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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 Mismatch negativity (MMN) is an extensively validated biomarker of cognitive function across both normative and clinical populations and has previously been localized to supratemporal auditory cortex. MMN is thought to represent a comparison of the features of the present stimulus versus a mnemonic template formed by the prior stimuli. Methods We used concurrent thalamic and primary auditory cortical (A1) laminar recordings in 7 macaques to evaluate the relative contributions of core (lemniscal) and matrix (nonlemniscal) thalamic afferents to MMN generation. Results We demonstrated that deviance-related activity is observed mainly in matrix regions of auditory thalamus, MMN generators are most prominent in layer 1 of cortex as opposed to sensory responses that activate layer 4 first and sequentially all cortical layers, and MMN is elicited independent of the frequency tuning of A1 neuronal ensembles. Consistent with prior reports, MMN-related thalamocortical activity was strongly inhibited by ketamine. Conclusions Taken together, our results demonstrate distinct matrix versus core thalamocortical circuitry underlying the generation of a higher-order brain response (MMN) versus sensory responses.

BACKGROUND: Accumulating evidence suggests the involvement of abnormal glutamateric neurotransmission and N-methyl-D-aspartate receptor (NMDAR) hypofunction in the pathophysiology of psychotic disorders. The purpose of this study was to quantify in vivo glutamate (Glu) and glycine (Gly) levels in patients with first-episode psychosis as well as age-matched healthy controls with MR spectroscopy. METHODS: The subjects were 46 patients with first-episode psychosis (20 schizophrenia-spectrum disorders (SZ), 26 bipolar disorder (BD)) and 50 age-matched healthy controls (HC). Glu and Gly levels were measured in vivo in the anterior cingulate cortex (ACC) and posterior cingulate cortex (PCC) of the subjects by using the echo-time (TE)-averaged proton MR spectroscopy technique ((1)H-MRS) at 4 T (i.e., modified PRESS sequence: 24 TE steps with 20 ms increments). Metabolite levels were quantified using LCModel with simulated basis sets. RESULTS: Significantly higher Glu and Gly levels were found in both the ACC and PCC of patients with first-episode psychosis as compared to healthy controls. Glu and Gly levels were positively correlated in patients. SZ and BD patients showed similar abnormalities. CONCLUSIONS: Our findings demonstrate abnormally elevated brain Glu and Gly levels in patients with first-episode psychosis by means of TE-averaged (1)H-MRS at 4 T. The findings implicate dysfunction of NMDAR and glutamatergic neurotransmission in the pathophysiology of the acute early phase of psychotic illnesses.

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.

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.

Background Deficits in affect recognition are prominent features of schizophrenia. Within the auditory domain, patients show difficulty in interpreting vocal emotional cues based on intonation (prosody). The relationship of these symptoms to deficits in basic sensory processing has not been previously evaluated. Methods Forty-three patients and 34 healthy comparison subjects were tested on two affective prosody measures: voice emotion identification and voice emotion discrimination. Basic auditory sensory processing was measured using a tone-matching paradigm and the Distorted Tunes Test (DTT). A subset of subjects was also tested on facial affect identification and discrimination tasks. Results Patients showed significantly impaired performance on all emotion processing tasks. Within the patient group, a principal components analysis demonstrated significant intercorrelations between basic pitch perception and affective prosodic performance. In contrast, facial affect recognition deficits represented a distinct second component. Prosodic affect measures correlated significantly with severity of negative symptoms and impaired global outcome. Conclusions These results demonstrate significant relationships between basic auditory processing deficits and impaired receptive prosody in schizophrenia. The separate loading of auditory and visual affective recognition measures suggests that within-modality factors may be more significant than cross-modality factors in the etiology of affect recognition deficits in schizophrenia.

D-serine, a selective full agonist at the glycine site of N-methyl-D-aspartate glutamate receptor, might presently be the compound of choice for counteracting the hypothesized dysfunction of this receptor class in schizophrenia. Studies performed with Taiwanese patients indicate that D-serine significantly improves schizophrenia symptoms when used as adjuvant to conventional neuroleptics but not to clozapine. We assessed the efficacy and safety of D-serine adjuvant treatment for Occidental schizophrenia patients treated with newer atypical antipsychotics.Thirty-nine risperidone- or olanzapine-treated schizophrenia patients participated in a double-blind, placebo-controlled, 6-week crossover trial with 30 mg/kg/day D-serine added to their antipsychotic medication. Measures of clinical efficacy and side effects were determined biweekly throughout the study. Clinical laboratory parameters and amino acid serum levels were monitored.D-serine administration induced increased serine serum levels (p.001) and resulted in significant (p.001) improvements in negative, positive, cognitive, and depression symptoms, as measured by the Positive and Negative Syndrome Scale. For approximately one third of the sample, D-serine treatment resulted in significant (20%) reductions in Brief Psychiatric Rating Scale total scores. D-serine was well tolerated, and no detrimental changes in clinical laboratory parameters were noted.These findings 1) indicate that risperidone and olanzapine efficacy might be augmented with D-serine adjuvant treatment; 2) confirm D-serine efficacy against main schizophrenia symptom domains; and 3) warrant the assessment of D-serine antipsychotic monotherapy for this illness.

Background Lamotrigine, a novel anticonvulsant drug having modulatory effects on glutamatergic neurotransmission, improves mood and cognition parameters in bipolar disorder. Recent studies suggest that when added to clozapine, lamotrigine treatment may result in significant positive symptoms reductions in schizophrenia. Similar effects were not observed in an open trial in which lamotrigine was used as adjuvant to nonclozapine antipsychotics. Methods Thirty-eight treatment-resistant schizophrenia inpatients receiving conventional and atypical antipsychotics enrolled in a 10-week, double-blind, placebo-controlled study, in which they were randomized in a 2:1 ratio to receive adjuvant treatment with lamotrigine, gradually titrated to a 400 mg/day dose, or placebo. Of these, 31 completed the trial. Measures of clinical efficacy and side effects were determined every other week. Serum levels of amino acids were assessed at the beginning and end of the study. Results In primary last observation carried forward analysis, no statistically significant between-group differences were observed; however, the completers' analyses revealed that lamotrigine treatment resulted in significant (p ≤ .05) reductions in positive and general psychopathology symptoms, as measured by the Positive and Negative Syndrome Scale. No significant differences in lamotrigine effects were noted between conventional versus atypical antipsychotics. Lamotrigine treatment was well tolerated, and glutamate serum levels remained stable throughout the study. Conclusions These preliminary findings 1) support the hypothesis that lamotrigine adjuvant treatment may improve positive symptoms and general psychopathology in schizophrenia, 2) suggest that beneficial effects may be achieved when lamotrigine is added to both conventional and atypical antipsychotics, and 3) warrant additional, larger scale trials.

Clinical trials indicate that glycine site agonists of the N-methyl-D-aspartate (NMDA) receptors may reduce negative and cognitive symptoms in treatment-resistant schizophrenia when used as adjuvants to conventional antipsychotics but possibly not to clozapine. In this study, we assessed whether high-dose glycine may also be therapeutically beneficial when added to olanzapine and risperidone treatment.Seventeen olanzapine- or risperidone-treated schizophrenia patients participated in a double-blind, placebo-controlled, 6-week crossover treatment trial with.8 g/kg/day glycine added to their ongoing antipsychotic medication. Clinical assessments were performed biweekly throughout the study. Clinical laboratory parameters and amino acid serum levels were monitored.Glycine treatment was well tolerated and resulted in a significant (p.0001) 23% +/- 8% reduction in negative symptoms. Significant improvements were also registered in cognitive and positive symptoms. The negative symptoms improvement remained significant even following covariation for changes in other symptom clusters and extrapyramidal side effects. High posttreatment glycine serum levels significantly predicted (r =.60) clinical response.These findings indicate that the efficacy of olanzapine and risperidone may be augmented using high-dose adjuvant glycine treatment and suggest that these atypical antipsychotics may affect NMDA receptor-mediated neurotransmission differently than clozapine.

Background: Phencycline (PCP, “angel dust”) and other noncompetitive antagonists of N-methyl-d-aspartate (NMDA)-type glutamatergic neurotransmission induce psychotic effects in humans that closely resemble positive, negative, and cognitive symptoms of schizophrenia. Behavioral effects of PCP in rodents are reversed by glycine (GLY) and other NMDA augmenting agents. In rodents, behavioral effects of PCP are mediated, in part, by secondary dysregulation of subcortical dopaminergic neurotransmission. This study evaluates effects of GLY and GLY transport antagonists on behavioral and neurochemical consequences of PCP administration in rodents. Methods: Two separate experiments were performed. In the first, effects of GLY on PCP-induced stimulation of dopaminergic neurotransmission in nucleus accumbens were evaluated using in vivo microdialysis in awake animals. In the second, effects of a series of GLY transport antagonists were evaluated for potency in inhibiting PCP-induced hyperactivity. Results: In microdialysis studies, GLY significantly inhibited PCP-induced stimulation of subcortical DA release in a dose-dependent fashion. In behavioral studies, the potency of a series of GLY transport antagonists for inhibiting PCP-induced hyperactivity in vivo correlated significantly with their potency in antagonizing GLY transport in vitro. Conclusions: These findings suggest, first, that GLY reverses not only the behavioral, but also the neurochemical, effects of PCP in rodents. Second, the findings suggest that GLY transport antagonists may induce similar effects to GLY, and may therefore represent an appropriate site for targeted drug development.

Background Schizophrenia is a neurocognitive disorder with a wide range of cognitive and sensory impairments. Early visual processing has been shown to be especially impaired. This article investigates the integrity of binocular depth perception (stereopsis) in schizophrenia. Methods Seventeen schizophrenia patients and 19 healthy control subjects were compared on the Graded Circles Stereo Test. Results of stereoacuity were compared between patients and control subjects using t test. Results Schizophrenia patients demonstrated significantly ( p = .006) reduced stereoacuity (mean = 142 arcseconds) versus control subjects (mean = 55 arcseconds). At the normative level for adults, patients performed below chance. Conclusions These findings demonstrate an impairment of binocular depth perception and further confirm deficits of early visual processing in schizophrenia. Findings are discussed in context of magnocellular/dorsal stream processing with implications for visual processing and cognitive deficits.

Event-related potential (ERP) studies report that the positive deflection following stimulus evaluation at 300 msec (P3) in hyperactive children is augmented by methylphenidate (MP). This study investigates P3 and preceding ERP components using an auditory oddball task in attention-deficit hyperactivity disorder (ADHD). Mismatch negativity, negativity at 100 and 200 msec, and positivity at 200 msec and 300 msec (P3) were obtained from 14 control and hyperkinetic children. ADHD children who responded to MP were tested on two separate days while receiving either MP or placebo. Controls were tested once. No differences were found between groups for ERP components preceding P3. P3 amplitude was significantly larger under MP than under placebo, but did not differ from controls. Under MP, differences in P3 amplitude unexpectedly occurred when no response was required. A P3 amplitude increase under MP and the unexpected P3 suggest that MP affects attention regulation.

P300 (P3) is a long-latency cognitive event-related potential (ERP) elicited by relevant target stimuli. P3 was recorded from 11 schizophrenics and 13 normal controls during a cued visual continuous performance task (CPT-AX). Cue-target sequences were presented at short and long interstimulus intervals (ISIs), in order to investigate working memory in schizophrenia. There was no significant between-group difference in P3 amplitude to validly or invalidly cued targets at short ISI. In contrast, P3 amplitude to invalidly cued targets at long ISI was significantly greater in schizophrenics than in controls, suggesting decreased ability to encode or maintain inhibitory representations of stimulus context. P3 amplitude is typically reduced in schizophrenic subjects in the auditory modality, and normal or reduced in the visual modality. This study, which demonstrates a paradoxical P3 increase to targets at long ISI, suggests that P3 impairment in schizophrenia cannot be attributed solely to structural deficits within P3-generator regions.

Background Mismatch negativity (MMN) and visual P1 are established event-related potential (ERP) markers of impaired auditory and visual sensory function in schizophrenia. Differential relationships of these measures with premorbid and present function and with clinical course have been noted previously in independent cohorts, but measures have not yet been compared within the same patient group. Methods Twenty-six schizophrenia patients and 19 control subjects participated in a simultaneous visual and auditory ERPs experiment. Attended visual ERPs were obtained to low- and high-spatial frequency stimuli. Simultaneously, MMN was obtained to unattended pitch, duration, and intensity deviant stimuli. Premorbid function, symptom, and global outcome measures were obtained as correlational measures. Results Patients showed substantial P1 reductions to low- but not high-spatial frequency stimuli, unrelated to visual acuity. Patients also exhibited reduced MMN to all deviant types. No significant correlations were observed between visual ERPs and premorbid or global outcome measures or illness duration. In contrast, MMN amplitude correlated significantly and independently with premorbid educational achievement, cognitive symptoms, global function, and illness duration. The MMN to duration versus other deviants was differentially reduced in individuals with poor premorbid function. Conclusions Visual and auditory ERP measures are differentially related to the pathophysiology of schizophrenia. Visual deficits correlate poorly with functional measures and illness duration and serve primarily as trait vulnerability markers. The MMN deficits are independently related to premorbid function and illness duration, suggesting independent neurodevelopmental and neurodegenerative contributions. The lack of correlation between auditory and visual ERPs in schizophrenia suggests contributions from divergent underlying neurophysiological processes.

Abnormalities of auditory information processing represent a core feature of schizophrenic psychopathology. Event-related potentials (ERP) provide an objective index of the information processing deficits associated with schizophrenia and a tool for investigation of the underlying pathophysiology. The best established abnormality is a decrease in the amplitude of auditory P300. In an “oddball” paradigm, P300 is preceded by a series of earlier, negative-polarity ERP components that index discrete, prior information-processing events. The earliest such component, mismatch negativity (MMN), is elicited whenever a deviant, “oddball” stimulus interrupts a sequence of repetitive standard stimuli. MMN is generated principally within primary auditory cortex or adjacent structures on the superior temporal plane, suggesting that it indexes the earliest cortical event in the cognitive processing of auditory information. In the present study, MMN was studied in a group of 14 chronic schizophrenic subjects relative to 12 age- and IQ-matched normal controls in a passive auditory oddball paradigm in order to test the hypothesis that auditory information processing is impaired in schizophrenia, even at the level of primary sensory cortex. Schizophrenic subjects showed a significant reduction in MMN amplitude relative to controls, with a trend toward a greater deficit on the left than the right side. The finding of impaired MMN generation in schizophrenia suggests that information processing is impaired even at the level of auditory cortex and that the pathophysiological processes underlying information processing dysfunction in schizophrenia are widespread throughout the cortex, rather than limited to high-order association cortex such as prefrontal or mesial temporal cortex.

Background In a previous pilot study, MK-0777—a γ-aminobutyric acid (GABA) A α2/α3 partial agonist—was reported to improve delayed memory and cognitive measures of prefrontal cortical function in people with schizophrenia. The current study was designed to further examine the efficacy and safety of MK-0777 for the treatment of cognitive impairments in schizophrenia. Methods Sixty people with DSM-IV schizophrenia entered a 4-week, multi-center, double-blind, placebo-controlled, randomized clinical trial. Participants were randomized to: MK-0777 3 mg b.i.d. ( n = 18); MK-0777 8 mg b.i.d. ( n = 21); or placebo ( n = 21). Participants were clinically stable. The Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery, AX-Continuous Performance Test, and N-Back were used to assess cognition. The University of California San Diego (UCSD) Performance Based Skills Assessment-2 and the Schizophrenia Cognition Rating Scale assessed functional capacity and served as functional outcome coprimary measures. Results There were no significant group differences on the primary outcome measure, the MATRICS Consensus Cognitive Battery composite score. Secondary analyses suggested that participants randomized to placebo performed significantly better on visual memory and reasoning/problem-solving tests than participants assigned to either MK-0777 dose. There were no significant group differences on the AX-Continuous Performance Test or N-Back d prime scores or UCSD Performance-Based Skills Assessment–2 and Schizophrenia Cognition Rating Scale total scores. In general, MK-0777 was well-tolerated with minimal side effects. Conclusions The study results suggest that MK-0777 has little benefit for cognitive impairments in people with schizophrenia. The GABA A receptor remains a promising target, but a more potent partial agonist with greater intrinsic activity at the GABA A α2 site might be needed for cognitive enhancement in schizophrenia.

Background Deficits in amplitudes of auditory event-related potentials (ERP) indexing preattentive, automatic (mismatch negativity, MMN) and controlled, attention-dependent (N2, P3) auditory information processing have been well described in chronic schizophrenia. Normal MMN, but deficient N2 and P3 have been reported in first-episode patients. No study has investigated these ERPs concurrently in first-episode patients; thus, reported differences in MMN, N2 and P3 generation may reflect differences in patient samples rather than genuine differences in abnormal generation of these ERPs. Methods We recorded MMN, N2 and P3 in 26 first-episode patients, 25 recent-onset patients within 1.5 to 5 years after first admission, 25 chronic patients and 39 healthy controls. Results Recent-onset and chronic, but not first-episode patients showed reduced MMN. However, among first-episode patients those with low premorbid educational achievement demonstrated significantly reduced MMN. All patient groups showed pronounced N2 deficits and, to a variable extent, abnormalities in P3 generation. Conclusions Abnormalities in N2 and P3 generation appear to reflect premorbid neuropathology, whereas MMN deficits may index both ongoing disease processes associated with illness progression as well as premorbid neurocognitive impairment. ERPs may provide tools to assess static and progressive neuropathology in schizophrenia. These findings need confirmation in longitudinal studies.

Background: Facilitation of N -methyl-d-aspartate (NMDA) receptor–mediated neurotransmission via administration of glycine site agonists of the NMDA receptor (e.g., glycine, d-serine), and glycine transport inhibitors may represent an innovative pharmacologic strategy in schizophrenia; however, given the potential involvement of NMDA receptors in the neurotoxicity of excitatory amino acids, possible neurotoxic effects of glycinergic compounds need to be explored. Furthermore, studying brain adaptations to chronic administration of glycine site agonists may provide insights into the therapeutic mechanisms of these drugs. Methods: Adult rats were randomized to one of three nutritional regimens (no glycine supplementation, 1 g/kg/day, or 5 g/kg/day glycine supplementation) and to one of three treatment durations (1, 3, or 5 months). Serum glycine and serine levels at sacrifice and brain sections were examined using histologic markers of neurodegeneration (cresyl violet and silver impregnation staining) and immunohistochemical staining of glial fibrillary acidic protein, microtubule-associated protein, and neurofilament 200. To explore additional neural adaptations to high-dose glycine treatment, immunostaining was also performed for class B, N-type Ca 2+ channels. Results: Serum glycine levels increased dose dependently during glycine nutrition, whereas serine levels were not changed. In hippocampal dentate gyrus, the percentage of hypertrophied astrocytes transiently increased at 1 month. At 3 and 5 months of glycine treatment, the density of class B, N-type Ca 2+ channels was reduced in parietal cortex and hippocampus. No evidence of neuronal or glial cell excitotoxic damage or degeneration was registered at either of the treatment intervals studied. Conclusions: These findings demonstrate for the first time that in vivo administration of high-dose glycine may induce brain morphological changes without causing neurotoxic effects. A reduction in density of class B, N-type Ca 2+ channels in specific brain regions may represent one general adaptation to long-term, high-dose glycine treatment.

Background: Simple speech sounds such as /ba/ and /da/ differ in the frequency composition of their underlying formants. Normal volunteers asked to identify intermediate phonemes along the /ba/ to /da/ continuum abruptly switch from perceiving “ba” to perceiving “da”. The present study investigates precision of phonemic processing in schizophrenia. Methods: Categorical perception of speech sounds was evaluated in 15 schizophrenic and 14 control subjects, using a forced-choice phonemic discrimination paradigm. Results: Patients and controls were equally able to recognize endpoint forms of both phonemes, but differed significantly in their perception of intermediate forms near the center of the continuum. Patients also showed a significantly shallower response curve, suggesting an impairment in boundary definition. Despite their impairment in categorical perception, schizophrenic subjects showed normal adaptation of response when test stimuli were preceded by a series of /ba/ or /da/ stimuli from the endpoints of the continuum. Conclusions: The present results suggest that precision of phonemic processing is impaired in schizophrenia. This categorical perception deficit may represent upward generalization of impaired memory-dependent acoustic processing. Deficits in the precision of cortical processing may contribute significantly to cognitive dysfunction in schizophrenia.

An eight-weekdouble-blindplacebo-controlledstudycomparingsertindoleat 12,20and24mgklaywithhaloperidolat 4,8 and 16mgldaywas conductedin497hospitalizedpatientswithschizophrenia. Evaluationsof movementratingscales,EPSrelatedadverseeventsanduse of rmti-EPS medicationsfoundno statisticallysignificantdifferencesbetweensertindole and placebo.The incidenoeof EPS was not dose related in the sertindolegroup, and all doses of haloperidolproducedsignificantly moreEPSthanplacebo.