Finding the right dose: NMDAR modulating treatments for cognitive and plasticity deficits in schizophrenia and the role of pharmacodynamic target engagement.

Cognitive impairment associated with schizophrenia (CIAS) and related deficits in learning (plasticity) are amongst the leading causes of disability in schizophrenia. Despite this, there are no FDA approved treatments for CIAS, and the development of treatments has been limited by numerous Phase II/III failures of compounds that showed initial promise in small-scale studies. N-methyl-d-aspartate-type glutamate receptors (NMDAR) have been proposed to play an important role in schizophrenia; moreover, NMDAR has a well characterized role in cognition, learning and neuroplasticity. We review prior published clinical trials in CIAS focusing on NMDAR modulator treatments, focusing on published and recent developments of the use of novel NMDAR-modulating treatments for CIAS both alone and combined with plasticity/learning paradigms to enhance learning. We will use this discussion of prior studies to highlight the importance of incorporating pharmacodynamic target engagement biomarkers early in treatment development, which can help predict which compounds will succeed or fail in Phase III. A range of direct and indirect NMDAR modulators will be covered, including d-serine, d-cycloserine, memantine, glycine and "first generation" glycine transport inhibitors (GTI, e.g. sarcosine and bitopertin), as well as recent positive studies of iclepertin, a novel GTI and luvadaxistat, a D-amino acid oxidase inhibitor (DAAO-I) that increases brain d-serine levels and indirect non-invasive brain stimulation NMDAR modulating treatments. Several examples of successful use of pharmacodynamic target engagement biomarkers for dose/drug discovery will be emphasized, including mismatch negativity (MMN), auditory steady state (ASSR) and time-frequency event-related potential (TF-ERP) approaches.

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.

Augmentation of learning in schizophrenia by D-serine is related to auditory and frontally-generated biomarkers: A randomized, double-blind, placebo-controlled study.

Auditory cognition is impaired in schizophrenia, and typically engages a complex, distributed, hierarchical network, including both auditory and frontal input. We recently demonstrated proof of principle for the target engagement of an N-methyl-D-aspartate-type glutamate receptor (NMDAR) agonist + auditory targeted remediation (d-serine+AudRem) combination, showing significant improvement in auditory-learning induced plasticity and mismatch negativity. In this secondary analysis, we report on frontal EEG outcomes, assessing for both generalized effects and the mechanism of auditory plasticity. 21 schizophrenia or schizoaffective disorder participants were randomized to three 1x weekly AudRem + double-blind d-serine (100 mg/kg) visits. In AudRem, participants indicated which paired tone was higher in pitch. The focus of this secondary analysis was a frontally (premotor) mediated EEG outcome- event-related desynchronization in the b band (b-ERD), which was shown to be sensitive to AudRem in previous studies. d-Serine+AudRem led to significant improvement in b-ERD power across the retention and motor preparation intervals (F 1,18 =6.0, p=0.025) vs. AudRem alone. b-ERD was significantly related to baseline cognition, but not auditory-learning induced plasticity. The principal finding of this prespecified secondary analysis are that in addition to improving auditory based biomarkers, the d-serine+AudRem combination led to significant improvement in biomarkers thought to represent frontally mediated dysfunction, suggesting potential generalization of effects. Changes in auditory-learning induced plasticity were independent of these frontally mediated biomarkers. Ongoing work will assess whether d-serine+AudRem is sufficient to remediate cognition or whether targeting frontal NMDAR deficits with higher-level remediation may also be required. Trial Registration: NCT03711500.

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.

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.

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.

Mismatch negativity as an index of target engagement for excitation/inhibition-based treatment development: a double-blind, placebo-controlled, randomized, single-dose cross-over study of the serotonin type-3 receptor antagonist CVN058.

Serotonin type-3 receptor (5-HT3R) antagonists show potential as a treatment for cognitive deficits in schizophrenia. CVN058, a brain-penetrant, potent and selective 5-HT3R antagonist, shows efficacy in rodent models of cognition and was well-tolerated in Phase-1 studies. We evaluated the target engagement of CVN058 using mismatch negativity (MMN) in a randomized, double-blind, placebo-controlled, cross-over study. Subjects were stable outpatients with schizophrenia or schizoaffective disorder treated with antipsychotics. Subjects were not permitted to use other 5-HT3R modulators or serotonin reuptake inhibitors. Each subject received a high (150 mg) and low (15 mg or 75 mg) oral dose of CVN058 and placebo in a randomized order across 3 single-day treatment visits separated by at least 1 week. The primary pre-registered outcome was amplitude of duration MMN. Amplitude of other MMN deviants (frequency, intensity, frequency modulation, and location), P50, P300 and auditory steady-state response (ASSR) were exploratory endpoints. 19 of 22 randomized subjects (86.4%) completed the study. Baseline PANSS scores indicated moderate impairment. CVN058 150 mg led to significant improvement vs. placebo on the primary outcome of duration MMN (p = 0.02, Cohen's d = 0.48). A significant treatment effect was also seen in a combined analysis across all MMN deviants (p < 0.001, d = 0.57). Effects on location MMN were independently significant (p < 0.007, d = 0.46). No other significant effects were seen for other deviants, doses or EEG measures. There were no clinically significant treatment related adverse effects. These results show MMN to be a sensitive target engagement biomarker for 5-HT3R, and support the potential utility of CVN058 in correcting the excitatory/inhibitory imbalance in schizophrenia.

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.

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.

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".

Double blind, two dose, randomized, placebo-controlled, cross-over clinical trial of the positive allosteric modulator at the alpha7 nicotinic cholinergic receptor AVL-3288 in schizophrenia patients.

Despite their theoretical rationale, nicotinic alpha-7 acetylcholine (nα7) receptor agonists, have largely failed to demonstrate efficacy in placebo-controlled trials in schizophrenia. AVL-3288 is a nα7 positive allosteric modulator (PAM), which is only active in the presence of the endogenous ligand (acetylcholine), and thus theoretically less likely to cause receptor desensitization. We evaluated the efficacy of AVL-3288 in a Phase 1b, randomized, double-blind, placebo-controlled, triple cross-over study. Twenty-four non-smoking, medicated, outpatients with schizophrenia or schizoaffective disorder and a Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) ≥62 were randomized. Each subject received 5 days of AVL-3288 (10, 30 mg) and placebo across three separate treatment weeks. The primary outcome measure was the RBANS total scale score, with auditory P50 evoked potential suppression the key target engagement biomarker. Secondary outcome measures include task-based fMRI (RISE task), mismatch negativity, the Scale for the Assessment of Negative Symptoms of Schizophrenia (SANS) and the Brief Psychiatric Rating Scale (BPRS). Twenty-four subjects were randomized and treated without any clinically significant treatment emergent adverse effects. Baseline RBANS (82 ± 17) and BPRS (41 ± 13) scores were consistent with moderate impairment. Primary outcomes were negative, with non-significant worsening for both active groups vs. placebo in the P50 and minimal between group changes on the RBANS. In conclusion, the results did not indicate efficacy of the compound, consistent with most prior results for the nα7 target.

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.

Significant improvement in treatment resistant auditory verbal hallucinations after 5 days of double-blind, randomized, sham controlled, fronto-temporal, transcranial direct current stimulation (tDCS): A replication/extension study.

BACKGROUND: Transcranial direct current stimulation (tDCS) is a potentially novel treatment for antipsychotic-resistant auditory verbal hallucinations (AVH) in schizophrenia. Nevertheless, results have been mixed across studies. METHODS: 89 schizophrenia/schizoaffective subjects (active: 47; Sham: 42) were randomized to five days of twice-daily 20-min active tDCS vs. sham treatments across two recruitment sites. AVH severity was assessed using the Auditory Hallucination Rating Scale (AHRS) total score. To assess target engagement, MRI was obtained in a sub sample. RESULTS: We observed a statistically significant, moderate effect-size change in AHRS total score across one-week and one-month favoring active treatment following covariation for baseline symptoms and antipsychotic dose (p = 0.036; d = 0.48). Greatest change was observed on the AHRS loudness item (p = 0.003; d = 0.69). In exploratory analyses, greatest effects on AHRS were observed in patients with lower cognitive symptoms (d = 0.61). In target engagement analysis, suprathreshold mean field-strength (>0.2 V/m) was seen within language-sensitive regions. However, off-target field-strength, which correlated significantly with less robust clinical response, was observed in anterior regions. CONCLUSIONS: This is the largest study of tDCS for persistent AVH conducted to date. We replicate previous reports of significant therapeutic benefit, but only if medication dosage is considered, with patients receiving lowest medication dosage showing greatest effect. Response was also greatest in patients with lowest levels of cognitive symptoms. Overall, these findings support continued development of tDCS for persistent AVH, but also suggest that response may be influenced by specific patient and treatment characteristics. CLINICALTRIALS.GOV: NCT01898299.

Sensory and cross-network contributions to response inhibition in patients with schizophrenia.

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.