Functional dysconnectivity of visual and somatomotor networks yields a simple and robust biomarker for psychosis.

People with psychosis exhibit thalamo-cortical hyperconnectivity and cortico-cortical hypoconnectivity with sensory networks, however, it remains unclear if this applies to all sensory networks, whether it arises from other illness factors, or whether such differences could form the basis of a viable biomarker. To address the foregoing, we harnessed data from the Human Connectome Early Psychosis Project and computed resting-state functional connectivity (RSFC) matrices for 54 healthy controls and 105 psychosis patients. Primary visual, secondary visual ("visual2"), auditory, and somatomotor networks were defined via a recent brain network partition. RSFC was determined for 718 regions via regularized partial correlation. Psychosis patients- both affective and non-affective-exhibited cortico-cortical hypoconnectivity and thalamo-cortical hyperconnectivity in somatomotor and visual2 networks but not in auditory or primary visual networks. When we averaged the visual2 and somatomotor network connections and subtracted the thalamo-cortical and cortico-cortical connectivity values, a robust psychosis biomarker emerged (p=2e-10, Hedges' g=1.05). This "somato-visual" biomarker was present in antipsychotic-naive patients and did not depend on confounds such as psychiatric comorbidities, substance/nicotine use, stress, or anxiety. It had moderate test-retest reliability (ICC=.61) and could be recovered in five-minute scans. The marker could discriminate groups in leave-one-site-out cross-validation (AUC=.79) and improve group classification upon being added to a well-known neurocognition task. Finally, it could differentiate later-stage psychosis patients from healthy or ADHD controls in two independent data sets. These results introduce a simple and robust RSFC biomarker that can distinguish psychosis patients from controls by the early illness stages.

Increased whole-brain functional heterogeneity in psychosis during rest and task.

Past work has shown that people with schizophrenia exhibit more cross-subject heterogeneity in their functional connectivity patterns. However, it remains unclear whether specific brain networks are implicated, whether common confounds could explain the results, or whether task activations might also be more heterogeneous. Unambiguously establishing the existence and extent of functional heterogeneity constitutes a first step toward understanding why it emerges and what it means clinically. METHODS: We first leveraged data from the HCP Early Psychosis project. Functional connectivity (FC) was extracted from 718 parcels via principal components regression. Networks were defined via a brain network partition (Ji et al., 2019). We also examined an independent data set with controls, later-stage schizophrenia patients, and ADHD patients during rest and during a working memory task. We quantified heterogeneity by averaging the Pearson correlation distance of each subject's FC or task activity pattern to that of every other subject of the same cohort. RESULTS: Affective and non-affective early psychosis patients exhibited more cross-subject whole-brain heterogeneity than healthy controls (ps < 0.001, Hedges' g > 0.74). Increased heterogeneity could be found in up to seven networks. In-scanner motion, medication, nicotine, and comorbidities could not explain the results. Later-stage schizophrenia patients exhibited heterogeneous connectivity patterns and task activations compared to ADHD and control subjects. Interestingly, individual connection weights, parcel-wise task activations, and network averages thereof were not more variable in patients, suggesting that heterogeneity becomes most obvious over large-scale patterns. CONCLUSION: Whole-brain cross-subject functional heterogeneity characterizes psychosis during rest and task. Developmental and pathophysiological consequences are discussed.

When do contrast sensitivity deficits (or enhancements) depend on spatial frequency? Two ways to avoid spurious interactions.

Studies across a broad range of disciplines-from psychiatry to cognitive science to behavioural 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-analysing a publicly available data set, we show that-when using raw contrast sensitivity data-schizophrenia patients exhibit an apparent contrast sensitivity impairment that lessens with spatial frequency, 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, disappeared when 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.

Dorsal attention network activity during perceptual organization is distinct in schizophrenia and predictive of cognitive disorganization.

Visual shape completion is a canonical perceptual organization process that integrates spatially distributed edge information into unified representations of objects. People with schizophrenia show difficulty in discriminating completed shapes, but the brain networks and functional connections underlying this perceptual difference remain poorly understood. Also unclear is whether brain network differences in schizophrenia occur in related illnesses or vary with illness features transdiagnostically. To address these topics, we scanned (functional magnetic resonance imaging, fMRI) people with schizophrenia, bipolar disorder, or no psychiatric illness during rest and during a task in which they discriminated configurations that formed or failed to form completed shapes (illusory and fragmented condition, respectively). Multivariate pattern differences were identified on the cortical surface using 360 predefined parcels and 12 functional networks composed of such parcels. Brain activity flow mapping was used to evaluate the likely involvement of resting-state connections for shape completion. Illusory/fragmented task activation differences ('modulations') in the dorsal attention network (DAN) could distinguish people with schizophrenia from the other groups (AUCs > .85) and could transdiagnostically predict cognitive disorganization severity. Activity flow over functional connections from the DAN could predict secondary visual network modulations in each group, except in schizophrenia. The secondary visual network was strongly and similarly modulated in each group. Task modulations were dispersed over more networks in patients compared to controls. In summary, DAN activity during visual perceptual organization is distinct in schizophrenia, symptomatically relevant, and potentially related to improper attention-related feedback into secondary visual areas.

Visual system assessment for predicting a transition to psychosis.

The field of psychiatry is far from perfect in predicting which individuals will transition to a psychotic disorder. Here, we argue that visual system assessment can help in this regard. Such assessments have generated medium-to-large group differences with individuals prior to or near the first psychotic episode or have shown little influence of illness duration in larger samples of more chronic patients. For example, self-reported visual perceptual distortions-so-called visual basic symptoms-occur in up to 2/3rds of those with non-affective psychosis and have already longitudinally predicted an impending onset of schizophrenia. Possibly predictive psychophysical markers include enhanced contrast sensitivity, prolonged backward masking, muted collinear facilitation, reduced stereoscopic depth perception, impaired contour and shape integration, and spatially restricted exploratory eye movements. Promising brain-based markers include visual thalamo-cortical hyperconnectivity, decreased occipital gamma band power during visual detection (MEG), and reduced visually evoked occipital P1 amplitudes (EEG). Potentially predictive retinal markers include diminished cone a- and b-wave amplitudes and an attenuated photopic flicker response during electroretinography. The foregoing assessments are often well-described mechanistically, implying that their findings could readily shed light on the underlying pathophysiological changes that precede or accompany a transition to psychosis. The retinal and psychophysical assessments in particular are inexpensive, well-tolerated, easy to administer, and brief, with few inclusion/exclusion criteria. Therefore, across all major levels of analysis-from phenomenology to behavior to brain and retinal functioning-visual system assessment could complement and improve upon existing methods for predicting which individuals go on to develop a psychotic disorder.

Activity flow underlying abnormalities in brain activations and cognition in schizophrenia.

Cognitive dysfunction is a core feature of many brain disorders, including schizophrenia (SZ), and has been linked to aberrant brain activations. However, it is unclear how these activation abnormalities emerge. We propose that aberrant flow of brain activity across functional connectivity (FC) pathways leads to altered activations that produce cognitive dysfunction in SZ. We tested this hypothesis using activity flow mapping, an approach that models the movement of task-related activity between brain regions as a function of FC. Using functional magnetic resonance imaging data from SZ individuals and healthy controls during a working memory task, we found that activity flow models accurately predict aberrant cognitive activations across multiple brain networks. Within the same framework, we simulated a connectivity-based clinical intervention, predicting specific treatments that normalized brain activations and behavior in patients. Our results suggest that dysfunctional task-evoked activity flow is a large-scale network mechanism contributing to cognitive dysfunction in SZ.

Brain network mechanisms of visual shape completion.

Visual shape completion recovers object shape, size, and number from spatially segregated edges. Despite being extensively investigated, the process's underlying brain regions, networks, and functional connections are still not well understood. To shed light on the topic, we scanned (fMRI) healthy adults during rest and during a task in which they discriminated pac-man configurations that formed or failed to form completed shapes (illusory and fragmented condition, respectively). Task activation differences (illusory-fragmented), resting-state functional connectivity, and multivariate patterns were identified on the cortical surface using 360 predefined parcels and 12 functional networks composed of such parcels. Brain activity flow mapping (ActFlow) was used to evaluate the likely involvement of resting-state connections for shape completion. We identified 36 differentially-active parcels including a posterior temporal region, PH, whose activity was consistent across 95% of observers. Significant task regions primarily occupied the secondary visual network but also incorporated the frontoparietal, dorsal attention, default mode, and cingulo-opercular networks. Each parcel's task activation difference could be modeled via its resting-state connections with the remaining parcels (r=.62, p<10-9), suggesting that such connections undergird shape completion. Functional connections from the dorsal attention network were key in modelling task activation differences in the secondary visual network. Dorsal attention and frontoparietal connections could also model activations in the remaining networks. Taken together, these results suggest that shape completion relies upon a sparsely distributed but densely interconnected network coalition that is centered in the secondary visual network, coordinated by the dorsal attention network, and inclusive of at least three other networks.

A Whole-Brain and Cross-Diagnostic Perspective on Functional Brain Network Dysfunction.

A wide variety of mental disorders have been associated with resting-state functional network alterations, which are thought to contribute to the cognitive changes underlying mental illness. These observations appear to support theories postulating large-scale disruptions of brain systems in mental illness. However, existing approaches isolate differences in network organization without putting those differences in a broad, whole-brain perspective. Using a graph distance approach-connectome-wide similarity-we found that whole-brain resting-state functional network organization is highly similar across groups of individuals with and without a variety of mental diseases. This similarity was observed across autism spectrum disorder, attention-deficit hyperactivity disorder, and schizophrenia. Nonetheless, subtle differences in network graph distance were predictive of diagnosis, suggesting that while functional connectomes differ little across health and disease, those differences are informative. These results suggest a need to reevaluate neurocognitive theories of mental illness, with a role for subtle functional brain network changes in the production of an array of mental diseases. Such small network alterations suggest the possibility that small, well-targeted alterations to brain network organization may provide meaningful improvements for a variety of mental disorders.

Smaller visual arrays are harder to integrate in schizophrenia: Evidence for impaired lateral connections in early vision.

Long-range horizontal connections in early vision undergird a well-studied "collinear facilitation" effect, wherein a central low-contrast target becomes more detectable when flanked by collinear elements. Collinear facilitation is weaker in schizophrenia. Might lateral connections be responsible? To consider the possibility, we had 38 schizophrenia patients and 49 well-matched healthy controls judge the presence of a central low-contrast element flanked by collinear or orthogonal high-contrast elements.   The display (target+flankers) was scaled in size to produce a lower and higher spatial frequency ("SF") condition (4 and 10 cycles/deg, respectively).  Larger stimulus arrays bias processing towards feedback connections from higher-order visual areas; smaller arrays bias processing toward lateral connections. Patients had impaired facilitation relative to controls at higher but not lower SFs. Combining data from a past study on "contour integration" (in which subjects sought to detect chains of co-circular elements), we found correlated integration and facilitation performance at the higher SF and a similar effect of spatial scaling across SF, suggesting a common mechanism. In an exploratory analysis, worse contrast thresholds (without facilitation) correlated strongly with more premorbid dysfunction. In schizophrenia, inter-element filling-in worsens at smaller spatial scales potentially because of its increased reliance on impaired lateral connections in early vision.

The Audio-Visual Abnormalities Questionnaire (AVAQ): Development and validation of a new instrument for assessing anomalies in sensory perception in schizophrenia spectrum disorders.

BACKGROUND: Anomalies in visual and auditory perception represent an important aspect of the symptomatic manifestation of schizophrenia (ScZ). However, there are currently no instruments available that allow the assessment of the full range of auditory and visual abnormalities using a self-report measure. METHODS: We developed the 85-item Audio-Visual Abnormalities Questionnaire (AVAQ) to assess abnormalities in auditory and visual processing. The AVAQ was validated in an online-sample of 355 healthy participants to establish the factorial structure, internal consistency and reliability of the instrument. In addition, participants completed the Autism-Spectrum Quotient (AQ) and the Schizotypal Personality Questionnaire (SPQ) to establish convergent validity regarding autistic and schizotypal traits. RESULTS: High internal consistency was observed for the total AVAQ-scale (α = 0.99) as well as for the visual (α = 0.98), auditory (α = 0.96) and the audio-visual subscales (α = 0.83). Principal component analyses demonstrated one factor comprising 78 items. The AVAQ was positively correlated with the SPQ (r = 0.69, p < .001) as well as the AQ (r = 0.38, p < .001). Correlations with the SPQ were highest for unusual perceptual experiences (r = 0.72, p < .001) and lowest for social anxiety (r = 0.30, p < .001). CONCLUSION: The AVAQ demonstrated excellent reliability, internal consistency and construct validity. Accordingly, the instrument could be useful for characterizing sensory dysfunctions across the schizophrenia spectrum that could guide interventions as well as aid the development of biomarkers.

Intact illusory contour formation but equivalently impaired visual shape completion in first- and later-episode schizophrenia.

Visual shape completion is a fundamental process that constructs contours and shapes on the basis of the geometric relations between spatially separated edge elements. People with schizophrenia are impaired at distinguishing visually completed shapes, but when does the impairment emerge and how does it evolve with illness duration? The question bears on the debate as to whether cognition declines after illness onset. To address the issue, we tested healthy controls (n = 48), first-episode psychosis patients (n = 23), and chronic schizophrenia patients (n = 49) on a classic psychophysical task in which subjects discriminated the relative orientations of four sectored circles that either formed or did not form visually completed shapes (illusory and fragmented conditions, respectively). Visual shape completion was quantified as the extent to which performance in the illusory condition exceeded that of the fragmented. Half of the trials incorporated wire edge elements, which augment contour salience and improve shape completion. Each patient group exhibited large visual shape completion deficits that could not be explained by differences in age, motivation, or orientation tuning. Patients responded normally to changes in illusory contour salience, indicating that they were forming but not adequately employing such contours for discriminating shapes. Shape completion deficits were most apparent for patients with cognitive disorganization, poor premorbid early adolescent functioning, and normal orientation discrimination. Visual shape completion deficits emerge maximally by the first psychotic episode and arise from higher-level disturbances that are related to premorbid functioning and disorganization. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Intact perception of coherent motion, dynamic rigid form, and biological motion in chronic schizophrenia.

BACKGROUND: Prior studies have documented biological motion perception deficits in schizophrenia, but it remains unclear whether the impairments arise from poor social cognition, perceptual organization, basic motion processing, or sustained attention/motivation. To address the issue, we had 24 chronic schizophrenia patients and 27 healthy controls perform three tasks: coherent motion, where subjects indicated whether a cloud of dots drifted leftward or rightward; dynamic rigid form, where subjects determined the tilt direction of a translating, point-light rectangle; and biological motion, where subjects judged whether a human point-light figure walked leftward or rightward. Task difficulty was staircase controlled and depended on the directional variability of the background dot motion. Catch trials were added to verify task attentiveness and engagement. RESULTS: Patients and controls demonstrated similar performance thresholds and near-ceiling catch trial accuracy for each task (uncorrected ps > 0.1; ds < 0.35). In all but the coherent motion task, higher IQ correlated with better performance (ps < 0.001). CONCLUSION: Schizophrenia patients have intact perception of motion coherence, dynamic rigid form, and biological motion at least for our sample and set-up. We speculate that previously documented biological motion perception deficits arose from task or stimulus differences or from group differences in IQ, attention, or motivation.

Self-Reported Visual Perceptual Abnormalities Are Strongly Associated with Core Clinical Features in Psychotic Disorders.

BACKGROUND: Past studies using the Bonn Scale for the Assessment of Basic Symptoms (hereafter, Bonn Scale) have shown that self-reported perceptual/cognitive disturbances reveal which persons have or will soon develop schizophrenia. Here, we focused specifically on the clinical value of self-reported visual perceptual abnormalities (VPAs) since they are underexplored and have been associated with suicidal ideation, negative symptoms, and objective visual dysfunction. METHOD: Using the 17 Bonn Scale vision items, we cross-sectionally investigated lifetime occurrence of VPAs in 21 first-episode psychosis and 22 chronic schizophrenia/schizoaffective disorder (SZ/SA) patients. Relationships were probed between VPAs and illness duration, symptom severity, current functioning, premorbid functioning, diagnosis, and age of onset. RESULTS: Increased VPAs were associated with: earlier age of onset; more delusions, hallucinations, bizarre behavior, and depressive symptoms; and worse premorbid social functioning, especially in the childhood and early adolescent phases. SZ/SA participants endorsed more VPAs as compared to those with schizophreniform or psychotic disorder-NOS, especially in the perception of color, bodies, faces, object movement, and double/reversed vision. The range of self-reported VPAs was strikingly similar between first-episode and chronic patients and did not depend on the type or amount of antipsychotic medication. As a comparative benchmark, lifetime occurrence of visual hallucinations did not depend on diagnosis and was linked only to poor premorbid social functioning. CONCLUSION: A brief 17-item interview derived from the Bonn Scale is strongly associated with core clinical features in schizophrenia. VPAs hold promise for clarifying diagnosis, predicting outcome, and guiding neurocognitive investigations.

Contour interpolation: A case study in Modularity of Mind.

In his monograph Modularity of Mind (1983), philosopher Jerry Fodor argued that mental architecture can be partly decomposed into computational organs termed modules, which were characterized as having nine co-occurring features such as automaticity, domain specificity, and informational encapsulation. Do modules exist? Debates thus far have been framed very generally with few, if any, detailed case studies. The topic is important because it has direct implications on current debates in cognitive science and because it potentially provides a viable framework from which to further understand and make hypotheses about the mind's structure and function. Here, the case is made for the modularity of contour interpolation, which is a perceptual process that represents non-visible edges on the basis of how surrounding visible edges are spatiotemporally configured. There is substantial evidence that interpolation is domain specific, mandatory, fast, and developmentally well-sequenced; that it produces representationally impoverished outputs; that it relies upon a relatively fixed neural architecture that can be selectively impaired; that it is encapsulated from belief and expectation; and that its inner workings cannot be fathomed through conscious introspection. Upon differentiating contour interpolation from a higher-order contour representational ability ("contour abstraction") and upon accommodating seemingly inconsistent experimental results, it is argued that interpolation is modular to the extent that the initiating conditions for interpolation are strong. As interpolated contours become more salient, the modularity features emerge. The empirical data, taken as a whole, show that at least certain parts of the mind are modularly organized.

Disruptions in neural connectivity associated with reduced susceptibility to a depth inversion illusion in youth at ultra high risk for psychosis.

Patients with psychosis exhibit a reduced susceptibility to depth inversion illusions (DII) in which a physically concave surface is perceived as convex (e.g., the hollow mask illusion). Here, we examined the extent to which lessened susceptibility to DII characterized youth at ultra high risk (UHR) for psychosis. In this study, 44 UHR participants and 29 healthy controls judged the apparent convexity of face-like human masks, two of which were concave and the other convex. One of the concave masks was painted with realistic texture to enhance the illusion; the other was shown without such texture. Networks involved with top-down and bottom-up processing were evaluated with resting state functional connectivity magnetic resonance imaging (fcMRI). We examined regions associated with the fronto-parietal network and the visual system and their relations with susceptibility to DII. Consistent with prior studies, the UHR group was less susceptible to DII (i.e., they were characterized by more veridical perception of the stimuli) than the healthy control group. Veridical responses were related to weaker connectivity within the fronto-parietal network, and this relationship was stronger in the UHR group, suggesting possible abnormalities of top-down modulation of sensory signals. This could serve as a vulnerability marker and a further clue to the pathogenesis of psychosis.

Seeing more clearly through psychosis: Depth inversion illusions are normal in bipolar disorder but reduced in schizophrenia.

Schizophrenia patients with more positive symptoms are less susceptible to depth inversion illusions (DIIs) in which concave objects appear as convex. It remains unclear, however, the extent to which this perceptual advantage uniquely characterizes the schizophrenia phenotype. To address the foregoing, we compared 30 bipolar disorder patients to a previously published sample of healthy controls (N=25) and schizophrenia patients (N=30). The task in all cases was to judge the apparent convexity of physically concave faces and scenes. Half of the concave objects were painted with realistic texture to enhance the convexity illusion and the remaining objects were untextured to reduce the illusion. Subjects viewed objects stereoscopically or via monocular motion parallax depth cues. For each group, DIIs were stronger with texture than without, and weaker with stereoscopic information than without, indicating a uniformly normal response to stimulus alterations across groups. Bipolar patients experienced DIIs more frequently than schizophrenia patients but as commonly as controls, irrespective of the face/scene category, texture, or viewing condition (motion/stereo). More severe positive and disorganized symptoms predicted reduced DIIs for schizophrenia patients and across all patients. These results suggest that people with schizophrenia, but not bipolar disorder, more accurately perceive object depth structure. Psychotic symptoms-or their accompanying neural dysfunction-may primarily drive the effect presumably through eroding the visual system's generalized tendency to construe unusual or ambiguous surfaces as convex. Because such symptoms are by definition more common in schizophrenia, DIIs are at once state-sensitive and diagnostically specific, offering a potential biomarker for the presence of acute psychosis.

Visual integration dysfunction in schizophrenia arises by the first psychotic episode and worsens with illness duration.

Visual integration dysfunction characterizes schizophrenia, but prior studies have not yet established whether the problem arises by the first psychotic episode or worsens with illness duration. To investigate the issue, we compared chronic schizophrenia patients (SZs), first episode psychosis patients (FEs), and well-matched healthy controls on a brief but sensitive psychophysical task in which subjects attempted to locate an integrated shape embedded in noise. Task difficulty depended on the number of noise elements co-presented with the shape. For half of the experiment, the entire display was scaled down in size to produce a high spatial frequency (HSF) condition, which has been shown to worsen patient integration deficits. Catch trials-in which the circular target appeared without noise-were also added so as to confirm that subjects were paying adequate attention. We found that controls integrated contours under noisier conditions than FEs, who, in turn, integrated better than SZs. These differences, which were at times large in magnitude (d = 1.7), clearly emerged only for HSF displays. Catch trial accuracy was above 95% for each group and could not explain the foregoing differences. Prolonged illness duration predicted poorer HSF integration across patients, but age had little effect on controls, indicating that the former factor was driving the effect in patients. Taken together, a brief psychophysical task efficiently demonstrates large visual integration impairments in schizophrenia. The deficit arises by the first psychotic episode, worsens with illness duration, and may serve as a biomarker of illness progression. (PsycINFO Database Record