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.

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.

Seeing the World as it is: Mimicking Veridical Motion Perception in Schizophrenia Using Non-invasive Brain Stimulation in Healthy Participants.

Schizophrenia (Sz) is a mental health disorder characterized by severe cognitive, emotional, social, and perceptual deficits. Visual deficits are found in tasks relying on the magnocellular/dorsal stream. In our first experiment we established deficits in global motion processing in Sz patients compared to healthy controls. We used a novel task in which background optic flow produces a distortion of the apparent trajectory of a moving stimulus, leading control participants to provide biased estimates of the true motion trajectory under conditions of global stimulation. Sz patients were significantly less affected by the global background motion, and reported trajectories that were more veridically accurate than those of controls. In order to study the mechanism of this effect, we performed a second experiment where we applied transcranial electrical stimulation over area MT+ to selectively modify global motion processing of optic flow displays in healthy participants. Cathodal and high frequency random noise stimulation had opposite effects on trajectory perception in optic flow. The brain stimulation over a control site and in a control task revealed that the effect of stimulation was specific for global motion processing in area MT+. These findings both support prior studies of impaired early visual processing in Sz and provide novel approaches for measurement and manipulation of the underlying circuits.

Neural Substrates of Auditory Emotion Recognition Deficits in Schizophrenia.

Deficits in auditory emotion recognition (AER) are a core feature of schizophrenia and a key component of social cognitive impairment. AER deficits are tied behaviorally to impaired ability to interpret tonal ("prosodic") features of speech that normally convey emotion, such as modulations in base pitch (F0M) and pitch variability (F0SD). These modulations can be recreated using synthetic frequency modulated (FM) tones that mimic the prosodic contours of specific emotional stimuli. The present study investigates neural mechanisms underlying impaired AER using a combined event-related potential/resting-state functional connectivity (rsfMRI) approach in 84 schizophrenia/schizoaffective disorder patients and 66 healthy comparison subjects. Mismatch negativity (MMN) to FM tones was assessed in 43 patients/36 controls. rsfMRI between auditory cortex and medial temporal (insula) regions was assessed in 55 patients/51 controls. The relationship between AER, MMN to FM tones, and rsfMRI was assessed in the subset who performed all assessments (14 patients, 21 controls). As predicted, patients showed robust reductions in MMN across FM stimulus type (p = 0.005), particularly to modulations in F0M, along with impairments in AER and FM tone discrimination. MMN source analysis indicated dipoles in both auditory cortex and anterior insula, whereas rsfMRI analyses showed reduced auditory-insula connectivity. MMN to FM tones and functional connectivity together accounted for ∼50% of the variance in AER performance across individuals. These findings demonstrate that impaired preattentive processing of tonal information and reduced auditory-insula connectivity are critical determinants of social cognitive dysfunction in schizophrenia, and thus represent key targets for future research and clinical intervention. SIGNIFICANCE STATEMENT: Schizophrenia patients show deficits in the ability to infer emotion based upon tone of voice [auditory emotion recognition (AER)] that drive impairments in social cognition and global functional outcome. This study evaluated neural substrates of impaired AER in schizophrenia using a combined event-related potential/resting-state fMRI approach. Patients showed impaired mismatch negativity response to emotionally relevant frequency modulated tones along with impaired functional connectivity between auditory and medial temporal (anterior insula) cortex. These deficits contributed in parallel to impaired AER and accounted for ∼50% of variance in AER performance. Overall, these findings demonstrate the importance of both auditory-level dysfunction and impaired auditory/insula connectivity in the pathophysiology of social cognitive dysfunction in schizophrenia.

Efference copy failure during smooth pursuit eye movements in schizophrenia.

Abnormal smooth pursuit eye movements in patients with schizophrenia are often considered a consequence of impaired motion perception. Here we used a novel motion prediction task to assess the effects of abnormal pursuit on perception in human patients. Schizophrenia patients (n = 15) and healthy controls (n = 16) judged whether a briefly presented moving target ("ball") would hit/miss a stationary vertical line segment ("goal"). To relate prediction performance and pursuit directly, we manipulated eye movements: in half of the trials, observers smoothly tracked the ball; in the other half, they fixated on the goal. Strict quality criteria ensured that pursuit was initiated and that fixation was maintained. Controls were significantly better in trajectory prediction during pursuit than during fixation, their performance increased with presentation duration, and their pursuit gain and perceptual judgments were correlated. Such perceptual benefits during pursuit may be due to the use of extraretinal motion information estimated from an efference copy signal. With an overall lower performance in pursuit and perception, patients showed no such pursuit advantage and no correlation between pursuit gain and perception. Although patients' pursuit showed normal improvement with longer duration, their prediction performance failed to benefit from duration increases. This dissociation indicates relatively intact early visual motion processing, but a failure to use efference copy information. Impaired efference function in the sensory system may represent a general deficit in schizophrenia and thus contribute to symptoms and functional outcome impairments associated with the disorder.

Lower-level oculomotor deficits in schizophrenia during multi-line reading: Evidence from return-sweeps.

Reading fluency deficits in schizophrenia (Sz) have been attributed to dysfunction in both lower-level, oculomotor processing and higher-level, lexical processing, according to the two-hit deficit model. Given that prior work examining reading deficits in individuals with Sz has primarily focused on single-line and single-word reading tasks, eye movements that are unique to passage reading, such as return-sweep saccades, have not yet been examined in Sz. Return-sweep saccades are large eye movements that are made when readers move from the end of one line to the beginning of the next line during natural passage reading. Examining return-sweeps provides an opportunity to examine lower-level, oculomotor deficits during reading under circumstances when upcoming higher-level, lexical information is not available for visual processing because visual acuity constraints do not permit detailed lexical processing of line-initial words when return-sweeps are programmed. To examine the source of reading deficits in Sz, we analysed an existing data set in which participants read multi-line passages with manipulations to line spacing. Readers with Sz made significantly more return-sweep targeting errors followed by corrective saccades compared with healthy controls. Both groups showed similar effects of line spacing on return-sweep targeting accuracy, suggesting similar sensitivities to visual crowding during reading. Furthermore, the patterns of fixation durations in readers with Sz corroborate prior work indicating reduced parafoveal processing of upcoming words. Together, these findings suggest that lower-level visual and oculomotor dysfunction contribute to reading deficits in Sz, providing support for the two-hit deficit model.

Consequences of magnocellular dysfunction on processing attended information in schizophrenia.

Schizophrenia is associated with perceptual and cognitive dysfunction including impairments in visual attention. These impairments may be related to deficits in early stages of sensory/perceptual processing, particularly within the magnocellular/dorsal visual pathway. In the present study, subjects viewed high and low spatial frequency (SF) gratings designed to test functioning of the parvocellular/magnocellular pathways, respectively. Schizophrenia patients and healthy controls attended to either the low SF (magnocellularly biased) or high SF (parvocellularly biased) gratings. Functional magnetic resonance imaging (fMRI) and recordings of event-related potentials (ERPs) were carried out during task performance. Patients were impaired at detecting low-frequency targets. ERP amplitudes to low-frequency gratings were diminished, both for the early sensory-evoked components and for the attend minus unattend difference component (the selection negativity), which is regarded as a neural index of feature-selective attention. Similarly, fMRI revealed that activity in extrastriate visual cortex was reduced in patients during attention to low, but not high, SF. In contrast, activity in frontal and parietal areas, previously implicated in the control of attention, did not differ between patients and controls. These findings suggest that impaired sensory processing of magnocellularly biased stimuli lead to impairments in the effective processing of attended stimuli, even when the attention control systems themselves are intact.

Dose-Dependent Augmentation of Neuroplasticity-Based Auditory Learning in Schizophrenia: A Double-Blind, Placebo-Controlled, Randomized, Target Engagement Clinical Trial of the NMDA Glutamate Receptor Agonist d-serine.

BACKGROUND: Patients with schizophrenia show reduced NMDA glutamate receptor-dependent auditory plasticity, which is rate limiting for auditory cognitive remediation (AudRem). We evaluate the utility of behavioral and neurophysiological pharmacodynamic target engagement biomarkers, using a d-serine+AudRem combination. METHODS: Forty-five participants with schizophrenia or schizoaffective disorder were randomized to 3 once-weekly AudRem visits + double-blind d-serine (80, 100, or 120 mg/kg) or placebo in 3 dose cohorts of 12 d-serine and 3 placebo-treated participants each. In AudRem, participants indicated which paired tone was higher in pitch. The primary outcome was plasticity improvement, operationalized as change in pitch threshold between AudRem tones [(test tone Hz - reference tone Hz)/reference tone Hz] between the initial plateau pitch threshold (mean of trials 20-30 of treatment visit 1) to pitch threshold at the end of visit(s). Target engagement was assessed by electroencephalography outcomes, including mismatch negativity (pitch primary). RESULTS: There was a significant overall treatment effect for plasticity improvement (p = .014). Plasticity improvement was largest within the 80 and 100 mg/kg groups (p < .001, d > 0.67), while 120 mg/kg and placebo-treated participants showed nonsignificant within-group changes. Plasticity improvement was seen after a single treatment and was sustained on subsequent treatments. Target engagement was demonstrated by significantly larger mismatch negativity (p = .049, d = 1.0) for the 100 mg/kg dose versus placebo. CONCLUSIONS: Our results demonstrate sufficient proof of principle for continued development of both the d-serine+AudRem combination and our target engagement methodology. The ultimate utility is dependent on the results of an ongoing larger, longer study of the combination for clinically relevant outcomes.

A Brazilian bottom-up strategy to address mental health in a diverse population over a large territorial area - an inspiration for the use of digital mental health.

Brazil is a continental country with a history of massive immigration waves from around the world. Consequently, the Brazilian population is rich in ethnic, cultural, and religious diversity, but suffers from tremendous socioeconomic inequality. Brazil has a documented history of categorizing individuals with culturally specific behaviors as mentally ill, which has led to psychiatric institutionalization for reasons that were more social than clinical. To address this, a "network for psychosocial care" was created in Brazil, that included mental health clinics and community services distributed throughout the country. This generates local support for mental health rehabilitation, integrating psychiatric care, family support and education/work opportunities. These clinics and community services are tailored to provide care for each specific area, and are more attuned to regional culture, values and neighborhood infrastructure. Here we review existing reports about the Brazilian experience, including advances in public policy on mental health, and challenges posed by the large diversity to the psychosocial rehabilitation.  In addition, we show how new digital technologies in general, and computational speech analysis in particular, can contribute to unbiased assessments, resulting in decreased stigma and more effective diagnosis of the mental diseases, with methods that are free of gender, ethnic, or socioeconomic biases.

Computational modeling of excitatory/inhibitory balance impairments in schizophrenia.

Deficits in glutamatergic function are well established in schizophrenia (SZ) as reflected in "input" dysfunction across sensory systems. By contrast, less is known about contributions of the GABAergic system to impairments in excitatory/inhibitory balance. We investigated this issue by measuring contrast thresholds for orientation detection, orientation discriminability, and orientation-tilt-aftereffect curves in schizophrenia subjects and matched controls. These measures depend on the amplitude and width of underlying orientation tuning curves, which, in turn, depend on excitatory and inhibitory interactions. By simulating a well-established V1 orientation selectivity model and its link to perception, we demonstrate that reduced cortical excitation and inhibition are both necessary to explain our psychophysical data. Reductions in GABAergic feedback may represent a compensatory response to impaired glutamatergic input in SZ, or a separate pathophysiological event. We also found evidence for the widely accepted, but rarely tested, inverse relationship between orientation discriminability and tuning width.

Stroop matching task: role of feature selection and temporal modulation.

We conducted an event-related potential (ERP) study to investigate the electrocortical dynamics of attentional feature-based processing in the Stroop matching task. Participants in the study (n = 37) compared the ink color of a colored word with the meaning of a color-word in white ink. The two task stimuli were presented simultaneously or with SOAs (Stimulus Onset Asynchrony) of 400 and 1,200 ms. The Stroop matching effect was maximal during SOA-0, was reduced at SOA-400, and was inverted at SOA-1200. We focused the ERP analysis on the N1 component. Paralleling the behavioral results, the N1 amplitude was greater for congruent stimuli than incongruent stimuli during SOA-0. This difference was attenuated at SOA-400, and at SOA-1200, an inverse pattern was observed. The results provide evidence that early selection processing participated in the Stroop matching task phenomenon and also suggest that the temporal modulation of early attention is a function of task characteristics such as SOA.

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.

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.

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.

Grant Report on d-Serine Augmentation of Neuroplasticity-Based Auditory Learning in Schizophrenia †.

We report on the rationale and design of an ongoing NIMH sponsored R61-R33 project in schizophrenia/schizoaffective disorder. This project studies augmenting the efficacy of auditory neuroplasticity cognitive remediation (AudRem) with d-serine, an N-methyl-d-aspartate-type glutamate receptor (NMDAR) glycine-site agonist. We operationalize improved (smaller) thresholds in pitch (frequency) between successive auditory stimuli after AudRem as improved plasticity, and mismatch negativity (MMN) and auditory θ as measures of functional target engagement of both NMDAR agonism and plasticity. Previous studies showed that AudRem alone produces significant, but small cognitive improvements, while d-serine alone improves symptoms and MMN. However, the strongest results for plasticity outcomes (improved pitch thresholds, auditory MMN and θ) were found when combining d-serine and AudRem. AudRem improvements correlated with reading and other auditory cognitive tasks, suggesting plasticity improvements are predictive of functionally relevant outcomes. While d-serine appears to be efficacious for acute AudRem enhancement, the optimal dose remains an open question, as does the ability of combined d-serine + AudRem to produce sustained improvement. In the ongoing R61, 45 schizophrenia patients will be randomized to receive three placebo-controlled, double-blind d-serine + AudRem sessions across three separate 15 subject dose cohorts (80/100/120 mg/kg). Successful completion of the R61 is defined by ≥moderate effect size changes in target engagement and correlation with function, without safety issues. During the three-year R33, we will assess the sustained effects of d-serine + AudRem. In addition to testing a potentially viable treatment, this project will develop a methodology to assess the efficacy of novel NMDAR modulators, using d-serine as a "gold-standard".

Magnocellular pathway impairment in schizophrenia: evidence from functional magnetic resonance imaging.

Sensory processing deficits in schizophrenia have been documented for several decades, but their underlying neurophysiological substrates are still poorly understood. In the visual system, the pattern of pathophysiology reported in several studies is suggestive of dysfunction within the magnocellular visual pathway beginning in early sensory cortex or even subcortically. The present study used functional magnetic resonance imaging to investigate further the neurophysiological bases of visual processing deficits in schizophrenia and in particular the potential role of magnocellular stream dysfunction. Sinusoidal gratings systematically varying in spatial frequency content were presented to subjects at low and high levels of contrast to differentially bias activity in magnocellular and parvocellular pathways based on well established differences in neuronal response profiles. Hemodynamic responses elicited by different spatial frequencies were mapped over the occipital lobe and then over the entire brain. Retinotopic mapping was used to localize the occipital activations with respect to the boundaries of visual areas V1 and V2, which were demarcated in each subject. Relative to control subjects, schizophrenia patients showed markedly reduced activations to low, but not high, spatial frequencies in multiple regions of the occipital, parietal, and temporal lobes. These findings support the hypothesis that schizophrenia is associated with impaired functioning of the magnocellular visual pathway and further suggest that these sensory processing deficits may contribute to higher-order cognitive deficits in working memory, executive functioning, and attention.

Hierarchical deficits in auditory information processing in schizophrenia.

Deficits in auditory processing contribute significantly to impaired functional outcome in schizophrenia (SZ), but mediating factors remain under investigation. Here we evaluated two hierarchical components of early auditory processing: pitch-change detection (i.e. identifying if 2 tones have "same" or "different" pitch), which is preferentially associated with early auditory cortex, and serial pitch-pattern detection (i.e. identifying if 3 tones have "same" or "different" pitch, and, if "different", which one differed from the others), which depends also on auditory association regions. Deficits in pitch-change detection deficits in SZ have been widely reported and correlated with higher auditory disturbances such as Auditory Emotion Recognition (AER). Deficits in serial pitch-pattern discrimination have been less studied. Here, we investigated both pitch perception components, along with integrity of AER in SZ patients vs. controls using behavioral paradigms. We hypothesized that the deficits could be viewed as hierarchically organized in SZ, with deficits in low-level function propagating sequentially through subsequent levels of processing. Participants included 27 SZ and 40 controls. The magnitude of the deficits in SZ participants was large in both the pitch-change (d = 1.15) and serial pitch-pattern tasks (d = 1.21) with no significant differential task effect. The effect size of the AER deficits was extremely large (d = 2.82). In the SZ group, performance in both pitch tasks correlated significantly with impaired AER performance. However, a mediation analysis showed that serial pitch-pattern detection mediated the relationship between simpler pitch-change detection and AER in patients. Findings are consistent with hierarchical models of cognitive dysfunction in SZ with deficits in early information processing contributing to higher level impairments. Furthermore, findings are consistent with recent neurophysiological results suggesting similar level impairments for processing of simple vs. more complex tonal dysfunction 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.

A tale of two sites: Differential impairment of frequency and duration mismatch negativity across a primarily inpatient versus a primarily outpatient site in schizophrenia.

Deficits in mismatch negativity (MMN) generation are among the best replicated neurophysiological deficits in schizophrenia, with reduced amplitude reflecting impaired information processing at the level of supratemporal auditory cortex. Differential patterns of MMN dysfunction according to deviant types have been reported across studies, with some research groups showing impairment in duration MMN but not frequency MMN, and other research groups reporting both findings. We evaluate the hypothesis that recruitment setting, reflecting current functional status, might be an important determinant of the pattern of MMN dysfunction. Here, we evaluated patterns of MMN dysfunction, along with tone matching and neuropsychological performance in subjects drawn from 1) a predominant inpatient/residential care setting (Nathan Kline Institute) and 2) a predominant outpatient setting (Columbia University). As predicted, compared to healthy controls, deficits in duration MMN were observed across sites, whereas deficits in frequency MMN/tone matching were confined to the chronic inpatient setting. Within patients, the frequency MMN deficit was highly correlated with impairments in tone matching ability across sites (r=-0.52, p<0.0001), as well as impairments in verbal learning (r=-0.54, p<0.0001). Responses to standard stimuli in the MMN paradigm were assessed using measures of alpha evoked power and inter-trial coherence (ITC). While deficits in alpha ITC were observed across sites (both p<0.05), deficits in alpha power were observed at the inpatient (p=0.001) but not outpatient (p=0.2) site. Overall, these finding indicate that impairments of frequency MMN generation and response power to standard stimuli could be particularly linked to forms of schizophrenia that are associated with poor functional outcome.