
==== Front
Schizophr Res Cogn
Schizophr Res Cogn
Schizophrenia Research: Cognition
2215-0013
Elsevier

S2215-0013(24)00025-8
10.1016/j.scog.2024.100324
100324
Research Paper
Fixational eye movements and their associated evoked potentials during natural vision are altered in schizophrenia
Mayol-Troncoso Rocío acil
Gaspar Pablo A. acdel
Verdugo Roberto bef
Mariman Juan J. ghk
Maldonado Pedro E. pedro@uchile.cl
bej⁎
a Departamento de Psiquiatría y Salud Mental, Facultad de Medicina, Universidad de Chile
b Biomedical Neuroscience Institute (BNI)
c Millennium Nucleus to Improve the Mental Health of Adolescents and Youths, Imhay, Chile
d Clínica Alemana, Santiago, Chile
e Department of Neuroscience, Faculty of Medicine, Universidad de Chile
f Instituto Psiquiátrico Dr. José Horwitz Barak, Chile
g Department of Physical Therapy, Faculty of Arts and Physical Education, Universidad Metropolitana de Ciencias de la Educación, Santiago, Chile
h Department of Physical Therapy, Faculty of Medicine, Universidad de Chile
i Facultad de Psicología, Universidad Alberto Hurtado, Chile
j Nacional Center for Artificial Intelligence (CENIA), Chile
k Nucleus of wellbeing and human development, education research center (CIE-UMCE), Universidad Metropolitana de Ciencias de la educación
l Clínica Psiquiátrica Universitaria, Hospital Clínico de la Universidad de Chile, Laboratorio Psiquiatría Traslacional
⁎ Corresponding author at: Department of Neuroscience, Faculty of Medicine, Universidad de Chile, Av. Independencia 1027, Santiago 8380453, Chile. pedro@uchile.cl
15 8 2024
12 2024
15 8 2024
38 10032425 9 2023
17 7 2024
11 8 2024
© 2024 The Authors. Published by Elsevier Inc.
2024

https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Background

Visual exploration is abnormal in schizophrenia; however, few studies have investigated the physiological responses during selecting objectives in more ecological scenarios. This study aimed to demonstrate that people with schizophrenia have difficulties observing the prominent elements of an image due to a deficit mechanism of sensory modulation (active sensing) during natural vision.

Methods

An electroencephalogram recording with eye tracking data was collected on 18 healthy individuals and 18 people affected by schizophrenia while looking at natural images. These had a prominent color element and blinking produced by changes in image luminance.

Results

We found fewer fixations when all images were scanned, late focus on prominent image areas, decreased amplitude in the eye-fixation-related potential, and decreased intertrial coherence in the SCZ group.

Conclusions

The decrease in the visual attention response evoked by the prominence of visual stimuli in patients affected by schizophrenia is generated by a reduction in endogenous attention mechanisms to initiate and maintain visual exploration. Further work is required to explain the relationship of this decrease with clinical indicators.

Keywords

Visual exploration
Visual saliency
Schizophrenia
Evoked potentials
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pmc1 Introduction

People affected by schizophrenia (SCZ) exhibit different symptoms, such as hallucinations, delusions, cognitive impairment, motor symptoms, and, specifically, alterations in eye movements. >100 years ago, Diefendorf & Dodge (Diefendorf and Dodge, 1908) reported that eye tracking was impaired in schizophrenia; subsequently, this observation has been replicated numerous times (Benson et al., 2012; Jurišić et al., 2020; Morita et al., 2020).

SCZ shows several abnormalities when they are concentrated on the action of looking at an object. For example, they cannot align their eyes well with the target's speed (Kirenskaya et al., 2017; Maruff et al., 1996). They also demonstrate saccadic intrusion when they should perform a homogeneously smooth visual tracking. Several studies have also explored this abnormality during voluntary saccadic eye movements; in this paradigm, people were instructed to perform voluntary saccades towards an objective (pro-saccades) or a direction opposite to the target location (antisaccades) (Radant et al., 2007). These studies have concluded that SCZ has problems in the execution of antisaccades. These errors occur when the participants fail to inhibit a reflexive saccade before making the correct one (Hutton, 2008). They also present a significantly greater number of antisaccade errors and more significant latency in the answers and self-corrections (Curtis et al., 2001; Kallimani et al., 2009; Mazhari et al., 2011).

Some studies conducted in a more ecological environment, where the subjects explore natural images freely, showed that SCZ exhibits an atypical visual exploration. The latter behavior is characterized by a focused exploration -preferably in the center of the image- and by the performance of a smaller number of fixations and saccades in comparison with healthy control subjects (Beedie et al., 2011b). Which mechanisms can account for the difference in exploration patterns seen in SCZ? One parsimonious explanation is that SCZ patients may have a basal motor problem and thus display difficulties producing large saccades. Egaña et al. (2013) reported that when considering the number and the duration of fixations and saccades during free viewing of natural images, there were indeed differences between the healthy control subjects and SCZ ones; however, when the analysis included the microsaccades (Martinez-Conde et al., 2004), which are movements of amplitudes below one degree, there are no significant differences in the number and duration of fixations and saccades between healthy controls subjects and people affected by schizophrenia. Thus, the authors concluded that SCZ does not appear to display abnormalities in their basic eye movements but likely in top-down attentional processes, that is, the voluntary location of attention in specific characteristics, objects, or regions of a given space (Egaña et al., 2013).

Nonetheless, alteration of visual exploration can still be sustained on a deficit in a bottom-up mechanism: saliency. This automatic visual attention mechanism directs the observer towards selecting a stimulus by its physical characteristics; some stimuli are intrinsically visible or salient in a given context (Koch & Ullman, 1985; Itti and Koch, 2000, Itti, 2001; Peters et al., 2005). Prominent areas of an image are independent of the nature of the task, and saliency mechanisms operate very quickly and are mainly driven by elements bottom-up, that is, by image characteristics such as luminance, color, or contrast. Prior research has identified marked abnormalities in the perceptual organization in SCZ, predominantly attributed to deficits in bottom-up processing and disruption in basal visual perception based on incorrect processing of visual stimuli (bottom-up) (Butler et al., 2001, Butler et al., 2005; Martínez et al., 2008; Adámek et al., 2024). Keri et al. (2002) found that people affected with schizophrenia have a low sensitivity to visual contrast in medium frequencies and high on stationary stimuli, and this was higher for stimuli with a higher spatial frequency in a moving condition.

However, most studies in visual perception have been carried out in restrictive conditions where the stimulus is presented for a very short time or where the subjects are not allowed to move their eyes freely. This situation contrasts with natural vision when, more often than not, the changes in visual stimulus result from self-initiated eye movements. This active sensing (Bajcsy, 1988; Concha-Miranda et al., 2019) is a generalized mechanism of perception observed during free viewing and natural images (Bajcsy, 1988; Hofmann et al., 2013; Leszczynski and Schroeder, 2019). Devia et al. (2017) found that during active vision, stimuli arriving after every eye movement elicited more robust responses in visual areas, demonstrating that the nervous system engages a mechanism of sensory modulation that is precisely timed to the self-initiated stimulus changes (Henderson & Choi, 2015; Kazai and Yagi, 2003; Rajkai et al., 2008). To associate neural activity with gaze behavior during visual search, the researchers simultaneously measured electroencephalography (EEG) and eye movements, extracting brain activity that is synchronized with eye fixation, called eye fixation-related potentials (fERP) (Lee et al., 2021). fERPs reflect the “readiness” of the visual cortex to process the information to be fixated rather than responding to the stimulus itself (Rajkai et al., 2008; Ito et al., 2013). This potential is modulated by the processing of simple visual features, such as luminance or size (Kazai & Yagi, 1999), as well as the cognitive demands of a task.

A component of fERP appears at 200 ms before fixation onset (Kamienkowski et al., 2012; Kaunitz et al., 2014), and intracranial recordings of early visual areas show that the fERP has a suppressive component that starts before fixation onset (Rajkai et al., 2008; Podvalny et al., 2017). In visual studies, the most prominent element of the fERPs is called the lambda response (LR), which is recorded at the occipital sites. This is a positive component that occurs around 80 ms from the offset of the saccade (Kazai and Yagi, 2003; Rämä and Baccino, 2010) and when it begins at the onset of eye fixation (Yagi, 1979; Kazai and Yagi, 2003). This response has been suggested to have a common neural generator in the visual cortex (Kazai and Yagi, 2003; Ossandón et al., 2010). The LR has been the focus of increasing investigation in various contexts, including Guided-Search tasks and naturalistic reading in normal volunteers (Kaunitz et al., 2014; Dias et al., 2020). Kaunitz et al., 2014 presented a first approach towards brain responses in natural vision. They demonstrated that it is possible to obtain robust cognitive components through spatially unlimited eye movements in a real-world-like setting. In schizophrenia, there is limited evidence regarding fERP. Dias et al. (2020) employed a visually guided search task using eye tracking and EEG to explore how active visual detection contributes to behavioral changes. They found that the reduced visual span was associated with reduced fERP generation over posterior visual cortex. These results support a model suggesting that impaired visual active detection, restricts the visual field, thereby contributing to behavioral deficits in schizophrenia.

There are no studies that study fERP in free exploration with natural images in schizophrenia. Therefore, visual processing during natural vision reveals a broader mechanism of visual processing compared to the classical paradigm of examining the response to flash images. fERP appears to exhibit characteristical responses that can contribute to examining potential differential processing between persons affected with schizophrenia and healthy controls.

We hypothesize that visual exploration deficits in schizophrenia are caused, in part, by deficits in sensory processing of the bottom-up attention mechanism related to visual saliency. We concluded that this deficit would manifest during active sensing and should be associated with alteration in the early electroencephalographic visual response to visual stimuli after each fixation.

2 Methods

2.1 Subjects

Participants in this study included 18 patients (13 males, mean age 22.18 ± 7.5) and 18 healthy volunteers (7 males, mean age 20.92 ± 7.3), all participants were hispanic and right-handed. Clinical diagnoses were based on the DSM-4 diagnostic criteria (SCID) (Kübler, 2013). The Positive and Negative Syndrome Scale (Kay et al., 1987) was administered to assess the positive and negative symptoms in some of the SCZ patients. Schizophrenia patients were recruited from clinics in Santiago, Chile. All patients were on a stable dose of antipsychotics at the time of testing. Healthy volunteers with a history of SCID-defined axis I psychiatric disorder were excluded. Patients and healthy volunteers were excluded if they had any neurological or ophthalmologic disorders that might affect performance or if they met the criteria for alcohol or substance dependence within the last six months or alcohol/substance abuse within the last month. Subject groups did not differ in age, handedness or ethnicity. The years of education for Schizophrenia patients were 12.81 ± 4.4, and for healthy volunteers, 13.75 ± 3.8. A shorter version of the Wechsler Adult Intelligence Scale was applied to all participants (Reid-arndt et al., 2011), and there were no significant differences between the groups (p = 0.16). Informed consent was obtained from all subjects after the procedures were fully explained. The Ethics Committee in Human Research of the Faculty of Medicine, University of Chile, approved the experimental protocol and consent form.

2.2 Stimuli and task

A set of 240 photographic images was presented in color on a 32 “LED monitor (Samsung SyncMaster 1100P Plus) at an update frequency of 85 Hz and a 1920 × 1080 pixels resolution. The images were divided into the following categories: 1) Images with a prominent color area (PCA), that is, an element of the image stood out due to its color; 2) images with luminance changes in an area (LOA), in this category, the original image was presented first and then quickly followed by the modified image with an area of high luminance generating a blink, the time between the original image and the image with the luminance modification was 180 ms, to generate the blinking effectand 3) images presented without a particular superimposed area, which was considered control images (CIM). Each image was presented for 2.160 s. A 9-point calibration and validation procedure was performed at the beginning of the task. Drift correction was applied while the subjects fixated on a dot in the center of the screen (Fig. 1). After completing the calibration, subjects pressed a button to proceed to the next image. The distance between the subjects and the monitor was 72 cm. The task was designed using the Experiment Builder v1.4 program (SR et al., 2020).Fig. 1 Task. The images were divided into the following categories: 1) Images with a prominent color area (PCA), that is, an element of the image stood out due to its color, 2) images with changes in the luminance in an object or image area, generating a blink in an area of the image that will be brighter (LOA), and 3) images considered control images (CIM), which were presented without a particular superimposed area. Each image was presented for 2160 s. A central fixation point appeared every four images, where drift correction was conducted.

Fig. 1

The stimuli were images collected from the Internet and captured for this research. Each image has two potential locations for modification, but only one area is actually modified. These modifications are situated at either 10 or 20 visual degrees from the center and involve either a prominent color or a luminance change. The modifications are placed at these specific visual degrees to ensure that the center does not influence the initial visual exploration, as it is known that patients with schizophrenia tend to focus on the center (Beedie et al., 2011b). There is an equal distribution of modified areas at both the 10-degree and 20-degree locations. The diameter of the area where a prominence, whether colored or light, was included was 23.5 mm in all images. This procedure was done with Photoshop CS6.

To quantify the images' chromatic and luminance prominence, the Itti and Koch algorithm was used to identify the prominent areas of an image (Itti and Koch, 2000). This algorithm identifies the brightest areas with the highest contrast in an image so that the prominent region can be quantified; in the case of the CIM, the algorithm determined there were no specific luminous or chromatic prominences. The task duration was approximately 30 min, varying based on the length of breaks participants took. Participants were allowed to rest after every four images, coinciding with drift correction intervals.

2.3 Eye movements and data analysis

EyeLink II (SR Systems) eye-tracking device recorded eye movements at a sampling rate of 500 Hz. The information in the SR-Research results files (from now on referred to as the “SR algorithm”) was used to detect fixations and saccades made during the free image exploration. The SR algorithm established saccades based on a speed threshold of 30° / s and an acceleration threshold of 8000°/s2. With these parameters, we mainly identified saccades >0.5°.

The fixations were selected according to the SR algorithm, considering that the calculation of the angle between the previous/next fixation and the current fixation is directional. That is, the direction of the previous/next fixation concerning the current fix was determined as “LEFT” if the angle was >135° or lower than −135°, “UP” if the angle was between 45° and 135°, “RIGHT” if the angle was between −45° and 45°, and “DOWN” if the angle was between −135° and - 45°.

2.4 Electrophysiological recordings

The EEG data were recorded in a standard 64-channel assembly of 10–20 using a Biosemi Active-Two system (Biosemi, Amsterdam, The Netherlands) at 2048 Hz. The data were imported into MATLAB with the Fieldtrip toolbox (Oostenveld et al., 2011). The average of all the electrodes was used as a reference.

2.5 Electrophysiological analyses

The data for the fERP were filtered between 0.1 and 40 Hz. To analyze the potential fERP, the start of all fixations made in the whole image was identified in each of the three categories, and the fixations chosen lasted between 100 and 600 milliseconds. Then, we identified the time in which the fixations occurred in each category and aligned them with the start of the presentation of each image. After that, we changed the sampling rate of eye movements from 500 Hz to 2048 Hz, the same rate as the signal obtained in the electroencephalogram.

Finally, the fixation times were aligned with the electroencephalogram to perform later the data preprocessing, which consisted of the following steps: 1) The signal was segmented into epochs ranging from −250 ms to 550 ms (Kamienkowski et al., 2012); 2) we rejected artifacts related to jumps in the signal generated by electronic devices or spikes that could be present; 3) the sampling rate was changed to 512 Hz and independent component analysis (ICA) was performed for eye-movement correction, 4) the signal was averaged for each subject, filtered using a 40 Hz low pass filter, and corrected using a baseline between −200 ms and − 100 ms. To minimize remaining eye-movement contributions to fERP analyses, data were indexed by fixation onset, and data in any electrode channel (excluding Electrooculography (EOG)) with a change in amplitude >120 μV during a 200 ms time window were excluded from averaging (Dias et al., 2020), 4) finally, all the subjects were averaged, making a grand average. We considered the analysis window between −100 and 300 ms, which is the time of interest to analyze the effects of the fixation (Ries et al., 2018). The activity analyzed was on the Oz electrode to avoid lateralization or decrease activity since different activations have been observed in this component depending on the electrode (Rämä and Baccino, 2010).

Intertrial coherence (ITC) was calculated from Hilbert-transformed signals. Amplitude indicates the total amplitude, including prestimulus baseline activity and event-related spectral perturbations. Intertrial phase coherence indicates phase consistency across trials and ranges from 0 (random phase across trials) to 1 (identical phase across trials). Amplitude and ITC during stimulation were averaged and used for statistical analyses (Grove et al., 2021).

2.6 Statistics

We used a Kruskal-Wallis test (KWT) to compare each category's median fixation number and duration. The KWT test is a nonparametric test that compares two or more independent samples of equal or different sample sizes. For each participant, a percentage of first fixation in the salient area was calculated by dividing number of first fixations after stimulus onset that was in the salient area by the total number of first fixations within each condition. Similarly, a percentage of second, third, fourth, and fifth fixations in the salient area was also calculated for each participant per condition. An ANOVA test for repeated measurements to compare the percentage of the first five fixations in the salient area. The demographic data (age, education, and Global Intelligence measure) were compared using an independent samples t-test. A chi-square test was conducted to analyze gender differences between the groups. To assess the samples' normality for each feature, we used a Lilliefors test. All statistical analyses were performed in MATLAB 2014b The MathWorks Inc. (2014) and Prism 8. For fERP, the HC group was compared with the SCZ group in each category using a parametric independent sample t-test conducted for the Oz electrode. For ITC, cluster-based correction for multiple comparisons was used by comparing the performance of both groups in each category (Maris and Oostenveld, 2007).

3 Results

Eighteen participants diagnosed with schizophrenia and eighteen healthy controls participated in the study. All participants saw images with a prominent color area, light salience (a blink with brightness change), and an image in a natural environment with no specific salient elements.

3.1 Demographics

The demographics of both groups are shown in Table 1. We calculated chlorpromazine equivalent doses (daily) based on Kroken et al. (Kroken et al., 2009). All medication was administered orally (PO). There were significant gender differences between the groups (Chi-square value: 4.05 p-value: 0.0441).Table 1 Sociodemographic data.

Table 1	HC (n = 18)	SCZ (n = 18)	Significance (p < 0.05)	
Gender (M/F)	7/11	13/5	0.0441*	
Age, mean (SD)	20.92 (7.3)	22.18 (7.5)	n.s	
Education, mean(SD)	13.75 (3.8)	12.81 (4.4)	n.s	
Global Intelligence measure, mean (SD)	103 (14.45)	(n = 16)
96.06 (10.02)	n.s	
Age at illness onset, mean (SD)		(n = 13)
22.69 (7.19)		
Duration of illness (years), mean (SD)		(n = 13)
2.69 (2.86)		
PANSS positive, mean (SD)		(n = 6)
12 (3.4)		
PANSS negative, mean (SD)		(n = 6)
18.33 (6.15)		
PANSS general, mean (SD)		(n = 6)
46.33 (24.59)		
APD dose (CPZ equiv), mean (SD)		(n = 16)
294.7 (176. 54)		
APD = Antipsychotic Drug; CPZ = Chlorpromazine; F = female; HC = Healthy Controls; M = male; PANSS = Positive and Negative Syndrome Scale; SCZ = Schizophrenia, * chi-squared test, significant p<0.05.

3.2 Group comparison of eye movement measures

Many studies have reported that SCZ patients display a reduction in the number of visual fixations and an increment in their duration (Beedie et al., 2011b). This study compared the fixation number and duration on a free-viewing task. After comparing the fixation number median between groups, we found that the HC group performed more fixations in all categories than the SCZ group (p = 0.0139, p = 0.0056, p = 0.0090) (Fig. 2A). We found no significant differences when we measured fixation duration in all the images (Fig. 2B).Fig. 2 A) The median value of the number of fixations for both groups is in three categories. Significant differences were found in the three categories (*p < 0.05 or less for the Wilcoxon rank-sum test). B) Median fixation time in each condition. We plotted the median fixation duration for each experimental group while viewing every image category. Here, no significant differences were found (p > 0.05). C) Number of fixations in the salient area (No significant differences). D) Median fixation time in the salience area (significant differences in the PCA condition between groups p = 0.0150). E) Fixation percentage of the first five fixations in the saliency area. Significant differences were found when the groups performed the first and second fixation in the chromatic salient area (*P < 0.05). F) No significant differences were observed between the groups in the first five fixations in LOA.

Fig. 2

Then, we computed the numbers of fixations in PCA and LOA images. For each image, we measured the number of fixations in the region where the corresponding salience was located and compared the median values. These results showed no significant differences (p > 0.05) between groups (Fig. 2C). After that, we calculated the duration of fixations in the salience area for each category, and when comparing the medians, we found significant differences in the PCA condition between groups (p = 0.0150). In other words, the SCZ group stays focused longer in prominent chromatic areas. In contrast, the LOA condition showed no statistically significant differences (Fig. 2D).

As the number of fixations in salient image areas did not show significant differences between the groups, we asked ourselves when the participants looked at this area. It could be argued that saliency attracted observers to look in a particular direction (i.e., the effect could be partly due to low-level saliency) since the first fixations would be directed towards the salient image area. To test this, we evaluated the percentage of the first five fixations made in salient areas. Results showed that in PCA, there were significant differences between the groups in the initial two fixations within the protruding region (Fig. 2E). HC participants tended to look at the PCA elements in an image first (≈ 60 %), while the SCZ group did it as well, but later (in the third, fourth, and fifth fixation). An ANOVA test was performed for repeated measurements (p < 0.05), and Sidak was used in the multiple comparisons test to analyze the differences between the groups and in the fixation position. In the LOA category, no significant differences were observed between the groups (Fig. 2F).

3.3 Fixation event-related potential (fERP)

The parametric independent samples test was conducted for the Oz electrode, revealing significant differences between HC and SCZ groups in PCA (P < 0.0001) and LOA (p = 0.0036) between 50 and 100 ms (Fig. 3a and c). The amplitude differences between groups were significantly larger for HC than for SCZ in this time window. In the case of CIM, significant differences were observed before the start of fixation, between −50 ms and 0 times (P < 0.0001), and no difference was observed afterward (Fig. 3b). In this time window, the HC group showed greater negativity than the SCZ group.Fig. 3 Grand average fERP for HC (in blue) and SCZ groups (in red) in the different categories. Zero time indicates the start of fixation. The x-axis indicates the time in milliseconds, and the y-axis indicates the mean amplitude (μV). a) fERP PCA shows significant differences at 100 ms (P < 0.0001), b) fERP CIM, significant differences are observed prior to the start of fixation (P < 0.0001), c) fERP LOA shows significant differences in peak amplitude around 100 ms (p = 0.0036).

Fig. 3

3.4 Intertrial coherence (ITC)

A cluster-based permutation test was conducted to analyze different frequency bands, and the groups had significant differences in the beta band. In the exploratory analysis, the cluster-based permutation test revealed differences (p < 0.05) between groups in beta frequency. Thus, beta oscillations (12–25 Hz) were the focus of further analyses. Schizophrenia patients had significantly smaller beta ITC compared with healthy control subjects in all categories (Control = p < 0.05; Chromatic p < 0.01; Luminance = p < 0.05) (Fig. 4a,b,c).Fig. 4 ITC of HC and SCZ: a) The cluster-based permutation test revealed a significant difference between the groups in the control image (p < 0.05). b) There is a significant difference between the groups in prominent color areas (p < 0.01). c) There is a significant difference between the groups in the LOA category (p < 0.05). The x-axis indicates the time in milliseconds, and the y-axis indicates frequency. The color indicates intertrial phase coherence (ITC), red: SCZ group, blue: HC group.

Fig. 4

4 Discussion

The objective of this study was to demonstrate that people with schizophrenia present difficulties in observing the prominent elements of an image due to a deficit mechanism of sensory modulation (active sensing) during natural vision. Eye movements have been proposed as a marker in schizophrenia, as they provide a directly observable measure of visual orientation and the existence of attentional biases.

The results obtained from eye movements in the different categories allow us to verify that the SCZ group makes fewer fixations when they explore an image freely (Fig. 2A). This evidence is per previous studies (Beedie et al., 2011b; Dowiasch et al., 2016; Klein and Ettinger, 2008; Shiino et al., 2020; Dias et al., 2021). However, when a prominent area is added to the image, the visual behavior changes. Although the SCZ group makes fewer fixations than the HC group in all categories when analyzing the number of fixations located in the prominent area, no significant differences were observed, indicating that both groups observed the prominent image area. Then, the median time of all the fixations, when the groups scanned the image, was analyzed, and we found significant differences in PCA between the groups: the fixation duration in the SCZ group was longer than in the control group in this category.

The first definitions of the disease point out that in clinical descriptions of schizophrenia, there is a deterioration of the onset of volitional behavior (Frith et al., 2000; Kapur, 2011). The SCZ group shows average or lower latencies in rapid eye movements towards a new visual stimulus (visually-guided saccades). This is observed in the LOA category, where no significant differences were observed between the groups, while volitional saccades had increased latencies in patients with schizophrenia (Bender et al., 2013; Reilly et al., 2005, Reilly et al., 2008 ;Paul et al., 1996;Reuter et al., 2016).

Volitional saccadic movements require endogenous activation of a motor program generated by a stimulus (Munoz and Everling, 2004; Reuter et al., 2016). The results obtained in this task showed that the SCZ group spends more time in PCA, which could be related to a decrease in endogenous activation. Considering this evidence, we analyzed the moment in which people would look at the prominent areas of the image, that is, if they did it in the first fixations or later moments of the exploration. In the PCA category, we observed that the HC group directed the first fixations towards the prominent area, while the SCZ group made it in the fourth and fifth fixations. According to Reuter et al. (2016), changes in spatial attention can play a role in the latencies of volitional saccades because any saccade is preceded by a change of attention towards the place where a target will be observed (Stevens et al., 2012; Thakkar and Rolfs, 2019). In visually-guided saccades, attention shift is exogenous since the stimulus automatically captures attention (Yantis, 1996). The attention shift must be endogenous since there is no such stimulus onset in volitional saccades. Increased saccadic latencies may result from a change in endogenous attention shift rather than saccade initiation and shift of the eye position in a specific scene (Maruff et al., 1996).

In the LOA condition, there were no differences between the groups since attention is endogenous, and the stimulus guides eye movements. This would indicate that this type of attention is not affected in this group. Although we ensured methodologically that both categories were salient, the results indicate that color may have been less salient than changes in luminance, leading to differences in ocular behavior when evaluating the moment they chose to look at the outgoing area. In the PCA, the addition of color prominence could have introduced another element into the scene, potentially causing a delay in its observation. Conversely, in the LOA category, where the images were also in color, but the salient feature was the change in luminance of an area, participants were more likely to be drawn to the blinking area, resulting in increased attention from both groups, we interpret that this increased salience might have facilitated a faster and more prominent response in the luminance condition, potentially explaining the observed differences in attention shifts compared to the color condition. Additionally, the abrupt nature of the change in the luminance condition may have triggered a more automatic and exogenous reaction, in contrast to the more controlled and endogenous attention required in the color condition. In SZC it is suggested that there is no general impairment in attention control. Instead, there is an exaggerated allocation of attention to stimuli that strongly activate the magnocellular pathway, such as LOA stimuli (Luck and Gold, 2019).

4.1 Fixation event-related potential (fERP)

Many investigations using the event-related potential (ERP) method in schizophrenia have found decreases in the amplitudes of the early components in various situations, including the visual perception of verbal information, compared to the HC group (Nikolaev et al., 2013; Strelets et al., 2015; Tang and Niznikiewicz, 2020). Deficiencies in visual perception in patients with schizophrenia have been widely reported. The main findings have been a decrease in the amplitude of the P100 component of the event-related potential in response to different types of stimuli, which is why P100 has been proposed as a biomarker by some authors (Nikolaev et al., 2013; Mikanmaa et al., 2019; Tanaka et al., 2013). In conventional ERP studies, subjects are generally asked to keep their eyes on the screen, or the duration of the stimulus is short to avoid eye movements. However, cognitive processes such as reading, scene perception, and object identification require sequential saccadic eye movements, so fixation-related potential (fERP) is a type of ERP that measures brain activity in response to fixations, but in contrast to ERPs, subjects can move their eyes while performing the task (Dias et al., 2020; Rämä and Baccino, 2010; Yantis, 1996).

This work focuses on fERP. Since it was a free exploration task, significant differences were observed in fERP in all the images where the attention was bottom-up (chromatic and luminance), which shows that there are deficits in sensory processing.

Differences were observed before the initiation of fixation in CIM (about 20 ms prior to the initiation of fixation). According to primate studies, this negativity suppresses the constant spike activity of V1 neurons before excitation in response to a visual stimulus (Cavanaugh et al., 2002). This suppression is related to task requirements, such as detecting contrast at given locations to initiate a response to them, so this suppression improves task performance. In free exploration experiments with non-human primates, it has been observed that after fixation is registered in V1, the neuronal oscillation phase is organized coherently just after the initiation of fixation and is accompanied by increased spectral power in various frequency bands (Lakatos et al., 2009). In this line, Maldonado and Babul (2007) found that 30 ms after fixation, the synchronization between neurons in V1 increases. This process is followed by an increase in the firing rate from 90 to 200 ms, which coincides with the results found in this investigation.

In summary, we suggest that the decline in visual attention response triggered by PCA in schizophrenia patients stems from a reduction in endogenous attention mechanisms required to initiate and sustain visual exploration. Furthermore, there appears to be a diminution in sensory information processing, as evidenced by reduced amplitude at 100 ms in the fERP. This decline may lead to alterations in integrative processes essential for effective stimulus evaluation and appropriate response selection, potentially contributing to diminished visual exploration in these patients.

These findings provide insights into real-time neural dynamics during fixation in schizophrenia, emphasizing sensory processing deficits and attentional mechanisms during visual exploration, corroborating observations by Dias et al. (2020) regarding the role of neural dynamics and attentional mechanisms in influencing sensory processing impairments in SCZ. Both studies underscore the importance of electrophysiological markers in understanding schizophrenia pathology, providing a comprehensive view of sensory and attentional impairments in the disorder.

4.2 Intertrial coherence (ITC)

The analysis of intertrial coherence showed reduced beta ITC in schizophrenia patients, which is consistent with previous studies (Brockhaus-Dumke et al., 2008; Martinez et al., 2015; Balz et al., 2016). Reduced alpha ITC indicates that the beta phase at a given latency is inconsistent across trials. Imprecise beta phase synchronization in schizophrenia may affect various sensory and cognitive processes, such as deficits in visual information processing and visually based neurocognitive deficits (Martinez et al., 2015).

It is important to note that this is the first study that (1) considers the fERP in free exploration of natural images and (2) compares a population with a psychiatric illness and control subjects. Therefore, this study can help understand the neurophysiological mechanisms associated with SCZ. Despite its contributions, the study has some limitations. First, medications were not experimentally controlled. Schizophrenia patients were treated with various antipsychotic and other psychiatric medications that may have affected neural oscillations, and PANNS was not evaluated in all patients; thus, positive or negative symptoms could not be related to neurophysiological and behavioral measures. One symptom of SCZ that may be related to impaired visual exploration is cognitive dysfunction, including attention and visual perception (Adámek et al. et al., 2024). Relating cognitive symptoms to visual exploration can provide valuable information about the underlying mechanisms of these symptoms in schizophrenia. Negative symptoms can also be associated with alterations in visual exploration. Lack of motivation can result in reduced visual exploration of new stimuli or environments.

Sample sizes for the present study are relatively limited and there were significant gender differences between the groups. The extent to which results will replicate within larger samples has yet to be determined.

Future studies must clarify the relationship between clinical symptoms and neural oscillation in addition to considering a larger sample size matched by age and gender. These techniques offer unique insights into the sensory and perceptual processes underlying the disease, allowing a deeper understanding of its clinical manifestations.

Funding

This work was supported by Fondecyt postdoctoral 3190790 and funded by the National Center for Artificial Intelligence CENIA FB210017 , Basal ANID to P.M. and BNI, Project ACE 210007 .

CRediT authorship contribution statement

Rocío Mayol-Troncoso: Writing – review & editing, Writing – original draft, Validation, Project administration, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Pablo A. Gaspar: Writing – review & editing, Writing – original draft, Visualization, Validation, Methodology, Investigation, Funding acquisition, Formal analysis, Conceptualization. Roberto Verdugo: Writing – review & editing, Methodology, Investigation, Data curation. Juan J. Mariman: Writing – review & editing, Writing – original draft, Validation, Software, Methodology, Data curation. Pedro E. Maldonado: Writing – review & editing, Writing – original draft, Visualization, Supervision, Methodology, Investigation, Funding acquisition, Formal analysis, Data curation, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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