Failure of attention focus and cognitive control in schizophrenia patients with auditory verbal hallucinations: Evidence from dichotic listening

Schizophrenia Research 147 (2013) 301–309

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Failure of attention focus and cognitive control in schizophrenia patients with auditory verbal hallucinations: Evidence from dichotic listening Kenneth Hugdahl a, b, c,⁎, Merethe Nygård a, Liv E. Falkenberg a, Kristiina Kompus a, René Westerhausen a, b, Rune Kroken b, Erik Johnsen b, d, Else-Marie Løberg a, b a

Department of Biological and Medical Psychology, University of Bergen, Norway Division of Psychiatry, Haukeland University Hospital, Bergen, Norway Department of Radiology, Haukeland University Hospital, Bergen, Norway d Department of Clinical Medicine, Section Psychiatry, University of Bergen, Norway b c

a r t i c l e

i n f o

Article history: Received 30 October 2012 Received in revised form 12 March 2013 Accepted 8 April 2013 Available online 9 May 2013 Keywords: Auditory hallucinations Schizophrenia Dichotic listening Attention Executive function Cognitive control

a b s t r a c t Auditory verbal hallucinations (AVHs) are speech perceptions that lack an external source, phenomenologically experienced as “hearing voices”. A perceptual origin of an AVH experience in patients with schizophrenia can however not explain why the “voices” drain the attentional and cognitive capacity of the patients, making them unable to direct attention away from the “voices” and to cognitively suppress the experience. We recently reported how AVHs interfere with the perception of speech sounds, using a dichotic listening experimental paradigm. We now extend this finding by reporting on the interference caused by AVHs on attention and cognitive control, using a slight variation of the same dichotic listening paradigm. The patients (N = 148) were instructed to pay attention to and report from either the right or left ear syllable of the dichotic pair. We then correlated their PANSS score for the hallucination item (P3) with the performance score on the dichotic listening task. The results showed that AVHs interfered with the ability to report the right ear syllable when instructed to pay attention to the right side, which is a marker of inability to attend to an external speech stimulus. When instructed to pay attention to the left side, AVHs interfered with the ability to report the left ear syllable, which is a marker of inability to use cognitive control to suppress attending to the “voices”. The corresponding correlations for the emotional withdrawal (N2) negative symptom were all non-significant. The correlations were substantiated in an ANOVA with corresponding significant group differences between high versus low symptom score groups. The results thus extend our previous findings of a perceptual origination for AVHs by showing that AVHs interfere with the ability to attend to the outer world around the patient, and the ability to inhibit, or suppress, the “voices” once they occur. Future research should pin down the neuronal basis of both the origination and the attentional and cognitive control aspects of AVHs. © 2013 Elsevier B.V. All rights reserved.

1. Introduction Auditory verbal hallucinations, AVHs, are the most typical single symptom in schizophrenia (Wing et al., 1974; David, 1999). AVHs could be seen as a “marker” of a psychotic episode (Wing et al., 1974; Shergill et al., 1998; Hugdahl et al., 2009), occurring in more than 70% of patients with a schizophrenia diagnosis. In addition to the symptomatic aspects of AVHs, hearing “voices” also has cognitive correlates, which add to the mental and social burden of the disorder. Hallucinating patients seem to focus on the “voices”, i.e. they appear to have less ability to exhibit cognitive control of and disengage from the “voices” once they occur, and thus less ability to attend to events ⁎ Corresponding author at: Department of Biological and Medical Psychology, University of Bergen, Jonas Lies vei 91, N-5009 Bergen, Norway. E-mail address: [email protected] (K. Hugdahl). 0920-9964/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.schres.2013.04.005

around them (Chadwick and Birchwood, 1994). In neuropsychological terms this could be phrased such that AVHs attract attentional focus (Posner and Driver, 1992) and impair the patient's cognitive control abilities (Lezak, 1994). From this follows that AVHs should interfere with processing of an external stimulus such that the more frequent the hallucinations, the less would a patient be able to attend to and cognitively control an external sensory stimulus. Alternatively, it could be argued that it is the negative content of the AVH typically experienced by patients with schizophrenia that causes a break-down of higher cognitive functions, or an interaction between the two factors. This effect should moreover be enhanced for a stimulus that shares qualities with an AVH, e.g. when the patient is required to process an external auditory speech sound (see also Hugdahl et al., 2009). Several functional magnetic resonance (fMRI) and positron emission tomography (PET) studies have shown a reduction in cortical blood flow and neuronal activation in prefrontal and parietal brain areas in

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patients with schizophrenia in situations demanding cognitive control and attentional focus (Weinberger et al., 1986; Pfefferbaum and Zipursky, 1991; Gur and Gur, 1995; O'Leary et al., 1996; Carter et al., 1998; Hugdahl et al., 2004). The functional imaging studies are supported by structural imaging studies that have shown reduced grey matter volume in several cortical areas in hallucinating patients, including frontal, parietal and temporal lobe areas (Neckelmann et al., 2006; Williams, 2008). Although the imaging data lend support to the notion that brain areas involved in attention focus and cognitive control processes are affected in patients with AVHs, it alone does not reveal the origin of these effects. Hypothesis-driven behavior studies with directed predictions regarding the performance might be better suited to uncover the origin of these functional and structural brain changes. We would like to call the interference caused by AVHs for the processing of an external speech sound (cf. Hugdahl et al., 2012) the “voice interference”, hypothesis which predicts that (a) AVHs should interfere with attention and cognitive control demands associated with an external stimulus, (b) the interference should be stronger in patients the more frequently they experience AVHs. Moreover, as also mentioned above, the interference should be particularly strong for a stimulus presented within the same sensory modality, like an acoustically presented speech sound. Thus, we considered the so called “forced-attention” dichotic listening paradigm (see Hugdahl and Andersson, l986, see also Bryden et al., 1983) a possible paradigm for testing the voice interference hypothesis. The “forced-attention” paradigm makes it possible to study ability for attention focus and cognitive control in the same experimental set-up (cf. Løberg et al., 1999; Gadea et al., 2000; Hugdahl et al., 2009; Bouma and Gootjes, 2011; Falkenberg et al., 2011). This would be an advantage when testing patients with severe disorders since the task is simple to perform, and the overall processing demands and task difficulty do not vary for the different conditions, something that frequently confounds classic neuropsychological studies where overall difficulty of the tests used often varies. The “forced-attention” paradigm has been applied to numerous non-clinical and clinical groups (Løberg et al., 1999: Hugdahl, 2003; Gootjes et al., 2006; Løberg et al., 2006; Hugdahl et al., 2009; Pollmann, 2010; Bouma and Gootjes, 2011; Falkenberg et al., 2011; Hiscock and Kinsbourne, 2011; Kompus et al., 2011, 2012; Carlsson et al., 1994). We therefore here present an abbreviated version of the logic behind the paradigm. In the standard variant of the consonant-vowel (CV)-syllables dichotic listening paradigm, with no explicit instruction for attention focus or need for executive control, subjects report more correct items from the right ear compared to the left ear syllable of the dichotic pair on each trial. This is due to two factors, the preponderance of the contralateral auditory pathways (Rosenzweig, 1951; Kimura, 1967; Pollmann et al., 2002; Brancucci et al., 2004), and the superior processing ability of the left hemisphere (temporal lobe) for speech sounds (Kimura, 1967; van den Noort et al., 2008). The result is called a Right Ear Advantage (REA) (Shankweiler and Studdert-Kennedy, 1967; Bryden, 1988). By explicitly instructing the subject to focus attention on and report only from the right ear (originally labeled “forced-right” (FR) attention by Hugdahl and Andersson, l986), the REA is increased due to the synergistic action of the bottom-up, perceptual REA together with the top-down, cognitively demanding focus of attention on the right ear stimulus. In other words, the REA is increased because the bottom-up REA is aided by attention focus on the same side. The opposite situation, when the subject is explicitly instructed to focus attention on and report only from the left ear, is however fundamentally different from the FR situation. In this latter situation the bottom-up and top-down systems act antagonistically, and the result is a cognitive conflict (cf. Braver et al., 2002; Hugdahl et al., 2009; Westerhausen et al., 2010; Falkenberg et al., 2011) which is in need of cognitive control to be resolved. This situation was labeled “forced-left” (FL) attention

by Hugdahl and Andersson (l986), and would require the inhibition of a strong response tendency (to report the right ear stimulus), in addition to use top-down cognitive control to instead report the weaker stimulus element of the dichotic pair (the left ear stimulus). This would be in line with the sub-components of inhibition and shifting in the terminology used by Miyake et al. (2000). Thus, the FR and FL instruction conditions allow for the study of attention focus and cognitive control with the same experimental paradigm, where stimulus parameters stay constant between conditions. We now suggest that the “forced-attention” dichotic listening paradigm as it is described above would be ideal for a study of attention focus and cognitive control interference caused by AVHs. The specific predictions were that AVHs should cause interference with processing of the right ear signal in the FR instruction condition, and with the left ear signal in the FL instruction condition. Thus, there should be a significant negative correlation between scores on the Positive and Negative Syndrome Scale (PANSS) (Kay et al., 1987) hallucination (P3) item and number of correct reports for the right ear syllable in the FR instruction condition, and a corresponding significant negative correlation between the hallucination item score and correct reports for the left ear syllable in the FL instruction condition. Non-significant correlations were predicted for the left ear syllable in the FR condition, and for the right ear syllable in the FL condition, respectively. We selected the emotional withdrawal (N2) item as a control condition (cf. Hugdahl et al., 2012) where non-significant correlations were predicted for both the left and right ear syllables, and for both the FR and FL instruction conditions. We also correlated the left and right ear dichotic listening scores with the sum total of the PANSS positive and negative symptom scores as a measure of overall load on positive and negative symptoms. 2. Method 2.1. Subjects The subjects were 148 patients with a DSM-IV or ICD-10 diagnosis of schizophrenia. The patients were the same as the 160 participants who participated in the Hugdahl et al. (2012) study minus the 12 Turkish patients, where data on the FR and FL conditions were missing, thus, the total sample was 148. The data were collected from two sub-samples, from two different countries, Norway (n = 120), USA (n = 28). 1 The differences in sample size precluded however any meaningful statistical comparison between the sub-samples, the trend of the findings was however similar at both sites. The subjects in the Norway sample were interviewed for symptom severity using the PANSS. The USA sample underwent the Brief Psychiatric Rating Scale (BPRS) interview (Ventura et al., 1993), in which case the scores were converted to PANSS scores, since these scales are positively correlated (Nicholson et al., 1995). Patients were on medication, with either typical or atypical antipsychotic medication. The patients' age was between 18 and 73 years, and with 108 males and 40 females in the sample (a separate analysis on the 40 females showed that the direction of the correlations was similar as for the entire sample). The distribution of the 148 patients across the range of PANSS scores for the P3 and N2 symptoms is seen in Table 1. 2.2. The dichotic listening task The task used was the same as in the Hugdahl et al. (2012) study (with the modification of the “forced-instruction” conditions). In

1 Dichotic listening data from some of these patients have previously been published in Løberg et al. (1999) and Hugdahl et al. (2003, 2008), but in a different context and with different analyses. All data have been re-analyzed for the present study.

K. Hugdahl et al. / Schizophrenia Research 147 (2013) 301–309 Table 1 Distribution of subjects across the PANSS positive and negative symptom scores. PANSS score → PANSS symptom ↓ P3 hallucinations N2 emotional withdrawal

1

2

3

4

5

6

7

46 42

7 23

17 28

27 33

30 17

10 5

11 0

303

avoid the unlikely situation that a patient may have remembered the order in which the syllables were presented the first time they were tested. 2.3. Statistical analysis

brief, the DL task consisted of presentation of CV-syllables via headphones to the patients. The stimuli were paired presentations of the six stop-consonants /b/, /d/, /g/, /p/, /t/, and /k/ together with the vowel /a/ to form dichotic CV-syllable pairs of the type /ba – ga/, /ta – ka/ etc. The syllables were paired with each other for all possible combinations, thus yielding 36 dichotic pairs, including the homonymic pairs. To avoid confounding the eligibility of the CV-syllables for the different samples, all syllables were spoken in the respective languages, Norwegian and English, but with the same procedure being followed at the two sites. The homonymic pairs were not included in the statistical analysis. The maximum number of correct reports was thus 30 for each ear/instruction condition (FR, FL). Mean duration was 350–400 ms and the inter-trial interval was 4 s. The syllables were read through a microphone and digitized for later computer editing on a standard PC using state-of-the-art audio editing software (SWELL, Goldwave, CoolEdit). The syllables were recorded with a sampling rate of 44,000 Hz and an amplitude resolution of 16 bit. After digitization, each CV-pair was displayed on the PC screen and synchronized for simultaneous onset at the first identifiable energy release in the consonant segment between the right and left channels. The stimuli were played to the subject using digital play-back equipment, connected to high-performance headphones, with intensity between 70 and 75 dB. The subject was told that he/she would hear repeated presentations of the six CV-syllables (ba, da, ga, pa, ta, ka), and that he/she should report which one he/she heard from the six possible syllables after each trial. The subjects were furthermore told that “on some occasions there seems to be two sounds coming simultaneously”. They should ignore this and just report the syllable they heard first, or best. They were shown a cardboard sheet with all six syllables written before the experiment started (because of slight differences in the procedure between labs, the cardboard was not always shown). The subject was explicitly instructed to orally report, or to point to, one item on each trial irrespective of whether he/she perceived one or both items which one they perceived on each trial. This procedure was originally introduced by Bryden (1988) in order to reduce working memory loading as when the subject has to provide two responses, or as in the original Kimura (1961) studies when the subject had to withhold his/her response until four stimulus pairs had been presented, and then perform a recognition procedure. The subjects were tested with either a PC or a cassette player version of the DL test, using the same CV-syllables stimulus set-up and instructions. There were two different instructions given to the patients before the test started. In one instruction condition they were told to focus attention to and report from the right ear, and if they thought they heard something in the left ear, this should be ignored. As described in the Introduction, this was called the “forced-right” (FR) instruction condition. In the other condition, the patients were similarly told to focus attention to and report from the left ear, and if they thought that they heard something in the right ear, this should be ignored. Also as described in the introduction, this was called the “forced-left” (FL) instruction condition, following the terminology introduced by Hugdahl and Andersson (1986). The order of presentation of the FR and FL conditions was counterbalanced across patients. Thus, all parameters and instructions stayed constant across the two conditions, except for the single word “right” or “left” in the FR and FL instructions, respectively. The randomization of the order of presentation of the 36 CV-syllables was also different for the two conditions, to

Percentage correct reports, separate for the right and left ears, and for the FR and FL instruction conditions, were correlated with PANSS scores for the P3 and N2 items, as well as with the sum total score for positive and negative symptoms. Due to the ordinal scale of the PANSS scores (min 1–max 7) Spearman rank correlations (two-tailed) were computed. In order to get an estimate of the effects we calculated 95% confidence intervals (CI) around each significant correlation. Two analyses of variance were also conducted, separate for the P3 and N2 PANSS items that included right and left ear, FR and FL attention instruction as factors. The group factor involved splitting the patients into a “high” and “low” sub-group based on high or low PANSS scores. 3. Results XY-scatterplots for the right and left ear scores, and the P3 and N2 PANSS symptoms, separated for the FR and FL instruction conditions are shown in Figs. 1 and 2. Spearman non-parametric correlations for the PANSS P3 symptom item and the forced-right (FR) right and left ear scores, showed a significant negative correlation for the right ear score, r = − .416, p b .05, CI 95%: − .271 to − .513, see upper left-hand panel in Fig. 1. The corresponding left ear correlation was non-significant, r = − .065, see upper right-hand panel in Fig. 1. The corresponding correlations between the P3 hallucination item and the forced-left (FL) right and left ear scores, showed a non-significant correlation for the right ear score, r = −.115 (see lower left-hand panel of Fig. 1), and a significant negative correlation for the left ear score, r = −.253, CI 95%: −.398 to −.096 (see lower right-hand panel of Fig. 1). For the PANSS N2 emotional withdrawal symptom, all correlations were non-significant. For the correlation between the N2 symptom score and the FR right ear score, r = − .030, n.s., see upper left-hand panel in Fig. 2. The corresponding correlation coefficient for the FR left ear score was r = .055, n.s., see lower left-hand panel in Fig. 2. For the correlation between the N2 symptom score and the FL right ear score, r = .033, n.s., see upper right-hand panel in Fig. 2. The corresponding coefficient for the FL left ear score was r = .116, n.s., see lower right-hand panel in Fig. 2. The correlation between the FR right ear dichotic score and the PANSS sum positive score resulted in a significant negative correlation, r = − .418, p b .05, CI 95%: − .543 to − .275. The corresponding correlation for the FR left ear score was non-significant, r = − .074, n.s. These correlations are shown graphically in the upper right- and left-hand panels of Fig. 3. For the FL right ear DL correct reports and the PANSS sum positive score, the correlation was non-significant, r = − .106, n.s., while the FL left ear score and the PANSS sum positive score were significant, r = − .287, p b .05, CI 95%: − .429 to − .132. Fig. 4 shows the correlations for the sum total of the negative symptoms and FR and FL right and left ear DL reports. As for the single negative symptom all correlations with the sum total of negative symptoms were non-significant. Spearman r's were − .038, n.s. and .104, n.s. for the correlations with the FR right and left ear scores, respectively. The corresponding r's for the FL right and left ear scores were, r = .048, n.s. and .111, n.s., respectively. We further performed a separate ANOVA for the P3 symptom scores that were split into a “high” and “low” group, where patients with scores >4 were defined as the “high group”, and patients with PANSS scores b 4 were defined as the “low group”, thus a score of “4” was not included in order to divide into two groups. There were 70 patients in the P3 “low” group and 51 patients in the corresponding

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Fig. 1. Scatter-plots of the correlations between right- and left-ear scores (min 0–max 30) in the DL task and scores on the hallucinations (P3) symptom scores (min 1–max 7). The two upper panels show the scatter-plots for the FR instruction condition. The two lower panels show the corresponding scatter-plots for the FL instruction condition. The size of the “blobs” in the scatter plots corresponds to the number of subjects having the same xy-scores. FRRE = Forced-right instruction condition, right ear score, FRLE = Forced-right instruction condition, left ear score. FLRE = Forced-left instruction condition, right ear score, FLLE = Forced-left instruction condition, left ear score.

“high” group, with 27 patients (18%) having a score of 4, and thus omitted from the ANOVA. The P3 high and low groups were tested against correct right and left ear reports for the FR and FL conditions, respectively. There was a significant three-way interaction of Groups (High, Low) × Instruction (FR, FL) × Ear (Right, Left), F(1,72) = 4.397, p = .039. The interaction was followed-up with tests for simple main-effects using Fisher's LSD test, which showed a significant (p b .001) difference between the low and high P3 groups for the FR right ear score (Means: 16.60 and 11.85, respectively), and a corresponding significant difference between the groups for the FL left ear score (p = .012, Means: 13.93 and 11.93, respectively). Thus, the ANOVA supported the effects seen in the correlational analyses, with significant contrasts for the high and low P3 groups for the FR right ear score, and the FL left ear score. As a control, a corresponding ANOVA was run for the N2 high and low groups, with non-significant effects for all interactions, respectively.

4. Discussion The results showed that the more frequent the hallucinations, the less were these patients able to direct attention to the right ear syllable in the FR instruction condition, and to use cognitive control to increase reporting of the left ear syllable in the FL instruction condition. Thus, the current results add to the findings of the Hugdahl et al. (2012) study, using a similar experimental paradigm, by showing that AVHs seem to attract attention inward towards the “voices” rather than outward towards an external speech source. The results also add to a perceptual origination of AVHs by showing that patients experiencing AVHs fail to use cognitive control and executive functions to inhibit engaging in the “voices” once they occur. The current findings together with the findings in the Hugdahl et al. (2012) study therefore seem to support the cortical network model suggested by Hugdahl et al. (2009) of an involuntary perceptual quality of AVHs

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Fig. 2. Scatter-plots of the correlations between right- and left-ear scores (min 0–max 30) in the DL task and scores on the emotional withdrawal (N2) symptom scores (min 1–max 7). The two upper panels show the scatter-plots for the FR instruction condition. The two lower panels show the corresponding scatter-plots for the FL instruction condition. The size of the “blobs” in the scatter plots corresponds to the number of subjects having the same xy-scores. FRRE = Forced-right instruction condition, right ear score, FRLE = Forced-right instruction condition, left ear score. FLRE = Forced-left instruction condition, right ear score, FLLE = Forced-left instruction condition, left ear score.

originating in the left temporal plane in the peri-Sylvian region, which is maintained through an inward attention focus, failure of cognitive control of the "voices". Fig. 5 provides a graphical illustration of the model. It should be pointed out however that the model suggested by Hugdahl et al. (2009) is a neuronal model, based on fMRI data, while the current study and the study by Hugdahl et al. (2012) are behavioral studies. This may however not be a disadvantage when trying to provide empirical support for a theoretical model. On the contrary, we would like to argue that a neuronal model is strengthened if it gets empirical support from results collected in a different data domain. Based on the current and the Hugdahl et al. (2012) results we would like to suggest that AVHs can be described along three core dimensions. A first dimension is a perceptual dimension where the patient is allocating the source of the perception to an out-of-head. A second dimension is a cognitive dimension, with inward attention focus and failure of executive control to re-focus attention and inhibit

processing of the “voices”. A third core dimension, not studied in the current or Hugdahl et al. (2012) study, is an emotional dimension, in the sense that most AVHs are interpreted to have a negative emotional valence, often negatively commenting on how the patient dresses, behaves, talks etc., and sometimes even commanding particular acts to be performed by the patient. Thus, the two studies have together shown AVHs to have a speech perception and a cognitive dimension. The latter effect also fits previous studies of a general cognitive impairment effect in schizophrenia across several domains, and especially for attention and executive control (e.g. Saykin et al., 1991; Egeland et al., 2003a,b; Reichenberg, 2010; Fioravanti et al., 2012). What remains to be resolved in future studies is why AVHs are predominantly negative, i.e. to study the emotional dimension of AVHs (see Larøi et al. (2012) for an overview of the characteristic clinical and non-clinical features of AVHs). The correlation coefficients, although statistically significant, for the P3 symptom score and DL right and left ear reports in the FR and FL conditions may not seem overly impressive, seen isolated and on

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Fig. 3. Scatter-plots of the correlations between right- and left-ear scores (min 0–max 30) in the DL task and scores on the sum total of positive symptom scores. The two upper panels show the scatter-plots for the FR instruction condition. The two lower panels show the corresponding scatter-plots for the FL instructions condition. The size of the “blobs” in the scatter plots corresponds to the number of subjects having the same xy-scores. FRRE = Forced-right instruction condition, right ear score, FRLE = Forced-right instruction condition, left ear score. FLRE = Forced-left instruction condition, right ear score, FLLE = Forced-left instruction condition, left ear score.

its own (cf. Hugdahl and Öst, 1981). However, the pattern of correlations for the P3 item, also supported by the ANOVA, is difficult to disregard as artefactual random effects. This is strengthened by the use of a simple experimental design with minimalistic differences between the FR and FL conditions. It therefore seems reasonable to conclude that the opposite significant effects for the right ear in the FR condition and for the left ear in the FL condition, with non-significant effects for the non-attended ears, tap impaired attentional and executive control factors the more frequent AVHs are. This argument is further strengthened by the fact that neither an isolated negative symptom, nor the sum total of negative symptoms showed this pattern of correlations or ANOVA effects. The results also fit with other, neuropsychological test studies that have shown impairment of higher cognitive functions in schizophrenia in general (Gourovitch and Goldberg, 1996; Green et al., 2000; Reichenberg, 2010). Some of these studies have also shown that cognitive impairment is associated with positive symptoms (e.g. Berman et al., 1997). We now extend these results by showing that a specific set of cognitive functions is

associated with specific positive symptoms, like AVHs. This may explain the cognitive aspects of AVHs, what Badcock (2010) called “intrusive cognitions” caused by AVHs. Several recent papers have shown abnormal neuronal networks, sub-serving both the perceptual and cognitive aspects of AVHs (see e.g. Shergill et al., 2004; Woodruff, 2004; Allen et al., 2008; Hugdahl et al., 2009; Allen et al., 2012; Kompus et al., 2012). A possible implication of the current results is that it should be possible (at least in theory) to cognitively train AVH patients to learn to re-focus attention away from the “voices” and to cognitively inhibit such experiences. It should be noted that we are not advocating this as a treatment for schizophrenia, but rather as a focused training of overcoming the cognitive consequences of experiencing a single symptom. Such training could however have positive effects on other aspects of the disorder. Cognitive remediation has become a popular enterprise in neuropsychology and cognitive neuroscience (e.g. McGurk et al., 2007; Wykes and Huddy, 2009), with often positive transfer effects from the original training procedure that can be observed in both the visual (Dahlin et al., 2008) and in the auditory

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Fig. 4. Scatter-plots of the correlations between right- and left-ear scores (min 0–max 30) in the DL task and scores on the sum total of negative symptom scores. The two upper panels show the scatter-plots for the FR instruction condition. The two lower panels show the corresponding scatter-plots for the FL instructions condition. The size of the “blobs” in the scatter plots corresponds to the number of subjects having the same xy-scores. FRRE = Forced-right instruction condition, right ear score, FRLE = Forced-right instruction condition, left ear score. FLRE = Forced-left instruction condition, right ear score, FLLE = Forced-left instruction condition, left ear score.

(Soveri et al., 2012) sensory domains. Cognitive behavior therapy and cognitive training have also been used for therapy of patients with AVH, with a focus on changing how these patients attend to and control the “voices”. Lecomte et al. (2012) used cognitive behavior therapy in a randomized controlled trial with schizophrenia patients and waiting-list controls for early psychosis. The results showed significant improvements also after a 12 month period (see also Shergill et al., 1998; Wykes et al., 2008; Sommer et al., 2012). We would like to suggest a simplified training method based on the current results, where patients could have the dichotic paradigm on a portable PC or even as a smart-phone app (Bless et al., 2013). They would go through both DL instruction conditions on a daily basis, with the aim of improving their results for the right ear in the FR instruction condition, and for the left ear in the FL instruction condition. Preliminary data from our laboratory on a selected small number of patients have shown positive effects on control of the “voices” after a four month training period. The small number of patients precludes however any firm conclusions at

present. This is underscored by the fact that the current version of the training paradigm is directly taken from a research paradigm, and a more clinical version should be developed to better adjust to the clinical environment. Because the perceptual interference caused by the “voices” (Hugdahl et al., 2012) generally reduces the REA with more frequent hallucinations, it may be argued that the correlations for the PANSS P3 item and the dichotic listening right and left ear scores in the current study are confounded by a perceptual bias to start with. However, such a possibility should only affect the FR instruction condition and the corresponding decrease in the right ear reports with increasing frequency of hallucinations, but should not affect the right and left ear reports in the FL instruction condition. The fact that the DL reports in both the FR and FL instruction conditions were affected the more frequent the hallucinations would thus speak against a confounding interpretation. It is therefore not likely that a pre-existing perceptual deficit is confounding the current results.

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References

Fig. 5. Illustration of the network model presented in Hugdahl et al. (2009). The illustration in Fig. 5 is a modified version of the original figure. Fig. 5 shows the outline of an aberrant cortical network involved in the origination and maintenance of AVHs. The network is illustrated with black arrows where the broken lines indicate a deficient or impaired connection. It is suggested that AVHs are initiated through hyperactivity in the left peri-Sylvian region (1), which is maintained through an inward attention focus localized to the inferior parietal lobule (2), and failure of cognitive control of the “voices” (3) localized to the prefrontal cortex.

Together with the Hugdahl et al. (2012) results, it seems reasonable to conclude that AVHs have a speech perception quality to them, and that they as such are perceptual experiences to begin with. Furthermore, once they occur they are out of cognitive control for the patients, and thereby drain the attentional capacity inwards towards the “voice”. This conclusion, based on experimental behavioral data and derived from hypothesis-testing studies, is supported by the wealth of structural and functional neuroimaging studies (also including electrophysiology studies) that in addition localize the observed behavioral effects to dysfunctional cortical networks involving temporal, parietal and frontal lobe regions (even though the current study did not involve imaging data). It is important that consensus can be reached regarding the basic perceptual and cognitive features of AVHs, in order to allow the devotion of future research to the yet unknown aspects of AVHs, such as the emotional dimension, i.e. the predominantly negative valence of the “voices”, in addition to the underlying neurotransmitters causing these behavioral and activation abnormalities at the receptor level.

Role of funding source The current research was funded by grants to Kenneth Hugdahl from the European Research Council (ERC), the Research Council of Norway and the Western Health Authority of Norway, and from the Research Council of Norway to Else-Marie Løberg.

Contributors Kenneth Hugdahl analyzed the data and wrote the manuscript. Merethe Nygård tested patients and commented on the manuscript. Liv Falkenberg tested patients and commented on the manuscript. Kristiina Kompus read and commented on the manuscript. René Westerhausen read and commented on the manuscript. Erik Johnsen recruited patients and commented on the manuscript. Rune Kroken recruited patients and commented on the manuscript. Else-Marie Løberg recruited and tested patients and commented on the manuscript.

Conflict of interest The authors have no conflict of interest.

Acknowledgments Special thanks to Bjørn Rishovd Rund, University of Oslo, Norway and Michael F Green, UCLA, USA for re-analysis of dichotic listening and symptoms data collected in projects headed by them.

Allen, A., Laroi, F., McGuire, P.K., Aleman, A., 2008. The hallucinating brain: a review of structural and functional neuroimaging studies of hallucinations. Neurosci. Biobehav. Rev. 32, 175–191. Allen, P., Modinos, G., Hubl, D., Shields, G., Cachia, R., Jardri, R., Thomas, P., Woodward, T., Shotbolt, P., Plaze, P., Hoffman, R., 2012. Neuroimaging auditory hallucinations in schizophrenia: from neuroanatomy to neurochemistry and beyond. Schizophr. Bull. 38, 695–708. Badcock, J.C., 2010. The cognitive neuropsychology of auditory hallucinations: a parallel auditory pathways framework. Schizophr. Bull. 36, 576–584. Berman, I., Viegner, B., Merson, A., Allan, E., Pappas, D., Green, A.I., 1997. Differential relationships between positive and negative symptoms and neuropsychological deficits in schizophrenia. Schizophr. Res. 25 (1), 1–10. Bless, J.J., Westerhausen, R., Arciuli, J., Kompus, K., Gudmundsen, M., Hugdahl, K., 2013. Right on all occasions? - on the feasibility of laterality research using a smartphone dichotic listening application. Front. Psychol. 4, 42. http://dx.doi.org/10.3389/ fpsyg.2013.00042. Bouma, A., Gootjes, L., 2011. Effects of attention on dichotic listening in elderly and patients with dementia of the Alzheimer type. Brain Cogn. 76, 286–293. Brancucci, A., Babiloni, C., Babiloni, F., Galderisi, S., Mucci, A., Tecchio, F., Zappasodi, F., Pizzella, V., Romani, G.L., Rossini, P.M., 2004. Inhibition of auditory cortical responses to ipsilateral stimuli during dichotic listening: evidence from magnetoencephalography. Eur. J. Neurosci. 19, 2329–2336. Braver, T.S., Cohen, J.D., Barch, D.M., 2002. The role of prefrontal cortex in normal and disordered cognitive control: a cognitive neuroscience perspective. In: Stuss, D.T., Knight, R.T. (Eds.), Principles of Frontal Lobe Function. Oxford University Press, New York, pp. 428–448. Bryden, M.P., 1988. An overview of the dichotic listening procedure and its relation to cerebral organization. In: Hugdahl, K. (Ed.), Handbook of Dichotic Listening: Theory, Methods, and Research. Wiley & Sons, Chichester, UK, pp. 1–44. Bryden, M.P., Munhall, K., Allard, F., 1983. Attentional biases and the right-ear effect in dichotic listening. Brain Lang. 18, 236–248. Carlsson, G., Uvebrant, P., Hugdahl, K., Arvidsson, J., Wiklund, L.M., vonWendt, L., 1994. Verbal and nonverbal function of children with right versus left hemiplegic cerebral palsy of prenatal and perinatal origin. Dev. Med. Child Neurol. 36, 503–512. Carter, C.S., Perlstein, W., Ganguli, R., Brar, J., Mintun, M., Cohen, J.D., 1998. Functional hypofrontality and working memory dysfunction in schizophrenia. Am. J. Psychiatry 155, 1285–1287. Chadwick, P., Birchwood, M., 1994. The omnipotence of voices. A cognitive approach to auditory hallucinations. Br. J. Psychiatry 164, 190–201. Dahlin, E., Neely, A.S., Larsson, A., Bäckman, L., Nyberg, L., 2008. Transfer of learning after updating training mediated by the striatum. Science 320, 1510–1512. David, A.S., 1999. Auditory hallucinations: phenomenology, neuropsychology, and neuroimaging update. Acta Psychiatr. Scand. 395, 95–104. Egeland, J., Rund, B.R., Sundet, K., Landro, N.I., Asbjornsen, A., Lund, A., Roness, A., Stordal, K., Hugdahl, K., 2003a. Attention profile in schizophrenia compared with depression: differential effects of processing speed, selective attention and vigilance. Acta Psychiatr. Scand. 108, 276–284. Egeland, J., Sundet, K., Rund, B.R., Asbjørnsen, A., Hugdahl, K., Landrø, N.I., Lund, A., Roness, A., Stordal, K., 2003b. Sensitivity and specificity of memory dysfunction in schizophrenia: a comparison with major depression. J. Clin. Exp. Neuropsychol. 25, 79–93. Falkenberg, L.E., Specht, K., Westerhausen, R., 2011. Attention and cognitive control networks assessed in a dichotic listening fMRI study. Brain Cogn. 76, 276–285. Fioravanti, M., Bianchi, V., Cinti, M.E., 2012. Cognitive deficits in schizophrenia: an updated meta-analysis of the scientific evidence. BMC Psychiatry 12, 64. Gadea, M., Gomez, C., Espert, R., 2000. Test–retest performance for the consonantvowel dichotic listening test with and without attentional manipulations. J. Clin. Exp. Neuropsychol. 22, 793–803. Gootjes, L., Bouma, A., Van Strien, J.W., Schijndel, R.V., Barkhof, F., Scheltens, P., 2006. Corpus callosum size correlates with asymmetric performance on a dichotic listening task in healthy aging but not in Alzheimer's disease. Neuropsychologia 44, 208–217. Gourovitch, M.L., Goldberg, T.E., 1996. Cognitive deficits in schizophrenia: attention, executive functions, memory and language processing. In: Pantelis, C., Nelson, H.E., Barnes, T.R.E. (Eds.), Schizophrenia: A Neuropsychological Perspective. John Wiley & Sons Ltd., Chichester, pp. 71–86. Green, M.F., Kern, R.S., Braff, D.-L., Mintz, J., 2000. Neurocognitive deficits and functional outcome in schizophrenia: are we measuring “the right stuff”? Schizophr. Bull. 26, 119–136. Gur, R.C., Gur, R.E., 1995. Hypofrontality in schizophrenia. Lancet 345, 1383–1384. Hiscock, M., Kinsbourne, M., 2011. Attention and the right-ear advantage: what is the connection? Brain Cogn. 76, 263–275. Hugdahl, K., 2003. Dichotic listening in the study of auditory laterality. In: Hugdahl, K., Davidson, R.J. (Eds.), The Asymmetrical Brain. MIT Press, Cambridge, MA, pp. 441–478. Hugdahl, K., Andersson, L., 1986. The “forced-attention paradigm” in dichotic listening to CV-syllables: a comparison between adults and children. Cortex 22, 417–41432. Hugdahl, K., Løberg, E.-M., Falkenberg, L.E., Johnsen, E., Kompus, K., Kroken, R., Nygård, M., Westerhausen, R., Altekin, K., Özgören, M., 2012. Auditory verbal hallucinations in schizophrenia as aberrant lateralized speech perception: evidence from dichotic listening. Schizophr. Res. 140, 59–64. Hugdahl, K., Løberg, E.-M., Jørgensen, H.A., Lundervold, A., Lund, A., Green, M.F., Rund, B.R., 2008. Left hemisphere lateralization of auditory hallucinations in schizophrenia: a dichotic listening study. Cogn. Neuropsychiatry 13, 166–179. Hugdahl, K., Løberg, E.M., Nygård, M., 2009. Left temporal lobe structural and functional abnormality underlying auditory hallucinations in schizophrenia. Front. Neurosci. 3, 34–45.

K. Hugdahl et al. / Schizophrenia Research 147 (2013) 301–309 Hugdahl, K., Öst, L.G., 1981. On the difference between statistical and clinical significance. Behav. Assess. 3, 289–295. Hugdahl, K., Rund, B.R., Lund, A., Asbjørnsen, A., Egeland, J., Landrø, N.I., Roness, A., Stordal, K., Sundet, K., 2003. Attentional and executive dysfunctions in schizophrenia and depression: evidence from dichotic listening performance. Biol. Psychiatry 53, 609–616. Hugdahl, K., Rund, B.R., Lund, A., Asbjørnsen, A., Egeland, J., Landrø, N.I., Roness, A., Stordal, K., Sundet, K., Thomsen, T., 2004. Brain activation measured with fMRI during a mental arithmetic task in schizophrenia and major depression. Am. J. Psychiatry 161, 286–293. Kay, S.R., Fiszbein, A., Opler, L.A., 1987. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr. Bull. 13, 261–276. Kimura, D., 1961. Cerebral-dominance and the perception of verbal stimuli. Can. J. Psychol. 15, 166–171. Kimura, D., 1967. Functional asymmetry of the brain in dichotic listening. Cortex 3, 163–178. Kompus, K., Specht, K., Ersland, L., Juvodden, H.T., van Wageningen, H., Hugdahl, K., Westerhausen, R., 2012. A forced-attention dichotic listening fMRI study on 113 subjects. Brain Lang. 121, 240–247. Kompus, K., Westerhausen, R., Hugdahl, K., 2011. The “paradoxical” engagement of the primary auditory cortex in patients with auditory verbal hallucinations: a metaanalysis of functional neuroimaging studies. Neuropsychologia 49, 3361–3369. Larøi, F., Sommer, I.E., Blom, J.D., Fernyhough, C., Ffytche, D.H., Hugdahl, K., Johns, L.C., McCarthy-Jones, S., Preti, A., Raballo, A., Slotema, C.W., Stephane, M., Waters, F., 2012. The characteristic features of auditory verbal hallucinations in clinical and non-clinical groups: state-of-the-art overview and future directions. Schizophr. Bull. 38, 724–733. Lecomte, T., Leclerc, C., Wykes, T., 2012. Group CBT for early psychosis—are there still benefits one year later? Int. J. Group Psychother. 62, 309–321. Lezak, M., 1994. Neuropsychological Assessment, 4th edition. Oxford University Press, New York. Løberg, E.-M., Hugdahl, K., Green, M.F., 1999. Hemispheric asymmetry in schizophrenia: a “dual deficits” model. Biol. Psychiatry 45, 76–81. Løberg, E.-M., Jørgensen, H.A., Green, M.F., Rund, B.R., Lund, A., Diseth, Å., Øie, M., Hugdahl, K., 2006. Positive symptoms and duration of illness predict functional laterality and attention modulation in schizophrenia. Acta Psychiatr. Scand. 113, 322–331. McGurk, S.R., Twamley, E.W., Sitzer, D.I., McHugo, G.J., Mueser, K.T., 2007. A meta-analysis of cognitive remediation in schizophrenia. Am. J. Psychiatry 164, 1791–1802. Miyake, A., Friedman, N.P., Emerson, M.J., Witzki, A.H., Howerter, A., Wager, T.D., 2000. The unity and diversity of executive functions and their contributions to complex “Frontal Lobe” tasks: a latent variable analysis. Cogn. Psychol. 41, 49–100. Neckelmann, G., Specht, K., Lund, A., Ersland, L., Smievoll, A.I., Hugdahl, K., 2006. MR morphometry analysis of grey matter density reduction in schizophrenia: interactions with hallucinations. Int. J. Neurosci. 116, 9–23. Nicholson, I.R., Chapman, J.E., Neufeld, R.W.J., 1995. Variability in BPRS definitions of positive and negative symptoms. Schizophr. Res. 17, 177–185. O'Leary, D., Andreasen, N.C., Hurtig, R.R., Hichwa, R.D., Watkins, L., Boles Ponto, L.L., Rogers, M., Kirchner, P.T., 1996. A positron emission tomography study of binaurally and dichotically presented stimuli: effects of level of language and directed attention. Brain Lang. 53, 20–39. Pfefferbaum, A., Zipursky, R.B., 1991. Neuroimaging studies of schizophrenia. Schizophr. Res. 4, 193–208.

309

Pollmann, S., 2010. A unified structural-attentional framework for dichotic listening. In: Hugdahl, K., Westerhausen, R. (Eds.), The Two Halves of the Brain. MIT Press, Cambridge, MA. Pollmann, S., Maertens, M., von Cramon, D.Y., Lepsien, J., Hugdahl, K., 2002. Dichotic listening in patients with splenial and nonsplenial callosal lesions. Neuropsychology 16, 56–64. Posner, M.I., Driver, J., 1992. The neurobiology of selective attention. Curr. Opin. Neurobiol. 2, 165–169. Reichenberg, A., 2010. The assessment of neuropsychological functioning in schizophrenia. Dialogues Clin. Neurosci. 383–392. Rosenzweig, M.R., 1951. Representations of the two ears at the auditory cortex. Am. J. Physiol. 167, 147–158. Saykin, A.J., Gur, R.C., Gur, R.E., Mozley, P.D., Mozley, R.D., Resnick, S.M., Kester, D.B., Stafiniak, P., 1991. Arch. Gen. Psychiatry 48, 618–624. Shankweiler, D., Studdert-Kennedy, M., 1967. Identification of consonants and vowels presented to left and right ears. Q. J. Exp. Psychol. 19, 59–63. Shergill, S.S., Brammer, M.J., Amaro, E., Williams, S.C.R., Murray, R.M., McGure, P.K., 2004. Temporal course of auditory hallucinations. Br. J. Psychiatry 185, 516–517. Shergill, S.S., Murray, R.M., McGuire, P.K., 1998. Auditory hallucinations: a review of psychological treatments. Schizophr. Res. 32, 37–50. Sommer, I.E.C., Slotema, C.W., Daskalakis, Z.J., Derks, E.M., Blom, J.D., Van Der Gaag, M., 2012. The treatment of hallucinations in schizophrenia spectrum disorders. Schizophr. Bull. (EPub ahead of publication). Soveri, A., Tallus, J., Laine, M., Nyberg, L., Bäckman, L., Hugdahl, K., Tuomainen, J., Westerhausen, R., Hämäläinen, H., 2012. Modulation of auditory attention by training: evidence from dichotic listening. Exp. Psychol. 30, 1–9. Van den Noort, M., Specht, K., Rimol, L.M., Ersland, L., Hugdahl, K., 2008. A new verbal reports fMRI dichotic listening paradigm for studies of hemispheric asymmetry. NeuroImage 40, 902–911. Ventura, J., Green, M.F., Shaner, A., Liberman, R.P., 1993. Training and quality assurance with the Brief Psychiatric Rating Scale: ‘the drift buster’. Int. J. Methods Psychiatr. Res. 3, 221–244. Weinberger, D.R., Berman, K.F., Zec, R.F., 1986. Physiologic dysfunction of dorsolateral prefrontal cortex in schizophrenia. I. Regional blood flow evidence (rCBF). Arch. Gen. Psychiatry 43, 114–125. Westerhausen, Moosmann, Alho, K., Belsby, S.O., Hämäläinen, H., Medvedev, S., Specht, K., Hugdahl, K., 2010. Identification of attention and cognitive control networks in a parametric auditory fMRI study. Neuropsychologia 48, 2075–2081. Williams, L.M., 2008. Voxel based morphometry in schizophrenia: implications for neurodevelopmental connectivity models and cognition and affect. Expert. Rev. Neurother. 8, 1029–1036. Wing, J.K., Cooper, J.E., Sartorius, N., 1974. Measurement and Classification of Psychiatric Symptoms. Cambridge University Press, Cambridge. Woodruff, P.W.R., 2004. Auditory hallucinations: insights and questions from neuroimaging. Cogn. Neuropsychiatry 9, 73–92. Wykes, T., Huddy, V., 2009. Cognitive remediation for schizophrenia: it is even more complicated. Curr. Opin. Psychiatry 22, 161–167. Wykes, T., Steel, C., Everitt, B., Tarrier, N., 2008. Cognitive behavior therapy for schizophrenia: effect sizes, clinical models, and methodological rigor. Schizophr. Bull. 34, 523–537.