BackgroundSchizophrenia (Sz) and autism spectrum disorder (ASD) are associated with reduced accuracy offace emotion recognition (FER). Nevertheless, the underlying pathophysiological mechanisms may diverge, potentially related to differential processing patterns within the early visual system. Here, we investigated physiological-level responses to emotional faces. We hypothesized that Sz and ASD would be associated with convergent behavioral performance, but divergent pathophysiological mechanisms.Study designSimultaneous eye-tracking and continuous EEG data were obtained from 23 adults diagnosed with schizophrenia (Sz), 21 autistic adults, and 24 neurotypical controls (NC) in response to intact and chimeric emotion faces. Event-related potentials (ERP) were calculated from the ongoing EEG data using time- and time-frequency (TF) domain approaches. Symptoms were rated using the Positive and Negative Symptom Scale (PANSS) and the Autism Diagnostic Observation Schedule, Second Edition (ADOS-2) in Sz and ASD, respectively.Study resultsAs predicted, Sz and ASD were associated with similar levels of reduced FER accuracy relative to NC, but differential patterns of eye tracking and EEG-related activity. Rates of eye- vs. mouth-fixations were reduced across groups but did not correlate with FER. Nevertheless, the ability to utilize eye-information diverged across groups. Thus, when viewing chimeric faces, Sz was associated with reduced tendency to utilize eye information and increased tendency to utilize mouth information even when fixation location was considered. In TF analyses, reduced FER accuracy was associated with reduced initial sensory responses in Sz, as reflected in the theta-band time-frequency response. In contrast, in ASD, reduced FER accuracy was associated with increased alpha-frequency event-related desynchronization (alpha-ERD) consistent with hyper-engagement of secondary visual regions (V2). A combination of physiological and eye-tracking measures differentiated schizophrenia and ASD with >90% accuracy. V2 hyper-engagement in ASD correlated with both reduced FER accuracy and ADOS Social Interaction domain scores.ConclusionSchizophrenia and ASD are associated with divergent physiological-level alterations within the early visual system during emotional face processing, supporting models of magnocellular visual hypoactivity in schizophrenia but retinotectal visual hyperactivity leading to hyper-engagement of non-face regions (V2) by face stimuli in ASD. These alterations, in turn, may serve as targets for future intervention studies related to social cognition.

BackgroundThe human subcortical visual system is divided into distinct magnocellular, parvocellular and koniocellular pathways, which contribute differentially to specific aspects of early visual processing. Schizophrenia is associated with deficits in early-visual processing, especially involving N-methyl-D-aspartate receptor (NMDAR)-mediated non-linear gain within the subcortical magnocellular visual system. Nevertheless, methods for investigating the pathophysiological consequences remain limited. Flash-VEP can be obtained using either transient (tVEP) or steady-state (ssVEP) approaches. Flash stimuli also induce sustained reduction (“blocking”) of the posterior alpha rhythm. Red (vs. white) flash stimuli selectively suppress activity in magnocellular-recipient layers of primary visual cortex. Here, we investigated flash-VEP responses in schizophrenia, with emphasis on the potential utility for assessing selective pathophysiological involvement of the magnocellular and koniocellular pathways.MethodsWe obtained flash-VEP from 28 healthy control and 27 schizophrenia participants to white and red stimuli across a range of stimulation rates, and pattern-VEP from 29 control and 22 schizophrenia participants. A subset (17 control/15 schizophrenia) participated in both studies. We also obtained fMRI to 6-Hz white and red stimuli in an additional sample of 14 control and 14 schizophrenia participants. fMRI analyses focused on both visual cortex and inferior pulvinar nucleus.ResultsSchizophrenia participants showed increased flash-tVEP responses (d = 0.99, p < 0.001) despite significantly reduced pattern-tVEP (d = −0.99, p < 0.001). In addition, the ssVEP (photic driving) response was significantly reduced in schizophrenia, as reflected by reduced intertrial trial coherence (ITC) within the alpha frequency band (d = −0.78, p < 0.001). Alpha blocking was induced equivalently by white and red stimuli in HC, suggesting magnocellular involvement via the retinotectal system. The degree of blocking was significantly reduced in schizophrenia (d = −0.83, p = 0.003) and correlated significantly with neurocognitive impairment (rp = 0.65, p < 0.001). fMRI studies showed reduced pulvinar activation (d = −1.1, p = 0.008), along with aberrantly increased dorsal cortical activation (d = 0.98, p = 0.019).ConclusionThe findings reinforce the importance of subcortical visual dysfunction as a driver of impaired neurocognition in schizophrenia and provide a scalable mechanism for assessment of early-visual dysfunction within the clinical setting. Deficit patterns are consistent with concepts of impaired magnocellular and koniocellular visual function affecting both thalamocortical and retinotectal system function in schizophrenia.

We present a method for spatially resolving the electric field potential throughout the entire volume of the human brain from electroencephalography (EEG) data. The method is not a variation of the well-known 'source reconstruction' methods, but rather a direct solution to the EEG inverse problem based on our recently developed model for brain waves that demonstrates the inadequacy of the standard 'quasi-static approximation' that has fostered the belief that such a reconstruction is not physically possible. The method retains the high temporal/frequency resolution of EEG yet has spatial resolution comparable to (or better than) functional MRI (fMRI), without its significant inherent limitations. The method is validated using simultaneous EEG/fMRI data in healthy subjects, intracranial EEG data in epilepsy patients, comparison with numerical simulations, and a direct comparison with standard state-of-the-art EEG analysis in a well-established attention paradigm. The method is then demonstrated on a very large cohort of subjects performing a standard gambling task designed to activate the brain's 'reward circuit'. The technique uses the output from standard extant EEG systems and thus has potential for immediate benefit to a broad range of important basic scientific and clinical questions concerning brain electrical activity. By offering an inexpensive and portable alternative to fMRI, it provides a realistic methodology to efficiently promote the democratization of medicine.

The human visual system begins in the retina and projects to cortex through both the thalamocortical and retinotectal visual pathways. The thalamocortical system is divided into separate magnocellular and parvocellular divisions, which engage separate layers of the lateral geniculate nucleus (LGN) and project preferentially to the dorsal and ventral visual streams, respectively. The retinotectal system, in contrast, projects to the superior colliculus, pulvinar nucleus of the thalamus and amygdala. The pulvinar nucleus also plays a critical role in the integration of information processing across early visual regions.The functions of the visual system can be assessed using convergent EEG- and functional brain imaging approaches, increasingly supplemented by simultaneously collected eye-tracking information. These approaches may be used for tracing the flow of information from retina through early visual regions, as well as the contribution of these regions to higher-order cognitive processing. A pathway of increasing interest in relationship to neuropsychiatric disorders is the primate-specific "third visual pathway" that relies extensively on motion-related input and contributes preferentially to social information processing. Thus, disturbances in the brain's responsiveness to motion stimuli may be especially useful as biomarkers for early visual dysfunction related to impaired social cognition.Visual event-related potentials (ERPs) can be collected with high-fidelity and have proven effective for the study of neuropsychiatric disorders such as schizophrenia and Alzheimer's disease, in which alterations in visual processing may occur early in the disorder, andautism-spectrum disorder (ASD), in which abnormal persistence of early childhood patterns may persist into adulthood, leading to impaired functioning of visual social pathways. The utility of visual ERPs as biomarkers for larger clinical studies is limited at present by the need for standardization of visual stimuli across laboratories, which requires specialized protocols and equipment. The development of optimized stimulation protocols as well as newer headset-based systems may increase the clinical utility of present stimulation approaches.

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.

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.

Background Efficient processing of complex and dynamic social scenes relies on intact connectivity of many underlying cortical areas and networks, but how connectivity deficits affect this functioning in social cognition remains unknown. Here we measure these relationships using functionally based localization of social cognition areas, resting-state functional connectivity, and movie-watching data. Methods In 42 schizophrenia participants (SzP) and 41 healthy controls (HC), we measured the functional connectivity of areas localized by face-emotion processing, theory-of-mind, and attention tasks. We quantified the weighted shortest path length between visual and medial prefrontal theory-of-mind areas in both populations to assess the impact of functional connectivity deficits on network structure. We then correlated connectivity along the shortest path in each group with movie-evoked activity in a key node of the theory-of-mind network (TPJp). Results SzP had pronounced connectivity deficits in temporoparietal junction/posterior superior temporal sulcus (TPJ-pSTS) areas involved in face-emotion processing (t(81)=4.4, p=0.00002). In HC the shortest path connecting visual and medial prefrontal theory-of-mind areas passed through TPJ-pSTS, whereas in SzP the shortest path passed through prefrontal cortex (PFC). While movie-evoked TPJp activity correlated with connectivity along the TPJ-pSTS pathway in both groups (r=0.43, p=0.002), it additionally correlated with connectivity along the PFC pathway only in SzP (r SzP =0.56, p=0.003). Conclusions 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 deficits can have widespread impacts across cortex.

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.

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.

Transcranial Direct Current Stimulation (tDCS) is a non-invasive brain stimulation approach in which low level currents are applied across the scalp to influence brain function (rev. in1). tDCS and other non-invasive brain stimulation approaches have the potential to increase plasticity and enhance cortical function2, enhance neurorehabilitation3, and reverse deficits in neuropsychiatric disorders such as schizophrenia4. While most studies have focused on its effects on local excitability (for discussion see5), more recent studies have focused on network-level effects across cortical regions6. Here, we used the high temporal resolution of EEG combined with a well-studied (rev. in7) visuo-motor learning paradigm – the serial reaction time task (SRTT) - to investigate cortical network mechanisms underlying tDCS effects in patients with schizophrenia.

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.

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.

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.

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.