Disrupted third visual pathway function in schizophrenia: Evidence from real and implied motion processing.

Impaired motion perception in schizophrenia has been associated with deficits in social-cognitive processes and with reduced activation of visual sensory regions, including the middle temporal area (MT+) and posterior superior temporal sulcus (pSTS). These findings are consistent with the recent proposal of the existence of a specific 'third visual pathway' specialized for social perception in which motion is a fundamental component. The third visual pathway transmits visual information from early sensory visual processing areas to the STS, with MT+ acting as a critical intermediary. We used functional magnetic resonance imaging to investigate functioning of this pathway during processing of naturalistic videos with explicit (real) motion and static images with implied motion cues. These measures were related to face emotion recognition and motion-perception, as measured behaviorally. Participants were 28 individuals with schizophrenia (Sz) and 20 neurotypical controls. Compared to controls, individuals with Sz showed reduced activation of third visual pathway regions (MT+, pSTS) in response to both real- and implied-motion stimuli. Dysfunction of early visual cortex and pulvinar were also associated with aberrant real-motion processing. Implied-motion stimuli additionally engaged a wide network of brain areas including parietal, motor and frontal nodes of the human mirror neuron system. The findings support concepts of MT+ as a mediator between visual sensory areas and higher-order brain and argue for greater focus on MT+ contributions to social-cognitive processing, in addition to its well-documented role in visual motion processing.

Network-level mechanisms underlying effects of transcranial direct current stimulation (tDCS) on visuomotor learning in schizophrenia.

Motor learning is a fundamental skill to our daily lives. Dysfunction in motor performance in schizophrenia (Sz) has been associated with poor social and functional outcomes. Transcranial direct current stimulation (tDCS), a non-invasive electrical brain stimulation approach, can influence underlying brain function with potential for improving motor learning in Sz. We used a well-established Serial Reaction Time Task (SRTT) to study motor learning, in combination with simultaneous tDCS and EEG recording, to investigate mechanisms of motor and procedural learning deficits in Sz, and to develop refined non-invasive brain stimulation approaches to improve neurocognitive dysfunction. We recruited 27 individuals with Sz and 21 healthy controls (HC). Individuals performed the SRTT task as they received sham and active tDCS with simultaneous EEG recording. Reaction time (RT), neuropsychological, and measures of global functioning were assessed. SRTT performance was significantly impaired in Sz and showed significant correlations with motor-related and working memory measures as well as global function. Source-space time-frequency decomposition of EEG showed beta-band coherence across supplementary-motor, primary-motor and visual cortex forming a network involved in SRTT performance. Motor-cathodal and visual-cathodal stimulations resulted in significant modulation in coherence particularly across the motor-visual nodes of the network accompanied by significant improvement in motor learning in both controls and patients. Here, we confirm earlier reports of SRTT impairment in Sz and demonstrate significant reversal of the deficits with tDCS. The findings support continued development of tDCS for enhancement of plasticity-based interventions in Sz, as well as source-space EEG analytic approaches for evaluating underlying neural mechanisms.

Bottom-up and top-down contributions to impaired motion processing in schizophrenia.

Background and Hypothesis: Motion processing deficits in schizophrenia have been linked to impairments in higher-order social-cognitive processes. The neural underpinnings are not fully understood but it has been hypothesized that middle temporal area (MT+) may serve as a bridge between purely sensory and more cognitive proceseses. We investigated the interrelationship between MT+ sensory processing deficits and impairments in higher-order processing using naturalistic videos with explicit motion and static images with implied-motion cues. Study Design: Functional magnetic resonance imaging was used to evaluate cortical and subcortical brain regions associated with real- and implied-motion processing in 28 individuals with schizophrenia and 20 neurotypical controls. These measures were related to face emotion recognition and motion-perception deficits, as measured behaviorally. Study Results: Activation of MT+ was abnormal in schizophrenia during both real- and implied-motion processing. Dysfunction of early visual cortex and pulvinar were also associated with impaired real-motion processing. During implied-motion-perception, MT+ participated in a wider network involving sensorimotor and prefrontal nodes of the human mirror neuron system, known to play a role in social-cognitive processes. Perception of both real- and implied-motion engaged the posterior superior temporal sulcus, a key node of the social brain network. Conclusions: The findings support concepts of MT+ as a bridge between visual sensory areas and higher-order brain regions especially in relationship to face emotion recognition and social cognition. Our data argue for greater focus on MT+ contributions to social-cognitive processing, in addition to its well-documented role in visual motion processing.

The Road Not Taken: Disconnection of a Human-Unique Cortical Pathway Underlying Naturalistic Social Perception in Schizophrenia.

Background: Efficient processing of complex and dynamic social scenes relies on intact connectivity of many underlying cortical areas and networks, but how connectivity anomalies affect the neural substrates of social perception remains unknown. Here we measured these relationships using functionally based localization of social perception areas, resting-state functional connectivity, and movie-watching data. Methods: In 42 participants with schizophrenia (SzPs) and 41 healthy control subjects, we measured the functional connectivity of areas localized by face-emotion processing, theory-of-mind (ToM), and attention tasks. We quantified the weighted shortest path length between visual and medial prefrontal ToM areas in both populations to assess the impact of these changes in functional connectivity on network structure. We then correlated connectivity along the shortest path in each group with movie-evoked activity in a key node of the ToM network (posterior temporoparietal junction [TPJp]). Results: SzPs had pronounced decreases in connectivity in TPJ/posterior superior temporal sulcus (TPJ-pSTS) areas involved in face-emotion processing (t81 = 4.4, p = .00002). In healthy control subjects, the shortest path connecting visual and medial prefrontal ToM areas passed through TPJ-pSTS, whereas in SzPs, the shortest path passed through the prefrontal cortex. While movie-evoked TPJp activity correlated with connectivity along the TPJ-pSTS pathway in both groups (r = 0.43, p = .002), it additionally correlated with connectivity along the prefrontal cortex pathway only in SzPs (rSzP = 0.56, p = .003). Conclusions: These results suggest that connectivity along the human-unique TPJ-pSTS pathway affects both the network architecture and functioning of areas involved in processing complex dynamic social scenes. These results demonstrate how focal connectivity anomalies can have widespread impacts across the cortex.

Network-level mechanisms underlying effects of transcranial direct current stimulation (tDCS) on visuomotor learning impairments in schizophrenia.

Motor learning is a fundamental skill to our daily lives. Dysfunction in motor performance in schizophrenia (Sz) is associated with poor social and functional outcomes, but nevertheless remains understudied relative to other neurocognitive domains. Moreover, transcranial direct current stimulation (tDCS) can influence underlying brain function in Sz and may be especially useful in enhancing local cortical plasticity, but underlying neural mechanisms remain incompletely understood. Here, we evaluated performance of Sz individuals on the Serial Reaction Time Task (SRTT), which has been extensively used in prior tDCS research, in combination with concurrent tDCS and EEG source localization first to evaluate the integrity of visuomotor learning in Sz relative to other cognitive domains and second to investigate underlying neural mechanisms. Twenty-seven individuals with Sz and 21 healthy controls (HC) performed the SRTT task as they received sham or active tDCS and simultaneous EEG recording. Measures of motor, neuropsychological and global functioning were also assessed. Impaired SRTT performance correlated significantly with deficits in motor performance, working memory, and global functioning. Time-frequency ("Beamformer") EEG source localization showed beta-band coherence across supplementary-motor, primary-motor and visual cortex regions, with reduced visuomotor coherence in Sz relative to HC. Cathodal tDCS targeting both visual and motor regions resulted in significant modulation in coherence particularly across the motor-visual nodes of the network accompanied by significant improvement in motor learning in both controls and patients. Overall, these findings demonstrate the utility of the SRTT to study mechanisms of visuomotor impairment in Sz and demonstrate significant tDCS effects on both learning and connectivity when applied over either visual or motor regions. The findings support continued study of dysfunctional dorsal-stream visual connectivity and motor plasticity as components of cognitive impairment in Sz, of local tDCS administration for enhancement of plasticity, and of source-space EEG-based biomarkers for evaluation of underlying neural mechanisms.

Disruption of early visual processing in amyloid-positive healthy individuals and mild cognitive impairment.

BACKGROUND: Amyloid deposition is a primary predictor of Alzheimer's disease (AD) and related neurodegenerative disorders. Retinal changes involving the structure and function of the ganglion cell layer are increasingly documented in both established and prodromal AD. Visual event-related potentials (vERP) are sensitive to dysfunction in the magno- and parvocellular visual systems, which originate within the retinal ganglion cell layer. The present study evaluates vERP as a function of amyloid deposition in aging, and in mild cognitive impairment (MCI). METHODS: vERP to stimulus-onset, motion-onset, and alpha-frequency steady-state (ssVEP) stimuli were obtained from 16 amyloid-positive and 41 amyloid-negative healthy elders and 15 MCI individuals and analyzed using time-frequency approaches. Social cognition was assessed in a subset of individuals using The Awareness of Social Inference Test (TASIT). RESULTS: Neurocognitively intact but amyloid-positive participants and MCI individuals showed significant deficits in stimulus-onset (theta) and motion-onset (delta) vERP generation relative to amyloid-negative participants (all p < .01). Across healthy elders, a composite index of these measures correlated highly (r = - .52, p < .001) with amyloid standardized uptake value ratios (SUVR) and TASIT performance. A composite index composed of vERP measures significant differentiated amyloid-positive and amyloid-negative groups with an overall classification accuracy of > 70%. DISCUSSION: vERP may assist in the early detection of amyloid deposition among older individuals without observable neurocognitive impairments and in linking previously documented retinal deficits in both prodromal AD and MCI to behavioral impairments in social cognition.

Early auditory processing dysfunction in schizophrenia: Mechanisms and implications.

Schizophrenia is a major mental disorder that affects approximately 1% of the population worldwide. Cognitive deficits are a key feature of the disorder and a primary cause of long-term disability. Over the past decades, significant literature has accumulated demonstrating impairments in early auditory perceptual processes in schizophrenia. In this review, we first describe early auditory dysfunction in schizophrenia from both a behavioral and neurophysiological perspective and examine their interrelationship with both higher order cognitive constructs and social cognitive processes. Then, we provide insights into underlying pathological processes, especially in relationship to glutamatergic and N-methyl-D-aspartate receptor (NMDAR) dysfunction models. Finally, we discuss the utility of early auditory measures as both treatment targets for precision intervention and as translational biomarkers for etiological investigation. Altogether, this review points out the crucial role of early auditory deficits in the pathophysiology of schizophrenia, in addition to major implications for early intervention and auditory-targeted approaches.

Failure to engage the temporoparietal junction/posterior superior temporal sulcus predicts impaired naturalistic social cognition in schizophrenia.

Schizophrenia is associated with marked impairments in social cognition. However, the neural correlates of these deficits remain unclear. Here we use naturalistic stimuli to examine the role of the right temporoparietal junction/posterior superior temporal sulcus (TPJ-pSTS)-an integrative hub for the cortical networks pertinent to the understanding complex social situations-in social inference, a key component of social cognition, in schizophrenia. Twenty-seven schizophrenia participants and 21 healthy control subjects watched a clip of the film The Good, the Bad and the Ugly while high resolution multiband functional MRI images were collected. We used inter-subject correlation to measure the evoked activity, which we then compared to social cognition as measured by The Awareness of Social Inference Test (TASIT). We also compared between groups the TPJ-pSTS blood oxygen level-dependent activity (i) relationship with the motion content in the film; (ii) synchronization with other cortical areas involved in the viewing of the movie; and (iii) relationship with the frequency of saccades made during the movie. Activation deficits were greatest in middle TPJ (TPJm) and correlated significantly with impaired TASIT performance across groups. Follow-up analyses of the TPJ-pSTS revealed decreased synchronization with other cortical areas, decreased correlation with the motion content of the movie, and decreased correlation with the saccades made during the movie. The functional impairment of the TPJm, a hub area in the middle of the TPJ-pSTS, predicts deficits in social inference in schizophrenia participants by disrupting the integration of visual motion processing into the TPJ. This disrupted integration then affects the use of the TPJ to guide saccades during the visual scanning of the movie clip. These findings suggest that the TPJ may be a treatment target for improving deficits in a key component of social cognition in schizophrenia participants.

Disease-Specific Contribution of Pulvinar Dysfunction to Impaired Emotion Recognition in Schizophrenia.

One important aspect for managing social interactions is the ability to perceive and respond to facial expressions rapidly and accurately. This ability is highly dependent upon intact processing within both cortical and subcortical components of the early visual pathways. Social cognitive deficits, including face emotion recognition (FER) deficits, are characteristic of several neuropsychiatric disorders including schizophrenia (Sz) and autism spectrum disorders (ASD). Here, we investigated potential visual sensory contributions to FER deficits in Sz (n = 28, 8/20 female/male; age 21-54 years) and adult ASD (n = 20, 4/16 female/male; age 19-43 years) participants compared to neurotypical (n = 30, 8/22 female/male; age 19-54 years) controls using task-based fMRI during an implicit static/dynamic FER task. Compared to neurotypical controls, both Sz (d = 1.97) and ASD (d = 1.13) participants had significantly lower FER scores which interrelated with diminished activation of the superior temporal sulcus (STS). In Sz, STS deficits were predicted by reduced activation of early visual regions (d = 0.85, p = 0.002) and of the pulvinar nucleus of the thalamus (d = 0.44, p = 0.042), along with impaired cortico-pulvinar interaction. By contrast, ASD participants showed patterns of increased early visual cortical (d = 1.03, p = 0.001) and pulvinar (d = 0.71, p = 0.015) activation. Large effect-size structural and histological abnormalities of pulvinar have previously been documented in Sz. Moreover, we have recently demonstrated impaired pulvinar activation to simple visual stimuli in Sz. Here, we provide the first demonstration of a disease-specific contribution of impaired pulvinar activation to social cognitive impairment in Sz.

What you see is what you get: visual scanning failures of naturalistic social scenes in schizophrenia.

BACKGROUND: Impairments in social cognition contribute significantly to disability in schizophrenia patients (SzP). Perception of facial expressions is critical for social cognition. Intact perception requires an individual to visually scan a complex dynamic social scene for transiently moving facial expressions that may be relevant for understanding the scene. The relationship of visual scanning for these facial expressions and social cognition remains unknown. METHODS: In 39 SzP and 27 healthy controls (HC), we used eye-tracking to examine the relationship between performance on The Awareness of Social Inference Test (TASIT), which tests social cognition using naturalistic video clips of social situations, and visual scanning, measuring each individual's relative to the mean of HC. We then examined the relationship of visual scanning to the specific visual features (motion, contrast, luminance, faces) within the video clips. RESULTS: TASIT performance was significantly impaired in SzP for trials involving sarcasm (p < 10-5). Visual scanning was significantly more variable in SzP than HC (p < 10-6), and predicted TASIT performance in HC (p = 0.02) but not SzP (p = 0.91), differing significantly between groups (p = 0.04). During the visual scanning, SzP were less likely to be viewing faces (p = 0.0001) and less likely to saccade to facial motion in peripheral vision (p = 0.008). CONCLUSIONS: SzP show highly significant deficits in the use of visual scanning of naturalistic social scenes to inform social cognition. Alterations in visual scanning patterns may originate from impaired processing of facial motion within peripheral vision. Overall, these results highlight the utility of naturalistic stimuli in the study of social cognition deficits in schizophrenia.

Neurophysiological, Oculomotor, and Computational Modeling of Impaired Reading Ability in Schizophrenia.

Schizophrenia (Sz) is associated with deficits in fluent reading ability that compromise functional outcomes. Here, we utilize a combined eye-tracking, neurophysiological, and computational modeling approach to analyze underlying visual and oculomotor processes. Subjects included 26 Sz patients (SzP) and 26 healthy controls. Eye-tracking and electroencephalography data were acquired continuously during the reading of passages from the Gray Oral Reading Tests reading battery, permitting between-group evaluation of both oculomotor activity and fixation-related potentials (FRP). Schizophrenia patients showed a marked increase in time required per word (d = 1.3, P < .0001), reflecting both a moderate increase in fixation duration (d = .7, P = .026) and a large increase in the total saccade number (d = 1.6, P < .0001). Simulation models that incorporated alterations in both lower-level visual and oculomotor function as well as higher-level lexical processing performed better than models that assumed either deficit-type alone. In neurophysiological analyses, amplitude of the fixation-related P1 potential (P1f) was significantly reduced in SzP (d = .66, P = .013), reflecting reduced phase reset of ongoing theta-alpha band activity (d = .74, P = .019). In turn, P1f deficits significantly predicted increased saccade number both across groups (P = .017) and within SzP alone (P = .042). Computational and neurophysiological methods provide increasingly important approaches for investigating sensory contributions to impaired cognition during naturalistic processing in Sz. Here, we demonstrate deficits in reading rate that reflect both sensory/oculomotor- and semantic-level impairments and that manifest, respectively, as alterations in saccade number and fixation duration. Impaired P1f generation reflects impaired fixation-related reset of ongoing brain rhythms and suggests inefficient information processing within the early visual system as a basis for oculomotor dyscontrol during fluent reading in Sz.

Multimodal Computational Modeling of Visual Object Recognition Deficits but Intact Repetition Priming in Schizophrenia.

The term perceptual closure refers to the neural processes responsible for "filling-in" missing information in the visual image under highly adverse viewing conditions such as fog or camouflage. Here we used a closure task that required the participants to identify barely recognizable fragmented line-drawings of common objects. Patients with schizophrenia have been shown to perform poorly on this task. Following priming, controls and importantly patients can complete the line-drawings at greater levels of fragmentation behaviorally, suggesting an improvement in their ability to perform the task. Closure phenomena have been shown to involve a distributed network of cortical regions, notably the lateral occipital complex (LOC) of the ventral visual stream, dorsal visual stream (DS), hippocampal formation (HIPP) and the prefrontal cortex (PFC). We have previously demonstrated the failure of closure processes in schizophrenia and shown that the dysregulation in the sensory information transmitted to the prefrontal cortex plays a critical role in this failure. Here, using a multimodal imaging approach in patients, combining event related electrophysiological recordings (ERP) and functional magnetic resonance imaging (fMRI), we characterize the spatiotemporal dynamics of priming in perceptual closure. Using directed functional connectivity measures we demonstrate that priming modifies the network-level interactions between the nodes of closure processing in a manner that is functionally advantageous to patients resulting in the mitigation of their deficit in perceptual closure.

Network-level mechanisms underlying effects of transcranial direct current stimulation (tDCS) on visuomotor learning.

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation approach in which low level currents are administered over the scalp to influence underlying brain function. Prevailing theories of tDCS focus on modulation of excitation-inhibition balance at the local stimulation location. However, network level effects are reported as well, and appear to depend upon differential underlying mechanisms. Here, we evaluated potential network-level effects of tDCS during the Serial Reaction Time Task (SRTT) using convergent EEG- and fMRI-based connectivity approaches. Motor learning manifested as a significant (p<.0001) shift from slow to fast responses and corresponded to a significant increase in beta-coherence (p<.0001) and fMRI connectivity (p<.01) particularly within the visual-motor pathway. Differential patterns of tDCS effect were observed within different parametric task versions, consistent with network models. Overall, these findings demonstrate objective physiological effects of tDCS at the network level that result in effective behavioral modulation when tDCS parameters are matched to network-level requirements of the underlying task.

A roadmap for development of neuro-oscillations as translational biomarkers for treatment development in neuropsychopharmacology.

New treatment development for psychiatric disorders depends critically upon the development of physiological measures that can accurately translate between preclinical animal models and clinical human studies. Such measures can be used both as stratification biomarkers to define pathophysiologically homogeneous patient populations and as target engagement biomarkers to verify similarity of effects across preclinical and clinical intervention. Traditional "time-domain" event-related potentials (ERP) have been used translationally to date but are limited by the significant differences in timing and distribution across rodent, monkey and human studies. By contrast, neuro-oscillatory responses, analyzed within the "time-frequency" domain, are relatively preserved across species permitting more precise translational comparisons. Moreover, neuro-oscillatory responses are increasingly being mapped to local circuit mechanisms and may be useful for investigating effects of both pharmacological and neuromodulatory interventions on excitatory/inhibitory balance. The present paper provides a roadmap for development of neuro-oscillatory responses as translational biomarkers in neuropsychiatric treatment development.

Impaired Fixation-Related Theta Modulation Predicts Reduced Visual Span and Guided Search Deficits in Schizophrenia.

During normal visual behavior, individuals scan the environment through a series of saccades and fixations. At each fixation, the phase of ongoing rhythmic neural oscillations is reset, thereby increasing efficiency of subsequent visual processing. This phase-reset is reflected in the generation of a fixation-related potential (FRP). Here, we evaluate the integrity of theta phase-reset/FRP generation and Guided Visual Search task in schizophrenia. Subjects performed serial and parallel versions of the task. An initial study (15 healthy controls (HC)/15 schizophrenia patients (SCZ)) investigated behavioral performance parametrically across stimulus features and set-sizes. A subsequent study (25-HC/25-SCZ) evaluated integrity of search-related FRP generation relative to search performance and evaluated visual span size as an index of parafoveal processing. Search times were significantly increased for patients versus controls across all conditions. Furthermore, significantly, deficits were observed for fixation-related theta phase-reset across conditions, that fully predicted impaired reduced visual span and search performance and correlated with impaired visual components of neurocognitive processing. By contrast, overall search strategy was similar between groups. Deficits in theta phase-reset mechanisms are increasingly documented across sensory modalities in schizophrenia. Here, we demonstrate that deficits in fixation-related theta phase-reset during naturalistic visual processing underlie impaired efficiency of early visual function in schizophrenia.

Deficits in Pre-attentive Processing of Spatial Location and Negative Symptoms in Subjects at Clinical High Risk for Schizophrenia.

Deficits in mismatch negativity (MMN) generation are among the best-established biomarkers for cognitive dysfunction in schizophrenia and predict conversion to schizophrenia (Sz) among individuals at symptomatic clinical high risk (CHR). Impairments in MMN index dysfunction at both subcortical and cortical components of the early auditory system. To date, the large majority of studies have been conducted using deviants that differ from preceding standards in either tonal frequency (pitch) or duration. By contrast, MMN to sound location deviation has been studied to only a limited degree in Sz and has not previously been examined in CHR populations. Here, we evaluated location MMN across Sz and CHR using an optimized, multi-deviant pattern that included a location-deviant, as defined using interaural time delay (ITD) stimuli along with pitch, duration, frequency modulation (FM) and intensity deviants in a sample of 42 Sz, 33 CHR and 28 healthy control (HC) subjects. In addition, we obtained resting state functional connectivity (rsfMRI) on CHR subjects. Sz showed impaired MMN performance across all deviant types, along with strong correlation between MMN deficits and impaired neurocognitive function. In this sample of largely non-converting CHR subjects, no deficits were observed in either pitch or duration MMN. By contrast, CHR subjects showed significant impairments in location MMN generation particularly over right hemisphere and significant correlation between impaired location MMN and negative symptoms including deterioration of role function. In addition, significant correlations were observed between location MMN and rsfMRI involving brainstem circuits. In general, location detection using ITD stimuli depends upon precise processing within midbrain regions and provides a rapid and robust reorientation of attention. Present findings reinforce the utility of MMN as a pre-attentive index of auditory cognitive dysfunction in Sz and suggest that location MMN may index brain circuits distinct from those indexed by other deviant types.

Neural and functional correlates of impaired reading ability in schizophrenia.

Deficits in early auditory processing (EAP) are a core component of schizophrenia (SZ) and contribute significantly to impaired overall function. Here, we evaluate the potential contributions of EAP-related impairments in reading to functional capacity and outcome, relative to effects of auditory social cognitive and general neurocognitive dysfunction. Participants included 30-SZ and 28-controls of similar age, sex, and educational achievement. EAP was assessed using an auditory working memory (tone-matching) task. Phonological processing and reading Fluency were assessed using the Comprehensive Test of Phonological Processing and Woodcock-Johnson reading batteries, respectively. Auditory-related social cognition was assessed using measures of emotion/sarcasm recognition. Functional capacity and outcome were assessed using the UCSD Performance-based Skills Assessment and Specific Level of Functioning scale, respectively. fMRI resting-state functional-connectivity (rsFC) was used to evaluate potential underlying substrates. As predicted, SZ patients showed significant and interrelated deficits in both phonological processing (d = 0.74, p = 0.009) and reading fluency (d = 1.24, p < 0.00005). By contrast, single word reading (d = 0.35, p = 0.31) was intact. In SZ, deficits in EAP and phonological reading ability significantly predicted reduced functional capacity, but not functional outcome. By contrast, deficits in reading fluency significantly predicted impairments in both functional capacity and functional outcome. Moreover, deficits in reading fluency correlated with rsFC alterations among auditory thalamus, early auditory and auditory association regions. These findings indicate significant contributions of EAP deficits and functional connectivity changes in subcortical and early auditory regions to reductions in reading fluency, and of impaired reading ability to impaired functional outcome in SZ.

Bimodal distribution of tone-matching deficits indicates discrete pathophysiological entities within the syndrome of schizophrenia.

To date, no measures are available that permit differentiation of discrete, clinically distinct subtypes of schizophrenia (SZ) with potential differential underlying pathophysiologies. Over recent years, there has been increasing recognition that SZ is heterogeneously associated with deficits in early auditory processing (EAP), as demonstrated using clinically applicable tasks such as tone-matching task (TMT). Here, we pooled TMT performances across 310 SZ individuals and 219 healthy controls (HC), along with clinical, cognitive, and resting-state functional-connectivity MRI (rsFC-MRI) measures. In addition, TMT was measured in a group of 24 patients at symptomatic clinical high risk (CHR) for SZ and 24 age-matched HC (age range 7-27 years). We provide the first demonstration that the EAP deficits are bimodally distributed across SZ subjects (P < 0.0001 vs. unimodal distribution), with one group showing entirely unimpaired TMT performance (SZ-EAP+), and a second showing an extremely large TMT impairment (SZ-EAP-), relative to both controls (d = 2.1) and SZ-EAP+ patients (d = 3.4). The SZ-EAP- group predominated among samples drawn from inpatient sites, showed higher levels of cognitive symptoms (PANSS), worse social cognition and a differential deficit in neurocognition (MATRICS battery), and reduced functional capacity. rsFC-MRI analyses showed significant reduction in SZ-EAP- relative to controls between subcortical and cortical auditory regions. As opposed to SZ, CHR patients showed intact EAP function. In HC age-matched to CHR, EAP ability was shown to increase across the age range of vulnerability preceding SZ onset. These results indicate that EAP measure segregates between discrete SZ subgroups. As TMT can be readily implemented within routine clinical settings, its use may be critical to account for the heterogeneity of clinical outcomes currently observed across SZ patients, as well as for pre-clinical detection and efficacious treatment selection.

Differential Patterns of Visual Sensory Alteration Underlying Face Emotion Recognition Impairment and Motion Perception Deficits in Schizophrenia and Autism Spectrum Disorder.

BACKGROUND: Impaired face emotion recognition (FER) and abnormal motion processing are core features in schizophrenia (SZ) and autism spectrum disorder (ASD) that have been linked to atypical activity within the visual cortex. Despite overlaps, only a few studies have directly explored convergent versus divergent neural mechanisms of altered visual processing in ASD and SZ. We employed a multimodal imaging approach to evaluate FER and motion perception in relation to functioning of subcortical and cortical visual regions. METHODS: Subjects were 20 high-functioning adults with ASD, 19 patients with SZ, and 17 control participants. Behavioral measures of coherent motion sensitivity and FER along with electrophysiological and functional magnetic resonance imaging measures of visual pattern and motion processing were obtained. Resting-state functional magnetic resonance imaging was used to assess the relationship between corticocortical and thalamocortical connectivity and atypical visual processing. RESULTS: SZ and ASD participants had intercorrelated deficits in FER and motion sensitivity. In both groups, reduced motion sensitivity was associated with reduced functional magnetic resonance imaging activation in the occipitotemporal cortex and lower delta-band electroencephalogram power. In ASD, FER deficits correlated with hyperactivation of dorsal stream regions and increased evoked theta power. Activation of the pulvinar correlated with abnormal alpha-band modulation in SZ and ASD with under- and overmodulation, respectively, predicting increased clinical symptoms in both groups. CONCLUSIONS: SZ and ASD participants showed equivalent deficits in FER and motion sensitivity but markedly different profiles of physiological dysfunction. The specific pattern of deficits observed in each group may help guide development of treatments designed to downregulate versus upregulate visual processing within the respective clinical groups.

Early psychosis detection program in Chile: A first step for the South American challenge in psychosis research.

AIM: Early detection and intervention (EDI) is a main challenge in psychosis research. The Chilean schizophrenia (SZ) national program has universal support and treatment by law for all SZ patients, but this does not yet extend to earlier stages of illness. Therefore, we have piloted an ultra-high risk (UHR) program to demonstrate the utility and feasibility of this public health approach in Chile. METHODS: We introduce "The University of Chile High-risk Intervention Program," which is the first national EDI program for UHR youths. Longitudinal follow-up included clinical and cognitive assessments, and monitoring of physiological sensory and cognitive indices, through electroencephalographic techniques. RESULTS: We recruited 27 UHR youths over 2 years. About 92.6% met criteria for attenuated psychosis syndrome (APS). Mean Scale of Psychosis-Risk Symptoms (SOPS) ratings in the cohort were 6.9 (SD 4.6) for positive, 9.1 (SD 8.3) for negative, 5.4 (SD 5.3) for disorganized and 6.3 (SD 4.1) for general symptoms. About 14.8% met criteria for comorbid anxiety disorders and 44.4% for mood disorders. Most participants received cognitive behavioural therapy (62.9%) and were prescribed low dose antipsychotics (85.2%). The transition rate to psychosis was 22% within 2 years. CONCLUSIONS: We describe our experience in establishing the first EDI program for UHR subjects in Chile. Our cohort is similar in profile and risk to those identified in higher-income countries. We will extend our work to further optimize psychosocial and preventive interventions, to promote its inclusion in the Chilean SZ national program and to establish a South American collaboration network for SZ research.