Faculty Bibliography

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 2-hit deficit model (Dias et al., 2021). Given that prior work examining reading deficits in readers 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 analyzed an existing dataset (Dias et al., 2021) 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 to 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 corroborates 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 2-hit deficit model (Dias et al., 2021).

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.

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.

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.

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.

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".

Patients with schizophrenia show response inhibition deficits equal to or greater than those seen in impulse-control disorders, and these deficits contribute to poor outcome. However, little is known about the circuit abnormalities underlying this impairment. To address this, we examined stop signal task performance in 21 patients with schizophrenia and 21 healthy controls using event related potential (ERP) and resting state functional connectivity. Patients showed prolonged stop signal reaction time (SSRT) and reduced N1, N2, and P3 amplitudes compared to controls. Across groups, P3 amplitudes were maximal after SSRT (i.e., after the time associated with the decision to stop occurred), suggesting that this component indexed response monitoring. Multiple regression analyses showed that longer SSRTs were independently related to 1) patient status, 2) reduced N1 amplitude on successful stop trials and 3) reduced anticorrelated resting state functional connectivity between visual and frontoparietal cortical networks. This study used a combined multimodal imaging approach to better understand the network abnormalities that underlie response inhibition in schizophrenia. It is the first of its kind to specifically assess the brain's resting state functional architecture in combination with behavioral and ERP methods to investigate response inhibition 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 approximately 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 approximately 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.