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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.

Background Immunological, nutritional, and microbial factors have been implicated in the pathophysiology of schizophrenia, but the interrelationship among measures is understudied. In particular, an increase in the levels of the pro-inflammatory cytokine interleukin-6 (IL-6) is associated with all phases of the illness, and may be associated with other inflammatory markers. Vitamin D is a modulator of the immune system, and LPS antibodies are an indirect measure of gut barrier function. In this study we investigated potential contributing inflammatory mechanisms for IL-6 elevation. Methods We compared the levels of vitamin D, C-reactive protein (CRP), antibodies to lipopolysaccharide (LPS), and IL-6 in children, adolescents and young adults with psychosis (n = 47), individuals at clinical high risk for psychosis (n = 17) and unaffected comparison controls (n = 33). Participants were diagnosed by a psychiatrist, using a structured interview, the MINI-Neuropsychiatric Interview. 25(OH)D was measured in serum using chemiluminescent micro particle immunoassay, and anti-LPS antibodies, CRP and IL-6 levels were measured by ELISA. Results IL-6 and C-reactive protein levels were significantly elevated in the psychosis group relative to the unaffected control subjects. In the psychosis group, levels of IL-6 correlated positively with IgA anti-LPS antibodies and negatively correlated with vitamin D. Conclusions Our findings show a significant correlation between IL-6, anti-LPS antibodies and vitamin D deficiency in psychosis, suggesting the existence of multiple potential pathways related to IL-6 elevation in psychosis, and therefore multiple potential strategies for risk mitigation. Collectively these findings support hypotheses regarding interrelated inflammatory contributions to the pathophysiology of psychosis.

Sensory processing deficits are core features of schizophrenia, reflected in impaired generation of event-related potential (ERP) measures such as auditory mismatch negativity (MMN) and visual P1. To understand the potential time course of development of deficits in schizophrenia, we obtained MMN to unattended duration, intensity and frequency deviants, and visual P1 to attended LSF stimuli, in 43 healthy individuals ages 6 to 25 years (mean 17), and compared results to data from 30 adult schizophrenia patients (mean age 38). We analyzed “time-domain” measures of amplitude and latency, and event-related spectral perturbation (ERSP, “time-frequency”) to evaluate underlying neurophysiological mechanisms. Duration and intensity MMN amplitudes increased from childhood to late adolescence, while frequency MMN reached maximum amplitude during early development. As reported previously, in ERSP analyses, MMN activity corresponded primarily to theta-band (4–7 Hz) activity, while responses to standards occurred primarily in alpha (8–12 Hz) across age groups. Both deviant-induced theta and standard-induced alpha activity declined significantly with age for all deviant types. Likewise, visual P1 also showed an amplitude decline over development, reflecting a reduction in both evoked power and ITC. While MMN “difference” waveform ERP data suggest failure of maturation in schizophrenia, MMN ERSP analyses instead support a neurodegenerative process, as these isolate responses to deviants and standards, showing large low-frequency evoked power for both in children. Neurodegenerative processes are also supported by large visual P1 amplitudes and large low-frequency evoked power in children, in contrast with adult schizophrenia. Sensory processing deficits in schizophrenia may be related to accelerated synaptic pruning.

Persistent auditory verbal hallucinations (AVH) in schizophrenia are increasingly tied to dysfunction at the level of auditory cortex. AVH may reflect in part misattribution of internally generated thoughts to external spatial locations. Here, we investigated the association between persistent AVH and spatial localization abilities assessed both behaviorally and by mismatch negativity (MMN) to location deviants.Spatial- and tonal- discrimination abilities were assessed in patients (n=20) and controls (n=20) using free-field tones. MMN was assessed to spatial-location-, pitch- and duration-deviants. AVH and thought disorder were assessed using clinical evaluation.As predicted, patients showed significant reductions in behavioral spatial-discrimination (p0.0001) and tone-matching (p0.001) ability, along with impaired MMN generation to location (p0.03) and pitch (p0.05) deviants. Hallucinating (AVH+) and non-hallucinating (AVH-) subjects showed similar deficits in location MMN to left-hemifield stimuli (p0.0001 vs. control). By contrast, AVH- patients differed significantly from controls (p=0.009) and AVH+ patients (p=0.018) for MMN to right-lateral hemifield (left auditory cortex) stimuli, whereas AVH+ patients showed paradoxically preserved MMN generation (p=0.99 vs. controls). Severity of thought disorder correlated with impaired spatial discrimination, especially to right-hemifield stimuli (p=0.013), but did not correlate significantly with MMN or tone matching deficits.These findings demonstrate a significant relationship between auditory cortical spatial localization abilities and AVH susceptibility, with relatively preserved function of left vs. right auditory cortex predisposing to more severe AVH, and support models that attribute persistent AVH to impaired source-monitoring. The findings suggest new approaches for therapeutic intervention for both AVH and thought disorder in schizophrenia.

Social attachment is a biological and affective need. When this need is not met, people experience loneliness. Loneliness is associated with impaired social cognition, and is a risk factor for broad based morbidity across the adult lifespan even after controlling for multiple factors. However, little is known about loneliness in schizophrenia. Eighty-seven non-depressed individuals with schizophrenia or schizoaffective disorder (including 51 inpatients) and 58 control subjects completed the revised UCLA Loneliness scale. Social cognition was assessed with a self-report questionnaire and a performance-based task. Social trait perception was assessed with a facial task. Comorbid medical diagnoses were available for all inpatients. Patients reported greater loneliness levels than controls, while in- and out-patients did not significantly differ. In patients, loneliness was associated with self-report measures of social cognition. Patients' loneliness scores predicted a diagnosis of drug abuse/dependence, number of drugs used, hypertension and abnormal hemoglobin A1c levels. Patients experienced higher levels of loneliness than controls, independently of their objective social isolation. Loneliness did not rely on the same psychological processes in patients than in controls. Loneliness in schizophrenia is a symptom that deserves more scrutiny, particularly as it relates to the high prevalence of metabolic syndrome in this population.

Although social cognition deficits have been associated with schizophrenia, social trait judgments - or first impressions - have rarely been studied. These first impressions, formed immediately after looking at a person's face, have significant social consequences. Eighty-one individuals with schizophrenia or schizoaffective disorder and 62 control subjects rated 30 neutral faces on 10 positive or negative traits: attractive, mean, trustworthy, intelligent, dominant, fun, sociable, aggressive, emotionally stable and weird. Compared to controls, patients gave higher ratings for positive traits as well as for negative traits. Patients also demonstrated more ambivalence in their ratings. Patients who were exhibiting paranoid symptoms assigned higher intensity ratings for positive social traits than non-paranoid patients. Social trait ratings were negatively correlated with everyday problem solving skills in patients. Although patients appeared to form impressions of others in a manner similar to controls, they tended to assign higher scores for both positive and negative traits. This may help explain the social deficits observed in schizophrenia: first impressions of higher degree are harder to correct, and ambivalent attitudes may impair the motivation to interact with others. Consistent with research on paranoia and self-esteem, actively-paranoid patients' positive social traits judgments were of higher intensity than non-paranoid patients'.

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

In comparison to batteries of standard neuropsychological tests, cognitive neuroscience tests may offer a more specific assessment of discrete neurobiological processes that may be aberrant in schizophrenia. However, more information regarding psychometric properties and correlations with standard neuropsychological tests and functional measures is warranted to establish their validity as treatment outcome measures. The N-back and AX-Continuous Performance Task (AX-CPT) are two promising cognitive neuroscience tests designed to measure specific components of working memory and contextual processing respectively. In the current study, we report the psychometric properties of multiple outcome measures from these two tests as well as their correlations with standard neuropsychological measures and functional capacity measures. The results suggest that while the AX-CPT and N-back display favorable psychometric properties, they do not exhibit greater sensitivity or specificity with functional measures than standard neurocognitive tests.

Introduction Conventional transcranial Direct Stimulation (tDCS) has the disadvantage of spreading the current beyond the underlying cortical targets. More recent High-Definition tDCS (HD) is known to increase the spatial focality of the current. While anodal stimulation is generally thought to enhance cortical excitability and cathodal to reduce excitability, polarity-specificity of tDCS effects have been observed not to follow a simple general rule. The impact of tDCS at a network-level of brain modulation appears as a critical factor to explain its behavioral effects. Here, we propose to compare the effect of conventional-tDCS and HD-tDCS on a sequence-learning task (Serial-Response-Time-Task, SRTT) involving a network of visual and motor brain regions. Method The study involved 10 healthy participants. The SRTT generates fast (when the sequence is predicted in advance) and slow (when not) reaction times (RTs). During the task, participants were blinded for four 2 mA tDCS configurations (types: conventional, HD; conditions: active, sham). The active electrode was visual-POz cathodal. Continuous-EEG was acquired during tDCS. Results We observed a significant tDCS type condition on trial-by-trial RTs (F(1.46529) = 68.17, P Conclusions Visuomotor sequence learning improvement caused by tDCS involves a specific shift from a slow to a fast mode of processing. The visual HD-tDCS is superior over conventional-tDCS on this improvement and may be due to a focusing effect of the stimulation to the motion-perception network involved in the task. This argues for a network-level of tDCS-induced neuroplasticity rather than a local-level effect. The results raise the possibility of the usefulness of HD-tDCS in neurorehabilitation strategies for visuomotor dysfunctions.

Summary Background Antagonists of N-methyl-D-aspartate-type glutamate receptors (NMDAR) induce symptoms that closely resemble those of schizophrenia, including negative symptoms. D-serine is a naturally occurring NMDAR modulator that reverses the effects of NMDAR antagonists in animal models of schizophrenia. D-serine effects have been assessed previously for treatment of established schizophrenia, but not in the early stages of the disorder. We aimed to assess effects of D-serine on negative symptoms in at risk individuals. Methods We did a double-blind, placebo-controlled, parallel-group randomised clinical trial at four academic US centres. Individuals were eligible for inclusion in the study if they were at clinical high risk of schizophrenia, aged between 13–35 years, had a total score of more than 20 on the Scale of Prodromal Symptoms (SOPS), and had an interest in participation in the clinical trial. Exclusion criteria included a history of suprathreshold psychosis symptoms (ie, no longer qualifying as prodromal) or clinical judgment that the reported symptoms from the SOPS were accounted for better by another disorder (eg, depression). Randomisation was done using a generated list with block sizes of four. Participants were stratified by site, with participants, investigators, and assessors all masked through use of identical looking placebos and centralised drug dispensation to study assignment. D-serine (60 mg/kg) was given orally in divided daily doses for 16 weeks. The primary endpoint was for negative SOPS, measured weekly for the first 6 weeks, then every 2 weeks. Participants who received at least one post-baseline assessment were included in analysis. Serum cytokine concentrations were collected at baseline, midpoint, and endpoint to assess the mechanism of action. Safety outcomes including laboratory assessments were obtained for all individuals. This trial is registered with ClinicalTrials.gov, number NCT00826202. Findings We enrolled participants between April 2, 2009, and July 23, 2012. 44 participants were randomly assigned to receive either D-serine (n=20) or placebo (n=24); 35 had assessable data (15 D-serine, 20 placebo). D-serine induced a 35·7% (SD 17·8) improvement in negative symptoms, which was significant compared with placebo (mean final SOPS negative score 7·6 [SEM 1·4] for D-serine group vs 11·3 [1·2] for placebo group; d=0·68, p=0·03). Five participants who received D-serine and nine participants who received placebo discontinued the study early because of withdrawn consent or loss to follow-up (n=8), conversion to psychosis (n=2), laboratory-confirmed adverse events (n=2), or protocol deviations (n=2). Interpretation This study supports use of NMDAR-based interventions, such as D-serine, for treatment of prodromal symptoms of schizophrenia. On the basis of observed effect sizes, future studies with sample sizes of about 40 per treatment group would be needed for confirmation of beneficial effects on symptoms and NMDAR-related inflammatory changes. Long-term studies are needed to assess effects on psychosis conversion in individuals at clinical high risk of schizophrenia. Funding National Institutes of Health.

The efficacy of compounds having agonistic activity at the glycine site associated with the N-methyl-D-aspartate receptor (NMDAR) is presently assessed in psychiatric disorders. In contrast to NMDAR antagonists, the neuropsychiatric effects of NMDAR agonists in the healthy human organism are not known. We studied neuropsychiatric and neurochemical effects of the NMDAR-glycine site obligatory co-agonist d-serine (DSR) in healthy subjects using a randomized, controlled crossover challenge design including a baseline assessment day and two DSR/placebo administration days. Thirty-five subjects aged 23-29 years participated in the study and received a 2.1 g orally administered DSR dose. The main outcome measures were the changes in scores of mood-related Visual Analogue Scale (VAS), Continuous Performance Test-Identical Pairs (CPT-IP), and Rey Auditory Verbal Learning Test (RAVLT). DSR acute administration: (1) was well tolerated and resulted at 2 h in ≥ 200 times increase in DSR serum levels; (2) elicited reduced VAS-measured depression and anxiety feelings; (3) improved attention and vigilance as measured by CPT-IP D-prime score; (4) preferentially improved performance in RAVLT list 7 reflecting ability to retain information over interference; (5) had significant but nonspecific effects on Category Fluency and Benton Visual Retention tests; and (6) did not affect glycine and glutamate serum levels. These data indicate that in healthy subjects, DSR reduces subjective feelings of sadness and anxiety and has procognitive effects that are overall opposed to the known effects of NMDAR antagonists. The findings are relevant to translational research of NMDAR function and the development of NMDAR-glycine site treatments for specific psychiatric entities. ClinicalTrials.gov: Behavioral and Cognitive Effects of the N-methyl-D-aspartate Receptor (NMDAR) Co-agonist D-serine in Healthy Humans; http://www.clinicaltrials.gov/ct2/show/NCT02051426?term=NCT02051426rank=1; NCT02051426.

Schizophrenia patients exhibit impairments in auditory-based social cognition, indicated by deficits in detection of prosody, such as affective prosody and basic pitch perception. However, little is known about the psychometric properties of behavioral tests used to assess these functions. The goal of this paper is to characterize the properties of prosody and pitch perception tasks and to investigate whether they can be shortened. The pitch perception test evaluated is a tone-matching task developed by Javitt and colleagues (J-TMT). The prosody test evaluated is the auditory emotion recognition task developed by Juslin and Laukka (JL-AER). The sample includes 124 schizophrenia patients (SZ) and 131 healthy controls (HC). Properties, including facility and discrimination, of each item were assessed. Effects of item characteristics (e.g., emotion) were also evaluated. Shortened versions of the tests are proposed based on facility, discrimination, and/or ability of item characteristics to discriminate between patients and controls. Test–retest reliability is high for patients and controls for both the original and short forms of the J-TMT and JL-AER. Thus, the original as well as short forms of the J-TMT and JL-AER are suggested for inclusion in clinical trials of social cognitive and perceptual treatments. The development of short forms further increases the utility of these auditory tasks in clinical trials and clinical practice. The large SZ vs. HC differences reported here also highlight the profound nature of auditory deficits and a need for remediation.

Background Among the various cognitive and affective evaluations that contribute to decisions about whether to engage in a future activity, three affective evaluations are particularly relevant: 1) interest in the activity itself, 2) the pleasure anticipated from the activity and 3) the excitement experienced while looking forward to the activity. In addition to these pre-activity evaluations, affective evaluations that are done after the activity is completed impact people's motivation to repeat the same activity. Although extant research suggests that these affective processes may be impaired in schizophrenia, it is not clear whether these impairments are mostly secondary to cognitive deficits. Method In three independent studies utilizing simple laboratory tasks with minimal cognitive demands, patients with schizophrenia or schizoaffective disorder and healthy control subjects evaluated their pleasure, interest, and excitement immediately before and after completing the tasks. Results Patients' anticipated pleasure and posttest evaluations of pleasure and interest were significantly greater than controls'. No group differences were found for excitement. In patients, there were significant negative correlations between anticipated pleasure, pretest excitement and depression scores, and between pretest interest and negative symptoms. Conclusions In these experiments, immediate affective evaluations reported by participants with schizophrenia or schizoaffective disorder were greater or similar to controls'. This finding is consistent with recent affective research showing that experiences of pleasure are intact in schizophrenia. These results emphasize the need to disentangle affective from cognitive processes in order to better understand the complex impairments present in schizophrenia spectrum disorders.

The last fifteen years have seen a great increase in our understanding of the role of glutamate in schizophrenia (SCZ). The glutamate hypothesis focuses on disturbances in brain glutamatergic pathways and impairment in signaling at glutamate receptors. Proton Magnetic Resonance Spectroscopy ((1)H-MRS) is an MR-based technique that affords investigators the ability to study glutamate function by measuring in vivo glutamatergic indices in the brains of individuals with SCZ. (1)H-MRS studies have been performed comparing glutamatergic levels of individuals with SCZ and healthy control subjects or studying the effect of antipsychotic medications on glutamatergic levels. In this article we summarize the results of these studies by brain region. We will review the contribution of (1)H-MRS studies to our knowledge about glutamatergic abnormalities in the brains of individuals with SCZ and discuss the implications for future research and clinical care.

Heschl’s gyrus (HG) is reported to have a normal left>right hemispheric volume asymmetry, and reduced asymmetry in schizophrenia. Primary auditory cortex (A1) occupies the caudal-medial surface of HG, but it is unclear if A1 has normal asymmetry, or whether its asymmetry is altered in schizophrenia. To address these issues, we compared bilateral gray matter volumes of HG and A1, and neuron density and number in A1, in autopsy brains from male subjects with or without schizophrenia. Comparison of diagnostic groups did not reveal altered gray matter volumes, neuron density, neuron number or hemispheric asymmetries in schizophrenia. With respect to hemispheric differences, HG displayed a clear left>right asymmetry of gray matter volume. Area A1 occupied nearly half of HG, but had less consistent volume asymmetry, that was clearly present only in a subgroup of archival brains from elderly subjects. Neuron counts, in layers IIIb-c and V-VI, showed that the A1 volume asymmetry reflected differences in neuron number, and was not caused simply by changes in neuron density. Our findings confirm previous reports of striking hemispheric asymmetry of HG, and additionally show evidence that A1 has a corresponding asymmetry, although less consistent than that of HG.

Patients meeting criteria for the risk syndrome for psychosis have treatment needs including positive and negative symptoms and cognitive impairment. These features could potentially respond to NMDA glycine-site agonists. The present objective was to determine which symptoms or domains of cognition promise to show the greatest response to glycine in risk syndrome patients. We conducted two short-term pilot studies of glycine used without adjunctive antipsychotic medication. In the first trial, 10 risk syndrome subjects received open-label glycine at doses titrated to 0.8 g/kg/d for 8 weeks, followed by discontinuation and 16 weeks of evaluation for durability of effects. In the second, 8 subjects were randomized to double-blind glycine vs. placebo for 12 weeks, followed by open-label glycine for another 12 weeks. Patients were evaluated every 1-2 weeks with the Scale Of Psychosis-risk Symptoms (SOPS) and before and after treatment with a neurocognitive battery. Within-group and between-group effect sizes were calculated. Effect sizes were large for positive (open-label within-group -1.10, double-blind between-group -1.11) and total (-1.39 and -1.15) symptoms and medium-to-large (-0.74 and -0.79) for negative symptoms. Medium or large effect sizes were also observed for several neurocognitive measures in the open-label study, although data were sparse. No safety concerns were identified. We conclude that glycine was associated with reduced symptoms with promising effect sizes in two pilot studies and a possibility of improvement in cognitive function. Further studies of agents that facilitate NMDA receptor function in risk syndrome patients are supported by these preliminary findings.

Although many resting state fMRI human studies have been published, the number of such rodent studies is considerably less. The reason for this is the severe technical challenge of high magnetic field small rodent imaging. Local magnetic field susceptibility changes at air tissue boundaries cause image distortion and signal losses. The current study reports measures of functional connectivity in mice using only isoflurane for the anesthetic. Because all anesthetic agents will alter cerebral blood flow and cerebral metabolism, the impact these changes have on neuronal connectivity has yet to be fully understood, however this work reports for the first time that reliable functional connectivity measures in mouse brain can be obtained with isoflurane.

In healthy humans, passage reading depends upon a critical organizing role played by the magnocellular/dorsal visual pathway. In a recent study, we found a significant correlation between orthographic reading deficits in schizophrenia and deficits in contrast sensitivity to low spatial frequency stimuli, suggesting an underlying magnocellular processing abnormality. The interrelationship between magnocellular dysfunction and passage reading impairments in schizophrenia was investigated in 21 patients with schizophrenia and 17 healthy control volunteers using behavioral and functional MRI (fMRI) based measures. fMRI activation patterns during passage- and single-word reading were evaluated in relation to cortical areas with differential sensitivity to low versus high spatial frequency cortical regions indentified using a phase-encoded fMRI paradigm.On average, patients with schizophrenia read at the 6th grade level, despite completion of more than 12years of education and estimated normal pre-morbid IQ. Schizophrenia patients also showed significantly impaired contrast sensitivity to low spatial frequencies and abnormal neural activity in response to stimulation with low spatial frequencies, consistent with dysfunction of magnocellular processing. Further, these magnocellular deficits were predictive of poor performance on a standardized psychoeducational test of passage reading. These findings suggest that reading is an important index of cognitive dysfunction in schizophrenia and highlight the contribution of magnocellular dysfunction to overall cognitive impairments in schizophrenia.

Background Cognitive dysfunction is a key predictor of functional disability in schizophrenia. Davunetide (AL-108, NAP) is an intranasally administered peptide currently being developed for treatment of Alzheimer's disease and related disorders. This study investigates effects of davunetide on cognition in schizophrenia. Method Sixty-three subjects with schizophrenia received davunetide at one of two different doses (5, 30 mg) or placebo for 12 weeks in a multicenter, double-blind, parallel-group randomized clinical trial. The MATRICS Consensus Cognitive Battery (MCCB) assessed cognitive effects. The UCSD Performance-based Skills Assessment (UPSA) and the Schizophrenia Cognition Rating Scale (SCoRS) assessed functional capacity. Subjects continued their current antipsychotic treatment during the trial. Results There were no significant differences in MCCB change between davunetide and placebo over the three treatment arms (p = .45). Estimated effect-size (d) values were .34 and .21 favoring the 5 and 30 mg doses vs. placebo, respectively. For UPSA, there was a significant main effect of treatment across study arms (p = .048). Between-group effect size (d) values were.74 and .48, favoring the 5 and 30 mg doses, respectively. No significant effects were observed on the SCoRS or on symptom ratings. No significant side effects or adverse events were observed. Conclusion Davunetide was well tolerated. Effects of davunetide on MCCB-rated cognition were not significant relative to placebo. In contrast, a significant beneficial effect was detected for the UPSA. Based upon effect-size considerations, sample sizes of at least 45–50 subjects/group would be required to obtain significant effects on both MCCB and UPSA, providing guidance for continued clinical development in schizophrenia.

New efforts to develop treatments for cognitive dysfunction in mental illnesses would benefit enormously from biomarkers that provide sensitive and reliable measures of the neural events underlying cognition. Here, we evaluate the promise of event-related potentials (ERPs) as biomarkers of cognitive dysfunction in schizophrenia. We conclude that ERPs have several desirable properties: 1) they provide a direct measure of electrical activity during neurotransmission; 2) their high temporal resolutions make it possible to measure neural synchrony and oscillations; 3) they are relatively inexpensive and convenient to record; 4) animal models are readily available for several ERP components; 5) decades of research has established the sensitivity and reliability of ERP measures in psychiatric illnesses; and 6) feasibility of large N (>500) multisite studies has been demonstrated for key measures. Consequently, ERPs may be useful for identifying endophenotypes and defining treatment targets, for evaluating new compounds in animals and in humans, and for identifying individuals who are good candidates for early interventions or for specific treatments. However, several challenges must be overcome before ERPs gain widespread use as biomarkers in schizophrenia research, and we make several recommendations for the research that is necessary to develop and validate ERP-based biomarkers that can have a real impact on treatment development.

Postmortem and in vivo studies of schizophrenia frequently reveal reduced cortical volume, but the underlying cellular abnormalities are incompletely defined. One influential hypothesis, especially investigated in Brodmann’s area 9 of prefrontal cortex, is that the number of neurons is normal, and the volume change is caused by reduction of the surrounding neuropil. However, studies have differed on whether the cortex has the increased neuron density that is predicted by this hypothesis. In a recent study of bilateral planum temporale (PT), we reported smaller volume and width of the outer cortex (layers I-III), especially in the left hemisphere, among subjects with schizophrenia. In the present study, we measured neuron density and size in the same PT samples, and also in prefrontal area 9 of the same brains. In the PT, separate stereological measurements were made in layers II, IIIc, and VI, whereas area 9 was sampled in layer IIIb-c. In both cortical regions, there was no significant effect of schizophrenia on neuronal density or size. There was, nevertheless, a trend-level right>left hemispheric asymmetry of neuron density in the PT, which may partially explain the previously reported left>right asymmetry of cortical width. In schizophrenia, our findings suggest that closer packing of neurons may not always explain reduced cortical volume, and subtly decreased neuron number may be a contributing factor.

Background Three temporal stages in the evaluation of positive affect can be identified: anticipation, experience (hedonia) and memory. In schizophrenia, despite research indicating non-impaired hedonic capacities, little is known about anticipation and memory of positive affect. Moreover, the role of positive affect evaluations on motivation has rarely been studied in schizophrenia. Method Seventy individuals with schizophrenia and 35 non-patient control participants completed an evocative emotional task consisting of pictures and sounds. Following each presentation, participants rated their hedonic experience. Ratings of pre-test anticipated and post-test remembered pleasures were also obtained. Finally, explicit motivation to repeat the task was assessed. Results Compared to control participants, schizophrenia participants demonstrated similar levels of anticipation, hedonia and motivation, as well as significantly increased remembered pleasure. In schizophrenia, affective processes had lower correlations with motivation than in controls, and only remembered pleasure predicted motivation. Moreover, the predictive value of hedonia was significantly lower in schizophrenia. Conclusions The affective and cognitive processes involved in the anticipation, experience and memory of positive affective events showed no deficit, and to the contrary, immediately remembered pleasure was higher in schizophrenia. However, important deficits resided in the inter-connectivity between affective evaluations and motivational processes. The major deficit in schizophrenia participants' reward system was not in hedonic experiences but in the translation of pleasurable experiences into motivational states.

Schizophrenia is a severe mental disorder associated with a characteristic constellation of symptoms and neurocognitive deficits. At present, etiological mechanisms remain relatively unknown, although multiple points of convergence have been identified over recent years. One of the primary convergence points is dysfunction of N-methyl-D-aspartate (NMDAR)-type glutamate receptors. Antagonists of NMDAR produce a clinical syndrome that closely resembles, and uniquely incorporates negative and cognitive symptoms of schizophrenia, along with the specific pattern of neurocognitive dysfunction seen in schizophrenia. Genetic polymorphisms involving NMDAR subunits, particularly the GRIN2B subunit have been described. In addition, polymorphisms have been described in modulatory systems involving the NMDAR, including the enzymes serine racemase and D-amino acid oxidase/G72 that regulate brain D-serine synthesis. Reductions in plasma and brain glycine, D-serine and glutathione levels have been described as well, providing potential mechanisms underlying NMDAR dysfunction. Unique characteristics of the NMDAR are described that may explain the characteristic pattern of symptoms and neurocognitive deficits observed in schizophrenia. Finally, the NMDAR complex represents a convergence point for potential new treatment approaches in schizophrenia aimed at correcting underlying abnormalities in synthesis and regulation of allosteric modulators, as well as more general potentiation of pre- and post-synaptic glutamatergic and NMDAR function.

D-serine is an allosteric modulator of the brain N-methyl-d-aspartate (NMDA) receptor and a potential novel treatment of schizophrenia. Double-blind studies have been performed at 30 mg/kg/day (approximately 2 g/day) with encouraging results, but no formal dose escalation studies have been performed. We describe the first evaluation of the efficacy and safety of d-serine at doses30 mg/kg/day; a 4-week, open-label trial of adjunctive D-serine (30, 60 or 120 mg/kg/day).42 antipsychotic-stabilized patients with schizophrenia or schizoaffective disorder participated. PANSS was obtained bi-weekly and neuropsychological (MATRICS) was obtained pre- and post medication phase. The pharmacokinetics/pharmacodynamics (PK/PD), and safety of dosesor =30 mg/kg was also evaluated.Significant improvement in symptoms and neuropsychological measures was noted across doses. On the PANSS, improvement was observed for positive (p=0.006;d=0.46), negative (p0.001;d=0.68), general (p=0.001;d=0.53), and total (p0.0001;d=0.74) symptoms. On MATRICS, while only non-significant improvement was noted at 30 mg/kg, highly significant, large effect size improvement was noted on the composite score (p0.01;d=1.0) for dosesor =60 mg/kg, leading to a significant dose-by-time interaction (p0.01). In PK analyses, significant dose-dependent increases in plasma D-serine levels were seen during the study, predictive of significantly increased brain levels. Furthermore, increases in plasma levels correlated with improved symptomatic and neuropsychological function.These findings support double-blind investigation of D-serine at dosesor =60 mg/kg/d, and suggest effectiveness in treatment of both persistent symptoms and neurocognitive dysfunction.

Deficits in visual processing are now recognized as a core feature of schizophrenia. In the 1940s, Louis Thurstone developed a series of tests designed to evaluate specific aspects of visual perceptual processing including the Closure Flexibility Test (CFT), which was designed to measure "the ability to hold a configuration in mind despite distraction." The present study evaluated patients' performance on this task and its relationship to other tests of neuropsychological function, particularly to a measure of sustained visual attention. Thirty-nine patients with schizophrenia or schizoaffective disorder and 40 controls participated. The CFT was administered both in its original form (10 min) and also in a briefer form (3 min) in which only a portion of stimuli were given. Patients showed highly significant large effect-size deficits on both the original (d=1.6) and brief (d=1.2) CFT. Between-group deficits in performance survived co-variation for IQ. In addition, the CFT score was significantly related to performance on the MATRICS measure of attention/vigilance, the Continuous Performance Test-Identical Pairs version (CPT-IP). This correlation remained significant even after controlling for non-specific intercorrelations among neurocognitive measures. Results confirm the severity of early visual processing deficits in schizophrenia. In addition, the CFT is a brief, easy to administer alphabet-independent, paper-and-pencil test with established psychometric properties that may be useful as an index of the sustained visual attention construct in schizophrenia.

Approved therapeutic uses for gamma-hydroxybutyric acid (GHB) (or sodium oxybate), a gamma-aminobutyric acid type B and GHB receptor agonist, include narcolepsy in the United States and Europe and alcohol abuse treatment in Italy. Possible efficacy of GHB in schizophrenia has also been proposed. A tolerability concern regarding use of GHB is its abuse potential. Given the high comorbidity of substance disorders and schizophrenia, a systematic assessment of the published literature is crucial.The aim of this review was to assess the tolerability and abuse liability of GHB in the context of future clinical studies as a potential treatment for insomnia in patients with schizophrenia.A literature search in English (inception through April 2009, inclusive) was conducted of MEDLINE, EMBASE, and PsycINFO using the search term GHB. All articles whose abstracts mentioned human use of GHB were read in their entirety. The reference sections of identified articles were reviewed for publications that might have been missed by the initial search.GHB is abused by a small percentage of people (1%) as a "club drug" and is commonly associated with enhanced sexual experiences (65%), euphoria (41%), somnolence (71%), and confusion (24%), according to a recent study. A review of all available emergency room case series suggests that while GHB can be associated with serious coma necessitating intubation, the number of reported fatal cases associated with GHB appears limited. Clarity on the lethality of GHB is complicated by instability of GHB in postmortem samples and frequent concomitant ingestions. Furthermore, formal abuse liability studies do not support high abuse propensity for GHB, mainly because oversedation and dizziness may lead most individuals to find GHB unpleasant at high doses. As supported by 2 large studies, there is limited evidence to suggest widespread use as an agent in sexual assault. Years of clinical use in narcolepsy do not support the development of tolerance or withdrawal in those subjects without substance dependence.Tolerability and abuse liability issues, while a concern with GHB given its abuse potential, do not preclude further study of the potential use for insomnia in nondually diagnosed schizophrenia. Full cognizance must be taken of risk/benefit tradeoffs, and to the development of improved formulations with decreased abuse liability.

Background Loss aversion in decision-making refers to a higher sensitivity to losses than to gains. Loss aversion is conceived as an affective interference in cognitive processes such as judgment and decision-making. Loss aversion in non-risky choices has not been studied in schizophrenia. Method Forty-two individuals with schizophrenia and 42 non-patient control subjects, matched by gender and age, were randomized to two different scenarios (a buying scenario and a selling scenario). Subjects were asked to evaluate the price of a decorated mug. Schizophrenia subjects were re-tested four weeks later with the other scenario. Results Contrary to non-patient controls, schizophrenia subjects did not show loss aversion. In the schizophrenia group, absence of loss aversion was correlated with age, duration of illness, number of months in State hospitals, and poorer performance in the Wisconsin Card Sorting Test, but not with current psychopathology and two domains of emotional experience. Conclusions Absence of loss aversion in schizophrenia represents a deficit in the processing of emotional information during decision-making. It can be interpreted as a lack of integration between the emotional and the cognitive systems, or to a more diffuse and de-differentiated impact of emotional information on decision-making. Future studies should bring more clarity to this question.

Background A hallmark of visuospatial neglect syndrome is that patients with lesions to right parietal cortex misbisect horizontal lines far rightward of veridical center. Neurologically normal subjects misbisect lines with a systematic leftward bias (pseudoneglect). Both phenomena, as well as neuroimaging studies, disclose a predominant right-hemisphere control of spatial attention. Numerous studies of patients with schizophrenia have implicated global deficits of either right or left hemisphere function, as well as compromised integrity of the corpus callosum. Methods To better understand the functional implications of schizophrenia we utilized a forced-choice tachistoscopic line bisection task to probe the status of right-hemisphere control of spatial attention, and compared left- versus right-hand unimanual responses to index the degree of callosal transfer of visuospatial information in both patient and control groups. Results In contrast to the significant leftward bisection errors of control subjects, patients exhibit no significant leftward error. Whereas control subjects evince a significant correlation between left- and right-hand bisection errors, patients lack a significant intermanual correlation. Conclusions The lack of significant leftward bisection error of patients implies a deficit of right-hemisphere function. The lack of a significant correlation between left- and right-hand bisection errors in patients implies a loss of callosal integrity.

Many risk genes interact synergistically to produce schizophrenia and many neurotransmitter interactions have been implicated. We have developed a circuit-based framework for understanding gene and neurotransmitter interactions. NMDAR hypofunction has been implicated in schizophrenia because NMDAR antagonists reproduce symptoms of the disease. One action of antagonists is to reduce the excitation of fast-spiking interneurons, resulting in disinhibition of pyramidal cells. Overactive pyramidal cells, notably those in the hippocampus, can drive a hyperdopaminergic state that produces psychosis. Additional aspects of interneuron function can be understood in this framework, as follows. (i) In animal models, NMDAR antagonists reduce parvalbumin and GAD67, as found in schizophrenia. These changes produce further disinhibition and can be viewed as the aberrant response of a homeostatic system having a faulty activity sensor (the NMDAR). (ii) Disinhibition decreases the power of gamma oscillation and might thereby produce negative and cognitive symptoms. (iii) Nicotine enhances the output of interneurons, and might thereby contribute to its therapeutic effect in schizophrenia.

Background Variation at the dysbindin gene ( DTNBP1 ) has been associated with increased risk for schizophrenia in numerous independent samples and recently with deficits in general and domain-specific cognitive processing. The relationship between dysbindin risk variants and sensory-level deficits in schizophrenia remains to be explored. We investigated P1 performance, a component of early visual processing on which both patients and their relatives show deficits, in carriers and noncarriers of a known dysbindin risk haplotype. Methods Event-related potential responses to simple visual isolated-check stimuli were measured using high-density electrical scalp recordings in 26 individuals meeting DSM-IV criteria for schizophrenia, comprising 14 patients who were carriers of the dysbindin risk haplotype and 12 patients who were nonrisk haplotype carriers. Results Carriers of the dysbindin risk haplotype demonstrated significantly reduced P1 amplitudes compared with noncarriers. A large effect size of d=.89 was calculated for the difference in P1 amplitude over scalp sites where the deficit was maximal. Conclusions The P1 deficits associated with a dysbindin risk haplotype previously identified in our sample presents functional confirmation of its deleterious effect on brain activity. Building on evidence of dysbindin's role in higher cognitive function, these early visual processing deficits suggest a generalized role for dysbindin in brain function and is likely to be part of the mechanism by which illness susceptibility is mediated.

Schizophrenia has been associated with deficits in visual perception and processing, but there is little information about their temporal development and stability. We assessed visual form perception using the Rorschach Comprehensive System (RCS) in 23 individuals at clinical high risk for psychosis, 15 individuals with recent onset schizophrenia (≤ 2 years since onset), and 34 with chronic schizophrenia (≥ 3 years since onset). All three groups demonstrated reduced conventional form perception (X+%), as compared with published norms, but did not differ significantly from one another. In contrast, the high-risk group had significantly better performance on an index of clarity of conceptual thinking (WSUM6) compared to the chronic schizophrenia patients, with the recent onset group scoring intermediate to the high-risk and chronic schizophrenia groups. The results suggest that individuals at clinical high risk for psychosis display substantial deficits in visual form perception prior to the onset of psychosis and that these deficits are comparable in severity to those observed in individuals with schizophrenia. Therefore, visual form perception deficits may constitute a trait-like risk factor for psychosis in high-risk individuals and may potentially serve as an endophenotype of risk for development of psychosis. Clarity of conceptual thinking was relatively preserved among high-risk patients, consistent with a relationship to disease expression, not risk. These deficits are discussed in the context of the putative neurobiological underpinnings of visual deficits and the developmental pathophysiology of psychosis in schizophrenia.

Perceptual organization represents a basic and essential function that occurs at an intermediate level of visual processing. Much of the previous research on perceptual organization in schizophrenia employed indirect measurements, or included factors beyond sensory processing. The aims of the present study were to determine the integrity of perceptual organization in schizophrenia, as well as to determine the stimulus duration necessary to perform perceptual organization. Psychophysical measurements were compared between patients with schizophrenia and matched control subjects. Participants viewed dot patterns briefly presented on a computer monitor, and indicated whether stimuli appeared grouped as vertical or horizontal lines. Grouping was based upon either relative proximity or similarity in color. Across trials, relative proximity or color similarity was progressively reduced until stimuli became bi-stable (perceived as either of two patterns of grouping), establishing the grouping threshold. In separate conditions, stimuli were immediately followed by a mask to limit processing. Stimulus duration was progressively reduced until stimuli became bi-stable, establishing the critical stimulus duration (CSD). Schizophrenia patients demonstrated elevated grouping thresholds for grouping by proximity as well as color similarity. In addition, CSD was significantly extended for the schizophrenia group, with a nearly four-fold increase in duration of processing. These results provide direct evidence of impairment in schizophrenia for perceptual organization based upon spatial relationships and feature similarity, and suggest deficits in low-level perceptual organization processes. Although this study did not directly investigate the physiological correlates underlying perceptual impairments, these results are consistent with a theory of impaired lateral connections within visual cortical areas in schizophrenia.

Background: Deficits in working memory performance are among the most widely replicated findings in schizophrenia. Roles of encoding vs. memory retention in working memory remain unresolved. The present study evaluated working memory performance in schizophrenia using an AX-type continuous performance test (AX-CPT) paradigm. Methods: Participants included 48 subjects with schizophrenia and 27 comparison subjects. Behavior was obtained in 3 versions of the task, which differed based upon ease of cue interoperability. In a simple cue version of the task, cue letters were replaced with red or green circles. In the complex cue version, letter/color conjunctions served as cues. Results: In the base version of the task, patients showed increased rates of false alarms to invalidly cued targets, similar to prior reports. However, when the cue stimuli were replaced with green or red circles to ease interpretation, patients showed similar false alarm rates to controls. When feature conjunction cues were used, patients were also disproportionately affected relative to controls. No significant group by interstimulus interval interaction effects were observed in either the simple or complex cue conditions, suggesting normal retention of information even in the presence of overall performance decrements. Conclusions: These findings suggest first, that cue manipulation disproportionately affects AX-CPT performance in schizophrenia and, second, that substantial behavioral deficits may be observed on working memory tasks even in the absence of disturbances in mnemonic retention.

Patients with schizophrenia show impairments in motion processing, along with deficits in lower level processing primarily involving the magnocellular visual pathway. The present study investigates potential magnocellular contributions to impaired motion processing in schizophrenia using a combined neurophysiological and behavioral approach. As compared to prior motion studies in schizophrenia, thresholds were determined for both incoherent and coherent visual motion. In this study, velocity discrimination thresholds were measured for schizophrenia patients (n = 14) and age-matched normal control subjects (n = 16) using a staircase procedure. Early visual processing was evaluated using steady-state visual evoked potentials (ssVEP), with stimuli biased toward activation of either the magnocellular or parvocellular visual pathways through luminance contrast manipulation. Patients with schizophrenia showed poor velocity discrimination for both incoherent and coherent motion, with no significant group × task interaction. Further, when coherent motion performance was measured at individually determined incoherent motion thresholds, accuracy levels for patients were similar to controls, also indicating similarity of deficit for incoherent vs. coherent motion discrimination. Impairments in velocity discrimination correlated significantly with reduced amplitude of ssVEP elicited by magnocellular – but not parvocellular – selective stimuli. This study demonstrates that deficits in motion processing in schizophrenia are significantly related to reduced activation of the magnocellular visual system. Further, this study supports and extends prior reports of impaired motion processing in schizophrenia, and indicates significant bottom-up contributions to higher-order cognitive impairments.

Humans are capable of recognizing objects, often despite highly adverse viewing conditions (e.g., occlusion). The term “perceptual closure” has been used to refer to the neural processes responsible for “filling-in” missing information in the visual image under such conditions. Closure phenomena have been linked to a group of object recognition areas, the so-called lateral–occipital complex (LOC). Here, we investigated the spatiotemporal dynamics of perceptual closure processes by coregistering data from high-density electrical recordings (ERPs) and functional magnetic resonance imaging (fMRI) while subjects participated in a perceptual closure task. Subjects were presented with highly fragmented images and control scrambled images. Fragmented images were calibrated to be ‘just’ recognizable as objects (that is, perceptual closure was necessary), whereas the scrambled images were unrecognizable. Comparison of responses to these two stimulus classes revealed the neural processes underlying perceptual closure. fMRI revealed an object recognition system that mediates these closure processes, the core of which consists of the LOC regions. ERP recordings resulted in the well-characterized N CL component (for negativity associated with closure), a robust relative negativity over bilateral occipito-temporal scalp that occurs in the 230–400 ms timeframe. Our investigations further revealed an extended network of dorsal and frontal regions, also involved in perceptual closure processes. Inverse source analysis showed that the major generators of N CL localized to the identical regions within LOC revealed by the fMRI recordings and detailed the temporal dynamics across these LOC regions including interactions between LOC and these other nodes of the object recognition circuit.