Do deficits in the magnocellular priming underlie visual derealization phenomena? Preliminary neurophysiological and self-report results in first-episode schizophrenia patients

SCHRES-06022; No of Pages 9 Schizophrenia Research xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

Schizophrenia Research journal homepage: www.elsevier.com/locate/schres

Do deficits in the magnocellular priming underlie visual derealization phenomena? Preliminary neurophysiological and self-report results in first-episode schizophrenia patients D. Núñez a,b,⁎, R. Oelkers-Ax b,c, S. de Haan b, M. Ludwig b, H. Sattel d, F. Resch c, M. Weisbrod b,e, T. Fuchs b a

Faculty of Psychology, University de Talca, Chile Psychiatry Department, Centre for Psychosocial Medicine, University of Heidelberg, Voßstr. 4, 69115 Heidelberg, Germany c Department of Child and Adolescent Psychiatry, University of Heidelberg, Blumenstraße 8, 69115 Heidelberg, Germany d Department of Psychosomatic Medicine and Psychotherapy, Klinikum rechts der Isar, Technische Universitaet Muenchen, Langerstraße 3, 81675 Munich, Germany e Klinikum Karlsbad-Langensteinbach, Guttmannstrasse 1, 76307 Karlsbad, Germany b

a r t i c l e

i n f o

Article history: Received 16 April 2014 Received in revised form 4 August 2014 Accepted 19 August 2014 Available online xxxx Keywords: First-episode schizophrenia Visual evoked potentials N80 component Magnocellular priming Self-disorders Visual derealization phenomena

a b s t r a c t Background: Early visual impairments probably partially caused by impaired interactions between magnocellular (M) and parvocellular (P) pathways (M priming deficit), and disturbances of basic self-awareness or self-disorders (SDs) are core features of schizophrenia. The relationships between these features have not yet been studied. We hypothesized that the M priming was impaired in first-episode patients and that this deficit was associated with visual aspects of SDs. Aim: To investigate early visual processing in a sample of first-episode schizophrenia patients and to explore the relationships between M and P functioning and visual aspects of SDs addressed by the Examination of Anomalous Self-Experience (EASE) interview. Method: Nine stimulating conditions were used to investigate M and P pathways and their interaction in a pattern reversal visually evoked potential (VEP) paradigm. N80 at mixed M- and P-conditions was used to investigate magnocellular priming. Generators were analyzed using source localization (Brain Electrical Source Analysis software: BESA). VEPs of nineteen first-episode schizophrenia patients were compared to those of twenty matched healthy controls by a bootstrap resample procedure. Visual aspects of SDs were analyzed through a factor analysis to separate symptom clusters of derealization phenomena. Thereafter, the associations between the main factors and the N80 component were explored using linear mixed models. Results: Factor analyses separated two EASE factors (“distance to the world”, and “intrusive world”). The N80 component was represented by a single dipole located in the occipital visual cortex. The bootstrap analysis yielded significant amplitude reductions and prolonged latencies in first-episode patients relative to controls in response to mixed M–P conditions, and normal amplitudes and latencies in response to isolated P- and M-biased stimulation. Exploratory analyses showed significant negative correlations between the N80 amplitude values at mixed M–P conditions and the EASE factor “distance to the world”, i.e. relatively higher amplitudes in the patient group were associated with higher subjective perceived derealization (“distance to the world”). Conclusions: The early VEP component N80 evoked by mixed M–P conditions is assumed to be a correlate of M priming, and showed reduced amplitudes and longer latencies in first-episode patients. It probably reflects a hypoactivation of the M-pathway. The negative association between visual SDs (derealization phenomena characterized by visual experiences of being more distant to the world), and the M priming deficit was counterintuitive. It might indicate a dysregulated activity of the M-pathway in patients with SDs. Further research is needed to better understand this preliminary finding. © 2014 Elsevier B.V. All rights reserved.

1. Introduction ⁎ Corresponding author at: Facultad de Psicología, Universidad de Talca, Avenida Lircay s/n, Talca, Chile. Tel.: +56 71 2201775. E-mail addresses: [email protected] (D. Núñez), [email protected] (R. Oelkers-Ax), [email protected] (H. Sattel), [email protected] (F. Resch), [email protected] (M. Weisbrod), [email protected] (T. Fuchs).

The visual magnocellular (M) system transmits rapid and lowresolution information critical for orienting attention in space preferentially to parieto-occipital visual areas. The parvocellular (P) system conducts slow and high-resolution information critical for object recognition to temporal–occipital cortex (Butler et al.,

http://dx.doi.org/10.1016/j.schres.2014.08.019 0920-9964/© 2014 Elsevier B.V. All rights reserved.

Please cite this article as: Núñez, D., et al., Do deficits in the magnocellular priming underlie visual derealization phenomena? Preliminary neurophysiological and self-report r..., Schizophr. Res. (2014), http://dx.doi.org/10.1016/j.schres.2014.08.019

2

D. Núñez et al. / Schizophrenia Research xxx (2014) xxx–xxx

2005). Visual schizophrenia impairments, a core feature of the illness (Javitt, 2009), are suggested to be partly caused by early processing deficits of the M pathway. This might include disturbed interactions between both visual systems (Butler et al., 2007; Laycock et al., 2007), which would affect the organizing function that the M system normally exerts on the P system (M priming). The visual object recognition at least involves: a rapid activation of parietal attentional mechanisms (Cheng et al., 2004), and an initial object representation in frontal areas (Bar et al., 2006) by inputs from the M pathway (Laykock et al., 2007); lateral projections from the M pathway to the ventral stream (Doniger et al., 2002; Chen et al., 2007); and feedback projections from higher-level to lower-level areas (Kveraga et al., 2007). The brain network associated with this process (Sehatpour et al., 2008) originates from the dorsal (M) stream visual cortex, which provides low template resolution and informational inputs to both ventral stream and frontal brain areas for a more detailed exploration of visual stimuli (Sehatpour et al., 2006). This function is impaired in schizophrenia, leading to deficits at an intermediate level of visual processing, like the disruption observed in perceptual closure process. This impairment is regarded as the result of disturbed modulation of ventral stream visual areas (Lateral Occipital Complex; LOC) via impaired lateral M inputs (Donniger et al., 2002), and not as a consequence of intrinsic LOC dysfunctions (Sehatpour et al., 2010). It fits in with a recent electrophysiological evidence revealing that during a perceptual closure task, the processing of patients is altered from early to late event related potentials (ERP) (P100 and Ncl respectively), but not at the intermediate ERP (N180) representing the initial stages of object recognition (Azadmehr et al., 2013). Visual evoked potentials (VEPs), one of the most commonly used paradigms to address mechanisms underlying visual information processing, consistently elicit a three-phasic pattern with three major components (Barnikol et al., 2006). Amplitude reductions and delayed latencies have been reported for the earliest component (N80), a negative deflection with onset latency between 40–70 ms, peaking around 70–90 ms after stimulus onset (Schechter et al., 2005; Butler et al., 2007), and mainly driven by parvocellular inputs (Foxe et al., 2008). Significant N80 amplitude reductions in response to mixed M–P conditions, regarded as an electrophysiological correlate of the M priming, were observed in early onset schizophrenia patients many years after first-episode, but not in adult onset patients (Núñez et al., 2013). This finding points toward an M priming deficit in early onset patients and is compatible with the neurodevelopmental hypothesis of schizophrenia, probably reflecting brain maturational abnormalities of visual area V1/V2 (Henze et al., 2010; Schultz et al., 2011) and parietal lobes (Kumra et al., 2004) which play an important role in visual information processing. Evidence coming from behavioral studies indicates that M impairments are linked to visual symptoms in the early stages of the illness (Kéri and Benedek, 2007), probably leading to both disturbed highlighting of relevant information and slower visual information processing (Kiss et al., 2010). Kéri et al. (2005) reported significant relationships with abnormal subjective perceptual experiences, which include unclear seeing, partial sight, photopsia, micro-macropsia, changes in perception of others' faces and figures, skewed sight/disturbed perspective, and disturbed sense of distance, among others (Kéri, 2008). These anomalous visual experiences seem to be more pronounced in the early stages of the illness (Klosterkötter et al., 2001). Moreover, significant associations with M impairments were found in high-risk psychosis subjects and never-medicated first-episode schizophrenia patients (Kéri et al., 2005; Kéri and Benedek, 2007; Kiss et al., 2010; Akroyd, 2013). Electrophysiological evidence for the M impairment in first episode schizophrenia is scant. Katsanis et al. (1996) did not find significant differences in amplitude and latencies between patients and controls. In contrast, Yeap et al. (2008) reported reduced P100 amplitudes in patients, suggesting that early visual impairments might be present before the illness onset. To our knowledge, the associations between M impairments and perceptual subjective anomalies in first-episode

schizophrenia patients have not been investigated using electrophysiological data. A particular kind of subjective anomalies, probably manifested at the beginning of the illness, gravitating around a basic disturbance of selfawareness, is currently being investigated, mainly as a consequence of the increasing interest in both early detection and prevention of psychosis (Raballo et al., 2011; Nelson et al., 2012). These anomalies, termed self-disorders (SDs) (Møller et al., 2011), involve a wide range of changes concerning the experience of self, identity and intersubjectivity. They express real complaints of patients and might be considered as a potential trait phenotype for the clinical characterization of the schizophrenia spectrum disorders (Parnas et al., 2011; Raballo et al., 2011). One available scale for addressing self-disorders is the Examination of Anomalous Self-Experience (EASE, Parnas et al., 2005), reported as a reliable and internally consistent tool to evaluate the subjective experience in first-episode schizophrenia patients (Møller et al., 2011). The present study analyzed both source waveforms derived from the EEG signals elicited by pattern-reversal visual evoked potentials and anomalous self-experiences using the EASE interview in first-episode schizophrenia patients and their matched controls. The main focus was the first VEP component (N80) at mixed M–P conditions as a correlate for magnocellular priming of the parvocellular system (Núñez et al., 2013). Two hypotheses were assessed: (1) The M priming is impaired in first-episode patients with schizophrenia. It is reflected either in reduced amplitudes and/or prolonged latencies of the N80 component in patients relative to controls in conditions addressing M-priming, i.e. combined conditions (M- and P-stimulation). For isolated M- and P-conditions, intact responses were expected. (2) The M priming deficit is associated with a specific pattern of anomalous self-experience (Parnas et al., 2005), especially with anomalous experiences of the visual channel which result in derealization experiences such as a diminished sense of presence and feeling distant from the world. 2. Material and methods 2.1. Subjects Nineteen first-episode schizophrenia patients (ICD-10: F2; FEP) treated in the Psychiatric Hospital of the University of Heidelberg between 2008 and 2011 were recruited and compared to twenty matched controls (CG) recruited during the same period (Table 1). Patients exhibiting either neurological co-morbidity or other psychiatric diseases were not included in the study. Control subjects without exhibiting neurological or psychiatric disorders and without any firstTable 1 Demographic characteristics of patient (FEP) and control groups (CG)—mean (standard deviation). N

Gender (m = male, f = female) Age at testing (years)

Education ≤12 years of education ≥13 years of education Premorbid-verbal IQ PANSS positive PANSS negative PANSS general Visual acuity (right) Visual acuity (left) Antipsychotic medication Chlorpromazine equivalent + SD (mg)

CG

FEP

20

19

11 m, 9 f 23.3 (3.7) Range [16.4–29.9]

13 m, 6 f 23.22 (2.8) Range [18.5–27.1]

5 15 27.0 (6.7)

6 14 26.2 (5.0) 11.1 (3.5) 17.0 (4.6) 31.6 (6.0) .85 (.12) .85 (.11)

.93 (.13) .93 (.14)

p

ns

ns ns ns

ns ns

349.6 (+335.5)

Please cite this article as: Núñez, D., et al., Do deficits in the magnocellular priming underlie visual derealization phenomena? Preliminary neurophysiological and self-report r..., Schizophr. Res. (2014), http://dx.doi.org/10.1016/j.schres.2014.08.019

D. Núñez et al. / Schizophrenia Research xxx (2014) xxx–xxx

3

degree relatives suffering from schizophrenic spectrum disorder were recruited. All patients were characterized as recent onset (the duration of illness was not longer than two years). Therefore, the age of patients was used as predictor for the age of illness onset without systematic bias. 17 of the 19 patients were receiving anti-psychotics (16 with atypical, 1 with typical medication). The mean ± SD chlorpromazine dose was 349.69 ± 335.55 mg/day. Diagnosis was verified using the Mini-International Neuropsychiatric Interview (MINI-SCID, Sheehan et al., 1998). Patients and controls did not differ in terms of pre-morbid IQ measured by the Mehrfachwahl-Wortschatz-Intelligenztest (Lehr, 1977). Severity of schizophrenic symptoms was assessed using the Positive and Negative Syndrome Scale (PANSS, Kay et al., 1987). Self-disorders were addressed by the Examination of Anomalous Self-Experience (EASE; Parnas et al., 2005). Visual acuity was tested before subjects went to the rest of the examination. No significant between-group differences were found (right and left vision: t = 1.62, p = 0.1). All participants provided written informed consent. The study was approved by the local ethics committee and conducted according to the Declaration of Helsinki.

baseline-corrected with the first 128 ms of the epoch as the baseline interval. Eye movements and blinks were corrected using the Gratton and Coles algorithm (Gratton et al., 1983) as implemented in Brain Vision Analyzer. Artifacts exceeding 150 μV in amplitude were rejected. Additionally, segments were manually checked to remove remaining artifacts. Thereafter, data were re-referenced to the average reference. Averages were analyzed for peak latencies and peak-to-peak amplitudes of the main components. The electrophysiological signals of the N80 component were analyzed at a single electrode level (peak values, Oz electrode, 70–110 ms). Data were exported to the Brain Electrical Source Analysis (BESA 2000, version 5.1.8; BESA GmbH, Gräfelfing, Germany), and subsequently filtered (high-pass filter = 1.6 Hz; low-pass filter = 45, 24 dB/octave; zero-phase filter). To characterize the VEP source waveforms, a time-window from − 50 ms before stimulus to 400 ms after stimulus was used. Baseline was corrected relative to the interval −50 to 0 ms. Specific time windows to create a model for the earliest VEP components were used and are described below. A realistic approximation of the head model as provided by BESA was used (isotropic, cr 80).

2.2. Stimuli: visual-evoked potential paradigm

2.5. Dipole analysis

The paradigm has been previously described in Núñez et al. (2013). Briefly, nine stimulus conditions were used to isolate M and P pathways and to simultaneously activate both systems. Combined functions of the M and P systems were evaluated using conditions 1–3 (black and white checkerboard pattern, sharp edges, and increasing spatial frequency; M–P_syn), which differentially activate the two systems: The activity of the M and the P system respectively decreases and increases with a decreasing spatial frequency (Zemon and Gordon, 2006). The response involving the M system input on the P system (M priming) was investigated using conditions 4–6 (asynchronous flicker masking; M–P_asyn). These conditions assess the P-biased response with maximal M activation: Asynchronous rapid flicker (8 Hz) evokes a maximal M response but prevents it from appearing in the averaged potential due to an asynchronous response relative to pattern stimulus onset (Vassilev et al., 1994). Conditions 1–6, therefore, are characterized by magnocellular priming on the parvocellular system (M priming). Nearly isolated P function was assessed using isoluminant red–green stimulation (conditions 7–8) (P-biased) (Tobimatsu et al., 1996). The M-biased function was assessed using a sinusoidally modulated blackand-white checkerboard pattern at low spatial frequency (60 min of arc, condition 9) without sharp edges (M-biased) (Alexander et al., 2005).

Dipole sources and source waveforms of the N80 component were estimated using Brain Electrical Source Analysis (BESA) software. Based on grand averages (all conditions, control group) dipoles were sequentially fitted over specific time windows, using location and orientation as parameters. A single dipole and a pair of dipoles were fitted in a time window of 70–95 ms and 97–130 ms, respectively. Additionally, a single dipole was fitted between 140–200 ms. The grand average dipole model was applied to the data from each individual subject. Equivalent dipoles were sequentially fitted, however, for these early components, location was fixed, and only orientation was fitted without further constraints. This model was applied to the corresponding subject for each condition without any refitting. Following the procedure described in Núñez et al. (2013), dipole models were built on the basis of the healthy control group, and subsequently applied to the patient's group.

2.3. Electrophysiological recording The EEG was recorded with a 64-channel Quickamp Amplifier (FA Brain Product GMBH, Gilching, Germany). Stimuli were presented using the Presentation software (Neurobehavioural Systems, Inc., Albany, USA). Electrodes were named according to their equivalent position in the extended 10–20 system, with small deviations indicated by a single quote ('). Impedance of the electrodes was 5 kΩ. The hardware filter was set as follows: low cutoff: DC, high cutoff: 200 Hz and notch: off. The sampling rate was 1000 Hz. In all, 64 sintered silver/silver chloride electrodes were fixed using equidistant electrode caps (Easycap, Falk Minow System, Herrsching, Germany). The average reference was used during the EEG recording. Vertical and horizontal electro-oculograms (VEOG and HEOG) were recorded by electrodes placed above and below the left eye (VEOG) and at the outer canthi of both eyes (HEOG). 2.4. EEG data processing Data were pre-processed using Brain Vision Analyzer, version 1.05 (Brain Products GmbH, Germany). Data were then segmented into epochs of 1048 ms (−128 ms to 920 ms post-stimulus). Epochs were

2.5.1. Statistical analysis To analyze the N80 source waveforms, experimental conditions were pooled into four categories according to their stimulating properties: black–white combined conditions with direct M and P inputs (conditions 1–3, M–P_syn), asynchronous flicker masking combined conditions with only indirect M and direct P inputs (conditions 4–6, M–P_asyn), isoluminant red–green P-biased conditions (conditions 7–8, P-biased), and sinusoidal black–white M-biased condition (condition 9, M-biased). M–P_syn and M–P_asyn were M priming conditions, whereas P-biased and M-biased were not. We performed statistical analyses of source waveforms with MATLAB (Version 7.11, MathWorks Inc., Natick, MA, USA). We assessed latencies and amplitudes using bootstrap technique based on critical t-intervals. Bootstrap was used because peaks of the N80 could not reliably be picked from all individual data sets. We proceeded as follows: peaks were taken from the bootstrap grandaverage resamples (1000 resamples). In a next step, we performed a one-sided t-test in which the standard deviation of the resample distribution (latencies and amplitudes) was multiplied by the critical t-value for α = 5%. We were thus able – via the resulting error – to assess the significance of the differences between groups (Efron and Tibshirani, 1993). Differences between groups were labeled as significant when the mean value plus the t-critical interval of one group did not touch the mean of the other group. We determined the characteristics of self disorders through the “Examination of Anomalous Self-Experience” (EASE, Parnas et al., 2005) interview, an in-depth phenomenological interview which explores a wide range of “experiential or subjective anomalies that may be considered as disorders of basic or ‘minimal’ self-awareness” (Parnas et al.,

Please cite this article as: Núñez, D., et al., Do deficits in the magnocellular priming underlie visual derealization phenomena? Preliminary neurophysiological and self-report r..., Schizophr. Res. (2014), http://dx.doi.org/10.1016/j.schres.2014.08.019

4

D. Núñez et al. / Schizophrenia Research xxx (2014) xxx–xxx

2005). It allows distinguishing five clinical subtypes of altered visual perception (captivation by details; diminished presence: distance to the world; diminished presence plus derealization; fluid global derealization; intrusive derealization), rated as not present, questionable, mild, moderate or severe (scores = 0, 1, 2, 3 and 4 respectively). The interviews were carried out by clinicians specifically trained in the EASE. To reduce complexity and focus particularly on visual aspects of SDs, we conducted a principal component analysis (PCA) using all items addressing these visual aspects. For this analysis we selected patients' data only, as these symptoms were very rare in control subjects and isolated independent factors. Thereafter, to generate new hypotheses and to inspire a better understanding of the potential meaning of the electrophysiological results, we conducted an exploratory analysis bridging electrophysiological data (VEP N80 component) and phenomenological data (EASE visual sum scores built according to the 2 factors extracted by PCA: 1 = presence of SDs; 0 = absence of SDs). We applied nonparametric correlations for single measurements (M-biased) and linear mixed models (LMM, Singer, 1998) for multiple measurements within a patient (all other conditions). Here the association between visual self-disturbances and VEP N80 amplitude for those conditions using repeated measures (M–P_syn, M–P_asyn, P-biased conditions) was estimated: The subjects were chosen as level of analysis, the experimental conditions as repeated measurement level (3 levels for M–P_syn conditions: single conditions 1, 2 and 3; 3 levels for M–P_asyn conditions: single conditions 4, 5 and 6; and 2 levels for P-conditions: single conditions 7, and 8) and the EASE factors as covariates (higher EASE scores indicate higher psychopathology). Finally the means of the groups of patients affected by visual disturbances of the derealization type present or not present were compared using LMM.

the M priming: P driven but dependent on M input (directly or indirectly) (Núñez et al., 2013). As shown in Supplementary data (Fig. 2) both scalp and source waveforms (Oz electrode) showed a similar pattern. 3.2.2. N80 dipole analysis Fig. 1 illustrates the grand-average model obtained for healthy control subjects over the modeled epoch (70–200 ms). The neural activity underlying the N80 component in controls was represented by a single dipole fitted in the 70–95 ms time interval located in the visual cortex, near to the medial occipital cortex (mean amplitude = − 39.60 μV; peak latency 89 ms; approximate Talairach coordinates: x = 1.9; y = − 92.1; z = − 19.5). The corresponding neural activity for the P100 component was represented by a pair of symmetrical dipoles fitted in the 97–130 ms time interval (mean amplitude = 22.18 μV; peak latency 108 ms; approximate Talairach coordinates: x = 17.2; y = − 74.7; z = − 1.4). Finally, the neural activity underlying the N160 component was represented by a single dipole fitted in the 140–200 ms time interval (mean amplitude = − 32.92 μV; peak latency 159 ms; approximate Talairach coordinates: x = 1.7; y = − 78.5; z = − 6.6). Explained variances at a single subject level were: N80 component = 80%; P100 component = 87%; and N160 component = 80%. 3.2.3. Source waveform analysis 3.2.3.1. N80 amplitude. Fig. 2 illustrates the N80 source waveforms across groups and conditions. The bootstrap analysis yielded a main effect of group with significant N80 amplitude reductions in patients relative to controls under mixed conditions that evoke a typical M priming (M–P_syn and M–P_asyn) (Table 3).

3. Results 3.2.3.2. N80 latency. As shown in Table 3, significantly longer N80 latencies (about 3 ms longer) were observed for patients as compared to controls in pooled M–P_syn and M–P_asyn conditions.

3.1. Visual aspects of the EASE interview As shown in Table 2, the factor analysis addressing visual aspects of EASE revealed a “distance to the world” perception against an “intrusive world” factor. The two factors seem to represent two different types of derealization accompanied by visual symptoms. 3.2. Electrophysiological results 3.2.1. Stimulation condition properties and physiological behavior of the N80 component To test the functional separation of M and P pathways, individual experimental conditions were analyzed for the control group using the bootstrap technique (see Supplementary data Fig. 1). As expected, results yielded by both the scalp data analysis and the source analysis were very similar. The highest N80 amplitudes were found in M–P_syn and M–P_asyn conditions with small pattern sizes, and strongly reduced amplitudes were observed in both P-biased and M-biased conditions. This finding reveals that the M- and P-pathways were successfully isolated, and suggests that N80 amplitude under M–P-syn and M–Pasyn conditions can be regarded as an electrophysiological correlate of Table 2 Principal component analysis. Rotated component matrix. Two independent factors could be extracted: “distance to the world”, “intrusive world”. EASE item

1.12.1 Captivation by details 2.4.2 Diminished presence: Distance to the world 2.4.3 Diminished presence + derealization 2.5.1 Fluid global derealization 2.5.2 Intrusive derealization

Component Distance to the world

Intrusive world

−0.021 0.804 0.801 0.872 −0.035

0.807 −0.172 0.318 −0.15 0.823

3.3. Relationships between electrophysiological and clinical data The linear mixed model indicated an association between the neurophysiological N80 impairment and subjective symptoms of anomalous self-experience: The LMM yielded a significant association (F = 4.51; p b 0.05) between the N80 amplitude in M–P_asyn conditions and the “distance to the world” factor, which includes visual items of the EASE representing visual derealization phenomena (diminished presence, subtype 3 (distance to the world plus derealization), and fluid global derealization, item 2.5.1). This indicates that relatively higher N80 amplitudes in patients were associated with higher subjective perceived derealization (“distance to the world”). The analysis did not reveal significant associations between the other conditions (M–P_syn, and P-biased) and SD visual factors. The Spearman's correlation coefficient yielded no significant associations between the amplitude values of the M-biased condition and SD visual factors (Table 4). The visual SD impairment in schizophrenia patients, represented by the presence of the “distance to the world” factor, was associated with increased N80 amplitudes in all experimental conditions (see Fig. 3). The N80 amplitude differences observed between patients with visual SDs and patients without these disturbances were not significant. Only a trend was observed for the M–P_asyn conditions (F = 2.06; p = 0.054). Finally, no significant correlations between the N80 components and severity of symptoms (PANNS scores: total, positive, negative) were observed. 4. Discussion The present study examined anomalous self-experiences subjectively and early visual processing objectively (using source waveforms of the VEP N80 component) in first-episode schizophrenia patients and healthy

Please cite this article as: Núñez, D., et al., Do deficits in the magnocellular priming underlie visual derealization phenomena? Preliminary neurophysiological and self-report r..., Schizophr. Res. (2014), http://dx.doi.org/10.1016/j.schres.2014.08.019

D. Núñez et al. / Schizophrenia Research xxx (2014) xxx–xxx

5

Fig. 1. Dipole solution for source localization of N80, P100, and N160 components. A) The N80 component: single dipole fitted over the 70–95 ms period. B) The P100 component: a pair of dipoles fitted over the 97–130 ms period. C) The N160 component: single dipole fitted over the 140–200 ms.

controls. One main finding revealed smaller amplitudes and longer latencies in patients relative to controls in response to conditions addressing the M priming (mixed M–P-conditions: M–P_syn and M–P_asyn) and no group differences in response to both P- and M-biased conditions. Additionally, we found a significant negative association between the N80 amplitude values at mixed M–P_asyn conditions and specific visual aspects of self-disorders, namely the factor “distance to the world”, a visual form of derealization. Then, in patients showing visual SDs, a better performance on the N80 amplitude correlates with disturbances of self-awareness, represented by positive scores on “distance to the world” factor. The electrophysiological results showing deficits in the N80 component in patients corroborate our previous finding of M priming impairment in (chronic) early onset schizophrenic patients in firstepisode subjects (Núñez et al., 2013). Based on the assumption that the N80 is mainly conveyed by the P pathway (Foxe et al., 2008), the present data support the previous evidence that the N80 component might be regarded as the electrophysiological M priming on the P pathway (Supplementary data Fig. 1). Additionally, the normal values we observed for both amplitudes and latency values in patients regarding P-biased conditions support anterior evidence demonstrating a specific M impairment in schizophrenia (Butler et al., 2007; Lalor et al., 2008; Martínez et al., 2008, 2011), and confirm our conclusion of a M priming impairment as a probable mechanism accounting for the early visual information processing deficit in schizophrenia. However, alternate possibilities could be considered. For instance, because of the complex interactions between M and P pathways, probably occurring

at different levels of cortical function, it is not possible to discard that the increased N80 amplitude observed in response to mixed M–P stimuli versus reduced amplitudes to M and P isolated conditions indicates an additive effect of both pathways rather than a priming effect. In the light of our electrophysiological results, this explanation seems to be insufficient to account for the observed higher M–P amplitudes. First, the amplitudes of M and P isolated conditions are quite small (near zero), then, a simple addition would not cause amplitudes as high as M–P amplitudes (see Supplementary data Fig. 1). On the other hand, if only additive effects were contributing to the N80 amplitude at M–P conditions, M–P_asyn conditions should be nearly as small as P-biased conditions, because the M answer is – due to its asynchronicity – not part of the resulting amplitude. Additionally, as we previously stated (Núñez et al., 2013), our paradigm did not address projections to higher cortical areas (e.g., prefrontal), and hence, the present results provide evidence for an impaired M enhancement of the P response in first episode schizophrenia patients, but not for answering the question of whether cortical activation via the M system itself is also impaired. Then, being not possible to absolutely rule out the alternate hypothesis discussed here, we argue that the pattern we observed (strongly reduced amplitudes in response to mixed M–P conditions with greater M activation and lesser P activation as compared to amplitudes evoked by mixed M–P conditions with greater P activation and lesser M activation) can be regarded as evidence for M visual input on P pathway, at least at the very early level of visual processing addressed by our paradigm, and within the early and posterior visual sensory network.

Please cite this article as: Núñez, D., et al., Do deficits in the magnocellular priming underlie visual derealization phenomena? Preliminary neurophysiological and self-report r..., Schizophr. Res. (2014), http://dx.doi.org/10.1016/j.schres.2014.08.019

6

D. Núñez et al. / Schizophrenia Research xxx (2014) xxx–xxx

Fig. 2. Between-group source waveform comparison. The pattern of source waveforms illustrates the main differences observed in M–P-syn and M–P-asyn for the N80 component.

To our knowledge this is the first neurophysiological study analyzing early visual processing and subjective anomalous experiences in first-episode schizophrenia patients. Our findings revealed a specific association between the M–P_asyn conditions and visual experiences of “being more distant to the world” (diminished presence, subtype 3, and derealization subtype 1) suggesting that the M priming impairment might be a possible mechanism associated with the abnormalities in Table 3 Bootstrap results: Amplitude and latency values, N80 component. Condition

M–P_syn

M–P_asyn

P-biased

M-biased

Values

Mean sd Lower Upper Mean sd Lower Upper Mean sd Lower Upper Mean sd Lower Upper

Amplitude

Latency

CG

FEP

CG

FEP

−66.94a 9.13 −82.73 −51.15 −48.92a 6.29 −59.79 −38.04 −10.30 3.80 −16.87 −3.73 −30.09 5.55 −39.69 −20.49

−46.73a 5.37 −56.04 −37.43 −36.69a 4.82 −45.04 −28.34 −6.82 4.35 −14.36 0.72 −21.44 3.37 −27.29 −15.60

86.73b 0.85 85.25 88.21 87.52b 0.94 85.89 89.14 96.47 1.99 93.02 99.91 79.67 1.18 77.62 81.72

89.08b 1.23 86.94 91.22 90.26b 1.24 88.11 92.40 98.85 1.91 95.54 102.16 81.73 3.63 75.43 88.02

Differences between groups were significant (5% level) when the mean plus the t-critical interval of one group (lower and upper limits) did not touch the mean of the other group. s.d. = standard deviation. a Significant differences between controls (CG) and patients (FEP), amplitude values. b Significant differences between CG and FEP, latency values.

these visual components of the SDs. This finding is in line with clinical evidence showing anomalous visual experiences in schizophrenia (Parnas et al., 2003), and supports behavioral studies revealing associations between these anomalies and M-pathway impairments in both people at high-risk for psychosis (Kéri and Benedek, 2007) and never medicated first-episode schizophrenia patients (Kiss et al., 2010). We argue that this association probably reflects the prominent role of the M-pathway at an early level of visual processing (Nassi and Callaway, 2009). The impaired flow of information from the M- to the P-system leads to slower processing of visual inputs (Slaghuis, 2004), disturbed highlighting of relevant information and diminished ability to focus attention to relevant details (Kéri, 2008). This deficit might impact on the phenomenological perception of the world, which appears meaningless, unclear or ambiguous, probably leading to difficulties in world immersion. In other words, a possible explanation is that the M priming deficit might be at least one part of the neurophysiological basis for subjective experiences of “visual” derealization with the feeling of being more distant to the world. Whereas the former reflects the neurophysiological mechanism underpinning early-stage visual information processing impairments, the latter could be its phenomenological manifestation. This argument is in concert with recent phenomenological statements according to which schizophrenia could be (more accurately) described as a disturbance of experienced self-presence (Sass, 2014). The selfdistortions observed in schizophrenic patients at a pre-reflective level of selfhood are in many cases related to the difficulties to process the outside world (Taylor, 2011). The lacking implicit sense of “being there” (presence or self-affection) is one of the basic components of subjective experience in schizophrenia (Sass and Parnas, 2003), and a “diminished presence” might arise from the disintegration of sensory inputs (Postmes et al., 2014). This in line with the model proposed by these authors, according to which SDs in schizophrenia can be regarded

Please cite this article as: Núñez, D., et al., Do deficits in the magnocellular priming underlie visual derealization phenomena? Preliminary neurophysiological and self-report r..., Schizophr. Res. (2014), http://dx.doi.org/10.1016/j.schres.2014.08.019

D. Núñez et al. / Schizophrenia Research xxx (2014) xxx–xxx

7

Table 4 Correlations between N80 amplitude and EASE visual factors. EASE visual factors

Condition Linear mixed model

Distance to the world Intrusive world

Spearman coefficient

M–P_asyn

M–P_syn

P-biased

M-biased

F = 4.51; p b 0.05⁎ F = 0.32; p = 0.37

F = 2.31; p = 0.14 F = 2.00; p = 0.17

F = 0.01; p = 0.92 F = 2.45; p = 0.13

r = −0.31; p = 0.19 r = −0.24; p = 0.31

⁎ Correlation is significant at the b 0,05 level.

as a consequence of a perceptual incoherence, probably resulting in a sensory imbalance obstructing integration of sensory input to one unified percept. The model posits a perceptual circle, where reduced sensory input is analogous to “diminished presence”, and suggests that the avoidance and the resulting distance between the inner and outer world might be understood as strategies aimed at coping with the incoherent sensory experiences deprived from aligning somatosensory feedback. The association observed between more pronounced N80 amplitude (M–P_asyn) and the presence of visual SDs of the “distance to the world” type is counterintuitive and differs from our initial assumptions. Some studies have suggested that the impairments at early stages of visual processing in schizophrenia might be associated with an overactivation of the M pathway (Bedwell et al., 2003; Renshaw et al., 1994), and it has been found that the absolute M hypersensitivity in first-episode patients is related to visual subjective anomalies (Kéri, 2008). As Kiss and colleagues argued (Kiss et al., 2010), this hypersensitivity probably leads to anomalous perceptual experiences, mainly to impaired sensory gating and information overload. However, and although the presence of visual SDs in patients was associated with higher N80 amplitude values, the amplitude reductions that we observed in this component seem to reflect a hypoactivation of the Mpathway, which fits in with evidence coming from studies performed with medicated chronic patients (Slaghuis, 2004; Butler et al., 2005; Martínez et al., 2011). Thus, whereas in the whole patient group smaller amplitudes might reflect a decreased activity of the M system, in patients with visual SDs higher amplitudes probably reflect a deregulated or dysregulated activity of the M-pathway. This can be interpreted as the result of a global delay and decrease of temporal connectivity within the early visual cortex, which is supported by literature revealing specific abnormal neuronal lateral connections in this area (Selemon, 2001; Must et al., 2004). Our results yielded an M priming deficit without an M-deficit. As shown in Table 3, we observed slightly reduced amplitudes and faintly longer latencies in patients as compared to controls, in response to Mbiased condition. This is partially consistent with our previous results, which showed normal amplitudes, but longer latencies in patients with early and adult schizophrenia onset, relative to their matched controls (Núñez et al., 2013). Then, we just could observe a discrete

Fig. 3. Mean values, N80 component, FEP groups. Increased amplitude values were observed in patients with visual SDs relative to those without SDs. The differences were not significant.

M-deficit, and group differences were not as high as other studies, which may be due to differences in the duration of illness. Whereas in the present study the duration of illness was not longer than two years, in the previous one, it was 6.9 and 5.5 years for adult and early onset patients respectively. Then, patients participating in the present study were probably less affected by factors related to the duration of illness, like medication effects. Although there is evidence showing that early visual impairments in schizophrenia would not be affected by antipsychotic medicaments, according to Cadenhead et al. (2013) it cannot be entirely ruled out. Our present results differ from Butler et al. (2007), who reported an impaired N80 response to M–P conditions, in a sample of patients with a duration of illness of 16.7 years (±1.8). To our understanding, these different findings might be due to the greater duration of illness in the Butler's study, and because of the usage of different paradigms (visual pattern reversal in our study versus sine-wave grating conditions in the Butler's study). Confounding effects were addressed. The N80 component was not affected by medication, which supports previous research (Schechter et al., 2005; Butler et al., 2007). On the other hand, only first-episode patients with recent onset were included. Therefore, our findings would not be affected by hospitalization or chronicity effects. Regarding clinical implications, early visual impairments in schizophrenia have been associated with perceptual deficits (Doniger et al., 2002), cognitive and social dysfunctions, and psychotic symptoms. Self-disorders are thought to be a trait feature of the illness (Møller et al., 2011), with predictive power of incident cases of schizophrenia spectrum disorders (Parnas et al., 2011; Henriksen and Parnas, 2012). In addition, SDs have been proposed as an early pre-morbid indicator for psychosis risk (Brent et al., 2014), and visual perception disturbances and derealization phenomena have been found to possess good psychometrical properties for predicting the transition from prodromal states to schizophrenia (Parnas et al., 2011). Thus, they may also serve as important clinical features for a differential diagnosis, particularly in the early detection of the illness (Klosterkötter et al., 2001). Derealization, optic and acoustic disturbances of perception as well as problems in the discrimination of experiences and fantasies on a clinical level were detected together with thought disturbances to form a prognostic bundle of basic symptoms (cognitive–perceptive basic symptoms, COPER): If one out of ten criteria was present, 67% of patients developed schizophrenic symptomatology within ten years and 20% even within the first year. Depersonalization on the other hand did not show any predictive quality (Schultze-Lutter and Ruhrmann, 2008). Finally, Parnas and Henriksen (2013) recently proposed that the effectiveness of the interventions aimed to improve the patient's compliance might be optimized “if they take the alterations of the patients' ontological-existential framework into account”. Some limitations to the present study deserve mentioning. Our experimental paradigm did not address projections to higher cortical areas. Then, the present study cannot detect whether cortical activation via the M-system itself is also impaired. As we previously mentioned, although our EEG results showing that M and P pathways were differentially activated and that mixed M–P conditions might represent informational inputs from M to P pathway, an additive effect of both pathways accounting for the increased N80 amplitudes we observed cannot be completely ruled out. Finally, according to the exploratory

Please cite this article as: Núñez, D., et al., Do deficits in the magnocellular priming underlie visual derealization phenomena? Preliminary neurophysiological and self-report r..., Schizophr. Res. (2014), http://dx.doi.org/10.1016/j.schres.2014.08.019

8

D. Núñez et al. / Schizophrenia Research xxx (2014) xxx–xxx

nature of the analyses a correction for multiple testing was not introduced, and the associations between the M priming deficit and visual experience of “being more distant to the world” cannot be interpreted as a causal relationship. However, the nonexistent associations with the two other factors give support for this specific pattern of relationship. Further research is needed to confirm this finding. In conclusion, our results add novel evidence to previous findings and replicated the magnocellular priming impairment for the first time in first-episode schizophrenia patients. Additionally, we provide initial neurophysiological evidence that the magnocellular impairments might underlie derealization phenomena of self-disturbances which go along with the experience of “distance to the visual world”. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.schres.2014.08.019. Role of the funding source This work is supported by the European Commission's Marie-Curie Research Training Network “DISCOS: Disorders and Coherence of the Embodied Self” (MCRTN-CT-2006035975).

Contributors Daniel Nunez performed source analysis and the statistical analyses, did literature searches and wrote the manuscript. Rieke Oelkers-Ax designed the study and directed its implementation, analysis and interpretation, including quality assurance and control. Sanneke de Haan and Max Ludwig performed the phenomenological interviews. Heribert Sattel gave support for statistical analyses. Franz Resch, Matthias Weisbrod and Thomas Fuchs reviewed the manuscript and revised critically for intellectual content.

Conflict of interest None of the authors have any conflicts of interest.

Acknowledgments The authors would like to thank all patients and control subjects for their participation.

References Akroyd, M., 2013. You can't spell schizophrenia without an ‘I’: how does early intervention in psychosis approach relate to the concept of schizophrenia as an ipseity disturbance? Early Interv. Psychiatry 7, 238–246. Alexander, K.R., Rajagopalan, A.S., Seiple, W., Zemon, V.M., Fishman, G.A., 2005. Contrast response properties of magnocellular and parvocellular pathways in retinitis pigmentosa assessed by the visual evoked potential. Invest. Ophthalmol. Vis. Sci. 46 (8), 2967–2973. Azadmehr, H., Rupp, A., Andermann, M., Pavicic, D., Herwig, H., Weisbrod, M., Resch, F., Oelkers-Ax, R., 2013. Object recognition deficit in early- and adult-onset schizophrenia regardless of age at disease onset. Psychiatry Res. Neuroimaging 214, 452–458. Bar, M., Kassam, K.S., Ghuman, A.S., Boshyan, J., Schmid, A.M., Dale, A.M., Hamalainen, M.S., Marinkovic, K., Schacter, D.L., Rosen, B.R., Halgren, E., 2006. Top-down facilitation of visual recognition. Proc. Natl. Acad. Sci. U.S.A. 103 (2), 449–454. Barnikol, U.B., Amunts, K., Dammers, J., Mohlberg, H., Fieseler, T., Malikovic, A., Zilles, K., Niedeggen, M., Tass, P.A., 2006. Pattern reversal visual evoked responses of V1/V2 and V5/MT as revealed by MEG combined with probabilistic cytoarchitectonic maps. Neuroimage 31 (1), 86–108. Bedwell, J.S., Brown, J.M., Miller, L.S., 2003. The magnocellular visual system and schizophrenia: what can the color red tell us? Schizophr. Res. 63, 273–284. Brent, B., Seidman, L., Thermenos, H., Holt, D., Matcheri, S., Keshavan, M., 2014. Selfdisturbances as a possible premorbid indicator of schizophrenia risk: a neurodevelopmental perspective. Schizophr. Res. 152, 73–80. Butler, P.D., Zemon, V., Schechter, I., Saperstein, A., Hoptman, M., Lim, K., Revheim, N., Silipo, G., Javitt, D.C., 2005. Early-stage visual processing and cortical amplification deficits in schizophrenia. Arch. Gen. Psychiatry 62, 495–504. Butler, P.D., Martinez, A., Foxe, J.J., Kim, D., Zemon, V., Silipo, G., Mahoney, J., Shpaner, M., Jalbrzikowski, M., Javitt, D.C., 2007. Subcortical visual dysfunction in schizophrenia drives secondary cortical impairments. Brain 130 (Pt 2), 417–430. Cadenhead, K., Dobkins, K., McGovern, J., Shafer, K., 2013. Schizophrenia spectrum participants have reduced visual contrast sensitivity to chromatic (red/green) and luminance (light/dark) stimuli: new insights into information processing, visual channel function, and antipsychotic effects. Front. Psychol. 4 (535), 1–8. http://dx.doi.org/10.3389/fpsyg. 2013.00535. Chen, C.M., Lakatos, P., Shah, A., Mehta, A., Givre, S., Javitt, D.C., Schroede, E., 2007. Functional anatomy and interaction of fast and slow visual pathways in macaque monkeys. Cereb. Cortex 17 (7), 1561–1569. Cheng, A., Eysel, U.T., Vidyasagar, T.R., 2004. The role of the magnocellular pathway in serial deployment of visual attention. Eur. J. Neurosci. 20 (8), 2188–2192.

Doniger, G.M., Foxe, J.J., Murray, M.M., Higgins, B.A., Javitt, D.C., 2002. Impaired visual object recognition and dorsal/ventral stream interaction in schizophrenia. Arch. Gen. Psychiatry 59 (11), 1011–1020. Efron, B., Tibshirani, R.J., 1993. An Introduction to Bootstrap. Chapman & Hall, New York. Foxe, J.J., Strugstad, E.C., Sehatpour, P., Molholm, S., Pasieka, W., Schroeder, C.E., McCourt, M.E., 2008. Parvocellular and magnocellular contributions to the initial generators of the visual evoked potential: high-density electrical mapping of the “C1” component. Brain Topogr. 21 (1), 11–21. Gratton, G., Coles, M.G., Donchin, E., 1983. A new method for off-line removal of ocular artifact. Electroencephalogr. Clin. Neurophysiol. 55 (4), 468–484. Henriksen, M., Parnas, J., 2012. Clinical manifestations of self-disorders and the gestalt of schizophrenia. Schizophr. Bull. 38 (4), 657–660. Henze, R., Brunner, R., Thiemann, U., Parzer, P., Richterich, A., Essig, M., Resch, F., Stieltjes, B., 2010. Gray matter alterations in first-admission adolescents with schizophrenia. J. Neuroimaging 21 (3), 241–246. Javitt, D.C., 2009. Sensory processing in schizophrenia: neither simple nor intact. Schizophr. Bull. 35 (6), 1059–1064. Katsanis, J., Iacono, W., Beiser, M., 1996. Visual event-related potentials in first-episode psychotic patients and their relatives. Psychophysiology 33, 207–217. Kay, S.R., Fiszbein, A., Opler, L.A., 1987. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr. Bull. 13 (2), 261–276. Kéri, S., 2008. The magnocellular pathway and schizophrenia. Vis. Res. 48 (9), 1181–1182 (author reply 1183–1185). Kéri, S., Benedek, G., 2007. Visual contrast sensitivity alterations in inferred magnocellular pathways and anomalous perceptual experiences in people at high-risk for psychosis. Vis. Neurosci. 24, 183–189. Kéri, S., Kiss, I., Kelemen, O., Benedek, G., Janka, Z., 2005. Anomalous visual experiences, negative symptoms, perceptual organization and the magnocellular pathway in schizophrenia: a shared construct? Psychol. Med. 35 (10), 1445–1455. Kiss, I., Fábián, Á., Benedek, G., Kéri, S., 2010. When doors of perception open: visual contrast sensitivity in never-medicated, first-episode schizophrenia. J. Abnorm. Psychol. 119 (3), 586–593. Klosterkötter, J., Hellmich, M., Steinmeyer, E., Schultze-Lutter, F., 2001. Diagnosing schizophrenia in initial prodromal phase. Arch. Gen. Psychiatry 58, 158–164. Kumra, S., Ashtari, M., McMeniman, M., Vogel, J., Augustin, R., Becker, D.E., Nakayama, E., Gyato, K., Kane, J.M., Lim, K., Szeszko, P., 2004. Reduced frontal white matter integrity in early-onset schizophrenia: a preliminary study. Biol. Psychiatry 55 (12), 1138–1145. Kveraga, K., Ghuman, A.S., Bar, M., 2007. Top-down predictions in the cognitive brain. Brain Cogn. 65 (2), 145–168. Lalor, E., Yeap, Sh., Reilly, R., 2008. Dissecting the cellular contributions to early visual sensory processing deficits in schizophrenia using the VESPA evoked response. Schizophr. Res. 98, 256–264. Laycock, R., Crewther, S.G., Crewther, D.P., 2007. A role for the ‘magnocellular advantage’ in visual impairments in neurodevelopmental and psychiatric disorders. Neurosci. Biobehav. Rev. 31 (3), 363–376. Lehrl, S., 1977. Mehrfachwahl-Wortschatz-Intelligenztest MWT-B [MWT-B: Multiple-choice Vocabulary Test]. Straube, Erlangen, Germany. Martínez, A., Hillyard, S.A., Días, E.C., Hagler Jr., D.J., Butler, P.D., Guilfoyle, D.N., Jalbrzikowski, M., Silipo, G., Javitt, D.C., 2008. Magnocellular pathway impairment in schizophrenia: from functional magnetic resonance imaging. J. Neurosci. 28 (30), 7492–7500. Martínez, A., Hillyard, S., Bickel, S., Días, E., Butler, P., Javitt, D.C., 2011. Consequences of magnocellular dysfunction on processing attended information in schizophrenia. Cereb. Cortex http://dx.doi.org/10.1093/cercor/bhr195. Møller, P., Haug, E., Raballo, A., Parnas, J., 2011. Examination of anomalous self-experience in first-episode psychosis: interrater reliability. Psychopathology 44, 386–390. Must, A., Janka, Z., Benedek, G., Kéri, S., 2004. Reduced facilitation effect of collinear flankers on contrast detection reveals impaired lateral connectivity in the visual cortex of schizophrenia patients. Neurosci. Lett. 357, 131–134. Nassy, J., Callaway, E., 2009. Parallel processing strategies of the primate visual system. Nature 2009 (10), 360–372. Nelson, B., Thompson, A., Yung, A., 2012. Basic self-disturbance predicts psychosis onset in the ultra high risk for psychosis “prodromal” population. Schizophr. Bull. 38 (6), 1277–1287. Núñez, D., Rauch, J., Herwig, K., Rupp, A., Andermann, M., Weisbrod, M., Resch, F., OelkersAx, R., 2013. Evidence for a magnocellular disadvantage in early-onset schizophrenic patients: a source analysis of the N80 visual-evoked component. Schizophr. Res. 144, 16–23. Parnas, J., Henriksen, M.G., 2013. Subjectivity and schizophrenia: another look at incomprehensibility and treatment nonadherence. Psychopathology 46 (5), 320–329. Parnas, J., Handest, P., Sæbye, D., Jansson, L., 2003. Anomalies of subjective experience in schizophrenia and psychotic bipolar illness. Acta Psychiatr. Scand. 108, 126–133. Parnas, J., Møller, P., Kircher, T., Thalbitzer, J., Jansson, L., Handest, P., Zahavi, D., 2005. EASE: examination of anomalous self-experience. Psychopathology 38, 236–258. Parnas, J., Raballo, A., Handest, P., Jansson, L., Vollmer-Larsen, Sæbye, D., 2011. Selfexperience in the early phases of schizophrenia: 5-year follow-up of the Copenhagen Prodromal Study. World Psychiatry 10, 200–204. Postmes, L., Sno, H.N., Goedhart, S., van der Stel, J., Heering, H.D., de Haan, L., 2014. Schizophrenia as a self-disorder due to perceptual incoherence. Schizophr. Res. 152, 41–50. Raballo, A., Sæbye, D., Parnas, J., 2011. Looking at the schizophrenia spectrum through the prism of self-disorders: an empirical study. Schizophr. Bull. 37 (2), 344–351. Renshaw, P.F., Yurgelun-Todd, D.A., Cohen, B.M., 1994. Greater hemodynamic response to photic stimulation in schizophrenic patients: an echo planar MRI study. Am. J. Psychiatry 151, 1493–1495.

Please cite this article as: Núñez, D., et al., Do deficits in the magnocellular priming underlie visual derealization phenomena? Preliminary neurophysiological and self-report r..., Schizophr. Res. (2014), http://dx.doi.org/10.1016/j.schres.2014.08.019

D. Núñez et al. / Schizophrenia Research xxx (2014) xxx–xxx Sass, L.A., 2014. Self-disturbance and schizophrenia: structure, specificity, pathogenesis (current issues, new directions). Schizophr. Res. 152, 5–11. Sass, L.A., Parnas, J., 2003. Schizophrenia, consciousness and the self. Schizophr. Bull. 29, 427–444. Schechter, I., Butler, P.D., Zemon, V.M., Revheim, N., Saperstein, A.M., Jalbrzikowski, M., Pasternak, R., Silipo, G., Javitt, D.C., 2005. Impairments in generation of early-stage transient visual evoked potentials to magno- and parvocellular-selective stimuli in schizophrenia. Clin. Neurophysiol. 116 (9), 2204–2215. Schultz, C., Wagner, G., Koch, K., Gaser, C., Roebel, M., Schachtzabel, C., Nenadic, I., Reichenbach, J., Sauer, H., Schlösser, R., 2011. The visual cortex in schizophrenia: alterations of gyrification rather than cortical thickness—a combined cortical shape analysis. Brain Struct. Funct. http://dx.doi.org/10.1007/s00429-011-0374-1. Schultze-Lutter, F., Ruhrmann, S., 2008. Früherkennung und Frühbehandlung von Psychosen. Verlag Uni-Med, Bremen-London-Boston. Sehatpour, P., Molholm, S., Javitt, D.C., Foxe, J.J., 2006. Spatiotemporal dynamics of human object recognition processing: An integrated high-density electrical mapping and functional imaging study of ‘‘closure’’ processes. Neuroimage 29, 605–618. Sehatpour, P., Molholm, Theodore, H., Schwartz, T., Mahoney, J., Ashesh, D., Mehta, A., Javitt, D.C., Stanton, P., Foxe, J., 2008. A human intracranial study of long-range oscillatory coherence across a frontal–occipital–hippocampal brain network during visual object processing. PNAS 105 (11), 4399–4404. Sehatpour, P., Dias, E., Butler, P., Revheim, N., Guilfoyle, D., Foxe, J., Javitt, D.C., 2010. Impaired visual object processing across an occipital–frontal–hippocampal brain network in schizophrenia. An integrated neuroimaging study. Arch. Gen. Psychiatry 67 (8), 772–782.

9

Selemon, L.D., 2001. Regionally diverse cortical pathology in schizophrenia: clues to the etiology of the disease. Schizophr. Bull. 27, 349–377. Sheehan, D.V., Lecrubier, Y., Sheehan, K.H., Amorim, P., Janavs, J., Weiller, E., Hergueta, T., Baker, R., Dunbar, G.C., 1998. The Mini-International Neuropsychiatric Interview (M.I. N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J. Clin. Psychiatry 59 (Suppl. 20), 22–33 (quiz 34–57). Singer, J., 1998. Using SAS PROC MIXED to fit multilevel models, hierarchical models, and individual growth models. J. Educ. Behav. Stat. 24 (4), 323–355. Slaghuis, W.L., 2004. Spatio-temporal luminance contrast sensitivity and visual backward masking in schizophrenia. Exp. Brain Res. 156 (2), 196–211. Taylor, J., 2011. A neural model of the loss of self in schizophrenia. Schizophr. Bull. 37 (6), 1229–1247. Tobimatsu, S., Tomoda, H., Kato, M., 1996. Human VEPs to isoluminant chromatic and achromatic sinusoidal gratings: separation of parvocellular components. Brain Topogr. 8 (3), 241–243. Vassilev, A., Stomonyakov, V., Manahilov, V., 1994. Spatial-frequency specific contrast gain and flicker masking of human transient VEP. Vis. Res. 34 (7), 863–872. Yeap, S., Kelly, S., Sehatpour, P., Magno, E., Garavan, H., Thakore, J., Foxe, J., 2008. Visual sensory processing deficits in schizophrenia and their relationship to disease state. Eur. Arch. Psychiatry Clin. Neurosci. 258, 305–316. Zemon, V., Gordon, J., 2006. Luminance-contrast mechanisms in humans: visual evoked potentials and a nonlinear model. Vis. Res. 46 (24), 4163–4180.

Please cite this article as: Núñez, D., et al., Do deficits in the magnocellular priming underlie visual derealization phenomena? Preliminary neurophysiological and self-report r..., Schizophr. Res. (2014), http://dx.doi.org/10.1016/j.schres.2014.08.019