Saccadic eye movements as markers of schizophrenia spectrum: Exploration in at-risk mental states
Introduction
Schizophrenia begins in adolescence and encompasses cognitive and sensory-motor deficits (Insel, 2010). Early symptoms and dysfunctions predate the onset of the disease. These include alterations in working memory (Seidman et al., 2010) and attention (Keefe et al., 2006). Fusar-Poli et al. (2012) reported that subjects with Ultra high risk (UHR), who were prone to psychosis, showed important deficit in working memory especially in its visuo-spatial dimension. The neurodevelopmental hypothesis postulates that schizophrenia is the delayed expression of early-acquired brain abnormalities (Rappoport et al., 2005). Cognitive deficits could be considered as vulnerability markers of this disease, found in both relatives of patients and UHR. Neurological Soft Signs (NSS) are discrete sensorimotor impairments (e.g. discrete motor dyscoordination, impairment in sequencing, balance, sensory integration – see Krebs and Mouchet, 2007), associated with deviant brain development (Gay et al., 2013). Validating their status as endophenotypic markers reflecting vulnerability to schizophrenia, NSS are found in relatives of patients and within families, and follow the transmission of the genetic risk (Gourion et al., 2003, Gourion et al., 2004). Eye movement tasks such as antisaccade (AS) or memory-guided saccades (MGS) have also been proposed as useful endophenotypes (Calkins et al., 2008) and NSS have been associated with eye movement abnormalities (Picard et al., 2009).
Eye movement paradigms are a useful tool to understand cognitive mechanisms involved in schizophrenia and their underlying neurophysiological correlates. In the antisaccade task (AS), subjects fixate a central cue, which is suddenly replaced by the onset of a peripheral target. Rather than reflexively shifting gaze to that target, subjects are instructed to look at the opposite mirror location (Hallett, 1978). In the memory-guided saccade task (MGS), subjects have to fixate on a cross in the center of a screen while a visual cue appears elsewhere; once the fixation cross disappears after a delay, they have to direct their gaze to the location where the stimulus appeared. AS and MGS involve inhibitory and working memory processes: AS requires disengagement of attention from a peripheral target, and working memory to make a reflexive saccade of the similar amplitude in the opposite direction (Crawford et al., 2011). MGS requires the subject to encode the spatial location of a stimulus, to manipulate visual–spatial information, maintain the representation of that location across a delay period, and finally, make a volitional response to the remembered target. Hence the subject has to refrain from making an anticipatory saccade, meaning that he/she has to wait for the extinction of the fixation point, and only at this moment, to make a saccade in a remembered location.
Correct performance of both AS and MGS requires suppression of making a saccade to the stimulus and initiation of the volitional response. However, in AS a volitional saccade has to be made immediately to the location, opposite to the peripheral target, whereas in MGS the volitional response has to be made after a delay.
Using the oculomotor delayed response task (Hikosaka and Wurtz, 1983), Luna et al. (2004) demonstrated that although basic aspects of working memory appear mature at the beginning of adolescence, the precision of corrective response still improves at the end of this period.
In schizophrenia, a large literature describes deficits in AS (Calkins et al., 2008, Nieman et al., 2000, Radant et al., 2007) and MGS (Calkins et al., 2008, McDowell and Clementz, 1996, Radant et al., 1997, Landgraf et al., 2008). These studies support a defect in the inhibitory control system and in working memory (Ross et al., 2000). Previous literature also showed that first-degree relatives of patients have altered AS (Calkins et al., 2008) and MGS (Calkins et al., 2008, Landgraf et al., 2008). Thus, inhibition errors and saccadic hypometria in MGS are cognitive endophenotypes of the disease (Landgraf et al., 2008), reflecting the vulnerability to schizophrenia. In UHR, only one study explored AS compared to patients with schizophrenia and controls, showing more errors in UHR and patients. Correlations were found between AS and spatial working memory (Nieman et al., 2007). Until now, no investigation explored MGS in UHR.
In order to examine the value of eye movements alteration as possible markers in at-risk mental states, we compared the sensitivity of AS and MGS in subjects expressing different degrees of vulnerability to schizophrenia spectrum compared to controls. Given that maintenance is central to working memory, we decided to select a MGS paradigm sensitive to maturation through adolescence and early adulthood, with an oculomotor delayed response task including different delays of response (Luna et al., 2004, Luna et al., 2008, Geier et al., 2009). Patients with schizophrenia, non-psychotic siblings, ultra-high-risk subjects and controls have been assessed. Our hypothesis was that eye movements would be altered in patients, and to a lesser degree in UHR and relatives. UHR subjects were clinically assessed using the CAARMS (Comprehensive Assessment of At-Risk Mental State, McGorry et al., 2003, French version Krebs et al., 2014), a semi-structured interview. The sensitivity of each eye movement task could be different depending on the level of expression of the vulnerability to schizophrenia and on the developmental load. We thus refined the analysis, taking into account the level of NSS.
Section snippets
Participants
Forty-six patients with schizophrenia (SZ) (DSM IVR APA, 2003), 23 ultra high-risk subjects (UHR), 39 full biological non psychotic siblings of patients (FS) and 47 healthy volunteers (C) were recruited in the University Department of Psychiatry of Sainte-Anne Hospital (SHU), Paris, France. Only 14 full siblings of the 46 patients participated in this study. All subjects underwent the Diagnostic interview for Genetic Studies to attest diagnosis for SZ, and to exclude any diagnosis in FS and C (
Population
Demographic and clinical characteristics of participants are presented in Table 1. A significant difference in age was found (F(3151) = 6.93, p < 10− 4). UHR were younger than the other three groups, with no differences between the other three groups. No difference was found for educational level. The level of symptoms (PANSS scores) was similar between SZ and UHR. There were significant differences in NSS scores (F(3152) = 16.65, p < 10− 4). Post hoc LSD test showed that SZ and UHR obtained higher
Discussion
Eye movement alterations have been widely explored in schizophrenia and schizophrenia spectrum and acknowledged as useful markers. There was until now no previous report in individuals with UHR and our study presents original results in this population. Here, we investigated the sensitivity of AS and MGS to detect eye movement alterations in SZ, FS, UHR compared to controls. In the MGS, patients, UHR and siblings made more errors than controls, with a higher significant difference between
Limitations
In terms of limitations, the small number of trials for each condition did not allow analyses of the possible effect of different eccentricity for AS, and/or memory delay on MSG performance. It could be interesting to test these effects with more trials for each variation of angle and for each memory delay. Moreover, the UHR group is quite small, mainly due to the exclusion of cannabis consumption or treatments in UHR subjects. We cannot exclude that some negative results could be due to lack
Conclusion
Findings reported in this study confirmed a global deficit in inhibitory processes in patients with schizophrenia according to our hypothesis and the literature, and showed the added value of exploring several tasks together. Indeed, the use of the different paradigms (antisaccade, memory-guided saccade) revealed distinct profiles depending on the stages of the disease, indicating that some alterations could be pure endophenotypic markers of vulnerability for schizophrenia, while other could be
Conflict of interest
Magali Seassau declares work for the e(ye)BRAIN company and author as co-inventor a patent (B110332FRA, 2011) for the detection of oculomotor abnormalities (parameter for binocular coordination) in patients with schizophrenia. Other authors declared no competing interests.
Role of the funding source
The authors received financial help from Fondation pour la Recherche en Psychiatrie et Santé Mentale (FRPSM).
Acknowledgements
This study was promoted by INSERM. Thanks to Audrey Vialatte who gave help for the tracks analyses, as well as Boris Chaumette and Nouhza Aba who gave help for the statistical analyses. Thanks to Paris Descartes Language Centre and especially Karine Debbash for revising the English version of the manuscript.
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