Faculty Bibliography

Schizophrenia is often referred to as a cognitive disorder. A deeper and broader view of the syndrome is emerging, however, based on increasing appreciation of its associated visual system changes, including alterations in retinal neural and vascular structure and function, alterations in occipital lobe morphology and function, and their relationships with neuroinflammation and cardiometabolic factors. These and other data suggest that schizophrenia is best conceptualized as a multisystem condition. Here, we emphasize that early visual system changes in schizophrenia provide a window to the brain and to the rest of the body and provide valuable biomarkers for understanding pathophysiology and predicting multiple relevant outcomes, including the onset of a first psychotic episode, long-term course, and cognitive decline. The usefulness of early visual system markers of brain and physical health has already been demonstrated in neurodevelopmental and neurodegenerative disorders. They have particularly strong potential applicability for schizophrenia, given its progressive neurodevelopmental characteristics.

BACKGROUND:Atypical perception of visual illusions is well-documented in schizophrenia (SZ) and thought to be a consequence of impairments in visual processes including perceptual organization (PO). The Ebbinghaus illusion, in which a circle appears larger or smaller depending on the size of surrounding circles, is facilitated by PO, and the extent to which the surrounds (i.e., context) influence perception of the center circle can be considered an index of context sensitivity. In the present study, as part of a broader investigation of the impact of a novel visual remediation (VR) program for people with SZ, the Ebbinghaus illusion was used to explore the effects of VR on context sensitivity. METHODS:Participants with SZ (n = 47) were randomly assigned to one of four conditions: VR only, an active control condition (AC), or one of two conditions combining VR and AC. At three assessment points, participants completed a size comparison task based on the Ebbinghaus illusion. Context sensitivity was compared between training groups and with baseline clinical characteristics. RESULTS:At baseline, participants were strongly context sensitive. After training, participants in the VR group, but not the AC-only group, became less influenced by context. The main effect of training group and the group × time interaction terms were not significant. Participants who were less symptomatic at baseline showed the greatest reductions in context sensitivity over time. CONCLUSIONS:These findings suggest that an adaptive reduction in the influence of irrelevant context is a potential effect of VR and may reflect improved attentional focus.

This study investigated relations between a measure of early-stage visual function and self-reported visual anomalies in individuals at clinical high risk for psychosis (CHR-P). Eleven individuals at CHR identified via the Structured Interview for Psychosis-Risk Syndromes (SIPS) were recruited from a CHR-P research program in NYC. The sample was ~36% female, ranging from 16 to 33 years old (M = 23.90, SD = 6.14). Participants completed a contrast sensitivity task on an iPad with five spatial frequencies (0.41-13 cycles/degree) and completed the self-report Audio-Visual Abnormalities Questionnaire. Higher contrast sensitivity (better performance) to low spatial frequencies was associated with higher perceptual (r = 0.616, p = 0.044) and visual disturbances (r = 0.667, p = 0.025); lower contrast sensitivity to a middle spatial frequency was also associated with higher perceptual (r = -0.604, p = 0.049) and visual disturbances (r = -0.606, p = 0.048). This relation between the questionnaire and contrast sensitivity to low spatial frequency may be indicative of a reduction in lateral inhibition and "flooding" of environmental stimuli. The association with middle spatial frequencies, which play a critical role in face processing, may result in a range of perceptual abnormalities. These findings demonstrate that self-reported perceptual anomalies occur in these individuals and are linked to performance on a measure of early visual processing.

Despite evidence that individuals with schizophrenia (SZ) have an intact desire for social relationships, they have small social networks and report high levels of loneliness. Difficulty with reinforcement learning (RL), the ability to update behavior based on feedback, may inhibit the formation and maintenance of social relationships in SZ. However, impaired RL in SZ has largely been demonstrated via monetary tasks. Thus, it remains unclear whether SZ are similarly impaired in social and monetary RL, or whether socialspecific factors may further inhibit their ability to learn from social feedback. Thirty-one individuals with SZ and 31 healthy controls (HCs) participated in a RL paradigm to test hypotheses about social versus monetary RL. SZ exhibited impaired RL compared to HCs in both social and monetary tasks. Further, a Group × Task interaction demonstrated that SZ was more impaired when learning from social than monetary reinforcement, F(1, 59) = 5.99, p =.017. This differential deficit to social RL was not accounted for by reported pleasure from social feedback, which did not differ between groups. Instead, SZ had poorer emotion recognition than HCs, t(1, 60) = 4.80, p,.001, particularly for negative emotions, and controlling for this eliminated the differential social RL impairment. These results suggest the possibility that difficulty recognizing social cues, especially those indicating negative feedback, may relate to a reduced ability to learn from others"™ feedback. Thus, future research could elucidate whether targeting these emotion recognition difficulties in treatment could serve as a potential mechanism for improving social functioning in SZ.

Contrast processing is a fundamental function of the visual system, and contrast sensitivity as a function of spatial frequency (CSF) provides critical information about the integrity of the system. Here, we used a novel iPad-based instrument to collect CSFs and fitted the data with a difference of Gaussians model to investigate the neurophysiological bases of the spatial CSF. The reliability of repeat testing within and across sessions was evaluated in a sample of 22 adults for five spatial frequencies (0.41-13 cycles/degree) and two temporal durations (33 and 500 ms). Results demonstrate that the shape of the CSF, lowpass versus bandpass, depends on the temporal stimulus condition. Comparisons with previous psychophysical studies and with single-cell data from macaques and humans indicate that the major portion of the CSF, spatial frequencies >1.5 cycles/degree regardless of temporal condition, is determined by a 'sustained' mechanism (presumably parvocellular input to primary visual cortex [V1]). Contrast sensitivity to the lowest spatial frequency tested appears to be generated by a 'transient' mechanism (presumably magnocellular input to V1). The model fits support the hypothesis that the high spatial frequency limb of the CSF reflects the receptive field profile of the center mechanism of the smallest cells in the parvocellular pathway. These findings enhance the value of contrast sensitivity testing in general and increase the accessibility of this technique for use by clinicians through implementation on a commercially-available device.

PURPOSE/OBJECTIVE:Frequency-domain measures were applied to characterize neural deficits in individuals with schizophrenia using transient visual evoked potentials (tVEP). These measures were compared with conventional time-domain measures to elucidate underlying neurophysiological mechanisms and examine the value of frequency analysis. METHODS:Four frequency bands of activity identified in previous work were explored with respect to magnitude (spectral power), timing (phase), a combined measure, magnitude-squared coherence (MSC), and compared to amplitudes and times of prominent deflections in the response. RESULTS:Band 2 power/MSC (14-28 Hz) captured the major deflections in the waveform and its power predicted N75-P100 amplitude for patients and controls. Band 3 power/MSC (30-40 Hz) correlated highly with the earliest deflection (P60-N75), reflecting input to primary visual cortex (V1) and produced the largest magnitude effect. Phase of the 24th harmonic component predicted P100 peak time for patients and controls and yielded the largest group difference. Cluster analyses including time- and frequency-domain measures identified subgroups of patients with differential neurophysiological effects. A small but significant difference in visual acuity was found between groups that appears to be neurally based: Acuity (range 0.63-1.6) was not correlated with any tVEP measures in controls nor with input timing to V1 (P60 peak time) in patients, but was correlated with later tVEP measures in patients. All but two of the patients were on antipsychotic medication: Medication level (chlorpromazine equivalents) was correlated negatively with tVEP time measures and positively with certain magnitude measures yielding responses similar to controls at high levels. CONCLUSIONS:Overall, frequency-domain measures were shown to be objective and recommended as an alternative to conventional, subjective time-domain measures for analyzing tVEPs and in distinguishing between groups (patients vs. controls and patient subgroups). The findings implicated a loss of excitatory input to V1 in schizophrenia. Acuity as measured in the current study reflected disease status, and medication level was associated with improved tVEP responses. These novel tVEP techniques may be useful in revealing neurophysiological processes affected in schizophrenia and as a clinical tool.

Studies across a broad range of disciplines-from psychiatry to cognitive science to behavioral neuroscience-have reported on whether the magnitude of contrast sensitivity alterations in one group or condition varies with spatial frequency. Significant interactions have often gone unexplained or have been used to argue for impairments in specific processing streams. Here, we show that interactions with spatial frequency may need to be re-evaluated if the inherent skew/heteroscedasticity was not taken into account or if visual acuity could plausibly differ across groups or conditions. By re-analyzing a publicly available data set, we show that-when using raw contrast sensitivity data-schizophrenia patients exhibit an apparent contrast sensitivity impairment at low, but not high, spatial frequencies, but that when using log-transformed data or when using generalized estimating equations, this interaction reversed. The reversed interaction, but not the overall contrast sensitivity deficit, would disappear if groups were matched on visual acuity. An analysis of the contrast threshold data yielded similar results. A caveat is that matching groups on acuity is probably only defensible if acuity differences arise from non-neural factors such as optical blur. Taken together, these analyses reconcile seemingly discrepant findings in the literature and demonstrate that reporting contrast sensitivity interactions with spatial frequency requires properly accounting for visual acuity and skew/heteroscedasticity.

Previous studies have shown that patients diagnosed with schizophrenia (SCZ) have deficits in early visual processing, namely contrast processing. The brain-derived neurotropic factor (BDNF) is an important measure to investigate neuroplasticity in some visual functions like visual perception. In this study, we investigated the relationship between visual processing and BDNF levels in first-episode SCZ patients. Thirty-nine healthy controls and 43 first-episode SCZ patients were enrolled. Contrast sensitivity measurements were conducted using low, mid- and high spatial frequencies. First-episode SCZ patients had higher contrast sensitivity than healthy controls for all frequencies, except for the middle spatial frequency. Negative correlations were found between BDNF, contrast sensitivity and clinical variables, mostly for middle and high spatial frequencies among females. Our results provide support for (i) the association of SCZ with alterations of magno- and parvocellular pathway functioning and (ii) decreased BDNF levels in first-episode SCZ patients. This study highlights the importance of using biomarkers along with other measures to investigate visual processing in SCZ and other disorders.

BACKGROUND:Individuals with schizophrenia exhibit deficits in visual contrast processing, though less is known about how these deficits impact neurocognition and functional outcomes. This study investigated effects of contrast sensitivity (CS) on cognition and capacity for independent living in schizophrenia. METHODS:Participants were 58 patients with schizophrenia (n = 49) and schizoaffective disorder (n = 9). Patients completed a psychophysical paradigm to obtain CS with stimuli consisting of grating patterns of low (0.5 and 1 cycles/degree) and high spatial frequencies (4, 7, 21 cycles/degree). Patients completed the MATRICS Consensus Cognitive Battery and Wechsler Adult Intelligence Scales, Third Edition to assess cognition, and the problem-solving factor of the Independent Living Scales to assess functional capacity. We computed bivariate correlation coefficients for all pairs of variables and tested mediation models with CS to low (CS-LSF) and high spatial frequencies (CS-HSF) as predictors, cognitive measures as mediators, and capacity for independent living as an outcome. RESULTS:Cognition mediated the relationship between CS and independent living with CS-LSF a stronger predictor than CS-HSF. Mediation effects were strongest for perceptual organization and memory-related domains. In an expanded moderated mediation model, CS-HSF was found to be a significant predictor of independent living through perceptual organization as a mediator and CS-LSF as a moderator of this relationship. CONCLUSION/CONCLUSIONS:CS relates to functional capacity in schizophrenia through neurocognition. These relationships may inform novel visual remediation interventions.

Individuals with schizophrenia have problems with visual contrast processing. The current study investigated contrast sensitivity (CS) in schizophrenia/schizoaffective disorder to elucidate the underlying neural mechanisms affected by this disorder and to identify critical testing conditions that distinguish individuals with the disorder from healthy individuals. Principal component analysis was applied to the data (N = 143) to separate responses from distinct visual pathways. Participants were 68 patients and 75 age-similar controls. CS was obtained using a forced-choice psychophysical paradigm with grating patterns of low to high spatial frequency presented at short and long durations. Linear mixed-effects models were used to examine differences in log CS with respect to group, duration, and stimulus condition. Lower CSs were found in patients compared to controls over all stimulus conditions with the magnitude of deficits dependent on both spatial frequency and stimulus duration. Log CSs to low and high spatial frequencies loaded onto separate principal components, supporting the existence of two psychophysical mechanisms, transient and sustained. Critical conditions were identified to tap each mechanism. Visual acuity was correlated moderately with log CS to high, but not low, spatial frequencies, and deficits found for acuity and CS to moderate/high spatial frequencies (4-21 cycles/degree) appear to reflect dysfunction in the sustained mechanism. CS deficits found at the lowest spatial frequency tested (0.5 cycles/degree) appear to reflect dysfunction in the transient mechanism. Both types of CS deficits may have diagnostic value and implications for social and neurocognitive deficits in this disorder.