Visual masking deficits in schizophrenia: a view into the genetics of the disease through an endophenotype.

Schizophrenia is a severe psychiatric disorder determined by a complex mixture of genetic and environmental factors. To better understand the contributions of human genetic variations to schizophrenia, we performed a genome-wide association study (GWAS) of a highly sensitive endophenotype. In this visual masking endophenotype, two vertical bars, slightly shifted in the horizontal direction, are briefly presented (vernier offset). Participants are asked to indicate the offset direction of the bars (either left or right). The bars are followed by a grating mask, which makes the task both spatially and temporally challenging. The inter-stimulus interval (ISI) between the vernier and the mask was determined in 206 patients with schizophrenia, 109 first-order relatives, and 143 controls. Usually, in GWAS studies, patients are compared to controls (i.e., a binary task) without considering the large differences in performance between patients and controls, as it occurs in many paradigms. The masking task allows for a particularly powerful analysis because the differences in ISI within the patient population are large. We genotyped all participants and searched for associations between human polymorphisms and the masking endophenotype using a linear mixed model. We did not identify any genome-wide significant associations (p < 5 × 10-8), indicating that common variants with strong effects are unlikely to contribute to the large inter-group differences in visual masking. However, we found significant differences in polygenetic risk scores (PRS) between patients and controls, and relatives and controls.

Neural Compensation Mechanisms of Siblings of Schizophrenia Patients as Revealed by High-Density EEG.

Visual backward masking (VBM) deficits are candidate endophenotypes of schizophrenia indexing genetic liability of the disorder. In VBM, a target is followed by a mask that deteriorates target perception. Schizophrenia patients and, to a lesser extent, their unaffected relatives show strong and reproducible VBM deficits. In patients, VBM deficits are associated with strongly decreased amplitudes in the evoked-related potentials (ERPs). Here, to unveil the neural mechanisms of VBM in schizophrenia, circumventing illness-specific confounds, we investigated the electroencephalogram correlates of VBM in unaffected siblings of schizophrenia patients. We tested 110 schizophrenia patients, 60 siblings, and 83 healthy controls. As in previous studies, patients showed strong behavioral deficits and decreased ERP amplitudes compared to controls. Surprisingly, the ERP amplitudes of siblings were even higher than the ones of controls, while their performances were similar. ERP amplitudes in siblings were found to correlate with performance. These results suggest that VBM is deteriorated in patients and siblings. However, siblings, unlike patients, can partially compensate for the deficits by over-activating a network of brain regions.

No evidence for a common factor underlying visual abilities in healthy older people.

The world's population is aging at an increasing rate. Even in the absence of neurodegenerative disorders, healthy aging affects perception and cognition. In the context of cognition, common factors are well established. Much less is known about common factors for vision. Here, we tested 92 healthy older and 104 healthy younger participants in 19 visual tests (including visual search and contrast sensitivity) and three cognitive tests (including verbal fluency and digit span). Unsurprisingly, younger participants performed better than older participants in almost all tests. Surprisingly, however, the performance of older participants was mostly uncorrelated between visual tests, and we found no evidence for a common factor. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Schizophrenia patients using atypical medication perform better in visual tasks than patients using typical medication.

Schizophrenia (SCZ) patients show deficits in many domains, including cognition and perception. However, results are often mixed. One reason for mixed results may be differences in medication. Very little is known about the role of medication in visual processing. Here, we investigated the effects of typical vs. atypical medication on contrast sensitivity (spatial frequencies ranging from 0.2 to 20 cycles per degree), vernier acuity, and visual backward masking. From a large pool of patients, we selected 50 patients (Study 1, conducted in Brazil) and 97 patients (Study 2, conducted in Georgia) taking either only typical or atypical medication. Patients with atypical medication performed significantly better than patients with typical medication for contrast sensitivity, vernier duration, and backward masking. As a secondary result, we found similar, but not significant, trends for the cognitive tasks (Stroop, Flanker, Trail-Making Test-B, Wisconsin Card Sorting Test and Continuous Performance Test) in the same patients. No correlations were found between demographics, psychopathology, chlorpromazine equivalents and visual processing. A conclusion of our study is that one needs to be careful comparing studies when medication is not comparable.

Is the perception of illusions abnormal in schizophrenia?

There seems to be no common factor for visual perception, i.e., performance in visual tasks correlates only weakly with each other. Similar results were found with visual illusions. One may expect common visual factors for individuals suffering from pathologies that alter brain functioning, such as schizophrenia. For example, patients who are more severely affected by the disease, e.g., stronger positive symptoms, may show increased illusion magnitudes. Here, in the first experiment, we used a battery of seven visual illusions and a mental imagery questionnaire. Illusion magnitudes for the seven illusions did not differ significantly between the patients and controls. In addition, correlations between the different illusions and mental imagery were low. In the second experiment, we tested 59 patients (mostly outpatients) with ten visual illusions. As for the first experiment, patients and controls showed similar susceptibility to all but one visual illusion. Moreover, there were no significant correlations between different illusions, symptoms, or medication type. Thus, it seems that perception of visual illusions is mostly intact in schizophrenia.

Electrophysiological correlates of visual backward masking in patients with first episode psychosis.

Visual backward masking is strongly impaired in patients with schizophrenia. Masking deficits have been proposed as potential endophenotypes of schizophrenia. Masking performance deficits manifest as strongly reduced amplitudes in the electroencephalogram (EEG). In order to fulfill the criteria of an endophenotype, masking deficits should not vary substantially across time and should be present at the first psychotic event. To verify whether these conditions are met for visual backward masking, we tested patients with first episode psychosis (n = 21) in a longitudinal study. Patients were tested with visual backward masking and EEG three times every six months over a period of one year. We found that the EEG amplitudes of patients with first episode psychosis were higher as compared to those of patients with schizophrenia but lower as compared to those of unaffected controls. More interestingly, we found that the EEG amplitudes of patients with first episode psychosis remained stable over the course of one year. Since chronic schizophrenia patients have strongly reduced amplitudes, we speculate that the neural correlates of masking deficits (EEG amplitudes) continue to decrease as the disease progresses.

Statistical Learning Impairments as a Consequence of Stroke.

Statistical learning is the implicit learning of the contingencies between sequential stimuli, typically from mere exposure. It is present from infancy onward, and plays a role in functions from language learning to selective attention. Despite these observations, there are few data on whether statistical learning capacity changes with age or after brain injury. In order to examine how brain injury affects the ability to learn and update statistical representations, we had young control and healthy elder participants, as well as participants with either left or right brain injury, perform an auditory statistical learning task. Participants listened to two languages with made-up words that were defined by the transition probability between syllables. Following passive listening, learning was assessed with a two-alternative forced choice test for the most familiar word. As in previous studies, we found that young controls have a learning capacity limitation for statistical learning; a second language is less well learned than the first, and this statistical learning capacity limit is attenuated with age. Additionally, we found that brain damaged patients, whether with left or right hemispheric damage, showed impaired statistical learning. This impairment was not explained by aphasia or cognitive deficits. As statistical learning is a critical skill for daily life, a better appreciation of the nature of this impairment will improve our understanding of the cognitive effects of brain injury and could lead to new rehabilitation strategies.

Sex-related differences in vision are heterogeneous.

Despite well-established sex differences for cognition, audition, and somatosensation, few studies have investigated whether there are also sex differences in visual perception. We report the results of fifteen perceptual measures (such as visual acuity, visual backward masking, contrast detection threshold or motion detection) for a cohort of over 800 participants. On six of the fifteen tests, males significantly outperformed females. On no test did females significantly outperform males. Given this heterogeneity of the sex effects, it is unlikely that the sex differences are due to any single mechanism. A practical consequence of the results is that it is important to control for sex in vision research, and that findings of sex differences for cognitive measures using visually based tasks should confirm that their results cannot be explained by baseline sex differences in visual perception.

Rethinking Body Ownership in Schizophrenia: Experimental and Meta-analytical Approaches Show no Evidence for Deficits.

Schizophrenia is a severe psychiatric disorder, in which patients experience an abnormal sense of self. While deficits in sensorimotor self-representation (agency) are well documented in schizophrenia, less is known about other aspects of bodily self-representation (body ownership). Here, we tested a large cohort (N = 59) of chronic schizophrenia patients and matched controls (N = 30) on a well-established body illusion paradigm, the Full Body Illusion (FBI). In this paradigm, changes in body ownership are induced through prolonged multisensory stimulation, in which participants are stroked on their back while seeing the stroking on the back of a virtual body. When the felt and seen stroking are synchronous, participants typically feel higher identification with the seen body as well as a drift in self-location towards it. However, when the stroking is asynchronous, no such changes occur. Our results show no evidence for abnormal body ownership in schizophrenia patients. A meta-analysis of previous work corroborates this result. Thus, while schizophrenia patients may be impaired in the sense of agency, their multisensory bodily self-representation, as tested here, seems to be unaffected by the illness.

Local versus global and retinotopic versus non-retinotopic motion processing in schizophrenia patients.

Schizophrenia impairs cognitive functions as much as perception. For example, patients perceive global motion in random dot kinematograms less strongly, because, as it is argued, the integration of the dots into a single Gestalt is complex and therefore deteriorated. Similarly, the perception of apparent motion is impaired, because filling-in of the illusory trajectory requires complex processing. Here, we investigated very complex motion processing using the Ternus-Pikler display. First, we tested whether the perception of global apparent motion is impaired in schizophrenia patients compared to healthy controls. The task requires both the grouping of multiple elements into a coherent Gestalt and the filling-in of its illusory motion trajectory. Second, we tested the perception of rotation in the same stimulus, which in addition requires the computation of non-retinotopic motion. Contrary to earlier studies, patients were not impaired in either task and even tended to perform better than controls. The results suggest that complex visual processing itself is not impaired in schizophrenia patients.

Crowding, grouping, and gain control in schizophrenia.

Visual paradigms are versatile tools to investigate the pathophysiology of schizophrenia. Contextual modulation refers to a class of paradigms where a target is flanked by neighbouring elements, which either deteriorate or facilitate target perception. It is often proposed that contextual modulation is weakened in schizophrenia compared to controls, with facilitating contexts being less facilitating and deteriorating contexts being less deteriorating. However, results are mixed. In addition, facilitating and deteriorating effects are usually determined in different paradigms, making comparisons difficult. Here, we used a crowding paradigm in which both facilitation and deterioration effects can be determined all together. We found a main effect of group, i.e., patients performed worse in all conditions compared to controls. However, when we discounted for this main effect, facilitation and deterioration were well comparable to controls. Our results indicate that contextual modulation can be intact in schizophrenia patients.

Does chronic nicotine consumption influence visual backward masking in schizophrenia and schizotypy?

Nicotine consumption is higher for people within the schizophrenia spectrum compared to controls. This observation supports the self-medication hypothesis, that nicotine relieves symptoms in, for example, schizophrenia patients. We tested whether performance in an endophenotype of schizophrenia (visual backward masking, VBM) is modulated by nicotine consumption in i) smoking and non-smoking schizophrenia patients, their first-degree relatives, and age-matched controls, ii) non-smoking and smoking university students, and iii) non-smoking, early and late onset nicotine smokers. Overall, our results confirmed that VBM deficits are an endophenotype of schizophrenia, i.e., deficits were highest in patients, followed by their relatives, students scoring high in Cognitive Disorganisation, and controls. Moreover, we found i) beneficial effects of chronic nicotine consumption on VBM performance, in particular with increasing age, and ii) little impact of clinical status alone or in interaction with nicotine consumption on VBM performance. Given the younger age of undergraduate students (up to 30 years) versus controls and patients (up to 66 years), we propose that age-dependent VBM deficits emerge when schizotypy effects are targeted in populations of a larger age range, but that nicotine consumption might counteract these deficits (supporting the self-medication hypothesis).

Priming and statistical learning in right brain damaged patients.

We investigated how right hemisphere lesions affected location priming and statistical learning in four groups of participants: young controls, older controls, and right brain damaged patients with or without spatial neglect. Using a version of the Maljkovic and Nakayama's (1994) priming task, but with all the targets presented at the mid-line, we biased the transition probability for targets to repeat their spatial location. The decrease in response time with spatial repetition allowed us to quantify priming, and the modulation of priming strength as a function of repeat probability allowed us to assess for statistical learning. Contrary to the healthy controls, right brain damage decreased (but did not abolish) spatial priming. Right brain damaged patients did not modulate the magnitude of the spatial priming effect with variation in repeat frequency, as did the control groups. We conclude that damage to the right hemisphere impairs spatial priming and that priming impairment co-exists with, and may contribute to an inability to learn environmental statistical regularities. Such deficits could contribute to functional deficits and a poorer response to rehabilitation.

Statistical learning as a tool for rehabilitation in spatial neglect.

We propose that neglect includes a disorder of representational updating. Representational updating refers to our ability to build mental models and adapt those models to changing experience. This updating ability depends on the processes of priming, working memory, and statistical learning. These processes in turn interact with our capabilities for sustained attention and precise temporal processing. We review evidence showing that all these non-spatial abilities are impaired in neglect, and we discuss how recognition of such deficits can lead to novel approaches for rehabilitating neglect.

Spatial probability cuing and right hemisphere damage.

In this experiment we studied statistical learning, inter-trial priming, and visual attention. We assessed healthy controls and right brain damaged (RBD) patients with and without neglect, on a simple visual discrimination task designed to measure priming effects and probability learning. All participants showed a preserved priming effect for item color. Contrary to healthy controls and RBD participants without neglect, RBD participants with neglect did not show positional priming and both RBD groups learned the underlying spatial probability distribution of target locations to a lesser degree. To see if the latter deficiency could be improved, we tested a patient with long standing chronic spatial neglect on three separate days and observed improved identification times for left sided, high probability, targets. In summary, we found preservation of priming per se in people with spatial neglect. However, this was only clearly demonstrable for color priming and not for positional priming. Associated with this impairment was a difficulty in learning the overall statistical structure of target locations. In a patient with severe persistent neglect we were able to demonstrate that the deficit in statistical learning was not absolute, as this subject improved his identification times for targets appearing in high probability regions of the test display.