity (dʹ) is reduced, and in CHR using a battery of computational tasks which can offer participants whose symptoms persisted, a bias towards individualized measures of uncertainty weighting, such responding “yes” (c) predicted non-remission. This ex- as expected volatility, belief-updating,38 and learning tends previous work showing that psychosis patients have rate.47,48 Task bases indicators of this type are likely to be worse general performance and make more false alarms cheaper and more practical to administer compared to than other psychiatric populations28 and evidence of an neuroimaging procedures that may also have the poten- association between psychotic experiences and response tial to predict outcomes. bias.13 Together, these results suggest that psychosis symp- We did not observe an association between SIs toms are associated with altered uncertainty processing.13 and functioning, in contrast with previous evidence It is notable that this association did not survive when linking with poorer functional outcomes in CHR par- assessing only CHR participants who were not taking an- ticipants with impaired performance on other cognitive tipsychotic medication at baseline (supplementary table tasks.22,49,50 This discrepancy could be because functional 3). This result could be explained by a decrease in sta- outcomes in the CHR participants in this study were tistical power, given that 23% of CHR participants were associated with general cognitive functioning rather removed in this second analysis, either because they were than probabilistic reasoning or uncertainty processing. taking antipsychotic medication at baseline or because Another explanation is that the rate of SIs on the WNT data about their medication use was missing. Another is low (only 13% of CHR participants reported hearing interpretation is that the association between response a SI in our task, similar to previous studies using this bias and non-remission in the main analysis was caused task27,28) which may have generated a floor effect in our by CHR participants who were taking antipsychotic data. Also, we did not observe an association between medication. This is possible given that some studies have affectively salient SIs and outcome, despite previous found that cognitive impairments in psychosis are influ- findings that psychosis patients are more likely to hear enced by antipsychotic use.40,41 affectively salient SIs.9,27,28 This hints that alterations Feeling uncertain about the valence of SIs was linked to in affective salience processing develop after changes subsequent clinical outcomes in CHR participants. This in uncertainty processing associated with outcomes in link to uncertainty is potentially in line with evidence that CHR individuals. 345 E. J. Hird et al Strengths of the study include its prospective design of beliefs and new information. This could reflect a and a large sample size of CHR individuals who were model in which early alterations in uncertainty proc- mostly medication-naive. However, the correct hit rate essing are associated with prolonged subthreshold on the WNT used was high (mean = 93%, SD = 15% psychosis symptoms and a greater likelihood of de- across participants), suggesting that it may have been veloping psychosis or non-remission from the CHR relatively easy for participants to detect true speech, state. Understanding these associations (and replica- and thus introduced a ceiling effect. We did not tailor tion) could allow the incorporation of measures of un- detection thresholds for the task because, within a SDT certainty into predictive models to stratify individuals analysis, it is assumed that all participants were exposed according to subsequent outcomes, and to tailor treat- to the same stimuli. Although the hit rate was high, the ments to individuals. false alarm rate (the variable of interest) was approxi- mately the same as in other studies.51 Also, we only car- ried out a cross-sectional single assessment at baseline, Supplementary Material and follow-up was only up to 2 years; it is possible that Supplementary material is available at https://academic. a more extensive longitudinal measure would provide a oup.com/schizophreniabulletin/. more sensitive insight into the association with outcome. Part of the CHR group were on antipsychotic medica- tion. It should also be acknowledged that only 36% (N Funding = 111) of the CHR participants had at least 1 outcome The European Network of National Schizophrenia measure (remission vs non-remission, or functioning) at Networks Studying Gene Environment Interactions follow-up. Group comparisons showed that as well as (EU-GEI) Project is funded by grant agreement being associated with CAARMS positive and negative HEALTH-F2- 2010-241909 (Project EU-GEI) from scores, attrition was associated with a lower age, fewer the European Community’s Seventh Framework years in education, and use of antipsychotic medication. Programme. Additional support was provided by a We, therefore, repeated the analysis only assessing parti- Medical Research Council Fellowship to M Kempton cipants who were not using antipsychotic medication at (grant MR/J008915/1), and by the Ministerio de Ciencia, baseline, and age and years in education were included Innovación e Universidades to N Barrantes-Vidal (project as covariates in all analyses. It is also important to note PSI2017-87512-C2-1-R). that although we provided instructions that responding “not sure” on a trial indicates uncertainty about the va- lence of a SI, some participants may have misunderstood Acknowledgment the task instructions, and their response “not sure” could indicate uncertainty as to whether speech was heard or The authors have declared that there are no conflicts of not. Future studies should check that participants un- interest in relation to the subject of this study. derstand this instruction post-task. Furthermore, the WNT does not explicitly ask participants to employ EU-GEI High-Risk Study Group top-down processing, rather relying on presentation of speech in some trials to induce an implicit expectation Philip McGuire1, Lucia R. Valmaggia2, Matthew J. of speech. This type of expectation may differ from ex- Kempton1, Maria Calem1, Stefania Tognin1, Gemma pectations induced explicitly, such as in tasks that show Modinos1, Lieuwe de Haan3,4, Mark van der Gaag5,6, Eva that hallucination-prone participants are more likely to Velthorst3,7, Tamar C. Kraan3, Daniella S. van Dam3, hear SIs upon explicit instruction to employ auditory Nadine Burger6, Barnaby Nelson8, Patrick McGorry8, imagery.52,53 Finally, it is not clear whether susceptibility Günter Paul Amminger8, Christos Pantelis8, Athena to SIs represents a novel marker for psychosis outcome, Politis8, Joanne Goodall8, Anita Riecher-Rössler9, or whether it formalizes the link between hallucina- Stefan Borgwardt9, Charlotte Rapp9, Sarah Ittig9, Erich tory experiences and psychosis risk which has already Studerus9, Renata Smieskova9, Rodrigo Bressan10, Ary been observed in epidemiological studies in the general Gadelha10, Elisa Brietzke11, Graccielle Asevedo10, Elson population.7,8 Asevedo10, Andre Zugman10, Neus Barrantes-Vidal12, In conclusion, we show that in CHR participants, Tecelli Domínguez-Martínez13, Pilar Torrecilla14, Thomas hearing SIs with uncertain valence was associated with R. Kwapil15, Manel Monsonet14, Lídia Hinojosa14, non-remission from the CHR state and transition to Mathilde Kazes16, Claire Daban16, Julie Bourgin16, Olivier psychosis. Uncertainty processing is altered in CHR Gay16, Célia Mam-Lam-Fook16, Marie-Odile Krebs16, participants, and our results suggest that this is also as- Dorte Nordholm17, Lasse Randers17, Kristine Krakauer17, sociated with future outcomes. Our findings relate to Louise Glenthøj17, Birte Glenthøj18, Merete Nordentoft17, computational perspectives of psychosis which explain Stephan Ruhrmann19, Dominika Gebhard19, Julia the disorder as an alteration in the precision-weighting Arnhold20, Joachim Klosterkötter19, Gabriele Sachs21, 346 Speech Illusions in Early Psychosis Iris Lasser21, Bernadette Winklbaur21, Philippe A. 17. Mental Health Center Copenhagen and Center for Delespaul22,23, Bart P. Rutten22, and Jim van Os122. 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